An Open-Label Extension of Study HGT-SAN-055 Evaluating Long Term Safety and Clinical Outcomes of Intrathecal Administration of rhHNS in Patients With Sanfilippo Syndrome Type A (MPS IIIA)
Phase: PHASE1
Conditions: Sanfilippo Syndrome
Sponsor: Shire

CLINICAL STUDY PROTOCOL 
 
 
NCT Number:   
NCT01299727 
 
Study Title:  
An Open-Label Extension of Study HGT-SAN-055 Evaluating Long-Term Safety 
and Clinical Outcomes of Intrathecal Administration of rhHNS in Patients 
with Sanfilippo Syndrome Type A (MPS IIIA) 
 
 
Study Number:  
HGT-SAN-067 
 
 
Protocol Version and Date:  
 
Original Protocol: 21 June 2010 
Amendment 1: 27 January 2011 
Amendment 2: 13 January 2012 
Amendment 3: 28 August 2012 
Amendment 4: 3 May 2013 
Amendment 5: 17 January 2014 
Amendment 6: 10 July 2014 
Amendment 7: 08 February 2016 
Amendment 8: 01 February 2017 

Clinical Trial Protocol:  HGT-SAN-067 
Study Title: 
An Open-Label Extension of Study HGT-SAN-055 Evaluating 
Long-Term Safety and Clinical Outcomes of Intrathecal 
Administration of rhHNS in Patients with Sanfilippo Syndrome Type 
A (MPS IIIA) 
Study Number: 
HGT-SAN-067 
Study Phase: 
I/II  
Product Name: 
Recombinant human heparan N-sulfatase (rhHNS) 
EudraCT Number: 2010-021348-16 
Indication: 
Sanfilippo Syndrome A 
Investigators: 
Multicenter 
 
 
Sponsor: 
Shire 
Medical Monitor: 
, MD 
 
Shire Human Genetic Therapies, Inc. 
700 Main Street  
Cambridge, MA 02139, USA 
Telephone:  
 
Fax:  
 (USA) 
 
 
Date 
Original Protocol: 
21 June 2010 
Confidentiality Statement 
This document is the proprietary and confidential property of Shire Human Genetic 
Therapies, Inc. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
2 
SYNOPSIS 
Sponsor: 
Shire 
Name of Finished Product: 
Recombinant human heparan N-sulfatase (rhHNS) 
Name of Active Ingredient: 
rhHNS 
Name of Inactive Ingredient: 
N/A 
Study Title: 
An Open-Label Extension of Study HGT-SAN-055 Evaluating Long-Term Safety and 
Clinical Outcomes of Intrathecal Administration of rhHNS in Patients with Sanfilippo 
Syndrome Type A (MPS IIIA)  
Study Number: 
HGT-SAN-067 
Study Phase:  I/II  
Primary Objective:  
To collect long-term safety and tolerability data in patients with Sanfilippo Syndrome Type A 
(MPS IIIA) who received rhHNS via a surgically implanted intrathecal drug delivery device 
(IDDD) in study HGT-SAN-055 and elected to continue therapy. 
Secondary Objectives: 
To collect as indications of drug efficacy, over an extended treatment period (as change from 
baseline), the following:  clinical, neurological, cognitive, behavioral, functional, and quality of 
life (QoL) assessments, together with potential imaging and biochemical biomarkers. 
Study Endpoints:  
The primary endpoint of this study is: 
To determine the long-term safety of intrathecal rhHNS administration, as measured by adverse 
events (by type and severity), changes in clinical laboratory testing (serum chemistry including 
liver function tests, hematology, and urinalysis), electrocardiograms, cerebrospinal fluid (CSF) 
chemistries (including cell counts and inflammatory markers), and anti-rhHNS antibodies (in 
CSF and serum). 
The secondary endpoints of this study are to collect over an extended treatment period (as 
change from baseline) clinical and potential surrogate biomarker efficacy data: 
• Standardized neurocognitive and behavioral assessments, Sanfilippo-specific behavioral 
rating scales, gross and fine motor assessments, functional adaptive rating scales, quality 
of life questionnaires, and Children’s Sleep Habits Rating Scale. 
• Concentration of rhHNS in cerebrospinal fluid (CSF) and serum. 
• Concentration of inflammatory cytokines in serum and CSF. 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
3 
• Concentration of safety and potential surrogate efficacy biomarkers in CSF, urine, and 
serum. 
• Concentration of heparan sulfate and heparan sulfate derivatives in urine and CSF  
• Brain magnetic resonance imaging (MRI) and auditory brainstem response (ABR), aka 
Brainstem Auditory Evoked Potentials. 
Study Design: 
This is a multicenter, multiple-dose, open-label extension of Study HGT-SAN-055 designed to 
evaluate the long-term safety and clinical activity and biomarker outcomes of intrathecal 
administration of 3 dose levels (10 mg and 45 mg once per month and 45 mg every other week 
[EOW]) of rhHNS via an IDDD in patients with MPS IIIA.   
Patients will continue in the treatment group as they participated in the HGT-SAN-055 study:  
• Group 1:  rhHNS administered by IT injection 10 mg once per month for a total of 6 months 
• Group 2:  rhHNS administered by IT injection 45 mg once per month for a total of 6 months 
• Group 3:  rhHNS administered by IT injection 45 mg EOW for a total of 6 months 
 
It is anticipated that all patients successfully completing the HGT-SAN-055 study will elect to 
continue to receive intrathecal (IT) rhHNS per their previous schedule in Study HGT-SAN-055 
by consenting to participate, without interruption, in the HGT-SAN-067 extension study.  Thus, 
for nomenclature of chronology purposes, the Baseline Visit for this extension study will be 
considered to be the first day the patient received his/her IT dose of rhHNS in Study 
HGT-SAN-055. 
Patients whose parents/legal guardians provide written informed consent/assent to participate in 
this study will check in with the study center 1 day prior to rhHNS dosing for safety assessments 
on each rhHNS treatment week.  If no safety concerns exist, the patient will subsequently receive 
IT administration of rhHNS on Day 2.  Patients will be discharged from the inpatient unit a 
minimum of 1 day following dosing with rhHNS and when deemed clinically stable by the 
Investigator.  The patient will have already received a standardized battery of 
neurodevelopmental assessments at the baseline and 6 month time points in the HGT-SAN-055 
study.  These same assessments and tests will also be performed at 12, 24, 36, and 48 months.  
Similarly, MRI of the head, ABR testing, CSF sampling via lumbar puncture and any other 
procedures requiring anesthesia will be performed at 12, 24, 36, and 48 months.   
All patients will undergo end of study procedures 30 (±7) days following their last administration 
of rhHNS.  End of study (EOS) procedures will include a standard battery of clinical laboratory 
tests (serum chemistry, hematology, and urinalysis) in CSF and blood, protocol specific 
laboratory testing (eg, anti-rhHNS antibody testing), neurodevelopmental testing, ABR, and 
MRI.  
All patients will be contacted by telephone for a Final Safety Follow-up, to be conducted at 
30 (±7) days after the EOS procedures to collect updated information on adverse events and 
concomitant medications, therapies, and procedures. 
It is anticipated that the IDDD will be used to obtain CSF samples and to deliver all 
administrations of rhHNS.  However, if a patient’s IDDD becomes nonfunctional or infected, it 
will be replaced so that the patient can remain on the study.   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
4 
 
If use of the IDDD is precluded on a scheduled day of dosing, the IDDD will be declared a 
failure; no study drug will be administered, nor CSF sample obtained on that visit.  Unlike the 
HGT-SAN-055 study, no study drug will be administered by lumbar puncture in this extension 
study.  Upon declaration of failure, the IDDD will be removed and the patient scheduled for 
re-implantation of a new IDDD at the earliest convenience, so that the patient may remain on, or 
remain as close as possible, to his/her original IT rhHNS dosing schedule.  Note:  Patients will 
require 1 week of recovery time from time of re-implantation, during which time the IDDD 
cannot be used, this may result in a delay in the next scheduled dose of rhHNS.  The patient will 
resume his or her original dosing schedule; no catch-up dosing will occur. 
 
If a patient discontinues or is withdrawn from the study or the study is stopped by the Sponsor, 
the IDDD will be removed as part of the End of Study Procedures.  
 
Study Population:  
A maximum of twelve patients are planned for this study.  To be eligible for participation, 
patients will have completed all study requirements in Study HGT-SAN-055 and will have 
elected to continue treatment with rhHNS. 
Diagnosis and Main Criteria for Inclusion 
Inclusion Criteria: 
Patients must meet all of the following criteria to be considered eligible for enrollment: 
1. Patients must have completed all study requirements and assessments for Study 
HGT-SAN-055 prior to enrolling in this extension study and must have no safety or medical 
issues that contraindicate participation. 
2. The patient, patient’s parent(s), or legally authorized guardian(s) must have voluntarily 
signed an Institutional Review Board / Independent Ethics Committee-approved informed 
consent form after all relevant aspects of the study have been explained and discussed with 
the patient.  The guardians’ consent and patient’s assent, as relevant, must be obtained. 
3. The patient has received and tolerated treatment with rhHNS, completed the End of Study 
visit, and has received at least 80% of the total planned infusions within the last 6 months in 
study HGT-SAN-055, (ie, at least 5/6 ([Group 1 or 2] or 10/12 infusions [Group 3]). 
4. Patients must be medically stable, in the opinion of the Investigator, to accommodate the 
protocol requirements, including travel, assessments, and IDDD surgery (if necessary for 
replacement purposes), without placing an undue burden on the patient/patient's family. 
 
Exclusion Criteria: 
Subjects will be excluded from the study if there is evidence of any of the following criteria at 
screening or at anytime during the study: 
1. The patient has experienced an adverse reaction to study drug in Study HGT-SAN-055 that 
contraindicates further treatment with rhHNS. 
2. The patient has a known hypersensitivity to the active ingredient or any excipients in rhHNS 
drug product. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
5 
3. The patient has significant non-MPS IIIA related central nervous system (CNS) impairment 
or behavioral disturbances that would confound the scientific integrity or interpretation of 
study assessments, as determined by the Investigator. 
4. The patient has significant MPS IIIA behavioral-related issues, as determined by the 
Investigator, which would preclude performance of study neurocognitive and developmental 
testing procedures. 
5. The patient is pregnant, breast feeding, or is a female patient of childbearing potential, who 
will not or cannot comply with the use of an acceptable method of birth control, such as 
condoms, barrier method, oral contraception, etc. 
6. The patient has any known or suspected hypersensitivity to anesthesia or is thought to have 
an unacceptably high risk for anesthesia due to airway compromise or other conditions. 
7. The patient has a history of poorly controlled seizure disorder. 
8. The patient is currently receiving psychotropic or other medications, which in the 
Investigator’s opinion, would be likely to substantially confound test results and the dose and 
regimen of which cannot be kept constant throughout the study. 
9. The patient cannot sustain absence from aspirin, non-steroidal medications, or medications 
that affect blood clotting within 1 week prior to a relevant study-related procedure (eg, 
device implantation if applicable), or has ingested such medications within 1 week before 
any procedures in which any change in clotting activity would be deleterious. 
10. The patient has received treatment with any investigational drug (other than rhHNS) intended 
as a treatment for MPS IIIA or used any other intrathecal delivery device other than what was 
used in Study HGT-SAN-055, within the 30 days prior to, or during the study, or is currently 
enrolled in another study that involves an investigational drug or device (screening through 
safety follow-up contact). 
11. The patient has received a hematopoietic stem cell or bone marrow transplant. 
12. The patient’s parent(s), or patient’s legal guardian(s) is/are unable to provide consent or the 
patient cannot provide assent, as appropriate, due to, but not limited to, the inability to 
understand the nature, scope, and possible consequences of the study, or do/does not agree to 
comply with the protocol defined schedule of assessments. 
Test Product; Dose; and Mode of Administration:  
Recombinant human heparan N-sulfatase (rhHNS) will be administered via an IDDD according 
to the same dosing regimen to which the patient was assigned in HGT-SAN-055 (ie, 10 mg 
monthly, 45 mg monthly, or 45 mg EOW).   
Reference Therapy; Dose; and Mode of Administration: Not Applicable 
Duration of Treatment:  
The study duration will be a maximum duration of 4 years of rhHNS treatment or until rhHNS is 
commercially available, the patient discontinues from the study, the Sponsor stops the study, or 
the Sponsor discontinues the development of rhHNS.  Study completion will be defined as the 
time at which a patient completes 4 years of rhHNS treatment (including participation in study 
HGT-SAN-055), or transitions to commercially available rhHNS or discontinues from this study 
for other reasons. 
Pharmacokinetic Variables: 
Pharmacokinetics will not be assessed in this study. 
 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
6 
Safety Assessments: 
Safety evaluations will include vital signs, physical examinations, adverse event (AE) 
assessments, and electrocardiograms (ECG); serum chemistry, hematology, and urine laboratory 
tests; and screening for antibodies to rhHNS (in CSF and serum).   
Statistical Methods:  
The statistical methodology supporting the trial will focus on descriptive rather than inferential 
approaches, given the early phase and objectives of the trial.  Data will be plotted and the mean, 
standard deviation, median, minimum, and maximum for each variable will be tabulated by dose 
group to look for gross trends over time which may be attributed to treatment.  For continuous 
data, 95% confidence interval around the mean will be presented. 
The analysis population consists of all eligible patients from HGT-SAN-055, who have agreed to 
participate in the extension study.  Safety analyses will be performed using the above mentioned 
population.  The data will be presented by dose group. 
Date of Original Protocol:  21 June 2010 
Date of Most Recent Protocol Amendment (if applicable):  N/A 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
7 
TABLE OF CONTENTS 
SYNOPSIS.................................................................................................................................2 
TABLE OF CONTENTS...........................................................................................................7 
LIST OF IN-TEXT TABLES..................................................................................................10 
LIST OF APPENDICES..........................................................................................................10 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..........................................12 
1 
INTRODUCTION ...........................................................................................................15 
1.1 
Disease Background...............................................................................................15 
1.2 
Nonclinical Overview............................................................................................17 
1.2.1 
Toxicology in Monkeys...............................................................................17 
1.2.2 
Efficacy in Murine and Canine Models of MPS IIIA..................................17 
1.3 
Clinical Development Program..............................................................................18 
1.4 
Extension Study Rationale.....................................................................................18 
2 
STUDY OBJECTIVES....................................................................................................20 
2.1 
Primary Objective..................................................................................................20 
2.2 
Secondary Objectives.............................................................................................20 
3 
STUDY ENDPOINTS.....................................................................................................21 
3.1 
Primary Endpoint...................................................................................................21 
3.2 
Secondary Endpoint...............................................................................................21 
4 
INVESTIGATIONAL PLAN..........................................................................................22 
4.1 
Overall Study Design and Plan..............................................................................22 
4.2 
Rationale for Study Design and Control Group.....................................................23 
4.3 
Study Duration and Dates......................................................................................23 
5 
STUDY POPULATION SELECTION ...........................................................................24 
5.1 
Study Population....................................................................................................24 
5.2 
Inclusion Criteria ...................................................................................................24 
5.3 
Exclusion Criteria ..................................................................................................24 
6 
STUDY TREATMENT(S)..............................................................................................26 
6.1 
Description of Treatment(s)...................................................................................26 
6.1.1 
Study Drug...................................................................................................26 
6.1.2 
Placebo or Control .......................................................................................26 
6.2 
Treatment(s) Administered....................................................................................26 
6.3 
Selection and Timing of Dose for Each Subject....................................................26 
6.4 
Cerebral Spinal Fluid Sample Procedure...............................................................26 
6.5 
Intrathecal Administration of rhHNS.....................................................................27 
6.6 
Method of Assigning Subjects to Treatment Groups.............................................27 
6.7 
Blinding..................................................................................................................27 
6.8 
Concomitant Therapy.............................................................................................27 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
8 
6.9 
Restrictions ............................................................................................................28 
6.9.1 
Prior Therapy ...............................................................................................28 
6.9.2 
Fluid and Food Intake..................................................................................28 
6.9.3 
Subject Activity Restrictions .......................................................................28 
6.10 
Treatment Compliance...........................................................................................28 
6.11 
Packaging and Labeling.........................................................................................28 
6.12 
Storage and Accountability....................................................................................29 
6.13 
Investigational Product Retention at Study Site ....................................................29 
7 
STUDY PROCEDURES .................................................................................................30 
7.1 
Informed Consent...................................................................................................30 
7.2 
Physical Examination.............................................................................................30 
7.3 
Height and Weight.................................................................................................31 
7.4 
Head Circumference ..............................................................................................31 
7.5 
Vital Signs..............................................................................................................31 
7.6 
Electrocardiography...............................................................................................31 
7.6.1 
Electrocardiograms ......................................................................................31 
7.7 
Clinical Laboratory Tests.......................................................................................31 
7.7.1 
Hematology..................................................................................................32 
7.7.2 
Serum Chemistry .........................................................................................32 
7.7.2.1 
Standard Serum Chemistry ................................................................32 
7.7.3 
Urinalysis.....................................................................................................32 
7.7.3.1 
Standard Urinalysis............................................................................33 
7.7.3.2 
Urine Heparan Sulfate and Heparan Sulfate Derivatives ..................33 
7.7.4 
Cerebrospinal Fluid Assessments ................................................................33 
7.7.4.1 
CSF Cell Counts ................................................................................33 
7.7.4.2 
CSF Heparan Sulfate Levels and Heparan Sulfate Derivatives.........33 
7.7.4.3 
Anti-rhHNS Antibodies .....................................................................34 
7.7.4.4 
CSF Biomarkers.................................................................................34 
7.7.5 
Sample Collection, Storage, and Shipping ..................................................34 
7.8 
Anesthesia..............................................................................................................34 
7.9 
Audiometry and Auditory Brainstem Response ....................................................34 
7.10 
MRI of the Head ....................................................................................................35 
7.11 
Surgical Re-implantation of the IDDD..................................................................35 
7.12 
Intracranial Pressure Measurement........................................................................35 
7.13 
Dispensing Study Drug..........................................................................................35 
7.14 
Pharmacokinetic Assessments ...............................................................................35 
7.15 
Neurological Examination .....................................................................................35 
7.16 
Serum Anti-rhHNS Antibody, Heparan Sulfate and Heparan Sulfate Derivative 
Determination ........................................................................................................36 
7.17 
Neurocognitive and Developmental Assessments.................................................36 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
9 
7.18 
Sleep Questionnaire:  Children’s Sleep Habits Rating Scale.................................37 
7.19 
Age-Dependent, Health-Related Quality of Life in Children................................37 
7.19.1 
Quality of Life Indicator:  CHQ-50 .............................................................37 
7.19.2 
Quality of Life Indicator:  CHQ-87 .............................................................38 
7.19.3 
Quality of Life Indicator:  ITQOL...............................................................38 
7.20 
Concomitant Medications, Therapies and Medical/Surgical Procedures ..............38 
7.21 
Adverse Events ......................................................................................................38 
7.21.1 
Adverse Events Assessments.......................................................................38 
7.21.2 
Definitions of Adverse Events and Serious Adverse Events.......................39 
7.21.2.1 
Adverse Event....................................................................................39 
7.21.2.2 
Serious Adverse Event.......................................................................40 
7.21.3 
Procedures for Recording and Reporting Adverse Events ..........................42 
7.21.3.1 
Reporting Serious Adverse Events ....................................................42 
7.21.3.2 
Eliciting Adverse Events....................................................................43 
7.21.3.3 
Protocol Deviations for Medical Emergency or Adverse Event........43 
7.22 
Pregnancy...............................................................................................................44 
7.23 
Removal of Subjects from the Trial or Study Drug...............................................44 
7.24 
Other Study Procedures .........................................................................................45 
7.25 
Appropriateness of Measurements.........................................................................45 
8 
STUDY ACTIVITIES .....................................................................................................46 
8.1 
Screening Visit/Baseline Visit...............................................................................46 
8.2 
Treatment:  Monthly, Weekly Assessments ..........................................................47 
8.2.1 
Week 1 (Groups 1 and 2); Week 1 and 3 (Group 3)....................................47 
8.2.1.1 
Day 1 (Pre-treatment) Assessments...................................................47 
8.2.1.2 
Day 2 (±2 days) Assessments and IDDD Injection of rhHNS...........48 
8.2.1.3 
Day 3 (Post IT Dose) Assessments....................................................48 
8.3 
End of Study/ Early Termination Procedures........................................................48 
8.4 
Safety Follow-up Visit (by Telephone) .................................................................49 
9 
QUALITY CONTROL AND ASSURANCE .................................................................50 
10 PLANNED STATISTICAL METHODS ........................................................................51 
10.1 
General Statistical Methodology............................................................................51 
10.2 
Determination of Sample Size ...............................................................................51 
10.3 
Analysis Populations..............................................................................................51 
10.4 
Demographics and Baseline Characteristics..........................................................52 
10.5 
Statistical Analysis of Pharmacokinetic Variables ................................................52 
10.6 
Efficacy, Safety, and Pharmacodynamic Evaluations ...........................................52 
10.6.1 
Primary Analyses.........................................................................................52 
10.6.1.1 
Safety Analysis ..................................................................................52 
10.6.1.2 
Clinical Laboratory Evaluations ........................................................53 
10.6.1.3 
Anti-rhHNS Antibody Formation......................................................53 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
10 
10.6.2 
Secondary Analysis......................................................................................54 
10.6.2.1 
Clinical Assessments .........................................................................54 
10.6.2.2 
Pharmacodynamic Analyses..............................................................54 
11 ADMINISTRATIVE CONSIDERATIONS....................................................................55 
11.1 
Investigators and Study Administrative Structure.................................................55 
11.2 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval ................................................................................................................55 
11.3 
Ethical Conduct of the Study.................................................................................55 
11.4 
Patient Information and Consent ...........................................................................55 
11.5 
Patient Confidentiality ...........................................................................................56 
11.6 
Study Monitoring...................................................................................................56 
11.7 
Case Report Forms and Study Records .................................................................57 
11.7.1 
Critical Documents ......................................................................................57 
11.8 
Data Monitoring Committee..................................................................................58 
11.9 
Protocol Violations/Deviations..............................................................................58 
11.10 Access to Source Documentation ..........................................................................58 
11.11 Data Generation and Analysis ...............................................................................58 
11.12 Premature Closure of the Study.............................................................................59 
11.12.1 Study Termination .......................................................................................59 
11.12.2 Site Termination...........................................................................................59 
11.13 Retention of Data...................................................................................................59 
11.14 Financial Disclosure...............................................................................................59 
11.15 Publication and Disclosure Policy .........................................................................59 
12 REFERENCE LIST .........................................................................................................61 
 
LIST OF IN-TEXT TABLES 
Table 7-1 Approximate Total Sample Volumes Collected Over the Duration of the Study     
From Each Patient by Group and Assay......................................................................30 
Table 7-2 Neurodevelopmental Assessments Tests...........................................................36 
Table 7-3 Sanfilippo-Specific Disability Assessment And Behavior Rating Scales.........37 
Table 7-4  
Adverse Event Severity................................................................................41 
Table 7-5 
Adverse Event Relatedness..........................................................................41 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events.............................................................................63 
Appendix 2 
Sample Neurological Exam ...............................................................67 
Appendix 3 
Neurodevelopmental and Behavioral Assessments ...........................71 
Appendix 4 
Investigator’s Signature .....................................................................75 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
11 
Appendix 5 
The National Cancer Institute Common Toxicity Criteria (NCI CTC)  
                                Version 3.0........................................................................................76 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
12 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ABR 
Auditory Brainstem Response 
AE 
adverse event 
ALB 
albumin 
ALK-P 
alkaline phosphatase 
ALT 
alanine aminotransferase (SGPT) 
AP 
alkaline phosphatase 
AST 
aspartate aminotransferase (SGOT) 
BSID-III 
Bayley Scales of Infant Development, Third Edition 
BBB 
blood brain barrier 
BUN 
blood urea nitrogen 
Ca 
calcium 
CFR 
Code of Federal Regulations 
CNS 
central nervous system 
CHQ-50 
Child Health Questionnaire™ Parent Form 50 
CHQ-87 
Child Health Questionnaire™ Child Form 87 
CK 
creatine kinase 
Cl 
chloride 
CO2 
carbon dioxide 
CRO 
contract research organization 
CSF 
cerebrospinal fluid 
DDD 
drug delivery device 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ERT 
enzyme replacement therapy 
EOS 
end of study 
EOW 
every other week 
FDA 
Food and Drug Administration 
FG 
formylglycine 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
13 
FPSS/TDS 
Four-Point Scoring System/Total Disability Score 
GAG 
glycosaminoglycan 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
Hct 
hematocrit 
Hgb 
hemoglobin 
HS 
heparan sulfate 
ICH 
International Conference on Harmonisation  
ICP 
intracranial pressure  
IDDD 
intrathecal drug delivery device 
IEC 
Independent Ethics Committee 
IgG 
immunoglobulin G 
IgE 
immunoglobulin E 
IND 
Investigational New Drug  
IRB 
Institutional Review Board 
IT 
intrathecal 
ITQOL 
Infant Toddler Quality of Life Questionnaire™ 
IV 
intravenous 
K 
potassium 
KABC-II 
Kaufman Assessment Battery for Children, Second Edition 
LDH 
lactic dehydrogenase 
LP 
lumbar puncture  
LSD 
lysosomal storage disease 
M6P 
mannose-6-phosphate 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MABC-2 
Movement Assessment Battery for Children, Second Edition 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
14 
MPS IIIA 
Mucopolysaccharidosis IIIA or Sanfilippo syndrome Type A 
MRI 
magnetic resonance imaging 
Na 
sodium  
QoL 
quality of life 
PE 
pressure-equalization 
RBC 
red blood cell (count) 
rhHNS 
recombinant human heparan N-sulfatase 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SBRS 
The Sanfilippo Behavior Rating Scale 
SGOT 
serum glutamic oxaloacetic transaminase (AST) 
SGPT 
serum glutamic pyruvic transaminase (ALT) 
Shire HGT 
Shire Human Genetic Therapies, Inc. 
TMF 
Trial Master File 
TX 
treatment 
UK 
United Kingdom 
US 
United States 
VABS-II 
Vineland Adaptive Behavior Scales  
WBC 
white blood cell (count) 
WHODRL 
World Health Organization Drug Reference List 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
15 
1 
INTRODUCTION 
The progressive and irreversible nature of lysosomal storage diseases (LSDs) present a challenge 
in the interpretation of clinical benefit derived from treatment in studies using enzyme 
replacement therapy (ERT).  Any short-term improvement and/or stabilization of clinically 
important manifestations of the disease may be viewed as clinically meaningful.  However, the 
demonstration of the different aspects of a long-term, clinically-meaningful improvement may be 
limited by the short duration of treatment in clinical studies.  Extended access to treatment 
through extension studies provides an opportunity for further evaluation of long-term safety and 
clinical outcomes for treated patients.  In this extension study, patients who completed study 
HGT-SAN-055, a phase I/II safety and dose-escalation trial, and elected to continue to receive 
recombinant human heparan N-sulfatase (rhHNS), will receive treatment through this extension 
protocol.  The patient’s treatment group, dosing regimen, and the intrathecal drug delivery device 
(IDDD) will be the same as that employed in study HGT-SAN-055. 
1.1 
Disease Background 
Sanfilippo syndrome, or Mucopolysaccharidosis (MPS) III, is a lysosomal storage disease (LSD) 
caused by loss in activity of 1 of 4 enzymes necessary for degradation of the glycosaminoglycan 
(GAG) heparan sulfate (HS) in lysosomes.  Four different subtypes (A, B, C, and D) have been 
identified and are each due to a specific enzyme deficiency involved in the lysosomal catabolism 
of HS.  MPS IIIA results from deficiency of the enzyme heparan N-sulfatase (sulfamidase).  In 
the absence of this enzyme, intermediates of the HS degradation process accumulate in the 
lysosomes of neurons and glial cells, with lesser accumulation outside the brain.   
MPS III is the most prevalent of all mucopolysaccharidoses, with subtypes A and B similar in 
prevalence, accounting for approximately 90% of all cases of MPS III.1  The birth prevalence of 
MPS IIIA has been estimated as 1.28 in 100,000 in Australia, 1.16 in 100,000 in the Netherlands, 
and 0.88 in 100,000 in Germany.1, 2,3  In summary, there is widespread geographic distribution of 
MPS IIIA, with an average global birth incidence of approximately 1 in 100,000.  
MPS IIIA symptoms arise on average at 7 months of age, with the average age of diagnosis at 
4.5 years for the majority of patients.4  Patients present a wide spectrum and severity of clinical 
symptoms.  The central nervous system (CNS) is the most severely affected organ system in 
patients with MPS IIIA, evidenced by deficits in language development, motor skills, and 
intellectual development.4  In addition, there are abnormal behaviors including, but not limited 
to, aggression and excess motor activity/hyperactivity that contribute to disturbances in sleep.4,5,6  
In contrast with other MPS types, the viscera are mildly affected, with transient enlargement of 
liver and spleen during childhood with no evidence of dysfunction.7  There are also reports of 
unexplained, recurrent and severe diarrhea.7  Overall, individuals with MPS IIIA have a marked 
developmental delay and significantly reduced lifespan of 15 years of age on average.7  A milder 
variant has recently been identified with slower progression and survival to later age in 
approximately 10% of German patients with MPS IIIA.8 
No effective, disease-modifying therapies are currently approved as treatments for this rare, 
devastating and disabling disease.   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
16 
A long-range goal of Shire Human Genetic Therapies, Inc. (Shire HGT) is to develop a 
recombinant human sulfamidase enzyme replacement therapy (ERT) for patients with MPS IIIA.  
A particular problem for lysosomal storage disorders that damage the brain such as MPS III is 
how to target ERT to the brain.9  In animal studies, ERT was administered into the cerebrospinal 
fluid (CSF) via an intrathecal (IT) route, because when administered intravenously (IV), it was 
shown to not cross the blood brain barrier (BBB) after the immediate postnatal period of life.10,11  
As the CNS in patients with MPS IIIA is the most severely affected body system, the main focus 
of the rhHNS clinical development program has been the development of ERT specifically for 
delivery directly to the CNS.  Recombinant human heparan N-sulfatase (rhHNS) has been 
developed specifically for delivery into the CSF via an IDDD due to the acknowledged 
impermeability of the BBB to macromolecules.  
Heparan N-sulfatase is a highly purified recombinant form of the naturally occurring human 
lysosomal enzyme sulfamidase.  It is expressed from the well characterized continuous human 
HT-1080 cell line as a 482 amino acid peptide, following cleavage of the 20 amino acid 
N-terminal signal peptide.  The mature protein in solution is a homodimeric glycoprotein of 
approximately 122 kDa, which undergoes post-translational modifications by conversion of 
Cys50 to formylglycine (FG), required for enzyme activity, and glycosylation at 4 of the 
5 potential N-linked glycosylation sites.  The rhHNS glycans contain mannose-6-phosphate 
(M6P) residues which target the protein for cellular uptake and internalization in its lysosomal 
site of action via the membrane-bound M6P receptors. 12, 13, 14, 15 
The first precedent for intraspinal ERT was recently published and has been shown to be both 
safe and effective for spinal cord compression in MPS I.16   In this study, a patient with 
mucopolysaccharidosis Type I received 4 intrathecal doses of enzyme (Laronidase) at 1-month 
intervals.  Safety evaluations included CSF opening pressure, serum chemistry and CSF protein, 
glucose and cell count, in addition to clinical efficacy studies.  No changes in safety evaluations 
were observed. 
In another recent study, a patient with MPS VI and spinal cord compression received intrathecal 
injections of enzyme (Galsulfase) monthly, for 4 months.  CSF analysis revealed no 
inflammatory reaction; no other side effects were noted.17 
Several MPS I patients have been treated since 2005 with intrathecal Laronidase (recombinant 
α-L-Idurunonidase) in 2 ongoing clinical trials (clinicaltrials.gov identifiers NCT00215527 and 
NCT00786968) studying efficacy on spinal cord compression.  No results of these trials have yet 
been published.  However, in June 2009 a study further investigating the effectiveness of 
intrathecal ERT as a treatment for another neurological symptom in MPS I, cognitive decline, 
was initiated (clinicaltrials.gov identifier NCT00852358).  This study is a 24-month, open label, 
prospective, randomized trial in 16 patients with MPS I, 6 years of age or older, who have 
documented evidence of cognitive decline.  In this study, the clinical safety of the regimen will 
be assessed by adverse events monitoring, cerebrospinal fluid (CSF) laboratory assessments, and 
clinical evaluations.  This study is ongoing; no efficacy or safety data have yet been published as 
of April 2010.18 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
17 
Finally, the Sponsor of this current study has initiated a Phase I/II clinical trial titled, “A Safety 
and Dose Ranging Study of Idursulfase (Intrathecal) Administration Via an Intrathecal Drug 
Delivery Device in Pediatric Patients With Hunter Syndrome Who Have Central Nervous 
System Involvement and Are Receiving Treatment With Elaprase®” (clinicaltrials.gov identifier 
NCT00920647), which is using a comparable (IDDD drug route of administration and dosing 
regimen) to the current protocol.  Given the similarity in dosing regimen any untoward safety 
signals from the idursulfase IT trial will be taken under careful consideration in this clinical trial. 
1.2 
Nonclinical Overview 
Nonclinical studies indicate that IT administration of recombinant human heparan N sulfatase 
(rhHNS) leads to uptake by target CNS tissues.  Preliminary PK and biodistribution results 
indicate that IT administration of rhHNS will provide the greatest chance of achieving a 
therapeutic effect in the Sanfilippo A population as compared to systemic administration.  
Likewise, CNS penetration from IV administration is unlikely to supply sufficient brain tissue 
levels to ameliorate the CNS manifestations of the disease.  Thus, the IT route of administration 
is hypothesized to be of benefit in stabilizing, improving, or preventing the CNS manifestations 
of MPS IIIA. 
1.2.1 
Toxicology in Monkeys 
In the pivotal, 6-month IT toxicity study in juvenile cynomolgus monkeys, the high dose of 
rhHNS was administered at 8.3 mg every other week (EOW).  This translates into a 138 mg/kg 
brain weight dose (ie, based on a 60 g juvenile monkey brain).  The CNS is considered a 
compartmentalized space, isolated by highly regulated flux mechanisms; thus, allometric scaling 
from animal to man is performed by normalizing doses to brain size.19  No rhHNS-related 
adverse effects were noted at the highest dose; thus, an ~13.8 × safety margin relative to the 
starting clinical dose (10 mg, given EOW) in study HGT-SAN-055, and a ~3 × safety margin 
relative to the highest anticipated clinical dose (45 mg, given EOW) was achieved.  
1.2.2 
Efficacy in Murine and Canine Models of MPS IIIA 
Efficacy has been demonstrated at a range of doses in nonclinical mouse and canine models.  In 
MPS IIIA mice, a dose-dependent reduction in the level of a heparan sulfate-derived monosulfate 
disaccharide was observed within the brain (up to 62% reduction compared with vehicle-treated 
mice) and spinal cord (up to 71% reduction).  An ultrastructural examination revealed a 
reduction in lysosomal vesicle formation in various cell types and fewer (ubiquitin-positive) 
axonal spheroids in several brain regions after repeated injections (5 to 20 µg) of rhHNS into the 
CSF of MPS III mutant mice via the cisterna magna (ie, IT).  The biochemical changes were 
accompanied by improved behavior, particularly in mice treated more frequently.20  
In the MPS IIIA mutant mouse model, intracisternal (ie, IT) injection of a single dose of 100 µg 
rhHNS resulted in a substantial (and sustained) reduction of biomarkers of disease activity 
(heparan sulfate-derived disaccharides, microgliosis, astrogliosis).21  Equally impressive was the 
improvement in neurobehavioral parameters (learning in the Morris water maze, normalization 
of aggression) in these mice post-dose.21   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
18 
One-hundred ug rhHNS per mouse translates into 200 mg/kg brain weight (ie, based on a 0.5 g 
mutant mouse brain); this is ~4.5 times the top human dose (45 mg) (human brain = ~1 kg).  
Efficacy at lower doses of rhHNS (eg, 20 ug, given IT, EOW or monthly) has been 
demonstrated.10  A 20 ug injection translates into a 40 mg human dose (ie, 40 mg per kilogram of 
brain weight).  Thus, this data further suggests that efficacy will be seen at the highest clinical 
dose (45 mg, EOW) in the proposed Phase I/II study.  
In the tolerized Huntaway (San A) dogs, 3 mg rhHNS was initially given IT on a weekly basis, 
then EOW, and had a significant effect on biomarkers of disease activity.22  The 3 mg dose in the 
dog translates into a 33 mg (per kg brain weight) human dose (based on a 90 g Huntaway dog 
brain).   
1.3 
Clinical Development Program 
Study HGT-SAN-053 and Study HGT-SAN-055 comprise the current Shire HGT MPS IIIA 
clinical development program to registration.  Study HGT-SAN-053 (also known as the 
Surrogate Endpoint Trial or SET) is an ongoing natural history study of untreated patients with 
MPS IIIA disease.  The study endpoints in the SET study (neurocognitive and behavioral 
assessments; CSF, urine, and serum biomarkers; and brain MRI) have been chosen as direct 
comparators for the HGT-SAN-055 treatment study. 
Study HGT-SAN-055 is a Phase I/II safety and ascending dose ranging study of recombinant 
human rhHNS administration via an intrathecal drug delivery device (IDDD) in patients with 
Sanfilippo Syndrome Type A (MPS IIIA).  The Phase I/II study was designed to determine the 
safety, tolerability, and dose frequency via ascending IT dose regimens of rhHNS administered 
via an IDDD to patients age ≥3 years of age with MPS IIIA who have quantifiable evidence of 
CNS pathology early in the course of the disease.  Patients who complete study HGT-SAN-055 
and elect to continue to receive rhHNS IT treatment will comprise the patient population for 
HGT-SAN-067. 
1.4 
Extension Study Rationale 
This extension study (Study HGT-SAN-067) will continue the evaluation of the effects of 
rhHNS administration on long-term safety and clinical activity and biomarker outcomes for 
patients who completed Study HGT-SAN-055 and elected to continue therapy with rhHNS.  
Patients who were enrolled in Study HGT-SAN-055 through Week 26 (patients who were dosed 
monthly) or Week 28 (patients who were dosed every other week) and completed the End of 
Study evaluations will be eligible for enrollment in this open-label extension study.  All patients 
enrolled in the extension study will continue to receive rhHNS at the same dose and schedule as 
that received in Study HGT-SAN-055.  The dose for each group will remain unchanged during 
this study unless safety and/or efficacy analyses of HGT-SAN-055 data indicate otherwise.  
Meaningful composite analysis of the optimum dose and regimen will come only after all 3 dose 
groups complete the entire HGT-SAN-055 study. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
19 
Study HGT-SAN-055 will be initiated in 2010.  There is no clinical information available to date 
on the use of rhHNS.  Please refer to the current edition of the rhHNS Investigator’s Brochure 
for further information. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
20 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective  
The primary objective(s) of this study is: 
To collect long-term safety and tolerability data in patients with Sanfilippo Syndrome Type A 
(MPS IIIA) who received rhHNS via a surgically implanted intrathecal drug delivery device 
(IDDD) in study HGT-SAN-055 and elected to continue therapy. 
2.2 
Secondary Objectives  
The secondary objectives of this study are: 
To collect as indications of drug efficacy, over an extended treatment period (as change from 
baseline), the following:  clinical, neurological, cognitive, behavioral, functional, and QoL 
assessments, together with potential imaging and biochemical biomarkers. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
21 
3 
STUDY ENDPOINTS 
3.1 
Primary Endpoint 
The primary endpoint of this study is: 
To determine the long-term safety of intrathecal rhHNS administration, as measured by adverse 
events (by type and severity), changes in clinical laboratory testing (serum chemistry including 
liver function tests, hematology, and urinalysis), electrocardiograms, CSF chemistries (including 
cell counts and inflammatory markers), and anti-rhHNS antibodies (in CSF and serum). 
3.2 
Secondary Endpoint  
The secondary endpoints of this study are to collect over an extended treatment period (as 
change from baseline) clinical and potential surrogate biomarker efficacy data:  
• Standardized neurocognitive and behavioral assessments, Sanfilippo-specific behavioral 
rating scales, gross and fine motor assessments, functional adaptive rating scales, quality 
of life questionnaires, and Children’s Sleep Habits Rating Scale. 
• Concentration of rhHNS in cerebrospinal fluid (CSF) and serum. 
• Concentration of inflammatory cytokines in serum and CSF. 
• Concentration of safety and potential surrogate efficacy biomarkers in CSF, urine, and 
serum. 
• Concentration of heparan sulfate and heparan sulfate derivatives in urine and CSF. 
• Brain magnetic resonance imaging (MRI) and auditory brainstem response (ABR), aka 
Brainstem Auditory Evoked Potentials. 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
22 
4 
INVESTIGATIONAL PLAN 
4.1 
Overall Study Design and Plan 
This study, HGT-SAN-067, is an open-label, long term, multicenter, extension of 
Study HGT-SAN-055.  The study is designed to evaluate the long-term safety, clinical activity, 
and biomarker outcomes of intrathecal administration of 3 dose levels (10 mg and 45 mg once 
per month and 45 mg EOW) of rhHNS via an IDDD in patients with MPS IIIA who completed 
HGT-SAN-055 and elected to continue to receive rhHNS treatment.  Patients will continue in the 
treatment group as previously received in the HGT SAN 055 study:  
• Group 1:  rhHNS administered by IT injection 10 mg once per month  
• Group 2:  rhHNS administered by IT injection 45 mg once per month  
• Group 3:  rhHNS administered by IT injection 45 mg EOW  
 
It is anticipated that all patients successfully completing the HGT-SAN-055 study will elect to 
continue to receive IT rhHNS per their previous schedule in Study HGT-SAN-055 by consenting 
to participate, without interruption, in the HGT-SAN-067 extension study.  Thus, for 
nomenclature of chronology purposes, the Baseline Visit for this extension study will be 
considered to be the first day the patient received his/her IT dose of rhHNS in Study 
HGT-SAN-055. 
Patients who participated in Study HGT-SAN-055 through Week 26 (patients dosed monthly) or 
Week 28 (patients dosed every other week) and completed the End of Study (EOS) will be 
eligible for enrollment after completing the HGT-SAN-055 EOS evaluations.  Patients will be 
screened for entry into the study based on their completed participation in Study HGT-SAN-055.  
Once eligibility is confirmed, the Investigator will fully inform the patient’s parent(s) or 
guardians(s) of the nature and scope of the study, potential risks and benefits of participation, the 
study procedures involved, and will answer all questions prior to the signing of the informed 
consent form.  The informed consent must be obtained prior to performing any study-related 
procedures.  Informed consent will be provided by the patient’s parent/legal guardian(s) prior to 
the start of the extension study procedures. 
Patients whose parents/legal guardians provide written informed consent/assent to participate in 
this study will check in with the study center 1 day prior to rhHNS dosing for safety assessments 
on each rhHNS treatment week.  If no safety concerns exist, the patient will subsequently receive 
IT administration of rhHNS on Day 2 (±2 days).  Patients will be discharged from the inpatient 
unit a minimum of 1 day following dosing with rhHNS and when deemed clinically stable by the 
Investigator.   
The patient will have already received a standardized battery of neurodevelopmental assessments 
at the Baseline and 6-month time points in the HGT-SAN-055 study.  These same assessments 
and tests will be performed at 12, 24, 36, and 48 months.  Similarly, MRI of the head, ABR 
testing, CSF sampling by means of lumbar puncture and any other procedures requiring 
anesthesia will be performed at 12, 24, 36, and 48 months.   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
23 
All patients will undergo end of study procedures 30 (±7) days following their last administration 
of rhHNS.  End of study procedures will include a standard battery of clinical laboratory tests 
(serum chemistry, hematology, and urinalysis) in CSF and blood, protocol specific laboratory 
testing (eg, anti-rhHNS antibody testing), neurodevelopmental testing, ABR, child health 
questionnaires, MRI, and concomitant medications and AE monitoring.  
All patients will be contacted by telephone for a Final Safety Follow-up, to be conducted at 
30 (±7) days after the EOS procedures to collect updated information on adverse events and 
concomitant medications, therapies, and procedures. 
It is anticipated that the IDDD will be used to obtain CSF samples and to deliver all 
administrations of rhHNS.  However, if a patient’s IDDD becomes nonfunctional or infected, it 
will be replaced so that the patient can remain on study.  If use of the IDDD is precluded on a 
scheduled day of dosing, the IDDD will be declared a failure; no study drug will be 
administered, nor CSF sample obtained on that visit.  Unlike the HGT-SAN-055 study, no study 
drug will be administered by lumbar puncture in this extension study.  Upon declaration of 
failure, the IDDD will be removed and the patient scheduled for re-implantation of a new IDDD 
(see Section 7.11) at the earliest convenience, so that the patient may remain on, or remain as 
close as possible, to his/her original IT rhHNS dosing schedule.  Note:  Patients will require 
1 week of recovery time from time of re-implantation, during which time the IDDD cannot be 
used, this may result in a delay in the next scheduled dose of rhHNS.  The patient will resume his 
or her original dosing schedule; no catch-up dosing will occur. 
If a patient discontinues the study, is withdrawn from the study, or the study is stopped by the 
Sponsor, the IDDD will be removed as part of the End of Study Procedures.  
An overview of the study appears in Appendix 1 Schedule of Events. 
4.2 
Rationale for Study Design and Control Group 
Study HGT-SAN-055 is an ongoing Phase I/II safety and ascending dose ranging study of 
intrathecal administration of rhHNS via an IDDD, in patients 3 years of age and older with MPS 
IIIA and early cognitive impairment.  This extension study is proposed to continue evaluation of 
the effects of intrathecal rhHNS administration on long-term safety and clinical outcomes for 
patients who completed Study HGT-SAN-055 and elected to continue treatment with rhHNS.  
4.3 
Study Duration and Dates 
The study duration will have a maximum duration of 4 years of rhHNS treatment or until rhHNS 
is commercially available, the patient discontinues from the study, the Sponsor stops the study, 
or the Sponsor discontinues the development of rhHNS.  Study completion will be defined as the 
time at which a patient completes 4 years of rhHNS treatment (including treatment in Study 
HGT-SAN-055), or transitions to commercially available rhHNS or discontinues from this study 
for other reasons. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
24 
5 
STUDY POPULATION SELECTION 
5.1 
Study Population 
Patients who have completed all study requirements in Study-HGT-SAN-055 and who elected to 
continue rhHNS treatment will be eligible to participate; a maximum of twelve patients are 
planned for this study.  
5.2 
Inclusion Criteria 
Each patient must meet the following criteria to be considered eligible for enrollment in this 
study. 
1. Patients must have completed all study requirements and assessments for Study 
HGT-SAN-055 prior to enrolling in this extension study and must have no safety or medical 
issues that contraindicate participation. 
2. The patient, patient’s parent(s), or legally authorized guardian(s) must have voluntarily 
signed an Institutional Review Board / Independent Ethics Committee-approved informed 
consent form after all relevant aspects of the study have been explained and discussed with 
the patient.  The guardians’ consent and patient’s assent, as relevant, must be obtained. 
3. The patient has received and tolerated treatment with rhHNS, completed the End of Study 
visit, and has received at least 80% of the total planned infusions within the last 6 months in 
study HGT-SAN-055 (ie, at least 5/6 ([Group 1 or 2] or 10/12 infusions [Group 3]). 
4. Patients must be medically stable, in the opinion of the Investigator, to accommodate the 
protocol requirements, including travel, assessments, and IDDD surgery (if necessary for 
replacement purposes), without placing an undue burden on the patient/patient's family. 
 
5.3 
Exclusion Criteria 
Subjects will be excluded from the study if there is evidence of any of the following criteria at 
screening or at anytime during the study: 
1. The patient has experienced an adverse reaction to study drug in Study HGT-SAN-055 that 
contraindicates further treatment with rhHNS. 
2. The patient has a known hypersensitivity to the active ingredient or any excipients in rhHNS 
drug product. 
3. The patient has significant non-MPS IIIA related central nervous system (CNS) impairment 
or behavioral disturbances that would confound the scientific integrity or interpretation of 
study assessments, as determined by the Investigator. 
4. The patient has significant MPS IIIA behavioral-related issues, as determined by the 
Investigator, which would preclude performance of study neurocognitive and developmental 
testing procedures. 
5. The patient is pregnant, breast feeding, or is a female patient of childbearing potential who 
will not or cannot comply with the use of an acceptable method of birth control, such as 
condoms, barrier method, oral contraception, etc. 
6. The patient has any known or suspected hypersensitivity to anesthesia or is thought to have 
an unacceptably high risk for anesthesia due to airway compromise or other conditions. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
25 
7. The patient has a history of poorly controlled seizure disorder. 
8. The patient is currently receiving psychotropic or other medications, which in the 
Investigator’s opinion, would be likely to substantially confound test results and the dose and 
regimen of which cannot be kept constant throughout the study. 
9. The patient cannot sustain absence from aspirin, non-steroidal medications, or medications 
that affect blood clotting within 1 week prior to a relevant study-related procedure (eg, 
device implantation if applicable), or has ingested such medications within 1 week before 
any procedures in which any change in clotting activity would be deleterious. 
10. The patient has received treatment with any investigational drug (other than rhHNS) intended 
as a treatment for MPS IIIA or used any other intrathecal delivery device other than what was 
used in Study HGT-SAN-055, within the 30 days prior to, or during the study, or is currently 
enrolled in another study that involves an investigational drug or device (screening through 
safety follow-up contact). 
11. The patient has received a hematopoietic stem cell or bone marrow transplant. 
12. The patient’s parent(s), or patient’s legal guardian(s) is/are unable to provide consent or the 
patient cannot provide assent, as appropriate, due to, but not limited to, the inability to 
understand the nature, scope, and possible consequences of the study, or do/does not agree to 
comply with the protocol defined schedule of assessments. 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
26 
6 
STUDY TREATMENT(S) 
6.1 
Description of Treatment(s) 
6.1.1 
Study Drug 
Recombinant human heparin N-sulfatase (rhHNS) drug product formulation is a sterile solution 
for injection in single-use vials for intrathecal (IT) administration.  It is formulated in an aqueous 
isotonic solution containing 15.0 mg/mL rhHNS in 145 mM sodium chloride, 0.005% (v/v) 
polysorbate 20, 5 mM sodium phosphate at pH 7.0. 
6.1.2 
Placebo or Control 
This study will not employ a placebo or control.   
6.2 
Treatment(s) Administered 
rhHNS for IT administration will be provided by Shire HGT.  rhHNS will be administered by an 
IDDD.  Following the review and signing of informed consent, patients will receive the same 
dose of rhHNS they received in Study HGT-SAN-055: 
• Group 1:  rhHNS administered by IT injection 10 mg once per month  
• Group 2:  rhHNS administered by IT injection 45 mg once per month  
• Group 3:  rhHNS administered by IT injection 45 mg every other week (EOW) 
 
6.3 
Selection and Timing of Dose for Each Subject 
The patient’s dose of rhHNS will be the same dose (10 mg and 45 mg once per month and 45 mg 
EOW) they received in Study HGT-SAN-055.  Patients will check in to the study center 1 day 
prior to intrathecal rhHNS dosing for safety assessments on each rhHNS treatment week, and if 
no safety concerns exist, will subsequently receive IT administration of rhHNS on Day 2.  
Patients will be discharged from the inpatient unit a minimum of 1 day following dosing with 
rhHNS and when deemed clinically stable by the Investigator.   
The IT injections are to be administered 28 days (±7 days [groups 1 and 2]) and 14 days (±3 days 
[group 3]) apart.  If a patient’s IDDD becomes nonfunctional, it will be replaced so that the 
patient can remain on study.  See Section 6.5 for a description on the replacement of a 
nonfunctional IDDD. 
6.4 
Cerebral Spinal Fluid Sample Procedure 
A total of 10 mL of CSF will be obtained in two 5 mL aliquots prior to each injection for safety 
evaluation using the IDDD.  A topical anesthetic agent may be applied over the skin covering the 
IDDD reservoir prior to CSF sampling.  However, CSF will not be obtained if use of the IDDD 
is precluded, with the exception at the EOS visit, when it may be obtained by means of a lumbar 
puncture (LP).  The performance of LP is at the discretion of the Investigator.  An intracranial 
pressure (ICP) measurement will be obtained whenever a LP is performed. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
27 
If a lumbar puncture is to be performed, the patient will be anesthetized via general anesthesia 
with appropriate airway management.  Once the patient is anesthetized, a lumbar puncture will 
be performed and a CSF sample will be obtained. 
6.5 
Intrathecal Administration of rhHNS 
rhHNS will be administered using an IDDD.  After appropriate pre-procedure assessments are 
completed, anesthesia cream will be applied to the skin over the port.  Patients may receive mild 
sedation to alleviate anxiety and/or to facilitate drug delivery.     
Patients will then receive their appropriate dose of rhHNS via slow push/ injection over 2 to 
5 minutes.  Replacement of fluid, including drug, to the CSF will be an approximate equal 
volume to that removed.  The patient’s vital signs will be continuously monitored.  The patient 
will also be monitored closely during enzyme administration and through the next 24 hours for 
any adverse clinical reactions.  The patient will be encouraged to lie down comfortably for 1 to 
3 hours post injection, although this may be difficult for the most hyperactive patients. 
If use of the IDDD is precluded on a scheduled day of dosing, the IDDD will be declared a 
failure; no study drug will be administered, nor CSF sample obtained on that visit.  Unlike the 
HGT-SAN-055 study, no study drug will be administered by lumbar puncture in this extension 
study.  Upon declaration of failure, the IDDD will be removed and the patient scheduled for 
re-implantation of a new IDDD (see Section 7.11) at the earliest convenience, so that the patient 
may remain on, or remain as close as possible, to his/her original IT rhHNS dosing schedule.  
Note:  Patients will require 1 week of recovery time from time of re-implantation, during which 
time the IDDD cannot be used, this may result in a delay in the next scheduled dose of rhHNS.  
The patient will resume his or her original dosing schedule; no catch-up dosing will occur. 
6.6 
Method of Assigning Subjects to Treatment Groups 
This is an open-label, non-randomized study; all patients enrolled in this study will be treated 
with rhHNS.  Patients will remain in the groups (1, 2, or 3) they were assigned to in 
Study HGT-SAN-055.  
6.7 
Blinding 
Not applicable; this trial is not blinded. 
6.8 
Concomitant Therapy 
All non-protocol treatments and procedures that occur from the time of informed consent (or 
assent, if applicable) through the safety follow-up contact are regarded as concomitant and will 
be documented on the appropriate pages of the electronic case report form (eCRF).  Concomitant 
therapy includes medications, therapies/interventions administered to patients, and 
medical/surgical procedures performed on the patients.  
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
28 
Every effort should be made to keep the patient’s symptomatic Sanfilippo syndrome Type A 
treatment constant throughout the study.  However, changes in medications are acceptable if 
necessary according to clinical judgment.  All changes will be recorded on the appropriate eCRF.  
Concomitant medication will be coded using World Health Organization Drug Reference List 
(WHODRL). 
6.9 
Restrictions 
6.9.1 
Prior Therapy 
Prior therapy excluded for this study consists of the following: 
• Psychotropic or other medications, which in the Investigator’s opinion, would be likely to 
substantially confound test results and the dose and regimen of which cannot be kept constant 
throughout the study. 
• The patient cannot sustain absence from aspirin, non-steroidal medications, or medications 
that affect blood clotting within 1 week prior to a relevant study related procedure (eg, device 
implantation if applicable) or medications within 1 week before any procedures in which any 
change in clotting activity would be deleterious. 
• The patient has received any investigational drug or device intended as a treatment for MPS 
IIIA within the 30 days prior to the study other than rhHNS or is enrolled in another study 
that involves an investigational drug or device. 
• Hematopoietic stem cell or bone marrow transplant. 
 
6.9.2 
Fluid and Food Intake  
Oral food and fluid intake are not restricted over the course of the study, with the exception of 
hospital standard pre-anesthesia dietary restrictions. 
6.9.3 
Subject Activity Restrictions 
There are no restrictions on patient activities in this study. 
6.10 Treatment Compliance 
rhHNS is administered under controlled conditions by the Investigator; therefore, full patient 
compliance with study treatment is anticipated in this study.  
6.11 Packaging and Labeling 
Drug product will be supplied in a 3 mL clear, colorless glass (Type 1) vial.  Each vial holds an 
extractable volume of 1 mL of rhHNS.  The closure is a gray, 13 mm stopper composed of butyl 
rubber with a fluoro resin lamination.  The overseal is an aluminum seal with a flip-off, plastic, 
tamper evident cap.  

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
29 
6.12 Storage and Accountability 
Drug product should be stored refrigerated (2 to 8°C); drug product may not be stored beyond 
the expiration date on the vial. 
6.13 Investigational Product Retention at Study Site 
All rhHNS study drug delivered to an Investigator will be recorded and accounted for throughout 
the study.  All rhHNS study drug must be recorded on a patient-by-patient basis.  The lot number 
of the IDDD and the date and time of administration of the study medication will be documented 
on the appropriate eCRF. 
All unused study medication and other study materials are to be returned to the Sponsor or its 
designee or disposed after Sponsor approval per site policy after the study has been completed. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
30 
7 
STUDY PROCEDURES 
7.1 
Informed Consent 
Study procedures will be conducted only after written informed consent for the patient to 
participate in this study is provided by the parent(s) or legal guardian(s) and assent from the 
patient (if applicable).  Detailed descriptions of patient evaluations required for this protocol are 
described in this section.  These evaluations will be performed during the indicated days and 
weeks of each study month (see Appendix 1 Schedule of Events). 
All data collected are to be recorded on the appropriate eCRF.  The approximate maximum total 
blood, urine, and CSF volumes to be collected from each patient by the end of this study for 
safety assessments are presented in Table 7-1. 
Table 7-1 Approximate Total Sample Volumes Collected Over the Duration of the 
Study From Each Patient by Group and Assay 
 
Groups 1 and 2 
Group 3 
Blood  
290 mL 
555 mL 
Urine 
530 mL 
1,010 mL 
CSF 
480 mL 
960 mL 
 
 
Blood, urine and CSF volumes to be collected for each clinical laboratory measurement are 
described in detail in the Laboratory and/or Study Operations Manual. 
7.2 
Physical Examination 
A physical examination of each patient will be performed as detailed in Appendix 1 Schedule of 
Events. 
Note:  if the patient’s hearing cannot be assessed during the physical examination, the patient 
will have an Ears, Nose, and Throat Evaluation performed under anesthesia at the baseline visit.  
If is determined that the patient requires pressure-equalization (PE) tubes, they may be implanted 
during that same visit.  See Section 7.9 for details.  Note:  Pressure-equalization tubes may be 
re-implanted if they fall out during this study. 
 
 
 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
31 
The physical examination findings will be recorded on the eCRF and will include a review of the 
patient’s general appearance as well as the following evaluations: 
- 
Head and neck 
- 
Eyes, ears, nose and throat 
- 
Chest and lungs 
- 
Cardiovascular 
- 
Abdomen 
- 
Skin 
- 
Lymphatic 
- 
Musculoskeletal 
- 
Neurological 
- 
Endocrine 
- 
Genitourinary 
 
7.3 
Height and Weight 
Height or length (cm), and weight (kg) measurements will be taken once.  All data will be 
recorded on the eCRF. 
7.4 
Head Circumference 
Head circumference will be measured once.  The data will be recorded on the eCRF. 
7.5 
Vital Signs 
Vital signs (blood pressure, heart rate, respiratory rate, and temperature measurements) will be 
measured and recorded on the eCRF. 
7.6 
Electrocardiography 
7.6.1 
Electrocardiograms 
An ECG will be performed.  Each ECG will include assessment of heart rate, sinus rhythm, atrial 
or ventricular hypertrophy, PR, QRS, QT, and QTc intervals.  The ECGs will be conducted in 
accordance with the clinical site’s standard practice(s), and will be read locally at the clinical 
site.  Identification of any clinically significant findings and/or conduction abnormalities will be 
recorded on the eCRF.   
7.7 
Clinical Laboratory Tests 
Blood, urine, and CSF samples will be collected as described below for clinical laboratory 
testing.  Procedures for collection and handling of samples are included in the Laboratory and/or 
Study Operations Manual.  
Patients will be in a seated or supine position during blood collection.  Clinical laboratory tests 
will include hematology, serum chemistry, and urinalysis. 
Laboratory Parameters  
Clinical laboratory tests will be performed at a central laboratory include the following: 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
32 
7.7.1 
Hematology 
• Hematocrit (Hct) 
• Hemoglobin (Hgb) 
• Mean corpuscular hemoglobin (MCH) 
• Mean corpuscular hemoglobin concentration (MCHC) 
• Mean corpuscular volume (MCV) 
• Platelet count 
• Red blood cell (RBC) count  
• White blood cell (WBC) count with differential  
 
7.7.2 
Serum Chemistry 
7.7.2.1 
Standard Serum Chemistry 
• Albumin (ALB) 
• Alkaline phosphatase (ALK-P) 
• Alanine aminotransferase (ALT; SGPT) 
• Aspartate aminotransferase (AST; SGOT) 
• Blood urea nitrogen (BUN) 
• Calcium (Ca) 
• Carbon dioxide (CO2) 
• Chloride (Cl) 
• Creatinine 
• Creatine kinase (CK) and subtypes 
• Gamma-glutamyl transferase (GGT) 
• Globulin 
• Glucose 
• Lactate dehydrogenase (LDH) 
• Phosphorus 
• Potassium (K) 
• Sodium (Na) 
• Total bilirubin 
• Direct bilirubin 
• Total cholesterol 
• Total protein 
• Triglycerides 
• Uric acid 
 
7.7.3 
Urinalysis  
Patient catheterization may be required for obtaining urine samples (if deemed necessary by the 
Investigator).   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
33 
7.7.3.1 
Standard Urinalysis 
The following urinalysis parameters will be performed at a central laboratory on urine samples: 
• Macroscopic examination  
• Microscopic examination of sediment  
• pH 
 
7.7.3.2 
Urine Heparan Sulfate and Heparan Sulfate Derivatives 
A urine sample will be collected for the determination of heparan sulfate and heparan sulfate 
derivatives and the analysis will be performed at Shire HGT laboratories.  A urine sample from 
each visit will be reserved for possible, exploratory biomarker studies that may provide new 
indicators or markers of MPS IIIA disease severity or progression. 
7.7.4 
Cerebrospinal Fluid Assessments 
Cerebrospinal fluid (CSF) samples (10 ml in two 5 ml aliquots; labeled separately and processed 
according to the study operations manual) will be obtained from patients through an implanted 
IDDD.  Should the IDDD become blocked or undergo mechanical complications, the CSF 
sample will not be obtained via lumbar puncture (LP), except when part of the EOS visit.  The 
performance of LP is at the discretion of the Investigator.  See Section 6.4 for further details. 
CSF sample collection, processing, and shipping instructions will be provided in the Laboratory 
and/or Study Operations Manual.  A CSF sample will be reserved for possible exploratory 
biomarker studies for MPS IIIA disease. 
Each CSF sample collected will be assessed for appearance and will be analyzed using the assays 
listed in Sections 7.7.4.1, 7.7.4.2, and 7.7.4.4.  In addition, as more is learned about Sanfilippo 
CNS pathology and etiology, future exploratory assays of CSF metabolites or protein or RNA 
may become available in the future (the samples maybe analyzed, if the assays are found 
applicable) and are thus not presently listed within this protocol. 
7.7.4.1 
CSF Cell Counts 
An aliquot of each CSF sample collected will be evaluated for CSF standard chemistries, 
glucose, protein, and cell counts.  These assessments will be performed at the local laboratory. 
7.7.4.2 
CSF Heparan Sulfate Levels and Heparan Sulfate Derivatives 
An aliquot of each CSF sample collected will be quick frozen as per the Laboratory and/or Study 
Operations Manual for subsequent determination of CSF heparan sulfate and heparan sulfate 
derivatives at Shire HGT laboratories. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
34 
7.7.4.3 
Anti-rhHNS Antibodies 
An aliquot of each CSF sample collected will be quick frozen as per the Laboratory and/or Study 
Operations Manual for subsequent determination of anti-rhHNS antibodies at Shire HGT 
laboratories. 
7.7.4.4 
CSF Biomarkers  
An aliquot of each CSF sample collected will be quick frozen as per the Laboratory and/or Study 
Operations Manual for subsequent determination of MPS exploratory biomarkers at Shire HGT 
laboratories. 
7.7.5 
Sample Collection, Storage, and Shipping 
Sample collection, processing, and shipping instructions will be provided in the Laboratory 
and/or Study Operations Manual to be provided by Shire HGT. 
7.8 
Anesthesia 
Administration of anesthesia/sedation will be given prior to obtaining CSF (when the use of the 
IDDD is precluded – see Section 6.4), prior to performing the MRI of the head, the ABR, the 
intracranial pressure (ICP), and the re-implantation of the IDDD (if applicable).  See Appendix 1 
for the Schedule of Events. 
Note:  the neurologic exam and the neurocognitive and developmental assessments must be 
performed prior to the administration of anesthesia. 
7.9 
Audiometry and Auditory Brainstem Response 
The rare attenuated patients with MPS IIIA with high levels of cognitive functioning will have 
hearing tests via clinical audiometry measurement performed using age-appropriate testing 
methods based on the child’s developmental age at the time of the testing.  It is anticipated that 
most of the cognitively-impaired and/or behaviorally-deteriorated patients with Sanfilippo A will 
be unable to co-operate with a (conscious) hearing evaluation.  In these instances, the 
Investigator will utilize his best clinical judgement to initially estimate the extent of hearing loss 
(if any) during the initial physical examination.  In this situation, specific evaluation of hearing 
loss will await examination of waveforms in the ABR (see below).  If the patient has a history of 
multiple instances of otitis media or evidence of clinically-significant otitis media on physical 
examination, which the Investigator believes causes significant conductive hearing loss and 
impairment of daily living, the Investigator will ask and offer the parent or guardian placement 
of PE tubes as part of the scheduled anesthesia.  A patient’s PE tubes may be replaced if they fall 
out during the course of this study. 
The auditory brainstem response (ABR) will be conducted under anesthesia.  The ABR findings 
will be considered within normal limits if, after applying appropriate correction factors, the 
waveforms reveal normal morphology.  

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
35 
7.10 MRI of the Head 
The regional brain volume will be assessed through an MRI of the head.  The patient will be 
under general anesthesia for this assessment.  The central reading for MRI data, across all sites, 
will be completed at the University of Minnesota Medical Center.  Refer to the Study Operations 
Manual for specific procedures and precautions. 
7.11 Surgical Re-implantation of the IDDD 
If a patient’s IDDD becomes nonfunctional or infected, it will be replaced so that the patient can 
remain on study.  Procedures for implantation will be detailed in the device’s Instructions for 
Use manual.  The patient will be under general anesthesia for this procedure.  Standard hospital 
procedure for surgery will be followed and will include an X-ray to confirm device placement at 
the mid-thoracic level.  A post-operative check of the IDDD will be performed on Day 7 
following surgery.  X-rays may be performed to check placement of the device, as needed, 
throughout the study.  Drug can only be administered via the IDDD. 
7.12 Intracranial Pressure Measurement 
Intracranial pressure measurement (ICP) (centimeters of H2O) will be conducted per standard 
hospital practice.  The measurement will be obtained whenever a LP is performed. 
7.13 Dispensing Study Drug 
rhHNS will be administered IT by means of an IDDD to patients in Dose Groups 1 and 2 on 
Day 2 (±2 days) of Week 1 of each treatment month and to patients in Dose Group 3 on Day 2 
(±2 days) of Weeks 1 and 3 of each treatment month. 
The patient may be mildly sedated for this procedure; rhHNS will be administered over 2 to 
5 minutes.  Please see Section 6.5 if the IDDD is not functioning.   
The patient must not receive aspirin, non-steroidal anti-inflammatory medications, or 
medications that affect clotting within 1 week prior to each IT injection. 
7.14 Pharmacokinetic Assessments 
Pharmacokinetic assessments will not be included in this study. 
7.15 Neurological Examination 
A neurological examination to monitor CNS changes in patient’s neurological status will be 
conducted during this study.  See Appendix 2 for a complete list of the neurological 
examinations. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
36 
7.16 Serum Anti-rhHNS Antibody, Heparan Sulfate and Heparan Sulfate 
Derivative Determination 
Blood samples will be collected prior to rhHNS injection and evaluated at Shire HGT 
laboratories for the determination of anti-rhHNS antibodies, heparan sulfate and heparan sulfate 
derivatives.  Samples will be reserved for potential future MPS IIIA research that may determine 
biomarkers of disease severity and progression.  
Two 5 mL blood samples will be collected from each patient at each designated time point.  One 
5 mL sample will be collected in a tube intended for serum specimens, while the second sample 
will be collected in a tube intended for plasma specimens.  Blood sample collection, processing, 
and shipping instructions will be provided in the Laboratory and or Study Operations Manual. 
7.17 Neurocognitive and Developmental Assessments 
Patients will undergo neurocognitive and neurobehavioral development testing.  The assessments 
are estimated to last between 2 and 4 hours and must be conducted prior to sedation or 
anesthesia.  
A full neurodevelopmental assessment, including global development, cognition, adaptive 
behavior, receptive and expressive language, and gross motor function, will be evaluated using 
standardized developmental and behavioral tests to provide a surrogate and quantifiable measure 
of global CNS neurodevelopmental/neurobehavioral function.  
For this study, outcome measures will be computed for each patient enrolled.  The psychometric 
instruments and Sanfilippo-specific assessments are summarized below in Table 7-2 and 
Table 7-3, respectively.  See Appendix 3 for details on these assessments. 
Table 7-2 Neurodevelopmental Assessments Tests  
Developmental or Cognitive 
Domain(s) 
Patient Age:  Representative Cognitive Test or 
Scale 
COGNITIVE DEVELOPMENT ASSESSMENT 
Summary score and sub-domains: 
- Cognitive 
- Motor 
 
0 to 42 months:  Bayley Scales of Infant 
Development-III (BSID-III) 23  
 
- Cognitive  
- Processing skills 
 
3 to 18 years:  Kaufman Assessment Battery for 
Children, Second Edition (KABC-II) 24  
GROSS AND FINE MOTOR SKILLS ASSESSMENT AND VOLUNTARY MOVEMENT 
Motor 
3.0 to 16:11 years:  Movement Assessment Battery 
for Children II (MABC-2) 25  
- Cognitive 
- Motor 
0 to 5 ½ years:  Bayley Scales of Infant 
Development III (BSID-III) 23 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
37 
Table 7-2 Neurodevelopmental Assessments Tests  
Developmental or Cognitive 
Domain(s) 
Patient Age:  Representative Cognitive Test or 
Scale 
ADAPTIVE BEHAVIOR 
Communication 
Daily Living 
Socialization 
Motor Skills 
0 to 90 years:  Vineland Adaptive Behavior Scales 
(VABS-II)  Second Edition 26 
 
Table 7-3 Sanfilippo-Specific Disability Assessment And Behavior Rating Scales 
Developmental or Cognitive 
Domain(s) 
Sanfilippo Specific Assessments 
Parent-scored behavioral inventory 
- communication:  understanding 
- communication:  expression 
- tantrums 
- specific behaviors inventory 
- mood & emotions inventory 
 
Sanfilippo Behavior Rating Scale (SBRS) 
MPS-specific disability score  
- cognitive functioning 
- expressive language 
- motor score 
Four-Point Scoring System/Total Disability Score 
(FPSS/TDS)4 
 
7.18 Sleep Questionnaire:  Children’s Sleep Habits Rating Scale  
A sleep questionnaire, Children’s Sleep Habits Rating Scale, will be administered to the patient's 
patients/legal guardian. 
7.19 Age-Dependent, Health-Related Quality of Life in Children 
The Quality of Life questionnaires will be administered as outlined in Sections 7.19.1, 7.19.2, 
and 7.19.3. 
7.19.1 
Quality of Life Indicator:  CHQ-50 
The Child Health Questionnaire™ Parent Form 50 Questions (CHQ-50) will be administered 
during the study.   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
38 
The questionnaire is a generic quality of life instrument, measuring 14 unique physical and 
psychosocial concepts, which was developed for children from 5 to 18 years of age 
7.19.2 
Quality of Life Indicator:  CHQ-87 
The Child Health Questionnaire™ Child Form 87 (CHQ-87) will be administered during the 
study.  The CHQ-87 is a child and adolescent self-report, developed for ages 10 and older, which 
assesses the child’s self-perceived physical and psychosocial well-being 
7.19.3 
Quality of Life Indicator:  ITQOL 
The Infant Toddler Quality of Life Questionnaire™ (ITQOL) will be administered during the 
study.  The ITQOL was developed for children at least 2 months of age up to 5 years and 
assesses the physical, mental, and social well being of the child and assesses the quality of the 
parent/guardian’s life.   
7.20 Concomitant Medications, Therapies and Medical/Surgical Procedures 
All non-protocol treatments that occur from the time of informed consent (assent if applicable) 
through the safety follow-up contact are regarded as concomitant and will be documented on the 
appropriate pages of the eCRF.  Concomitant therapy includes medication, 
therapies/interventions administered to patients, and medical/surgical procedures performed on 
the patients. 
Every effort should be made to keep symptomatic Sanfilippo syndrome Type A treatment 
constant throughout the study.  However, changes in medications are acceptable if necessary 
according to clinical judgment.  All changes will be recorded on the appropriate eCRF.  
Concomitant medication will be coded using WHODRL. 
7.21 Adverse Events 
7.21.1 
Adverse Events Assessments 
Adverse events will be monitored continuously throughout the study from the time the patient, 
patient's parent/legal guardian signs the informed consent/assent (if applicable) until the safety 
follow-up contact or until the event has resolved or stabilized, or an outcome is reached, 
whichever comes first.  
If the Investigator considers it necessary to report an AE in a study patient after the end of the 
observation period, he or she should contact the Sponsor to determine how the AE should be 
documented and reported. 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
39 
7.21.2 
Definitions of Adverse Events and Serious Adverse Events 
7.21.2.1 
Adverse Event 
An adverse event (AE) is any noxious, pathologic, or unintended change in anatomical, 
physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory 
changes occurring in any phase of a clinical study, whether or not considered study drug-related.  
This includes an exacerbation of a pre-existing condition.  Once the informed consent is signed, 
any adverse event prior to the start of study drug must be reported.  
AEs include: 
• Worsening (change in nature, severity, or frequency) of conditions present at the onset of the 
study 
• Intercurrent illnesses 
• Drug interactions 
• Events related to or possibly related to concomitant medications 
• Abnormal laboratory values (this includes significant shifts from baseline  within the range 
of normal that the Investigator considers to be clinically important) 
• Clinically significant abnormalities in physical examination, vital signs, and weight 
 
Throughout the study, the Investigator must record all AEs on the AE case report form (eCRF), 
regardless of the severity or relationship to study drug.  The Investigator should treat patients 
with AEs appropriately and observe them at suitable intervals until the events stabilize or 
resolve.  AEs may be discovered through observation or examination of the patient, questioning 
of the patient, complaint by the patient, or by abnormal clinical laboratory values. 
In addition, AEs may also include laboratory values that become significantly out of range.  In 
the event of an out-of-range value, the laboratory test should be repeated until it returns to 
normal or can be explained and the patient’s safety is not at risk.   
All adverse events should be recorded with causality assessment. 
The information presented below is intended to provide issues to consider for adverse events 
associated with intrathecal injections of rhHNS.  In general, these adverse events can be 
classified as follows:  
• Adverse events due to systemic exposure to rhHNS caused by the drug diffusion from the 
CSF to the peripheral circulation;  
• Adverse events related to the direct delivery of rhHNS to the intrathecal CSF space and 
meninges, and subsequent diffusion into brain parenchyma, via an intrathecal route  
• IDDD–related adverse events.   
 
Note:  the classification of potential adverse events and the examples presented below are based 
on purely theoretical considerations and/or published literature as there is no human experience 
with intrathecal rhHNS therapy to date. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
40 
POTENTIAL ADVERSE EVENTS:  INTRATHECAL RHHNS 
Adverse Events Due To Systemic Exposure To rhHNS 
Although rhHNS is given intrathecally only, some proportion of the drug will diffuse from the 
CSF into the peripheral circulation.  The resulting systemic exposure may cause events that are 
typically seen in patients receiving ERT via an intravenous administration, known as 
infusion-related reactions.  An infusion-related reaction is defined as an adverse event that 
(1) begins either during or within 24 hours after the start of the infusion, and (2) is judged as 
possibly or probably related to study drug.  Other AEs that occur prior to the infusion, along with 
AEs associated with protocol-defined testing and assessments (laboratory testing and physical 
examinations) that were performed prior to the infusion will not be defined as infusion-related 
reactions.   
Adverse Events Related to the Direct Delivery of rhHNS to the CNS Through Intrathecal 
Administration 
Examples of adverse events observed in other published clinical trials with 
intrathecally-administered peptides or proteins, include, but are not limited to the following:  
headache, fever, feeling of warmth, sensory parathesias (including feelings of warmth, tingling, 
or pain) or autonomic symptoms such as dry mouth or gustatory abnormalities (including loss of 
smell and metallic taste).  Changes in mental cognitive status or level of consciousness that are 
not caused by pre-medication may either occur acutely or develop post-injection, over time. 
Potential Adverse Events:  IDDD -Related Adverse Events 
Examples of adverse events related to the insertion or use of an IDDD include, but are not 
limited to, the following:  catheter disconnection or fracture, erosion of portal/catheter through 
the skin, fibrin sheath formation around catheter tip, hematoma, implant rejection, malposition of 
catheter, migration of portal/catheter, occlusion of portal/catheter, portal site or subcutaneous 
tract infection, and sepsis.   
In addition, there are risks associated with intraspinal access, which include the following:  
cerebrospinal fluid leaks, dura mater or epidural vein perforation, epidural or intrathecal space 
infection (which could result in meningitis), inadvertent epidural placement, pain on injection, 
and spinal cord or nerve injury. 
7.21.2.2 
Serious Adverse Event 
A serious AE (SAE) is any AE occurring at any dose that results in any of the following 
outcomes: 
• Death 
• Is life-threatening 
• Requires inpatient hospitalization 
• Requires prolongation of existing hospitalization 
• A persistent or significant disability or incapacity  

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
41 
• A congenital anomaly or birth defect 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization. 
The National Cancer Institute Common Toxicity Criteria (NCI CTC) Version 3.0 grading scale 
should be referenced when assessing the severity of an AE (see Appendix 5)  If an AE is not 
described in the NCI CTC, the severity should be recorded based on the scale provided in Table 
7-4.  The severity of all AEs/SAEs should be recorded on the appropriate eCRF page as Grade 1, 
2, 3, 4, or 5 corresponding, respectively, to a severity of mild, moderate, severe, life-threatening, 
or death. 
Table 7-4  Adverse Event Severity 
Severity 
Definition 
Grade 1 (Mild) 
No limitation of usual activities. 
Grade 2 (Moderate) 
Some limitation of usual activities. 
Grade 3 (Severe) 
Inability to carry out usual activities. 
Grade 4 (Life-threatening) 
Immediate risk of death. 
Grade 5 (Death related to an AE) 
Death 
 
Relationship of an adverse event or serious adverse event to study medication is to be determined 
by the Investigator based on the definitions in Table 7-5: 
Table 7-5 Adverse Event Relatedness 
Relationship to Product(s) 
Definition 
Not Related 
Unrelated to study drug. 
Possibly Related 
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of study drug, but which could also be 
explained by concurrent disease or other drugs or chemicals. 
Probably Related 
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of study drug, unlikely to be attributable to 
concurrent disease or other drugs and chemicals and which follows a 
clinically reasonable response on de-challenge.  The association of the 
clinical event or laboratory abnormality must also have some biologic 
plausibility, at least on theoretical grounds. 
Definitely related 
The event follows a reasonable temporal sequence from administration 
of the medication, follows a known or suspected response pattern to 
the medication, is confirmed by improvement upon stopping the 
medication (dechallenge) and reappears upon repeated exposure 
(rechallenge).   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
42 
Table 7-5 Adverse Event Relatedness 
Relationship to Product(s) 
Definition 
Note that this is not to be construed as requiring re-exposure of the 
patient to study drug; however, the determination of definitely related 
can only be used when recurrence of event is observed. 
 
7.21.3 
Procedures for Recording and Reporting Adverse Events 
7.21.3.1 
Reporting Serious Adverse Events 
Any SAE, regardless of relationship to study medication, which occurs in a patient after 
informed consent, should be recorded by the clinical site on an SAE form.  The SAE must be 
completely described on the patient’s eCRF, including the judgment of the Investigator as to the 
relationship of the SAE to the study drug or device.  The Investigator will promptly supply all 
information identified and requested by the Sponsor (or contract research organization [CRO]) 
regarding the SAE.  
The Investigator must report the SAE to the Shire Pharmacovigilance and Risk Management 
Department AND to the Shire HGT Medical Monitor on an SAE form.  This form must be 
completed and FAXED within 24 hours of the Investigator’s learning of the event to: 
Shire Pharmacovigilance and Risk Management Department: 
International FAX:  
 (UK) OR United States FAX:  
 
AND 
Shire HGT Medical Monitor:  
, MD 
 
FAX:  
 (USA) 
Any follow-up information must also be completed on an SAE form and faxed to the same 
numbers listed above. 
In the event of a severe and unexpected, fatal, or life-threatening SAE, the clinical site must 
contact the Shire HGT Medical Monitor by telephone; this is in addition to completing and 
transmitting the SAE form as stated above.  The following provides contact information for the 
Shire HGT Medical Monitor. 
 
 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
43 
If an SAE is assessed as severe and unexpected, or life-threatening, contact: 
, MD 
Shire Human Genetic Therapies, Inc. 
700 Main Street 
Cambridge, MA 02139, USA 
Telephone: 
Fax: 
(USA) 
Mobile: 
 
The Investigator must promptly report all required information to the Institutional Review Board 
(IRB)/ Independent Ethics Committee (IEC).  It is the responsibility of the Sponsor to ensure that 
each Investigator receives a copy of any CIOMS I/ MedWatch report that has been submitted to 
the appropriate regulatory agencies notifying them of an unexpected related SAE.  The 
Investigator or Sponsor must ensure that the IRB/IEC receives a copy of the report and that a 
copy is also filed within their study files.  
7.21.3.2 
Eliciting Adverse Events 
Patients should be asked non-leading questions (eg, “How do you feel?”) and further questions 
should be posed if there is indication of an AE.  The questioning should be conducted with due 
regard for objectivity and, in particular, the questioner should gather information regarding AEs 
from questioning the patient, the patient’s parent/guardian, spontaneous report by the patient or 
parent/guardian, laboratory reports, and any health care provider’s observations. 
The onset date, resolution date, treatment administered, and outcome of each AE must be 
recorded on the appropriate eCRF.  In addition, the relationship of each AE to study medication 
must be recorded. 
7.21.3.3 
Protocol Deviations for Medical Emergency or Adverse Event 
During and following a patient’s participation in the study, the Investigator should ensure that 
adequate medical care is provided to a patient for any AEs, including clinically significant 
laboratory test results.  The Investigator should inform the patient, the patient’s parent(s), or the 
patient’s legally authorized representative when medical care is needed for intercurrent 
illness(es) of which the Investigator becomes aware.  In an emergency situation, the Investigator 
should contact the Shire HGT Medical Monitor (see Section 7.21.3.1). 
Only when an emergency occurs that requires an immediate deviation from the protocol for the 
safety of a patient, will there be such a deviation and this will be only for that patient.  The 
Investigator or other physician in attendance in such an emergency must contact the Shire HGT 
Medical Monitor as soon as possible.   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
44 
The Investigator, along with the Shire HGT Medical Monitor, will make a decision as to whether 
or not the patient should continue in the study prior to the next scheduled dose.  The departure 
from the protocol and the grounds for it should be stated in the eCRF. 
7.22 Pregnancy 
Pregnancy and lactation are exclusion criteria.  The Sponsor must be notified in the event of a 
pregnancy occurring during the course of the study and through 30 days after the patient’s last 
dose of study drug.  Pregnancy is not to be reported as an AE; the pregnancy reporting form 
should be used to report the pregnancy.  The pregnancy will be followed up through delivery or 
final outcome. 
7.23 Removal of Subjects from the Trial or Study Drug 
The patient's parent or legal guardian acting on behalf of the patient is free to withdraw consent 
and discontinue participation in the study at any time without prejudice to further treatment.  
Since this is an extension trial, there will be no replacement of patients who discontinue the 
study for any reason. 
A patient’s participation in the study may be discontinued at any time at the discretion of the 
Investigator, Sponsor or Medical Monitor.  The following may be justifiable reasons for the 
Investigator, Sponsor or Medical Monitor to remove a patient from the study: 
• Adverse Event:  If a patient experiences an AE which, in the judgment of the investigator, the 
sponsor, or the medical monitor, presents an unacceptable consequence or risk to the patient. 
• Adverse Laboratory Experience:  If a patient has an adverse laboratory experience which, in 
the judgment of the investigator, the Sponsor, or the medical monitor, presents an 
unacceptable consequence or risk to the patient, the patient may be withdrawn from the 
study. 
• Comorbidity:  If a patient develops comorbidity during the course of the study that is 
independent of the study indication, and treatment is required that is not consistent with 
protocol requirements.  
• Intercurrent Illness:  If a patient develops an illness during the course of the study that is not 
associated with the condition under study, and which requires treatment that is not consistent 
with protocol requirements. 
• Refusal of Treatment:  If for any reason the patient refuses treatment during the study, the 
patient will be withdrawn from the study, and the reason for refusal will be documented on 
the eCRF.  Reasonable efforts will be made to monitor the patient for AEs following such 
discontinuation.  Such efforts will be documented in the eCRF. 
• Withdrawal of Informed Consent:  A patient’s parent or legally authorized guardian may 
withdraw his informed consent to participate in the study at any time. 
• Cerebrospinal fluid leukocyte count >100 cells per cubic millimeter for 2 consecutive 
months. 
• New onset seizure. 
• Anaphylactic reaction beyond reasonable management as described in the Investigator’s 
Brochure. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
45 
• Clinically problematic intubations or extubations which may preclude safe airway 
management and anesthesia. 
• Development of refractory spinal fluid leakage.  
• Clinically significant prolonged (eg greater than 24 to 48 hours) worsening in mental status, 
including development of new focal or non-focal neurological symptoms, or recurrence of a 
previously stable prior medical problem judged due to study drug or participation that is 
exclusive of effects from anesthesia. 
• Non-compliance, including failure to appear at 1 or more study visits. 
• The patient was erroneously included in the study. 
• The patient develops an exclusion criterion. 
• The study is terminated by the Sponsor. 
 
If a patient or the patient’s legal guardian(s), acting on behalf of the patient, discontinues 
participation in the study, or the patient is discontinued by the Investigator, the Patient 
Completion/Discontinuation Case Report Form (eCRF) describing the reason for discontinuation 
must be completed.  Any adverse events (AE’s) experienced up to the point of discontinuation 
must be documented on the AE eCRF.  If AEs are present when the patient withdraws from the 
study, the patient will be re-evaluated within 30 days of withdrawal.  All ongoing SAEs at the 
time of withdrawal will be followed until resolution. 
At the time of discontinuation or withdrawal, patients will be asked to participate in all safety 
and efficacy evaluations required for the end of study visit and for the safety follow-up visit.  
Participation in these EOS procedures will be strongly encouraged, but is voluntary for those 
patients electing to discontinue from the study.  The patient will be scheduled for the removal of 
the IDDD.  
7.24 Other Study Procedures 
This section is not applicable. 
7.25 Appropriateness of Measurements 
The neurocognitive and developmental assessments are intended to gauge which domains can be 
accurately measured, with which specific tools, despite the considerable behavioral and cognitive 
challenges in Sanfilippo syndrome.  The evaluation of these domains and the analysis of CSF, 
serum, and urine biomarkers will provide the pivotal data necessary to inform the clinical 
assessments and biomarkers used in possible future Sanfilippo syndrome ERT trials.  

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
46 
8 
STUDY ACTIVITIES 
Patients who participated in Study HGT-SAN-055 through Week 26 (patients who were dosed 
monthly) or Week 28 (patients who were dosed every other week) and completed the End of 
Study evaluations will be eligible for enrollment in this open-label extension study.  Informed 
consent will be provided by the patient’s parent(s)/legal guardian(s) prior to start of extension 
study procedures.   
If there are no safety concerns, patients who were previously treated with intrathecal rhHNS in 
Study HGT-SAN-055 and elect to continue rhHNS treatment will continue receiving monthly 
(Groups 1 and 2) or EOW (Group 3) intrathecal rhHNS in this extension study, as described in 
Appendix 1 Schedule of Events. 
8.1 
Screening Visit/Baseline Visit  
All Screening assessments for this study are to have been performed during the Week 26 
(Groups 1 and 2) or Week 28 (Group 3) (30 [±7] days after the last rhHNS administration) EOS 
procedures in HGT-SAN-055.  If less than 60 days have elapsed since completion of the EOS 
assessments for HGT-SAN-055, the assessments detailed in this Screening visit are not required 
to be repeated.  The Baseline Visit for this study will be the first day the patient received his/her 
IT dose of rhHNS in Study HGT-SAN-055.   
If more than 60 days have elapsed following the HGT-SAN-055 EOS procedures, patients will 
be evaluated for enrollment in HGT-SAN-067on a case-by-case basis by the Investigator.  A 
decision about enrollment will be made following discussion with the Medical Monitor.  If the 
patient is enrolled, the following assessments are to be repeated within 30 days prior to the first 
scheduled intrathecal rhHNS dose: 
• Physical examination 
• Height and weight 
• Head circumference 
• ECG 
• Vital signs 
• Hematology 
• Serum chemistry 
• Urinalysis 
• Neurological examination (performed prior to the administration of anesthesia) 
• Neurodevelopmental assessments (performed prior to the administration of anesthesia 
• General anesthesia:  administration of anesthesia will be given prior to the following 
assessments: 
• ABR 
• MRI of the head 
• CSF sample collection (chemistry, cell count, heparan sulfate and heparan sulfate derivatives, 
and other MPS exploratory biomarkers) via the IDDD 
• Urine heparan sulfate and heparan sulfate derivatives 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
47 
• Serum heparan sulfate and heparan sulfate derivatives 
• Anti-rhHNS antibody testing 
• Children’s Sleep Habits Rating Scale  
• CHQ-50 
• CHQ-87 
• ITQOL 
• Concomitant medications, therapies, and procedures 
• AE assessments 
 
8.2 
Treatment:  Monthly, Weekly Assessments 
Patients in Dose Groups 1 and 2 will receive rhHNS IDDD monthly, on Week 1, Day 2 
(±2 days).  Patients in dose Group 3 will receive rhHNS EOW, on Weeks 1 and 3, Day 2 
(±2 days).   
8.2.1 
Week 1 (Groups 1 and 2); Week 1 and 3 (Group 3) 
8.2.1.1 
Day 1 (Pre-treatment) Assessments 
• Informed consent (Week 1, Month 1 only) prior to study HGT-SAN-067 study procedures 
• Physical examination 
• Height and weight 
• Vital signs 
• Hematology 
• Serum Chemistry 
• Urinalysis 
• Neurological Examination (performed prior to the administration of anesthesia and the 
rhHNS IT injection) 
• Concomitant Medications, Therapies, and Procedures 
• AE assessments 
 
Note:  If the HGT-SAN-055 EOS (or Screening) assessments were performed within 7 days of 
first intrathecal rhHNS treatment in this study, the pre-treatment assessments described in this 
section do not need to be completed prior to the first treatment 
DAY 1 (PRE-TREATMENT) ADDITIONAL ASSESSMENTS PERFORMED ONLY AT MONTHS 12, 24, 36, 
AND 48 
• Head circumference 
• Visual and hearing assessments  
• Urine Heparan Sulfate and Heparan Sulfate Derivatives (Group 3:  obtained only at first 
week of each treatment month) 
• Serum Heparan Sulfate and Heparan Sulfate Derivatives (Group 3:  obtained only at first 
week of each treatment month) 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
48 
• Anti-rhHNS antibody testing 
• Auditory Brainstem Response (ABR) 
• MRI of the head  
• Full neurodevelopmental testing (performed prior to the administration of anesthesia and the 
rhHNS IT injection) 
• Children’s Sleep Habits Rating Scale  
• Child health questionnaire-50  
• Child health questionnaire-87  
• Infant toddler QOL Questionnaire  
 
8.2.1.2 
Day 2 (±2 days) Assessments and IDDD Injection of rhHNS 
• Physical examination 
• ECG (performed following IT study drug injection) 
• Vital signs 
• CSF sample collection (obtained prior to IT study drug injection) 
• rhHNS IT injection (Day 2 ±2 days) 
• neurological examination 
• Concomitant medications, therapies, and procedures 
• AE assessments 
 
8.2.1.3 
Day 3 (Post IT Dose) Assessments 
Patients will be discharged when deemed clinically stable by the Investigator. 
• Vital signs 
• Neurological examination  
• Concomitant medications, therapies, and procedures 
• AE assessments 
 
8.3 
End of Study/ Early Termination Procedures 
Patients who complete the study or who discontinue prior to the end of the study, will have EOS 
assessments performed 30 (±7 days) after their last dose of rhHNS.  Patients who discontinue or 
are withdrawn prior to study completion will be asked to participate in the end of study 
procedures at time of discontinuation.  Participation in these EOS procedures will be strongly 
encouraged, but is voluntary for those patients electing to discontinue from the study.  Note:  
scheduled removal of the IDDD will be required at study completion with sedation or anesthesia, 
as required. 
• Physical examination 
• Height and weight 
• Head circumference 
• Visual and hearing  

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
49 
• ECG 
• Vital signs 
• Hematology 
• Serum Chemistries 
• Urinalysis 
• Urine Heparan Sulfate and Heparan Sulfate Derivatives  
• Serum Heparan Sulfate and Heparan Sulfate Derivatives  
• Anti-rhHNS antibody testing 
• Auditory Brainstem Response (ABR) 
• MRI of the head  
• CSF sample collection  
• Neurological examination 
• Full neurodevelopmental testing  
• Children’s Sleep Habits Rating Scale  
• Child health questionnaire-50  
• Child health questionnaire-87  
• Infant toddler QOL Questionnaire  
• Concomitant medications, therapies, and procedures 
• AE assessments 
 
8.4 
Safety Follow-up Visit (by Telephone) 
Patients who complete the study will have a safety follow-up visit 30 Days (±7 days) 
Patients who discontinue or are withdrawn prior to study completion will be asked to participate 
in the safety follow-up visit at the time of discontinuation.  Participation in these procedures will 
be strongly encouraged, but is voluntary for those patients electing to discontinue from the study. 
• Concomitant medications, therapies, and procedures 
• AE assessments 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
50 
9 
QUALITY CONTROL AND ASSURANCE 
Training will occur at an investigator meeting or at the site initiation visit or both, and instruction 
manuals (eg, laboratory manuals and pharmacy manuals) will be provided to aid consistency in 
data collection and reporting across sites. 
Clinical sites will be monitored by Shire HGT or its designee to ensure the accuracy of data 
against source documents.  The required data will be captured in a validated clinical data 
management system that is compliant with the Food and Drug Administration (FDA) 21 Code of 
Federal Regulations (CFR) Part 11 Guidance.  The clinical trial database will include an audit 
trail to document any evidence of data processing or activity on each data field by each user.  
Users will be trained and given restricted access, based on their role in the study, through a 
password protected environment.   
Data entered in the system will be reviewed manually for validity and completeness against the 
source documents by a clinical monitor from Shire HGT or its designee.  If necessary, the study 
site will be contacted for corrections or clarifications; all missing data will be accounted for. 
SAE information captured in the clinical trial database will be reconciled with the information 
captured in the Pharmacovigilance database. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
51 
10 PLANNED STATISTICAL METHODS 
10.1 General Statistical Methodology 
This is an open-label extension of study HGT-SAN-055 to evaluate the long-term safety and 
clinical outcomes of intrathecal administration of rhHNS in patients with Sanfilippo syndrome 
type A (MPS IIIA).  The statistical methodology supporting the trial will focus on descriptive 
rather than inferential approaches, given the early phase and objectives of this trial.  
Data will be summarized by dose group (10 mg per month, 45 mg per month and 45 mg every 
other week) with respect to demographic and baseline characteristics, efficacy variables and 
safety variables.  Summary statistics for continuous variables will include the n, mean, standard 
deviation, median, minimum and maximum.  Categorical variables will be summarized in a 
contingency table by the frequency and percentage of patients in each category.  Data will be 
plotted to assess trends across time.  
All hypothesis tests will be 2-sided and will be performed at the 0.05 level.  Hypothesis testing 
will be viewed as exploratory.  Any resulting p-values will not be regarded as a firm support for 
conclusions, but rather suggestive of areas of examination in future studies.  In general, variables 
will be quantified as a change from the baseline value.  The null hypothesis will be that there is 
no difference in the change from baseline between dose groups.  Note that the baseline visit for 
this study will be the first day the patient received his/her IT dose of rhHNS in study 
HGT-SAN-055.  
The primary objective of this trial is to assess the long term safety of rhHNS administration via a 
surgically implanted intrathecal drug delivery device (IDDD).  Hence an extensive safety 
assessment will be performed.  The safety analyses will consist of all enrolled patients.  To 
evaluate safety, adverse experiences will be tabulated by dose group.  Vital signs, 
electrocardiograms, serum and CSF components and chemistries, hematology, and urinalysis 
safety monitoring will be listed for each patient and abnormal values will be flagged.  In 
addition, anti-rhHNS antibodies (in CSF and serum) will also be listed.  No formal statistical 
tests will be performed on the safety parameters. 
10.2 Determination of Sample Size 
Since this is an extension study, sample size is determined by the number of patients who 
completed HGT-SAN-055 (maximum of 12 patients) and enrolled in this study 
10.3 Analysis Populations 
The analysis population consists of all eligible patients from HGT-SAN-055 who have agreed to 
participate in the extension study.  Both safety and efficacy analyses would be performed using 
the above mentioned population.  

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
52 
10.4 Demographics and Baseline Characteristics 
Patient disposition for those enrolled will be presented in a summary table using number and 
percentage of patients enrolled, completed or discontinued/withdrew, by dose group.  The 
reasons for discontinuation/withdrawal will also be presented. 
Demographic and baseline characteristics (eg, age, race, ethnicity, medical history, and surgical 
history) will be reported in summary tables. 
10.5 Statistical Analysis of Pharmacokinetic Variables 
Not applicable 
10.6 Efficacy, Safety, and Pharmacodynamic Evaluations     
10.6.1 
Primary Analyses 
10.6.1.1 
Safety Analysis 
In general, safety assessments will be based on all assessments post-baseline.  The assessment of 
safety will be based primarily on the frequency of treatment-emergent adverse events, due to 
study drug and on the frequency of clinically notable abnormal vital sign and laboratory values.  
Changes from baseline will be calculated by subtracting the baseline value from the 
post-baseline value. 
All enrolled patients will be included in the safety analysis.  Patients will be grouped according 
to the actual dose received.   
No formal statistical test will be performed in the safety evaluations.  Vital sign measurements, 
clinical chemistry, and hematology safety monitoring will be listed for each patient, and 
abnormal values will be flagged.  These will also be summarized at each time point, including 
change from baseline. 
Adverse events will be recorded throughout the study and at early termination.  Adverse events 
and medical conditions will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 9.0 or later.  In all cases (with the exception of device-related events), 
adverse event summaries will be based on all adverse event recorded beginning on Study Day 1 
(treatment-emergent AEs). 
Adverse events will be summarized by presenting, for each treatment group, the number and 
percentage of patients having any adverse event, having an adverse event in system organ class, 
and having each individual adverse event.  Note that in any given category (eg, system organ 
class) a patient will only be counted once.  In addition, those events which resulted in death or 
were otherwise classified as serious will be presented in a separate listing.  The incidence of 
treatment-emergent adverse events (new or worsened from baseline) will be summarized by 
system organ class, severity, type of adverse event and relationship to trial medication.   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
53 
Adverse events that occur up to 30 days after the last dose of study drug will be considered 
“on-treatment”.  Adverse events which are deemed probably or possibly related to the device 
will be summarized by dose group and overall. 
Laboratory data will be listed by patient and dose group.  Patients with newly occurring 
abnormalities outside the normal range will be flagged and listed separately and summarized.  
Mean change from baseline values or shift tables will also be provided by dose group at each 
visit. 
Vital signs data will be listed by patient and dose group.  Furthermore, mean changes from 
baseline for vital sign data will be summarized for each dose group.  Shift tables may be 
presented, utilizing reference ranges.  Patients with notably abnormal values will be identified 
and listed separately along with their values. 
ECG assessments will be listed by patient and dose group.  Mean changes from baseline for ECG 
data will be summarized for each dose group.  Patients with any clinically significant findings 
and/or conduction abnormalities will be listed separately along with their values.   
For those patients who fail to complete the study, the reason for discontinuation will be listed by 
patient and dose group.   
Listings of all study safety data will be presented. 
10.6.1.2 
Clinical Laboratory Evaluations 
Descriptive summaries of clinical laboratory evaluations (hematology, serum chemistry, 
urinalysis) results will be presented in summary tables by evaluation visit using number of 
patients (n), mean, median, standard deviation, minimum, and maximum.  Changes from 
baseline will be summarized for each post-baseline visit.  The number of patients with clinically 
significant laboratory results or abnormal results during the study period will be presented in 
shift tables. 
For the laboratory measurements, shift tables will be presented in terms of Low (L), Normal (N), 
High (H), Missing (M).  High and Low measurements will be based on reference ranges 
provided by the laboratory at the study site. 
Clinical laboratory results will also be presented in data listings. 
10.6.1.3 
Anti-rhHNS Antibody Formation 
Anti-rhHNS antibody formation will be monitored throughout the study.  Results will be 
presented in summary tables by assay methodology used to identify antibodies, number and 
percentage of positive and negative specimens by evaluation visit and/or study week, and 
number and percentage of positive and negative specimens overall.  These results will also be 
presented in data listings.   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
54 
10.6.2 
Secondary Analysis 
10.6.2.1 
Clinical Assessments 
The change from baseline in neurocognitive assessment based scores will be examined by dose 
group.  Furthermore, the effect of rhHNS administration on QoL measures will be examined by 
presenting mean change from baseline across dose groups.  Other relevant assessments which 
might help in the understanding of clinical activity will also be analyzed.  
10.6.2.2 
Pharmacodynamic Analyses 
To determine the effects of rhHNS administration on biomarkers, mean change from baseline 
will be assessed at selected time points.  The heparin sulfate reduction (in CSF and urine) will be 
examined using mean change and the corresponding 95% confidence interval.  The concentration 
of inflammatory cytokines in serum and CSF will also be examined.  Other exploratory 
biomarkers in CSF, serum, and urine may also be examined. 
The effect of anti- rhHNS antibodies on the changes in CSF biomarkers may also be examined 
by presenting summary tables by antibody status. 
The planned analyses and presentations will be defined in the Statistical Analysis Plan (SAP). 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
55 
11 ADMINISTRATIVE CONSIDERATIONS 
11.1 Investigators and Study Administrative Structure 
Before initiation of the study, the Investigators must provide the Sponsor with a completed Form 
FDA 1572.  Study medications may be administered only under the supervision of the 
Investigators listed on this form.  Curriculum vitae must be provided for the Investigators and 
sub-investigators listed on Form FDA 1572. 
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, any amendments to the protocol, the study treatments, and their study related 
duties and functions.  The Investigator must maintain a list of sub-investigators and other 
appropriately qualified persons to whom he or she has delegated significant study related duties. 
11.2 Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval 
Before initiation of the study, the Investigator must provide the Sponsor with a copy of the 
written IRB/IEC approval of the protocol and the informed consent form.  This approval must 
refer to the informed consent form and to the study title, study number, and version and date of 
issue of the study protocol, as given by the Sponsor on the cover page of the protocol. 
Status reports must be submitted to the IRB/IEC at least once per year.  The IRB/IEC must be 
notified of completion of the study.  Within 3 months of study completion or termination, a final 
report must be provided to the IRB/IEC.  A copy of these reports will be sent to the study clinical 
monitor.  The Investigators must maintain an accurate and complete record of all submissions 
made to the IRB/IEC, including a list of all reports and documents submitted.  AEs which are 
reported to the U.S. Food and Drug Administration (FDA) or other Regulatory agencies 
(Investigational New Drug [IND] Safety Reports) must be submitted promptly to the IRB/IEC. 
11.3 Ethical Conduct of the Study 
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor and Investigators abide by 
good clinical practice (GCP) as described in the 21 CFR Parts 50, 56, and 312 and the 
International Conference on Harmonisation (ICH) GCP Guidelines.  Compliance with these 
regulations and guidelines also constitutes compliance with the ethical principles described in the 
Declaration of Helsinki (2008). 
11.4 Patient Information and Consent 
Before enrolling in the clinical study, the patient’s parent(s), or the patient’s legally authorized 
representative(s) must consent to participate after the nature, scope, and possible consequences 
of the clinical study have been explained in a form understandable to him or her.  An informed 
consent form that includes information about the study will be prepared and given to the 
patient’s parent(s), or the patient’s legally authorized representative(s).  This document will 
contain all FDA and ICH-required elements.   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
56 
The informed consent form must be in a language understandable to the patient’s parent(s), or 
the patient’s legally authorized representative(s) and must specify who informed the patient’s 
parent(s), or the patient’s legally authorized representative. 
After reading the informed consent document, the patient, patient’s parent(s), or the patient’s 
legally authorized representative(s) must give consent in writing.  The patient’s consent must be 
confirmed at the time of consent by the personally dated signature of the patient, patient’s 
parent(s) or the patient’s legally authorized representative(s) and by the personally dated 
signature of the person conducting the informed consent discussions.  If the patient, patient’s 
parent(s), or the patient’s legally authorized representative(s) is unable to read, oral presentation 
and explanation of the written informed consent form and information to be supplied must take 
place in the presence of an impartial witness.  Consent (or assent) must be confirmed at the time 
of consent orally and by the personally dated signature of the patient, patient’s parent(s) or by the 
patient’s legally authorized representative(s).  The witness and the person conducting the 
informed consent discussions must also sign and personally date the informed consent document.  
It should also be recorded and dated in the source document that consent was given. 
A copy of the signed and dated consent document(s) must be given to the patient’s parent(s), or 
the patient’s legally authorized representative(s).  The original signed and dated consent 
document will be retained by the Investigator. 
The Investigator will not undertake any measures specifically required solely for the clinical 
study until valid consent has been obtained. 
A model of the informed consent form to be used in this study will be provided to the sites 
separately from this protocol.  Where applicable, signed assent(s) to participate in the study must 
be obtained. 
11.5 Patient Confidentiality 
Patient names will not be supplied to the Sponsor.  Only the patient number and patient initials 
will be recorded in the eCRF, and if the patient name appears on any other document, it must be 
obliterated before a copy of the document is supplied to the Sponsor.  Study findings stored on a 
computer will be stored in accordance with local data protection laws.  The patients will be told 
that representatives of the Sponsor, a designated CRO, the IRB/IEC, or regulatory authorities 
may inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws.  The Investigator will maintain a personal patient 
identification list (patient numbers with the corresponding patient names) to enable records to be 
identified. 
11.6 Study Monitoring 
Monitoring procedures that comply with current Good Clinical Practice (GCP) guidelines will be 
followed.  On-site review of the eCRF's for completeness and clarity, cross-checking with source 
documents, and clarification of administrative matters will be performed. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
57 
The study will be monitored by the Sponsor or its designee.  On site monitoring will be 
performed by a representative of the Sponsor (Clinical Study Monitor) who will review the CRFs 
and source documents.  The site monitor will ensure that the investigation is conducted 
according to protocol design and regulatory requirements by frequent site visits and 
communications (letter, telephone, and facsimile). 
11.7 Case Report Forms and Study Records 
Case report forms are provided for each patient in electronic format.  Electronic Data Capture 
(EDC) will be used for this study.  The study data will be recorded from the source documents 
into the electronic clinical report form (eCRF).  The electronic files will be considered as the 
CRFs.  
All forms must be filled out by authorized study personnel.  All corrections to the original eCRF 
entry must indicate the reason for change.  The Investigator is required to sign the eCRF after all 
data have been captured for each patient.  If corrections are made after review and signature by 
the Investigator, he or she must be made aware of the changes, and his or her awareness 
documented by re-signing the eCRF.    
11.7.1 
Critical Documents 
Before Shire HGT initiates the trial (ie, obtains informed consent from the first patient), it is the 
responsibility of the Investigator to ensure that the following documents are available to Shire 
HGT or their designee: 
• Curricula vitae of Investigator and sub-investigator(s) (current, dated and signed or supported 
by an official regulatory document) 
• Current medical license of Investigator and sub investigator(s) 
• Signed and dated agreement of the final protocol 
• Signed and dated agreement of any amendment(s), if applicable 
• Approval/favorable opinion from the IRB/IEC clearly identifying the documents reviewed:  
protocol, any amendments, Patient Information/Informed Consent Form (Assent form if 
applicable), and any other written information to be provided regarding patients recruitment 
procedures 
• Copy of IRB/IEC approved Patient Information/Informed Consent Form (Assent Form if 
applicable)/any other written information/advertisement 
• Any additional regulatory approvals, ie national regulatory approvals 
• List of IRB/IEC Committee members/constitution 
• Financial agreement(s) 
• Documentation from central or local laboratory as applicable 
• 
Reference ranges 
• 
Certification/QA scheme/other documentation 
 
Regulatory approval and notification as required must also be available; these are the 
responsibility of Shire HGT.  All trial documents will be available in a Trial Master File (TMF) 
at the Investigator/trial site and at Shire HGT.      

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
58 
11.8 Data Monitoring Committee 
There will be no data monitoring committee for this study. 
11.9 Protocol Violations/Deviations 
The Investigator will conduct the study in compliance with the protocol.  The protocol will not 
be initiated until the IRB/IEC and the appropriate regulatory authorities have given 
approval/favorable opinion.  Modifications to the protocol will not be made without agreement 
of the Sponsor.  Changes to the protocol will require written IRB/IEC approval/favorable opinion 
prior to implementation, except when the modification is needed to eliminate an immediate 
hazard(s) to patients.  The IRB/IEC may provide, if applicable regulatory authorities permit, 
expedited review and approval/favorable opinion for minor change(s) in ongoing studies that 
have the approval/favorable opinion of the IRB/IEC.  The Sponsor will submit all protocol 
modifications to the regulatory authorities in accordance with the governing regulations.  A 
record of patients screened, but not entered into the study, is also to be maintained.   
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
patients, the Investigator will contact the Sponsor or its designee, if circumstances permit, to 
discuss the planned course of action.  Any departures from the protocol must be fully 
documented as a protocol deviation.  Protocol deviations will need to be reviewed by the medical 
monitor and may also be required to be submitted to the IRB/IEC 
Protocol modifications will only be initiated by the Sponsor and must be approved by the 
IRB/IEC and submitted to the FDA or other applicable international regulatory authority before 
initiation. 
11.10 Access to Source Documentation 
Regulatory authorities, the IEC/IRB, or the Sponsor may request access to all source documents, 
CRFs, and other study documentation for on-site audit or inspection.  Direct access to these 
documents must be guaranteed by the Investigator, who must provide support at all times for 
these activities.  Monitoring and auditing procedures that comply with current GCP guidelines 
will be followed.  On-site review of the CRFs for completeness and clarity, cross-checking with 
source documents, and clarification of administrative matters will be performed. 
11.11 Data Generation and Analysis 
The clinical database will be developed and maintained by a contract research organization or an 
electronic data capture technology provider as designated by Shire HGT.  Shire HGT or its 
designee will be responsible for performing study data management activities.  
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
Version 9.0 or later.  Concomitant medication will be coded using WHODRL.  Centralized 
laboratories will be employed as described in the study manual to aid in consistent measurement 
of efficacy and safety parameters. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
59 
11.12 Premature Closure of the Study 
11.12.1 Study Termination 
If the Sponsor or an Investigator discovers conditions arising during the study which indicate that 
the clinical investigation should be halted due to an unacceptable patient risk, the study may be 
terminated after appropriate consultation between Shire HGT and the Investigators.  In addition, 
a decision on the part of Shire HGT to suspend or discontinue development of the study material 
may be made at any time. 
11.12.2 Site Termination 
A specific site may be terminated separate from the general study for, but not limited to, the 
following conditions: 
• The discovery of an unexpected, significant, or unacceptable risk to the patients enrolled at 
the site. 
• Failure of the Investigator to enter patients at an acceptable rate. 
• Insufficient adherence by the Investigator to protocol requirements. 
 
11.13 Retention of Data 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application and until there are no pending or contemplated marketing applications or 
at least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product.  The Sponsor will notify the Investigator if these documents must be 
retained for a longer period of time.  It is the responsibility of the Sponsor to inform the 
Investigator or institution as to when these documents no longer need to be retained. 
11.14 Financial Disclosure 
The Investigator should disclose any financial interests in the Sponsor as described in 21 CFR 
Part 54 prior to beginning this study.  The appropriate form will be provided to the Investigator 
by the Sponsor, which will be signed and dated by the Investigator, prior to the start of the study.  
11.15 Publication and Disclosure Policy 
All information concerning the study material, such as patent applications, manufacturing 
processes, basic scientific data, and formulation information supplied by the Sponsor and not 
previously published are considered confidential and will remain the sole property of the 
Sponsor.  The Investigator agrees to use this information only in accomplishing this study and 
will not use it for other purposes. 
It is understood by the Investigator that the information developed in the clinical study may be 
disclosed as required to the authorized regulatory authorities and governmental agencies.   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
60 
In order to allow for the use of the information derived from the clinical studies, it is understood 
that there is an obligation to provide the Sponsor with complete test results and all data 
developed in the study in a timely manner. 
The Investigator and any other clinical personnel associated with this study will not publish the 
results of the study, in whole or in part, at any time, unless they have consulted with Shire HGT, 
provided Shire HGT a copy of the draft document intended for publication, and obtained Shire 
HGT’s written consent for such publication.  All information obtained during the conduct of this 
study will be regarded as confidential.  Shire HGT will use the information for registration 
purposes and for the general development of the drug. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
61 
12 REFERENCE LIST 
1. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. 
JAMA 1999;281:249-54. 
2. Poorthuis BJ, Wevers RA, Kleijer WJ, et al. The frequency of lysosomal storage diseases in 
The Netherlands. Hum Genet 1999;105:151-6. 
3. Baehner F, Schmiedeskamp C, Krummenauer F, et al. Cumulative incidence rates of the 
mucopolysaccharidoses in Germany. J Inherit Metab Dis 2005;28:1011-7. 
4. Meyer A, Kossow K, Gal A, et al. Scoring evaluation of the natural course of 
mucopolysaccharidosis type IIIA (Sanfilippo syndrome type A). Pediatrics 
2007;120:e1255-61. 
5. Cleary MA, Wraith JE. Management of mucopolysaccharidosis type III. Arch Dis Child 
1993;69:403-6. 
6. Fraser J, Wraith JE, Delatycki MB. Sleep disturbance in mucopolysaccharidosis type III 
(Sanfilippo syndrome): a survey of managing clinicians. Clin Genet 2002;62:418-21. 
7. Neufeld E, Muenzer J. The Mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, 
Valle D, eds. The metabolic and molecular bases of inherited disease. 8th ed. New York: 
McGraw-Hill; 2001:4 v. (xivii, 6338, I-104 p.). 
8. Meyer A, Kossow K, Gal A, et al. The mutation p.Ser298Pro in the sulphamidase gene 
(SGSH) is associated with a slowly progressive clinical phenotype in mucopolysaccharidosis 
type IIIA (Sanfilippo A syndrome). Hum Mutat 2008;29:770. 
9. Vellodi A. Lysosomal storage disorders. Br J Haematol 2005;128:413-31. 
10. Hemsley KM, Beard H, King BM, Hopwood JJ. Effect of high dose, repeated intra-CSF 
injection of sulphamidase on neuropathology in MPS IIIA mice. Genes Brain Behav 2008, 
7:740-753. 
11. Urayama A, Grubb JH, Sly WS, Banks WA. Mannose 6-phosphate receptor-mediated 
transport of sulfamidase across the blood-brain barrier in the newborn mouse. Mol Ther 
2008;16:1261-6. 
12. Bielicki J, Hopwood JJ, Melville EL, Anson DS. Recombinant human sulphamidase: 
expression, amplification, purification and characterization. Biochem J 1998;329 
( Pt 1):145-50. 
13. Di Natale P, Vanacore B, Daniele A, Esposito S. Heparan N-sulfatase: in vitro mutagenesis 
of potential N-glycosylation sites. Biochem Biophys Res Commun 2001;280:1251-7. 
14. Daniele A, Di Natale P. Heparan N-sulfatase: cysteine 70 plays a role in the enzyme catalysis 
and processing. FEBS Lett 2001;505:445-8. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
62 
15. Perkins KJ, Byers S, Yogalingam G, Weber B, Hopwood JJ. Expression and characterization 
of wild type and mutant recombinant human sulfamidase. Implications for Sanfilippo 
(Mucopolysaccharidosis IIIA) syndrome. J Biol Chem 1999;274:37193-9. 
16. Munoz-Rojas MV, Vieira T, Costa R, et al. Intrathecal enzyme replacement therapy in a 
patient with mucopolysaccharidosis type I and symptomatic spinal cord compression. Am J 
Med Genet A 2008;146A:2538-44. 
17. Munoz-Rojas MV, Horovitz DD, Jardim LB, et al. Intrathecal administration of recombinant 
human N-acetylgalactosamine 4-sulfatase to a MPS VI patient with pachymeningitis 
cervicalis. Mol Genet Metab 2010;99:346-50. 
18. Chen A, Dickson P, Shapiro E, Lyons B, S-H K, Guillaume D. A study of intrathecal enzyme 
replacement for cognitive decline in mucopolysaccharidosis 1. In. Abstracts for the 
Lysosomal Disease Network's WORLD Symposium Molecular Genetics and Metabolism; 
2010:S13-S4. 
19. Estimating the Maximum Safe Starting Dose in Clinical Trials for Therapeutics in Adult 
Healthy Volunteers. In. United States Food and Drug Administration, Center for Drug 
Evaluation and Research (CDER): July; 2005, Pharmacology and Toxicology. 
20. Hemsley KM, King B, Hopwood JJ. Injection of recombinant human sulfamidase into the 
CSF via the cerebellomedullary cistern in MPS IIIA mice. Mol Genet Metab 
2007;90:313-328. 
21. Hemsley KM, Luck AJ, Crawley AC, et al. Examination of intravenous and intra-CSF 
protein delivery for treatment of neurological disease. Eur J Neurosci 2009; 29:1389-96. 
22. Hemsley KM, Norman EJ, Crawley AC, et al. Effect of cisternal sulfamidase delivery in 
MPS IIIA Huntaway dogs-A proof of principle study. Mol Genet Metab 2009, doi: 
10.1016/j.ymgme.2009.07.013. 
23. Bayley N. Bayley Scales of Infant and Toddler Development: Third Edition. San Antonio, 
TX The Psychological Corporation; 2005. 
24. Kaufman S, Kaufman N. Kaufman Assessment Battery for Children, Second Edition 
(KABC-II). 
25. Henderson S, Sugden D, Barnett A. Movement Assessment Battery for Children (second 
ed.). London: Harcourt Assessment; 2007. 
26. Sparrow S, Balla D, Cicchetti D. Vineland Adaptive Behavior Scales (Second Edition). 4201 
Woodland Road Circle Pines, MN 55014-1796: American Guidance Service, Inc; 2005. 

Recombinant human heparan N-sulfatase (rhHNS) 
 
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
63 
Appendix 1 
Schedule of Events 
Table 1  Study Assessments for Patients Who Have Received 6 Months of Treatment With rhHNS (Study HGT-SAN-055) 
(Dose Groups 1 and 2) 
 
 
Week 1 Each Treatment Month 
 
Assessment 
Screening/
Baseline 
Visiti 
Pre-Tx
Day 1a, l 
IT administration
Day 2 
Day  
3d 
12, 24, 36, and 48 
months  
End of Studyf 
Safety 
Follow-uph 
Informed Consent/Enrollment 
 
● 
 
 
 
 
 
Physical Examination 
● 
● 
● 
 
 
● 
 
Height and Weight 
● 
● 
 
 
 
● 
 
Head Circumference 
● 
 
 
 
● 
● 
 
Visual and Hearing Assessment 
 
 
 
 
● 
● 
 
ECG 
● 
 
●b 
 
 
● 
 
Vital Signs 
● 
● 
● 
● 
 
● 
 
Hematology 
● 
● 
 
 
 
● 
 
Serum Chemistry 
● 
● 
 
 
 
● 
 
Urinalysis 
● 
● 
 
 
 
● 
 
Urine Heparan Sulfate and Heparan 
Sulfate Derivatives  
● 
 
 
 
●e 
● 
 
Serum Heparan Sulfate and Heparan 
Sulfate Derivatives 
● 
 
 
 
●e 
● 
 
Anti-rhHNS antibody testing (serum and 
CSF)j 
● 
 
 
 
● 
● 
 
Auditory Brainstem Response (ABR) 
● 
 
 
 
● 
● 
 
MRI of the Head 
● 
 
 
 
● 
● 
 
CSF Sample Collectionk 
● 
 
●c 
 
 
●c 
 
rhHNS administrationg 
 
 
● 
 
 
 
 
Neurological Examination 
● 
● 
● 
● 
 
● 
 
Full Neurodevelopmental Testing 
● 
 
 
 
● 
● 
 
Children’s Sleep Habits Rating Scale 
● 
 
 
 
● 
● 
 
Child Health Questionnaire-50 
● 
 
 
 
● 
● 
 
Child Health Questionnaire-87 
● 
 
 
 
● 
● 
 
Infant Toddler QOL Questionnaire 
● 
 
 
 
● 
● 
 

Recombinant human heparan N-sulfatase (rhHNS) 
 
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
64 
Table 1  Study Assessments for Patients Who Have Received 6 Months of Treatment With rhHNS (Study HGT-SAN-055) 
(Dose Groups 1 and 2) 
 
 
Week 1 Each Treatment Month 
 
Assessment 
Screening/
Baseline 
Visiti 
Pre-Tx
Day 1a, l 
IT administration
Day 2 
Day  
3d 
12, 24, 36, and 48 
months  
End of Studyf 
Safety 
Follow-uph 
Concomitant Medications, Therapies, 
and 
Procedures 
● 
● 
● 
● 
 
● 
● 
Adverse Event Monitoring 
● 
● 
● 
● 
 
● 
● 
Abbreviations:  ABR = Auditory brainstem response; CSF = cerebrospinal fluid; ECG = electrocardiogram; MRI = Magnetic resonance imaging; 
TX = treatment; 
a 
Week 1 only, and only performed if >7 days have elapsed since  HGT-SAN-055 EOS visit assessments. 
b 
ECG to be performed following administration of study drug. 
c 
A total of 10 mLs of CSF will be obtained in two 5 mL aliquots (labeled separately – process according to study operations manual).  An attempt will 
be made to obtain CSF sample via the IDDD prior to each administration of rhHNS and at the End of Study visit.  If it is not possible to obtain CSF 
using the IDDD, the IDDD will be replaced.  See Section 6.4 for details.  
d 
Patients will be discharged when deemed clinically stable by the Investigator. 
e 
Specimens collected once a month, at Day 1 of the first treatment week. 
f 
All patients who complete the study will have end of study assessments performed 30 (±7 days) after their last dose of study drug. 
g  
If a patient’s IDDD becomes nonfunctional or infected; it will be replaced so that the patient can remain on study.  See Section 6.5.  
h 
A safety follow up telephone call will be made 30 (±7 days) after End of Study Procedures. 
i 
Assessments will be required only if more than 60 days have elapsed following the HGT-SAN-055 procedures.  These assessments would be repeated 
within 30 days prior to the first scheduled rhHNS IT dose. 
j 
Blood sample drawn before IT injection of rhHNS. 
k 
CSF will be tested for standard chemistries, heparan sulfate and heparan sulfate derivatives, anti-rhHNS antibodies, and MPS exploratory biomarkers. 
 
 
 
 
 
 

Recombinant human heparan N-sulfatase (rhHNS) 
 
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
65 
Table 2  Study Assessments for Patients Who Have Received 6 Months of Treatment With rhHNS (Study HGT-SAN-055) 
(Dose Group 3) 
 
 
Week 1 and 3 Each Treatment Month 
 
Assessment 
Screening/Basel
ine Visiti 
Pre-Tx
Day 1a 
IT administration
Day 2 
Day  
3d, 
12, 24, 36, and 48 
months  
End of Studyf 
Safety 
Follow-uph 
Informed Consent/Enrollment 
 
● 
 
 
 
 
 
Physical Examination 
● 
● 
● 
 
 
● 
 
Height and Weight 
● 
● 
 
 
 
● 
 
Head Circumference 
● 
 
 
 
● 
● 
 
Visual and Hearing Assessment 
 
 
 
 
● 
● 
 
ECG 
● 
 
●b 
 
 
● 
 
Vital Signs 
● 
● 
● 
● 
 
● 
 
Hematology 
● 
● 
 
 
 
● 
 
Serum Chemistry 
● 
● 
 
 
 
● 
 
Urinalysis 
● 
● 
 
 
 
● 
 
Urine Heparan Sulfate and Heparan 
Sulfate Derivatives  
● 
 
 
 
●e 
● 
 
Serum Heparan Sulfate and Heparan 
Sulfate Derivatives 
● 
 
 
 
●e 
● 
 
Anti-rhHNS antibody testing (serum 
and CSF)j 
● 
 
 
 
● 
● 
 
Auditory Brainstem Response (ABR) 
● 
 
 
 
● 
● 
 
MRI of the Head 
● 
 
 
 
● 
● 
 
CSF Sample Collectionk 
● 
 
●c 
 
 
●c 
 
rhHNS administrationg 
 
 
● 
 
 
 
 
Neurological Examination 
● 
● 
● 
●j 
 
● 
 
Full Neurodevelopmental Testing 
● 
 
 
 
● 
● 
 
Children’s Sleep Habits Rating Scale 
● 
 
 
 
● 
● 
 
Child Health Questionnaire-50 
● 
 
 
 
● 
● 
 
Child Health Questionnaire-87 
● 
 
 
 
● 
● 
 
Infant Toddler QOL Questionnaire 
● 
 
 
 
● 
● 
 

Recombinant human heparan N-sulfatase (rhHNS) 
 
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
66 
Table 2  Study Assessments for Patients Who Have Received 6 Months of Treatment With rhHNS (Study HGT-SAN-055) 
(Dose Group 3) 
 
 
Week 1 and 3 Each Treatment Month 
 
Assessment 
Screening/Basel
ine Visiti 
Pre-Tx
Day 1a 
IT administration
Day 2 
Day  
3d, 
12, 24, 36, and 48 
months  
End of Studyf 
Safety 
Follow-uph 
Concomitant Medications, Therapies, 
and Procedures 
● 
● 
● 
● 
 
● 
● 
Adverse Event Monitoring 
● 
● 
● 
● 
 
● 
● 
Abbreviations:  ABR = Auditory brainstem response; CSF = cerebrospinal fluid; ECG = electrocardiogram; MRI = Magnetic resonance imaging ; 
TX = treatment; 
a 
Week 1 only, and only performed if >7 days have elapsed since  HGT-SAN-055 EOS visit assessments. 
b 
ECG to be performed following administration of study drug. 
c 
A total of 10 mLs of CSF will be obtained in two 5 mL aliquots (labeled separately – process according to study operations manual).  An attempt will 
be made to obtain CSF sample via the IDDD prior to each administration of rhHNS and at the End of Study visit.  If it is not possible to obtain CSF 
using the IDDD, the IDDD will be replaced.  See Section 6.4 for details.  
d 
Patients will be discharged when deemed clinically stable by the Investigator. 
e 
Specimens collected once a month, at Day 1 of the first treatment week. 
f 
All patients who complete the study will have end of study assessments performed 30 (±7 days) after their last dose of study drug. 
g  
If a patient’s IDDD becomes nonfunctional or infected; it will be replaced so that the patient can remain on study.  See Section 6.5. 
h 
A safety follow up telephone call will be made 30 (±7 days) after End of Study Procedures. 
i 
Assessments will be required only if more than 60 days have elapsed following the HGT-SAN-055 procedures.  These assessments would be repeated 
within 30 days prior to the first scheduled rhHNS IT dose. 
j 
Blood sample drawn before IT injection of rhHNS. 
k 
CSF will be tested for standard chemistries, heparan sulfate and heparan sulfate derivatives, anti-rhHNS antibodies, and MPS exploratory biomarkers. 
 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
67 
Appendix 2 
Sample Neurological Exam 
□ Not Done, Please provide reason:  ________________________________________ 
Exam date:  _____________ (Day/Mon/Year)    Name of Examiner:  _________________ 
Overall neurological impression 
□ Normal  
□ Abnormal 
 
Please mark normal, abnormal, or unable to determine for each item listed.  If any abnormalities 
are found, please specify the findings in the space provided. 
Items 
Status 
Please describe abnormalities 
Observation and mental status 
Alertness 
□ Normal  
□ Abnormal   
□ Not Done 
 
Interaction with care taker 
□ Normal  
□ Abnormal   
□ Not Done 
 
Activity level 
□ Normal  
□ Abnormal   
□ Not Done 
 
Involuntary movements 
□ Absent  
□ Present   
□ Not Done 
 
Cranial nerves 
Pupillary reaction to light 
□ Normal  
□ Abnormal   
□ Not Done 
 
Extra ocular movements 
□ Normal  
□ Abnormal   
□ Not Done 
 
Eye closure 
□ Normal  
□ Abnormal   
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
68 
Items 
Status 
Please describe abnormalities 
□ Not Done 
Facial symmetry 
□ Normal  
□ Abnormal   
□ Not Done 
 
Coordination/Sensory 
Rapid finger tapping 
□ Normal  
□ Abnormal   
□ Unable to Perform   
□ Not Done 
 
Finger to nose 
□ Normal  
□ Abnormal   
□ Unable to Perform   
□ Not Done 
 
Stand on one foot 
□ Normal  
□ Abnormal   
□ Unable to Perform   
□ Not Done 
 
Hop on one foot 
□ Normal  
□ Abnormal   
□ Unable to Perform   
□ Not Done 
 
Romberg 
□ Normal  
□ Abnormal   
□ Unable to Perform   
□ Not Done 
 
Deep tendon reflexes 
Biceps 
□ Normal  
□ Abnormal   
□ Not Done 
 
Patellar 
□ Normal  
□ Abnormal   
□ Not Done 
 
Ankle 
□ Normal  
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
69 
Items 
Status 
Please describe abnormalities 
□ Abnormal   
□ Not Done 
Deep tendon reflexes (continue) 
Ankle clonus 
□ Absent  
□ Present   
□ Not done 
 
Gait 
Natural walking 
□ Normal  
□ Abnormal   
□ Unable to Perform   
□ Not Done 
 
Straight line walking 
□ Normal  
□ Abnormal   
□ Unable to Perform   
□ Not Done 
 
Tandem walking 
□ Normal  
□ Abnormal   
□ Unable to Perform   
□ Not Done 
 
Other 
Specify:  ___________________ 
□ Normal  
□ Abnormal   
 
Specify:  ___________________ 
□ Normal  
□ Abnormal   
 
Specify:  ___________________ 
□ Normal  
□ Abnormal   
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
70 
Items 
Status 
Please describe abnormalities 
Specify:  ___________________ 
□ Normal  
□ Abnormal   
 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
71 
 
Appendix 3 
Neurodevelopmental and Behavioral Assessments 
Table 3-1 and Table 3-2 detail the specific psychometric instruments that will be used to provide 
measures of each of relevant neurobehavioral or developmental domain assessed.  The tables 
also summarize the rules used to select a test for a patient, the subtests included in each test, and 
the subscales generated by the test battery. 
Table 3-1 Summary of Neurodevelopmental Outcome Measures 
Domain 
Age 
Test 
Summary score and 
subdomains: 
- Cognitive 
- Motor 
0 to 42 months Bayley Scales of Infant Development, Third 
Edition (BSID-III)23 
- Cognitive  
- Processing skills 
3 to 18 years 
Kaufman Assessment Battery for Children, 
Second Edition (KABC-II)24 
Motor 
3.0 to 16:11 
years 
Movement Assessment Battery for Children, 
Second Edition (MABC-2)25 
Communication 
Daily Living 
Socialization 
Motor Skills 
0 to 90 years 
Vineland Adaptive Behavior Scales, Second 
Edition (VABS-II)26 
 
Table 3-2 Summary of Sanfilippo-specific Assessments 
Domain 
Assessment 
Parent-scored behavioral inventory 
- communication:  understanding 
- communication:  expression 
- tantrums 
- specific behaviors inventory 
- mood & emotions inventory 
Sanfilippo Behavior Rating Scale 
MPS-specific four-point scoring 
system/total disability score 
- cognition 
- expressive language 
- motor score 
Four-Point Scoring System/Total Disability 
Score (FPSS/TDS)4 
 
The term “neurodevelopmental” refers to the process by which the neurological system matures 
and changes over time.  Assessing these changes in a population of children whose neurological 
system is progressively more affected can be very challenging.   
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
72 
Typically, neurodevelopmental progress is reflected by the child’s abilities to perform certain 
skills (sitting, walking, and talking).  However, a child with a neurological disorder may be able 
to perform age appropriate skills, but with atypical patterns.  For example, the child may be able 
to walk, but his gait is not normal.  Most assessments will therefore measure the skills, but are 
not designed to capture the abnormalities in pattern or quality of the skill.   
These qualitative differences will be evident to the skilled test administrator/clinician who is 
familiar with the disorder.  However, only longitudinal tracking and repeated measures will 
reveal the significance of these abnormalities in overall function to the less experienced clinician.    
The rate at which different skills develop or regress over time will give insight into the disease 
process.  The next step is to determine how the learned skills are used for daily functional 
activities so that as the children grow up they become independent from caregivers.  These 
functional skills can be tracked to reflect quality of life issues for both parents and children.  
Neurodevelopmental assessments described below will be scheduled for administration in the 
morning and estimated to last between 2 and 4 hours. 
The list of assessments is discussed in detail in the Study Operations Manual and includes: 
Bayley Scales of Infant Development, Third Edition (BSID-III)23 
The Bayley Scales of Infant Development is a standard series of measurements used primarily to 
assess the motor (fine and gross), language (receptive and expressive), and cognitive 
development of infants and toddlers, ages 0 to 42 months.  This measure consists of a series of 
developmental play tasks and takes between 45 and 60 minutes to administer.  Raw scores of 
successfully completed items are converted to scale scores and to composite scores.  These 
scores are used to determine the child's performance compared with norms taken from typically 
developing children of their age (in months).  The assessment is often used in conjunction with 
the Social-Emotional Adaptive Behavior Questionnaire.  Completed by the parent or caregiver, 
this questionnaire establishes the range of adaptive behaviors that the child can currently achieve 
and enables comparison with age norms. 
Kaufman Assessment Battery for Children, Second Edition (KABC-II)24 
Purpose: 
The KABC-II measures a child’s cognitive ability and processing skills and was designed to 
minimize verbal instructions and responses.  In addition, the assessment contains little cultural 
content to provide a more accurate assessment of children from diverse backgrounds.  Thus 
language difficulties or cultural differences are minimized in the test battery’s results. 
Description: 
Investigators may choose either the Cattell-Horn-Carroll or the Luria model for a patient’s 
assessment.   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
73 
The Cattell-Horn-Carroll model is used with children from a mainstream cultural and language 
background and the Luria model is used for children with significantly limited verbal ability.  
Subtests are administered on four or five ability scales and interpreted using the chosen model.  
Movement Assessment Battery for Children, Second Edition (MABC-2)25 
Purpose: 
The Movement Assessment Battery for Children, Second Edition identifies, describes and guides 
treatment of motor impairment in children from 3.0 to 16:11 years of age. 
Description: 
The MABC-2 checklist is administered individually over approximately 30 minutes.  It yields 
both normative and qualitative measures of movement competence, manual dexterity, ball skills, 
static and dynamic balance. 
Vineland Adaptive Behavior Scales, Second Edition (VABS-II)26 
Purpose: 
The test measures adaptive behaviors, including the ability to cope with environmental changes, 
to learn new everyday skills and to demonstrate independence.  It is an instrument that supports 
the diagnosis of intellectual and developmental disabilities.  It encompasses ages from birth to 
90 years.  
Description: 
Adaptive behavior is a composite of various dimensions.  This test measures 5 domains:  
communication, daily living skills, socialization, motor skills, and maladaptive behavior 
(optional) and is administered in a semi-structured interview in through a questionnaire.  The 
scales of the VABS-II were organized within a 3-domain structure:  Communication, Daily 
Living, and Socialization.  This structure corresponds to the 3 broad domains of adaptive 
functioning by the American Association of Intellectual and Developmental Disabilities:  
Conceptual, Practical, and Social.  In addition, VABS-II offers a Motor Skills Domain and an 
optional Maladaptive Behavior Index.  The scores are interpreted by means of score equivalents 
for the raw scores in each domain, percentile ranks, age equivalents, adaptive levels, and 
maladaptive levels. 
Sanfilippo Behavior Rating Scale (SBRS) 
The Sanfilippo Behavior Rating Scale (SBRS) is a newly-developed scale designed by Drs. Elsa 
Shapiro and Michael Potegal to measure a cluster of behaviors known to occur in Sanfilippo 
syndrome.  The SBRS is a parent-scored behavioral inventory measuring (1) comprehensive 
language skills, (2) expressive language skills, (3) tantrums, (4) mood and emotions, and 
(5) other behaviors not otherwise classified. 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
74 
Four-Point Scoring System/Total Disability Score (FPSS/TDS)5 
The FPSS assesses motor function, expressive language, and cognitive function on a 0 to 3 point 
scale and can be used for individuals of all ages.  The total disability score is the average of the 
motor function, speech, and cognitive function scores. 

Recombinant human heparan N-sulfatase (rhHNS) 
Clinical Trial Protocol: HGT-SAN-067 
21 June 2010 
Appendix 4 
Investigator's Signature 
Study Title: 
An Open-Label Extension of Study HGT-SAN-055 
Evaluating Long-Term Safety and Clinical Outcomes of 
Intrathecal Administration of rhHNS in Patients with 
Sanfilippo Syndrome Type A (MPS IliA) 
Study Number: 
HGT-SAN-067 
Final Date: 
21 June 2010 
Amendment 1 Date: 
N/ A 
I have read the protocol described above. I agree to comply with all applicable regulations and 
to conduct the study as described in the protocol. <enter additional text> 
Signed: 
Signed: 
Shire 
Date: ___________ _ 
 MD 
 
, UK 
 MD 
Medical Monitor 
Shire HGT 
700 Main Street 
Cambridge, MA 01239 
Date: 
Confidential 
75 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 
 
21 June 2010 
Shire 
Confidential 
76 
Appendix 5 
The National Cancer Institute Common Toxicity Criteria (NCI 
CTC) Version 3.0 
 
 
 
 
 
 
 

Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, Version 3.0, DCTD, NCI, NIH, DHHS 
 
March 31, 2003 (http://ctep.cancer.gov), Publish Date: August 9, 2006 
Common Terminology Criteria for Adverse Events v3.0 (CTCAE) 
Publish Date: August 9, 2006 
Quick Reference 
The NCI Common Terminology Criteria for Adverse Events 
v3.0 is a descriptive terminology which can be utilized for 
Adverse Event (AE) reporting. A grading (severity) scale is 
provided for each AE term. 
Components and Organization  
CATEGORY 
A CATEGORY is a broad classification of AEs based on 
anatomy and/or pathophysiology. Within each CATEGORY, 
AEs are listed accompanied by their descriptions of severity 
(Grade). 
Adverse Event Terms 
An AE is any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medical treatment or procedure 
that may or may not be considered related to the medical 
treatment or procedure. An AE is a term that is a unique 
representation of a specific event used for medical 
documentation and scientific analyses. Each AE term is 
mapped to a MedDRA term and code. AEs are listed 
alphabetically within CATEGORIES. 
Short AE Name 
The ‘SHORT NAME’ column is new and it is used to simplify 
documentation of AE names on Case Report Forms.   
Supra-ordinate Terms  
A supra-ordinate term is located within a CATEGORY and is a 
grouping term based on disease process, signs, symptoms, 
or diagnosis. A supra-ordinate term is followed by the word 
‘Select’ and is accompanied by specific AEs that are all 
related to the supra-ordinate term. Supra-ordinate terms 
provide clustering and consistent representation of Grade for 
related AEs. Supra-ordinate terms are not AEs, are not 
mapped to a MedDRA term and code, cannot be graded and 
cannot be used for reporting. 
REMARK 
A ‘REMARK’ is a clarification of an AE. 
ALSO CONSIDER 
An ‘ALSO CONSIDER’ indicates additional AEs that are to be 
graded if they are clinically significant. 
NAVIGATION NOTE 
A ‘NAVIGATION NOTE’ indicates the location of an AE term 
within the CTCAE document. It lists signs/symptoms 
alphabetically and the CTCAE term will appear in the same 
CATEGORY unless the ‘NAVIGATION NOTE’ states differently. 
Grades 
Grade refers to the severity of the AE. The CTCAE v3.0 
displays Grades 1 through 5 with unique clinical descriptions 
of severity for each AE based on this general guideline: 
Grade 1 
Mild AE  
Grade 2 
Moderate AE 
Grade 3 
Severe AE 
Grade 4 
Life-threatening or disabling AE 
Grade 5 
Death related to AE 
A Semi-colon indicates ‘or’ within the description of the grade. 
An ‘Em dash’ (—) indicates a grade not available. 
Not all Grades are appropriate for all AEs. Therefore, some 
AEs are listed with fewer than five options for Grade 
selection. 
Grade 5 
Grade 5 (Death) is not appropriate for some AEs and 
therefore is not an option. 
The DEATH CATEGORY is new. Only one Supra-ordinate 
term is listed in this CATEGORY: ‘Death not associated with 
CTCAE term – Select’ with 4 AE options: Death NOS; 
Disease progression NOS; Multi-organ failure; Sudden death. 
Important: 
• 
Grade 5 is the only appropriate Grade 
• 
This AE is to be used in the situation where 
a death  
1. cannot be reported using a CTCAE v3.0 
term associated with Grade 5, or 
2. cannot be reported within a CTCAE 
CATEGORY as ‘Other (Specify)’ 
 
 
 
 
 
Contents 
ALLERGY/IMMUNOLOGY ............................................1 
AUDITORY/EAR............................................................2 
BLOOD/BONE MARROW .............................................4 
CARDIAC ARRHYTHMIA..............................................5 
CARDIAC GENERAL ....................................................7 
COAGULATION ..........................................................10 
CONSTITUTIONAL SYMPTOMS................................11 
DEATH ........................................................................13 
DERMATOLOGY/SKIN ...............................................14 
ENDOCRINE...............................................................17 
GASTROINTESTINAL.................................................19 
GROWTH AND DEVELOPMENT................................29 
HEMORRHAGE/BLEEDING ....................................... 30 
HEPATOBILIARY/PANCREAS ................................... 34 
INFECTION................................................................. 35 
LYMPHATICS ............................................................. 38 
METABOLIC/LABORATORY ...................................... 40 
MUSCULOSKELETAL/SOFT TISSUE........................ 43 
NEUROLOGY ............................................................. 47 
OCULAR/VISUAL........................................................ 52 
PAIN............................................................................ 55 
PULMONARY/UPPER RESPIRATORY...................... 56 
RENAL/GENITOURINARY.......................................... 60 
SECONDARY MALIGNANCY..................................... 63 
SEXUAL/REPRODUCTIVE FUNCTION ..................... 64 
SURGERY/INTRA-OPERATIVE INJURY ................... 66 
SYNDROMES............................................................. 68 
VASCULAR................................................................. 70 
 

 
ALLERGY/IMMUNOLOGY 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 1 - 
March 31, 2003, Publish Date: August 9, 2006 
Allergic reaction/ 
hypersensitivity  
(including drug fever) 
Allergic reaction 
Transient flushing or 
rash; drug fever <38°C 
(<100.4°F) 
Rash; flushing; urticaria; 
dyspnea; drug fever 
≥38°C (≥100.4°F) 
Symptomatic 
bronchospasm, with or 
without urticaria; 
parenteral medication(s) 
indicated; allergy-related 
edema/angioedema; 
hypotension 
Anaphylaxis 
Death 
REMARK: Urticaria with manifestations of allergic or hypersensitivity reaction is graded as Allergic reaction/hypersensitivity (including drug fever). 
ALSO CONSIDER: Cytokine release syndrome/acute infusion reaction. 
Allergic rhinitis  
(including sneezing, 
nasal stuffiness, 
postnasal drip) 
Rhinitis 
Mild, intervention not 
indicated  
Moderate, intervention 
indicated 
— 
— 
— 
REMARK: Rhinitis associated with obstruction or stenosis is graded as Obstruction/stenosis of airway – Select in the PULMONARY/UPPER RESPIRATORY CATEGORY. 
Autoimmune reaction 
Autoimmune reaction 
Asymptomatic and 
serologic or other 
evidence of autoimmune 
reaction, with normal 
organ function and 
intervention not indicated 
Evidence of autoimmune 
reaction involving a non-
essential organ or 
function (e.g., 
hypothyroidism) 
Reversible autoimmune 
reaction involving function 
of a major organ or other 
adverse event (e.g., 
transient colitis or 
anemia)  
Autoimmune reaction with 
life-threatening 
consequences 
Death 
ALSO CONSIDER: Colitis; Hemoglobin; Hemolysis (e.g., immune hemolytic anemia, drug-related hemolysis); Thyroid function, low (hypothyroidism). 
Serum sickness 
Serum sickness 
— 
— 
Present 
— 
Death 
NAVIGATION NOTE: Splenic function is graded in the BLOOD/BONE MARROW CATEGORY. 
NAVIGATION NOTE: Urticaria as an isolated symptom is graded as Urticaria (hives, welts, wheals) in the DERMATOLOGY/SKIN CATEGORY. 
Vasculitis 
Vasculitis 
Mild, intervention not 
indicated 
Symptomatic, non-
steroidal medical 
intervention indicated 
Steroids indicated 
Ischemic changes; 
amputation indicated 
Death 
Allergy/Immunology – 
Other (Specify, __) 
Allergy – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
AUDITORY/EAR 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 2 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Earache (otalgia) is graded as Pain – Select in the PAIN CATEGORY. 
Hearing:  
patients with/without 
baseline audiogram and 
enrolled in a monitoring 
program1 
Hearing (monitoring 
program) 
Threshold shift or loss of 
15 – 25 dB relative to 
baseline, averaged at 2 
or more contiguous test 
frequencies in at least 
one ear; or subjective 
change in the absence of 
a Grade 1 threshold shift 
Threshold shift or loss of 
>25 – 90 dB, averaged at 
2 contiguous test 
frequencies in at least 
one ear 
Adult only: Threshold shift 
of >25 – 90 dB, averaged 
at 3 contiguous test 
frequencies in at least 
one ear  
Pediatric:  
Hearing loss sufficient to 
indicate therapeutic 
intervention, including 
hearing aids (e.g., ≥20 dB 
bilateral HL in the speech 
frequencies; ≥30 dB 
unilateral HL; and 
requiring additional 
speech-language related 
services) 
Adult only: Profound 
bilateral hearing loss 
(>90 dB) 
Pediatric:  
Audiologic indication for 
cochlear implant and 
requiring additional 
speech-language related 
services  
— 
REMARK: Pediatric recommendations are identical to those for adults, unless specified. For children and adolescents (≤18 years of age) without a baseline test, pre-exposure/pre-
treatment hearing should be considered to be <5 dB loss. 
Hearing: 
patients without baseline 
audiogram and not 
enrolled in a monitoring 
program1  
Hearing (without 
monitoring program) 
— 
Hearing loss not requiring 
hearing aid or 
intervention (i.e., not 
interfering with ADL) 
Hearing loss requiring 
hearing aid or 
intervention (i.e., 
interfering with ADL) 
Profound bilateral hearing 
loss (>90 dB) 
— 
REMARK: Pediatric recommendations are identical to those for adults, unless specified. For children and adolescents (≤18 years of age) without a baseline test, pre-exposure/pre-
treatment hearing should be considered to be <5 dB loss. 
Otitis, external ear 
(non-infectious) 
Otitis, external  
External otitis with 
erythema or dry 
desquamation  
External otitis with moist 
desquamation, edema, 
enhanced cerumen or 
discharge; tympanic 
membrane perforation; 
tympanostomy 
External otitis with 
mastoiditis; stenosis or 
osteomyelitis 
Necrosis of soft tissue or 
bone 
Death 
ALSO CONSIDER: Hearing: patients with/without baseline audiogram and enrolled in a monitoring program1; Hearing: patients without baseline audiogram and not enrolled in a 
monitoring program1.  
Otitis, middle ear  
(non-infectious) 
Otitis, middle 
Serous otitis  
Serous otitis, medical 
intervention indicated 
Otitis with discharge; 
mastoiditis  
Necrosis of the canal soft 
tissue or bone 
Death 

 
AUDITORY/EAR 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 3 - 
March 31, 2003, Publish Date: August 9, 2006 
Tinnitus 
Tinnitus 
— 
Tinnitus not interfering 
with ADL 
Tinnitus interfering with 
ADL 
Disabling 
— 
ALSO CONSIDER: Hearing: patients with/without baseline audiogram and enrolled in a monitoring program1; Hearing: patients without baseline audiogram and not enrolled in a 
monitoring program1. 
Auditory/Ear – Other 
(Specify, __) 
Auditory/Ear – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
 
 
 
 
 
 
                                            
1 Drug-induced ototoxicity should be distinguished from age-related threshold decrements or unrelated cochlear insult. When considering whether an adverse event has occurred, it is 
first necessary to classify the patient into one of two groups. (1) The patient is under standard treatment/enrolled in a clinical trial <2.5 years, and has a 15 dB or greater threshold 
shift averaged across two contiguous frequencies; or (2) The patient is under standard treatment/enrolled in a clinical trial >2.5 years, and the difference between the expected age-
related and the observed threshold shifts is 15 dB or greater averaged across two contiguous frequencies. Consult standard references for appropriate age- and gender-specific 
hearing norms, e.g., Morrell, et al. Age- and gender-specific reference ranges for hearing level and longitudinal changes in hearing level. Journal of the Acoustical Society of America 
100:1949-1967, 1996; or Shotland, et al. Recommendations for cancer prevention trials using potentially ototoxic test agents. Journal of Clinical Oncology 19:1658-1663, 2001.  
In the absence of a baseline prior to initial treatment, subsequent audiograms should be referenced to an appropriate database of normals. ANSI. (1996) 
American National Standard: Determination of occupational noise exposure and estimation of noise-induced hearing impairment, ANSI S 3.44-1996. (Standard S 3.44). New York: 
American National Standards Institute. The recommended ANSI S3.44 database is Annex B. 

 
BLOOD/BONE MARROW 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 4 - 
March 31, 2003, Publish Date: August 9, 2006 
Bone marrow cellularity 
Bone marrow cellularity 
Mildly hypocellular or  
≤25% reduction from 
normal cellularity for age 
Moderately hypocellular 
or >25 – ≤50% reduction 
from normal cellularity for 
age  
Severely hypocellular or 
>50 – ≤75% reduction 
cellularity from normal for 
age  
— 
Death 
CD4 count  
CD4 count 
<LLN – 500/mm3 
<LLN – 0.5 x 109 /L 
<500 – 200/mm3  
<0.5 – 0.2 x 109 /L 
<200 – 50/mm3  
<0.2 x 0.05 – 109 /L 
<50/mm3  
<0.05 x 109 /L 
Death 
Haptoglobin  
Haptoglobin 
<LLN  
— 
Absent 
— 
Death 
Hemoglobin  
Hemoglobin 
<LLN – 10.0 g/dL  
<LLN – 6.2 mmol/L  
<LLN – 100 g/L 
<10.0 – 8.0 g/dL 
<6.2 – 4.9 mmol/L  
<100 – 80g/L 
<8.0 – 6.5 g/dL 
<4.9 – 4.0 mmol/L 
<80 – 65 g/L 
<6.5 g/dL 
<4.0 mmol/L  
<65 g/L 
Death 
Hemolysis (e.g., immune 
hemolytic anemia, drug-
related hemolysis) 
Hemolysis 
Laboratory evidence of 
hemolysis only (e.g., 
direct antiglobulin test 
[DAT, Coombs’] 
schistocytes) 
Evidence of red cell 
destruction and ≥2 gm 
decrease in hemoglobin, 
no transfusion 
Transfusion or medical 
intervention (e.g., 
steroids) indicated 
Catastrophic 
consequences of 
hemolysis (e.g., renal 
failure, hypotension, 
bronchospasm, 
emergency splenectomy) 
Death 
ALSO CONSIDER: Haptoglobin; Hemoglobin. 
Iron overload 
Iron overload 
— 
Asymptomatic iron 
overload, intervention not 
indicated  
Iron overload, 
intervention indicated  
Organ impairment (e.g., 
endocrinopathy, 
cardiopathy) 
Death 
Leukocytes (total WBC) 
Leukocytes 
<LLN – 3000/mm3 
<LLN – 3.0 x 109 /L  
<3000 – 2000/mm3 
<3.0 – 2.0 x 109 /L 
<2000 – 1000/mm3 
<2.0 – 1.0 x 109 /L 
<1000/mm3  
<1.0 x 109 /L 
Death 
Lymphopenia  
Lymphopenia 
<LLN – 800/mm3 
<LLN x 0.8 – 109 /L 
<800 – 500/mm3 
<0.8 – 0.5 x 109 /L 
<500 – 200 mm3 
<0.5 – 0.2 x 109 /L 
<200/mm3 
<0.2 x 109 /L 
Death 
Myelodysplasia 
Myelodysplasia 
— 
— 
Abnormal marrow 
cytogenetics (marrow 
blasts ≤5%)  
RAEB or RAEB-T 
(marrow blasts >5%) 
Death 
Neutrophils/granulocytes 
(ANC/AGC) 
Neutrophils 
<LLN – 1500/mm3  
<LLN – 1.5 x 109 /L 
<1500 – 1000/mm3 
<1.5 – 1.0 x 109 /L  
<1000 – 500/mm3 
<1.0 – 0.5 x 109 /L 
<500/mm3 
<0.5 x 109 /L 
Death 
Platelets 
Platelets 
<LLN – 75,000/mm3 
<LLN – 75.0 x 109 /L 
<75,000 – 50,000/mm3 
<75.0 – 50.0 x 109 /L 
<50,000 – 25,000/mm3  
<50.0 – 25.0 x 109 /L 
<25,000/mm3  
<25.0 x 109 /L 
Death 
Splenic function 
Splenic function 
Incidental findings (e.g., 
Howell-Jolly bodies) 
Prophylactic antibiotics 
indicated 
—  
Life-threatening 
consequences 
Death 
Blood/Bone Marrow – 
Other (Specify, __) 
Blood – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
CARDIAC ARRHYTHMIA 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 5 - 
March 31, 2003, Publish Date: August 9, 2006 
Conduction abnormality/ 
atrioventricular heart 
block  
– Select:  
Conduction abnormality 
– Select 
Asymptomatic, 
intervention not indicated 
– Asystole 
– AV Block-First degree 
– AV Block-Second degree Mobitz Type I (Wenckebach)  
– AV Block-Second degree Mobitz Type II 
– AV Block-Third degree (Complete AV block) 
– Conduction abnormality NOS 
– Sick Sinus Syndrome  
– Stokes-Adams Syndrome 
– Wolff-Parkinson-White Syndrome 
Non-urgent medical 
intervention indicated 
Incompletely controlled 
medically or controlled  
with device (e.g., 
pacemaker) 
Life-threatening (e.g., 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
Death 
Palpitations 
Palpitations 
Present 
Present with associated 
symptoms (e.g., 
lightheadedness, 
shortness of breath) 
— 
— 
— 
REMARK: Grade palpitations only in the absence of a documented arrhythmia. 
Prolonged QTc interval 
Prolonged QTc 
QTc >0.45 – 0.47 second 
 QTc >0.47 – 0.50 
second; ≥0.06 second 
above baseline 
QTc >0.50 second 
QTc >0.50 second; life-
threatening signs or 
symptoms (e.g., 
arrhythmia, CHF, 
hypotension, shock 
syncope); Torsade de 
pointes 
Death 
Supraventricular and 
nodal arrhythmia  
– Select: 
Supraventricular 
arrhythmia – Select 
Asymptomatic, 
intervention not indicated 
Non-urgent medical 
intervention indicated 
– Atrial fibrillation 
– Atrial flutter  
– Atrial tachycardia/Paroxysmal Atrial Tachycardia 
– Nodal/Junctional 
– Sinus arrhythmia  
– Sinus bradycardia 
– Sinus tachycardia  
– Supraventricular arrhythmia NOS 
– Supraventricular extrasystoles (Premature Atrial Contractions; Premature Nodal/Junctional Contractions) 
– Supraventricular tachycardia 
Symptomatic and 
incompletely controlled 
medically, or controlled 
with device (e.g., 
pacemaker) 
Life-threatening (e.g., 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
Death 
NAVIGATION NOTE: Syncope is graded as Syncope (fainting) in the NEUROLOGY CATEGORY. 

 
CARDIAC ARRHYTHMIA 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 6 - 
March 31, 2003, Publish Date: August 9, 2006 
Vasovagal episode 
Vasovagal episode 
— 
Present without loss of 
consciousness 
Present with loss of 
consciousness 
Life-threatening 
consequences  
Death 
Ventricular arrhythmia 
– Select: 
Ventricular arrhythmia 
– Select 
– Bigeminy 
– Idioventricular rhythm 
– PVCs 
– Torsade de pointes 
– Trigeminy 
– Ventricular arrhythmia NOS 
– Ventricular fibrillation  
– Ventricular flutter 
– Ventricular tachycardia 
Asymptomatic, no 
intervention indicated 
Non-urgent medical 
intervention indicated 
Symptomatic and 
incompletely controlled 
medically or controlled 
with device (e.g., 
defibrillator) 
Life-threatening (e.g., 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
Death 
Cardiac Arrhythmia  
– Other (Specify, __) 
Cardiac Arrhythmia – 
Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling  
Death 

 
CARDIAC GENERAL 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 7 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Angina is graded as Cardiac ischemia/infarction in the CARDIAC GENERAL CATEGORY. 
Cardiac 
ischemia/infarction 
Cardiac 
ischemia/infarction 
Asymptomatic arterial 
narrowing without 
ischemia 
Asymptomatic and testing 
suggesting ischemia; 
stable angina  
Symptomatic and testing 
consistent with ischemia; 
unstable angina; 
intervention indicated 
Acute myocardial 
infarction 
Death 
Cardiac troponin I (cTnI) 
cTnI 
— 
— 
Levels consistent with 
unstable angina as 
defined by the 
manufacturer 
Levels consistent with 
myocardial infarction as 
defined by the 
manufacturer 
Death 
Cardiac troponin T (cTnT) 
cTnT 
0.03 – <0.05 ng/mL 
0.05 – <0.1 ng/mL 
0.1 – <0.2 ng/mL 
0.2 ng/mL 
Death 
Cardiopulmonary arrest, 
cause unknown 
(non-fatal) 
Cardiopulmonary arrest 
— 
— 
— 
Life-threatening  
— 
REMARK: Grade 4 (non-fatal) is the only appropriate grade. CTCAE provides three alternatives for reporting Death: 
1. A CTCAE term associated with Grade 5.  
2. A CTCAE 'Other (Specify, __)’ within any CATEGORY. 
3. Death not associated with CTCAE term – Select in the DEATH CATEGORY. 
NAVIGATION NOTE: Chest pain (non-cardiac and non-pleuritic) is graded as Pain – Select in the PAIN CATEGORY. 
NAVIGATION NOTE: CNS ischemia is graded as CNS cerebrovascular ischemia in the NEUROLOGY CATEGORY. 
Hypertension 
Hypertension 
Asymptomatic, transient 
(<24 hrs) increase by >20 
mmHg (diastolic) or to 
>150/100 if previously 
WNL; intervention not 
indicated  
Pediatric: 
Asymptomatic, transient 
(<24 hrs) BP increase 
>ULN; intervention not 
indicated 
Recurrent or persistent 
(≥24 hrs) or symptomatic 
increase by >20 mmHg 
(diastolic) or to >150/100 
if previously WNL; 
monotherapy may be 
indicated  
Pediatric: 
Recurrent or persistent 
(≥24 hrs) BP >ULN; 
monotherapy may be 
indicated 
Requiring more than one 
drug or more intensive 
therapy than previously 
Pediatric: 
Same as adult 
Life-threatening 
consequences (e.g., 
hypertensive crisis) 
Pediatric: 
Same as adult 
Death 
REMARK: Use age and gender-appropriate normal values >95th percentile ULN for pediatric patients. 

 
CARDIAC GENERAL 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 8 - 
March 31, 2003, Publish Date: August 9, 2006 
Hypotension 
Hypotension 
Changes, intervention not 
indicated 
Brief (<24 hrs) fluid 
replacement or other 
therapy; no physiologic 
consequences 
Sustained (≥24 hrs) 
therapy, resolves without 
persisting physiologic 
consequences 
Shock (e.g., acidemia; 
impairment of vital organ 
function)  
Death 
ALSO CONSIDER: Syncope (fainting). 
Left ventricular diastolic 
dysfunction 
Left ventricular diastolic 
dysfunction 
Asymptomatic diagnostic 
finding; intervention not 
indicated 
Asymptomatic, 
intervention indicated 
Symptomatic CHF 
responsive to intervention 
Refractory CHF, poorly 
controlled; intervention 
such as ventricular assist 
device or heart transplant 
indicated  
Death 
Left ventricular systolic 
dysfunction 
Left ventricular systolic 
dysfunction 
Asymptomatic, resting 
ejection fraction (EF)  
<60 – 50%; shortening 
fraction (SF) <30 – 24% 
Asymptomatic, resting  
EF <50 – 40%; 
SF <24 – 15% 
Symptomatic CHF 
responsive to 
intervention; 
EF <40 – 20% 
SF <15% 
Refractory CHF or poorly 
controlled; EF <20%; 
intervention such as 
ventricular assist device, 
ventricular reduction 
surgery, or heart 
transplant indicated 
Death 
NAVIGATION NOTE: Myocardial infarction is graded as Cardiac ischemia/infarction in the CARDIAC GENERAL CATEGORY. 
Myocarditis 
Myocarditis 
— 
— 
CHF responsive to 
intervention 
Severe or refractory CHF 
Death 
Pericardial effusion 
(non-malignant) 
Pericardial effusion 
Asymptomatic effusion  
—  
Effusion with physiologic 
consequences 
Life-threatening 
consequences (e.g., 
tamponade); emergency 
intervention indicated 
Death 
Pericarditis 
Pericarditis 
Asymptomatic, ECG or 
physical exam (rub) 
changes consistent with 
pericarditis 
Symptomatic pericarditis 
(e.g., chest pain) 
Pericarditis with 
physiologic 
consequences (e.g., 
pericardial constriction) 
Life-threatening 
consequences; 
emergency intervention 
indicated 
Death 
NAVIGATION NOTE: Pleuritic pain is graded as Pain – Select in the PAIN CATEGORY. 
Pulmonary hypertension 
Pulmonary hypertension 
Asymptomatic without 
therapy 
Asymptomatic, therapy 
indicated 
Symptomatic 
hypertension, responsive 
to therapy 
Symptomatic 
hypertension, poorly 
controlled 
Death 
Restrictive 
cardiomyopathy  
Restrictive 
cardiomyopathy  
Asymptomatic, therapy 
not indicated 
Asymptomatic, therapy 
indicated 
Symptomatic CHF 
responsive to intervention 
Refractory CHF, poorly 
controlled; intervention 
such as ventricular assist 
device, or heart 
transplant indicated  
Death 

 
CARDIAC GENERAL 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 9 - 
March 31, 2003, Publish Date: August 9, 2006 
Right ventricular 
dysfunction 
(cor pulmonale) 
Right ventricular 
dysfunction 
Asymptomatic without 
therapy 
Asymptomatic, therapy 
indicated 
Symptomatic cor 
pulmonale, responsive to 
intervention 
Symptomatic cor 
pulmonale poorly 
controlled; intervention 
such as ventricular assist 
device, or heart 
transplant indicated  
Death 
Valvular heart disease 
Valvular heart disease 
Asymptomatic valvular 
thickening with or without 
mild valvular regurgitation 
or stenosis; treatment 
other than endocarditis 
prophylaxis not indicated 
Asymptomatic; moderate 
regurgitation or stenosis 
by imaging 
Symptomatic; severe 
regurgitation or stenosis; 
symptoms controlled with 
medical therapy 
Life-threatening; 
disabling; intervention 
(e.g., valve replacement, 
valvuloplasty) indicated 
Death 
Cardiac General – Other 
(Specify, __) 
Cardiac General – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
COAGULATION 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 10 - 
March 31, 2003, Publish Date: August 9, 2006 
DIC (disseminated 
intravascular coagulation) 
DIC 
— 
Laboratory findings with 
no bleeding 
Laboratory findings and 
bleeding 
Laboratory findings, life-
threatening or disabling 
consequences (e.g., CNS 
hemorrhage, organ 
damage, or 
hemodynamically 
significant blood loss) 
Death 
REMARK: DIC (disseminated intravascular coagulation) must have increased fibrin split products or D-dimer.  
ALSO CONSIDER: Platelets. 
 
Fibrinogen  
Fibrinogen 
<1.0 – 0.75 x LLN 
or <25% decrease from 
baseline 
<0.75 – 0.5 x LLN 
or 25 – <50% decrease 
from baseline 
<0.5 – 0.25 x LLN 
or 50 – <75% decrease 
from baseline 
<0.25 x LLN  
or 75% decrease from 
baseline or absolute 
value <50 mg/dL  
Death 
REMARK: Use % decrease only when baseline is <LLN (local laboratory value). 
INR (International 
Normalized Ratio of 
prothrombin time) 
INR 
 
>1 – 1.5 x ULN 
>1.5 – 2 x ULN 
>2 x ULN 
— 
— 
ALSO CONSIDER: Hemorrhage, CNS; Hemorrhage, GI – Select; Hemorrhage, GU – Select; Hemorrhage, pulmonary/upper respiratory – Select. 
PTT (Partial 
Thromboplastin Time)  
PTT 
>1 – 1.5 x ULN 
>1.5 – 2 x ULN 
>2 x ULN 
— 
— 
ALSO CONSIDER: Hemorrhage, CNS; Hemorrhage, GI – Select; Hemorrhage, GU – Select; Hemorrhage, pulmonary/upper respiratory – Select. 
Thrombotic 
microangiopathy (e.g., 
thrombotic 
thrombocytopenic 
purpura [TTP] or 
hemolytic uremic 
syndrome [HUS]) 
Thrombotic 
microangiopathy 
Evidence of RBC 
destruction 
(schistocytosis) without 
clinical consequences 
— 
Laboratory findings 
present with clinical 
consequences (e.g., renal 
insufficiency, petechiae) 
Laboratory findings and 
life-threatening or 
disabling consequences, 
(e.g., CNS hemorrhage/ 
bleeding or thrombosis/ 
embolism or renal failure) 
Death 
REMARK: Must have microangiopathic changes on blood smear (e.g., schistocytes, helmet cells, red cell fragments). 
ALSO CONSIDER: Creatinine; Hemoglobin; Platelets. 
Coagulation – Other 
(Specify, __) 
Coagulation – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
CONSTITUTIONAL SYMPTOMS 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 11 - 
March 31, 2003, Publish Date: August 9, 2006 
Fatigue  
(asthenia, lethargy, 
malaise) 
Fatigue 
Mild fatigue over baseline 
Moderate or causing 
difficulty performing some 
ADL 
Severe fatigue interfering 
with ADL 
Disabling 
— 
Fever  
(in the absence of 
neutropenia, where 
neutropenia is defined as 
ANC <1.0 x 109/L) 
Fever 
38.0 – 39.0°C  
(100.4 – 102.2°F) 
>39.0 – 40.0°C 
(102.3 – 104.0°F)  
>40.0°C 
(>104.0°F) for ≤24 hrs  
>40.0°C 
(>104.0°F) for >24 hrs 
Death 
REMARK: The temperature measurements listed are oral or tympanic. 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever).  
NAVIGATION NOTE: Hot flashes are graded as Hot flashes/flushes in the ENDOCRINE CATEGORY. 
Hypothermia 
Hypothermia 
— 
35 – >32°C 
95 – >89.6°F 
32 – >28°C  
89.6 – >82.4° F 
≤28 °C  
82.4°F or life-threatening 
consequences (e.g., 
coma, hypotension, 
pulmonary edema, 
acidemia, ventricular 
fibrillation) 
Death 
Insomnia 
Insomnia 
Occasional difficulty 
sleeping, not interfering 
with function 
Difficulty sleeping, 
interfering with function 
but not interfering with 
ADL 
Frequent difficulty 
sleeping, interfering with 
ADL 
Disabling 
— 
REMARK: If pain or other symptoms interfere with sleep, do NOT grade as insomnia. Grade primary event(s) causing insomnia. 
Obesity2 
Obesity 
— 
BMI 25 – 29.9 kg/m2 
BMI 30 – 39.99 kg/m2 
BMI ≥40 kg/m2 
— 
REMARK: BMI = (weight [kg]) / (height [m])2 
Odor  
(patient odor) 
Patient odor 
Mild odor 
Pronounced odor 
— 
— 
— 
Rigors/chills 
Rigors/chills 
Mild 
Moderate, narcotics 
indicated 
Severe or prolonged, not 
responsive to narcotics 
— 
— 
                                            
2 NHLBI Obesity Task Force. "Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults," The Evidence Report, Obes Res 6:51S-
209S, 1998.  

 
CONSTITUTIONAL SYMPTOMS 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 12 - 
March 31, 2003, Publish Date: August 9, 2006 
Sweating  
(diaphoresis) 
Sweating  
Mild and occasional 
Frequent or drenching 
— 
— 
— 
ALSO CONSIDER: Hot flashes/flushes.  
Weight gain  
Weight gain 
5 – <10% of baseline 
10 – <20% of baseline 
≥20% of baseline 
— 
— 
REMARK: Edema, depending on etiology, is graded in the CARDIAC GENERAL or LYMPHATICS CATEGORIES. 
ALSO CONSIDER: Ascites (non-malignant); Pleural effusion (non-malignant). 
Weight loss 
Weight loss 
5 to <10% from baseline; 
intervention not indicated 
10 – <20% from baseline; 
nutritional support 
indicated 
≥20% from baseline; tube 
feeding or TPN indicated 
— 
— 
Constitutional Symptoms 
– Other (Specify, __) 
Constitutional Symptoms 
– Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
DEATH 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 13 - 
March 31, 2003, Publish Date: August 9, 2006 
Death not associated with 
CTCAE term  
– Select: 
Death not associated with 
CTCAE term – Select 
– Death NOS 
– Disease progression NOS 
– Multi-organ failure 
– Sudden death 
— 
— 
— 
— 
Death 
REMARK: Grade 5 is the only appropriate grade. 'Death not associated with CTCAE term – Select' is to be used where a death: 
1. Cannot be attributed to a CTCAE term associated with Grade 5. 
2. Cannot be reported within any CATEGORY using a CTCAE 'Other (Specify, __)’.  

 
DERMATOLOGY/SKIN 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 14 - 
March 31, 2003, Publish Date: August 9, 2006 
Atrophy, skin 
Atrophy, skin 
Detectable 
Marked 
— 
— 
— 
Atrophy, subcutaneous 
fat 
Atrophy, subcutaneous 
fat 
Detectable 
Marked 
— 
— 
— 
ALSO CONSIDER: Induration/fibrosis (skin and subcutaneous tissue). 
Bruising  
(in absence of Grade 3 or 
4 thrombocytopenia) 
Bruising  
Localized or in a 
dependent area 
Generalized 
— 
— 
— 
Burn 
Burn 
Minimal symptoms; 
intervention not indicated  
Medical intervention; 
minimal debridement 
indicated  
Moderate to major 
debridement or 
reconstruction indicated  
Life-threatening 
consequences 
Death 
REMARK: Burn refers to all burns including radiation, chemical, etc. 
Cheilitis 
Cheilitis 
Asymptomatic 
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
— 
— 
Dry skin 
Dry skin 
Asymptomatic 
Symptomatic, not 
interfering with ADL 
Interfering with ADL 
— 
— 
Flushing 
Flushing 
Asymptomatic 
Symptomatic 
— 
— 
— 
Hair loss/alopecia 
(scalp or body) 
Alopecia 
Thinning or patchy 
Complete 
— 
— 
— 
Hyperpigmentation 
Hyperpigmentation 
Slight or localized 
Marked or generalized 
— 
— 
— 
Hypopigmentation 
Hypopigmentation 
Slight or localized 
Marked or generalized 
— 
— 
— 
Induration/fibrosis 
(skin and subcutaneous 
tissue) 
Induration  
Increased density on 
palpation 
Moderate impairment of 
function not interfering 
with ADL; marked 
increase in density and 
firmness on palpation 
with or without minimal 
retraction 
Dysfunction interfering 
with ADL; very marked 
density, retraction or 
fixation 
— 
— 
ALSO CONSIDER: Fibrosis-cosmesis; Fibrosis-deep connective tissue.  
Injection site reaction/ 
extravasation changes 
Injection site reaction 
Pain; itching; erythema 
Pain or swelling, with 
inflammation or phlebitis 
Ulceration or necrosis 
that is severe; operative 
intervention indicated  
— 
— 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever); Ulceration. 

 
DERMATOLOGY/SKIN 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 15 - 
March 31, 2003, Publish Date: August 9, 2006 
Nail changes 
Nail changes 
Discoloration; ridging 
(koilonychias); pitting 
Partial or complete loss of 
nail(s); pain in nailbed(s) 
Interfering with ADL  
— 
— 
NAVIGATION NOTE: Petechiae is graded as Petechiae/purpura (hemorrhage/bleeding into skin or mucosa) in the HEMORRHAGE/BLEEDING CATEGORY. 
Photosensitivity 
Photosensitivity 
Painless erythema 
Painful erythema 
Erythema with 
desquamation 
Life-threatening; disabling 
Death 
Pruritus/itching 
Pruritus 
Mild or localized 
Intense or widespread 
Intense or widespread 
and interfering with ADL  
— 
— 
ALSO CONSIDER: Rash/desquamation. 
Rash/desquamation  
Rash 
Macular or papular 
eruption or erythema 
without associated 
symptoms 
Macular or papular 
eruption or erythema with 
pruritus or other 
associated symptoms; 
localized desquamation 
or other lesions covering 
<50% of body surface 
area (BSA) 
Severe, generalized 
erythroderma or macular, 
papular or vesicular 
eruption; desquamation 
covering ≥50% BSA 
Generalized exfoliative, 
ulcerative, or bullous 
dermatitis 
Death 
REMARK: Rash/desquamation may be used for GVHD. 
Rash:  
acne/acneiform 
Acne 
Intervention not indicated  
Intervention indicated 
Associated with pain, 
disfigurement, ulceration, 
or desquamation 
— 
Death 
Rash:  
dermatitis associated with 
radiation  
– Select: 
– Chemoradiation 
– Radiation 
Dermatitis – Select  
Faint erythema or dry 
desquamation 
Moderate to brisk 
erythema; patchy moist 
desquamation, mostly 
confined to skin folds and 
creases; moderate 
edema 
Moist desquamation other 
than skin folds and 
creases; bleeding 
induced by minor trauma 
or abrasion 
Skin necrosis or 
ulceration of full thickness 
dermis; spontaneous 
bleeding from involved 
site  
Death 
Rash:  
erythema multiforme 
(e.g., Stevens-Johnson 
syndrome, toxic 
epidermal necrolysis) 
Erythema multiforme 
— 
Scattered, but not 
generalized eruption 
Severe (e.g., generalized 
rash or painful stomatitis); 
IV fluids, tube feedings, 
or TPN indicated 
Life-threatening; disabling 
Death 
Rash:  
hand-foot skin reaction 
Hand-foot 
Minimal skin changes or 
dermatitis (e.g., 
erythema) without pain  
Skin changes (e.g., 
peeling, blisters, 
bleeding, edema) or pain, 
not interfering with 
function  
Ulcerative dermatitis or 
skin changes with pain 
interfering with function  
— 
— 

 
DERMATOLOGY/SKIN 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 16 - 
March 31, 2003, Publish Date: August 9, 2006 
Skin breakdown/ 
decubitus ulcer 
Decubitus  
— 
Local wound care; 
medical intervention 
indicated 
Operative debridement or 
other invasive 
intervention indicated 
(e.g., hyperbaric oxygen)  
Life-threatening 
consequences; major 
invasive intervention 
indicated (e.g., tissue 
reconstruction, flap, or 
grafting) 
Death 
REMARK: Skin breakdown/decubitus ulcer is to be used for loss of skin integrity or decubitus ulcer from pressure or as the result of operative or medical intervention. 
Striae 
Striae 
Mild 
Cosmetically significant 
— 
— 
— 
Telangiectasia 
Telangiectasia 
Few 
Moderate number 
Many and confluent 
— 
— 
Ulceration 
Ulceration 
— 
Superficial ulceration  
<2 cm size; local wound 
care; medical intervention 
indicated 
Ulceration ≥2 cm size; 
operative debridement, 
primary closure or other 
invasive intervention 
indicated (e.g., hyperbaric 
oxygen)  
Life-threatening 
consequences; major 
invasive intervention 
indicated (e.g., complete 
resection, tissue 
reconstruction, flap, or 
grafting) 
Death 
Urticaria  
(hives, welts, wheals) 
Urticaria 
Intervention not indicated 
Intervention indicated for 
<24 hrs 
Intervention indicated for 
≥24 hrs 
— 
— 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever). 
Wound complication, 
non-infectious  
Wound complication, 
non-infectious 
Incisional separation of  
≤25% of wound, no 
deeper than superficial 
fascia 
Incisional separation 
>25% of wound with local 
care; asymptomatic 
hernia 
Symptomatic hernia 
without evidence of 
strangulation; fascial 
disruption/dehiscence 
without evisceration; 
primary wound closure or 
revision by operative 
intervention indicated; 
hospitalization or 
hyperbaric oxygen 
indicated 
Symptomatic hernia with 
evidence of strangulation; 
fascial disruption with 
evisceration; major 
reconstruction flap, 
grafting, resection, or 
amputation indicated 
Death 
REMARK: Wound complication, non-infectious is to be used for separation of incision, hernia, dehiscence, evisceration, or second surgery for wound revision. 
Dermatology/Skin – Other 
(Specify, __) 
Dermatology – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
ENDOCRINE 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 17 - 
March 31, 2003, Publish Date: August 9, 2006 
Adrenal insufficiency 
Adrenal insufficiency 
Asymptomatic, 
intervention not indicated 
Symptomatic, intervention 
indicated 
Hospitalization  
Life-threatening; disabling 
Death 
REMARK: Adrenal insufficiency includes any of the following signs and symptoms: abdominal pain, anorexia, constipation, diarrhea, hypotension, pigmentation of mucous membranes, 
pigmentation of skin, salt craving, syncope (fainting), vitiligo, vomiting, weakness, weight loss. Adrenal insufficiency must be confirmed by laboratory studies (low cortisol frequently 
accompanied by low aldosterone). 
ALSO CONSIDER: Potassium, serum-high (hyperkalemia); Thyroid function, low (hypothyroidism). 
Cushingoid appearance 
(e.g., moon face, buffalo 
hump, centripetal obesity, 
cutaneous striae) 
Cushingoid  
— 
Present 
— 
— 
— 
ALSO CONSIDER: Glucose, serum-high (hyperglycemia); Potassium, serum-low (hypokalemia). 
Feminization of male 
Feminization of male 
— 
— 
Present 
— 
— 
NAVIGATION NOTE: Gynecomastia is graded in the SEXUAL/REPRODUCTIVE FUNCTION CATEGORY. 
Hot flashes/flushes3 
Hot flashes 
Mild  
Moderate  
Interfering with ADL 
— 
— 
Masculinization of female 
Masculinization of female 
— 
— 
Present 
— 
— 
Neuroendocrine: 
ACTH deficiency 
ACTH  
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL; hospitalization 
indicated 
Life-threatening 
consequences (e.g., 
severe hypotension) 
Death 
Neuroendocrine: 
ADH secretion 
abnormality (e.g., SIADH 
or low ADH) 
ADH 
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL 
Life-threatening 
consequences 
Death 
Neuroendocrine: 
gonadotropin secretion 
abnormality 
Gonadotropin 
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL; osteopenia; 
fracture; infertility 
— 
— 
Neuroendocrine:  
growth hormone 
secretion abnormality 
Growth hormone  
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
— 
— 
— 
Neuroendocrine:  
prolactin hormone 
secretion abnormality 
Prolactin  
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL; amenorrhea; 
galactorrhea 
— 
Death 
                                            
3 Sloan JA, Loprinzi CL, Novotny PJ, Barton DL, Lavasseur BI, Windschitl HJ, "Methodologic Lessons Learned from Hot Flash Studies," J Clin Oncol 2001 Dec 1;19(23):4280-90 

 
ENDOCRINE 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 18 - 
March 31, 2003, Publish Date: August 9, 2006 
Pancreatic endocrine:  
glucose intolerance 
Diabetes 
Asymptomatic, 
intervention not indicated 
Symptomatic; dietary 
modification or oral agent 
indicated 
Symptoms interfering with 
ADL; insulin indicated 
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar non-ketotic 
coma)  
Death 
Parathyroid function, low 
(hypoparathyroidism) 
Hypoparathyroidism 
Asymptomatic, 
intervention not indicated 
Symptomatic; intervention 
indicated 
— 
— 
— 
Thyroid function, high 
(hyperthyroidism, 
thyrotoxicosis) 
Hyperthyroidism  
Asymptomatic, 
intervention not indicated 
Symptomatic, not 
interfering with ADL; 
thyroid suppression 
therapy indicated 
Symptoms interfering with 
ADL; hospitalization 
indicated  
Life-threatening 
consequences (e.g., 
thyroid storm) 
Death 
Thyroid function, low 
(hypothyroidism) 
Hypothyroidism 
Asymptomatic, 
intervention not indicated 
Symptomatic, not 
interfering with ADL; 
thyroid replacement 
indicated 
Symptoms interfering with 
ADL; hospitalization 
indicated  
Life-threatening 
myxedema coma 
Death 
Endocrine – Other  
(Specify, __) 
Endocrine – Other  
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
GASTROINTESTINAL 
Page 1 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 19 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Abdominal pain or cramping is graded as Pain – Select in the PAIN CATEGORY. 
Anorexia 
Anorexia 
Loss of appetite without 
alteration in eating habits 
Oral intake altered 
without significant weight 
loss or malnutrition; oral 
nutritional supplements 
indicated 
Associated with 
significant weight loss or 
malnutrition (e.g., 
inadequate oral caloric 
and/or fluid intake); IV 
fluids, tube feedings or 
TPN indicated 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Weight loss. 
Ascites (non-malignant) 
Ascites 
Asymptomatic 
Symptomatic, medical 
intervention indicated 
Symptomatic, invasive 
procedure indicated 
Life-threatening 
consequences 
Death 
REMARK: Ascites (non-malignant) refers to documented non-malignant ascites or unknown etiology, but unlikely malignant, and includes chylous ascites. 
Colitis 
Colitis 
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain; mucus 
or blood in stool 
Abdominal pain, fever, 
change in bowel habits 
with ileus; peritoneal 
signs 
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis, toxic 
megacolon) 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select.  
Constipation 
Constipation 
Occasional or intermittent 
symptoms; occasional 
use of stool softeners, 
laxatives, dietary 
modification, or enema 
Persistent symptoms with 
regular use of laxatives 
or enemas indicated 
Symptoms interfering 
with ADL; obstipation 
with manual evacuation 
indicated  
Life-threatening 
consequences (e.g., 
obstruction, toxic 
megacolon) 
Death 
ALSO CONSIDER: Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation); Obstruction, GI – Select. 
Dehydration 
Dehydration 
Increased oral fluids 
indicated; dry mucous 
membranes; diminished 
skin turgor 
IV fluids indicated <24 
hrs 
IV fluids indicated ≥24 hrs 
Life-threatening 
consequences (e.g., 
hemodynamic collapse) 
Death 
ALSO CONSIDER: Diarrhea; Hypotension; Vomiting. 
Dental:  
dentures or prosthesis 
Dentures  
Minimal discomfort, no 
restriction in activities  
Discomfort preventing 
use in some activities 
(e.g., eating), but not 
others (e.g., speaking) 
Unable to use dentures 
or prosthesis at any time 
— 
— 

 
GASTROINTESTINAL 
Page 2 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 20 - 
March 31, 2003, Publish Date: August 9, 2006 
Dental:  
periodontal disease  
Periodontal  
Gingival recession or 
gingivitis; limited bleeding 
on probing; mild local 
bone loss 
Moderate gingival 
recession or gingivitis; 
multiple sites of bleeding 
on probing; moderate 
bone loss 
Spontaneous bleeding; 
severe bone loss with or 
without tooth loss; 
osteonecrosis of maxilla 
or mandible  
— 
— 
REMARK: Severe periodontal disease leading to osteonecrosis is graded as Osteonecrosis (avascular necrosis) in the MUSCULOSKELETAL CATEGORY. 
Dental: 
teeth  
Teeth 
Surface stains; dental 
caries; restorable, without 
extractions 
Less than full mouth 
extractions; tooth fracture 
or crown amputation or 
repair indicated 
Full mouth extractions 
indicated 
— 
— 
Dental:  
teeth development 
Teeth development 
Hypoplasia of tooth or 
enamel not interfering 
with function 
Functional impairment 
correctable with oral 
surgery 
Maldevelopment with 
functional impairment not 
surgically correctable 
— 
— 
Diarrhea 
Diarrhea 
Increase of <4 stools per 
day over baseline; mild 
increase in ostomy output 
compared to baseline 
Increase of 4 – 6 stools 
per day over baseline; IV 
fluids indicated <24hrs; 
moderate increase in 
ostomy output compared 
to baseline; not 
interfering with ADL 
Increase of ≥7 stools per 
day over baseline; 
incontinence; IV fluids 
≥24 hrs; hospitalization; 
severe increase in 
ostomy output compared 
to baseline; interfering 
with ADL 
Life-threatening 
consequences (e.g., 
hemodynamic collapse) 
Death 
REMARK: Diarrhea includes diarrhea of small bowel or colonic origin, and/or ostomy diarrhea. 
ALSO CONSIDER: Dehydration; Hypotension. 
Distension/bloating, 
abdominal 
Distension 
Asymptomatic  
Symptomatic, but not 
interfering with GI 
function 
Symptomatic, interfering 
with GI function 
— 
— 
ALSO CONSIDER: Ascites (non-malignant); Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation); Obstruction, GI – Select.  

 
GASTROINTESTINAL 
Page 3 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 21 - 
March 31, 2003, Publish Date: August 9, 2006 
Dry mouth/salivary gland 
(xerostomia) 
Dry mouth 
Symptomatic (dry or thick 
saliva) without significant 
dietary alteration; 
unstimulated saliva flow 
>0.2 ml/min 
Symptomatic and 
significant oral intake 
alteration (e.g., copious 
water, other lubricants, 
diet limited to purees 
and/or soft, moist foods); 
unstimulated saliva 
0.1 to 0.2 ml/min 
Symptoms leading to 
inability to adequately 
aliment orally; IV fluids, 
tube feedings, or TPN 
indicated; unstimulated 
saliva <0.1 ml/min 
— 
— 
REMARK: Dry mouth/salivary gland (xerostomia) includes descriptions of grade using both subjective and objective assessment parameters. Record this event consistently throughout 
a patient’s participation on study. If salivary flow measurements are used for initial assessment, subsequent assessments must use salivary flow. 
ALSO CONSIDER: Salivary gland changes/saliva.  
Dysphagia 
(difficulty swallowing) 
Dysphagia 
Symptomatic, able to eat 
regular diet  
Symptomatic and altered 
eating/swallowing (e.g., 
altered dietary habits, 
oral supplements); IV 
fluids indicated <24 hrs 
Symptomatic and 
severely altered 
eating/swallowing (e.g., 
inadequate oral caloric or 
fluid intake); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences (e.g., 
obstruction, perforation) 
 
Death 
REMARK: Dysphagia (difficulty swallowing) is to be used for swallowing difficulty from oral, pharyngeal, esophageal, or neurologic origin. Dysphagia requiring dilation is graded as 
Stricture/stenosis (including anastomotic), GI – Select. 
ALSO CONSIDER: Dehydration; Esophagitis. 
Enteritis  
(inflammation of the small 
bowel) 
Enteritis 
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain; mucus 
or blood in stool 
Abdominal pain, fever, 
change in bowel habits 
with ileus; peritoneal 
signs 
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis) 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select; Typhlitis (cecal inflammation).  
Esophagitis 
Esophagitis 
Asymptomatic pathologic, 
radiographic, or 
endoscopic findings only 
Symptomatic; altered 
eating/swallowing (e.g., 
altered dietary habits, 
oral supplements); IV 
fluids indicated <24 hrs 
Symptomatic and 
severely altered 
eating/swallowing (e.g., 
inadequate oral caloric or 
fluid intake); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences 
Death 
REMARK: Esophagitis includes reflux esophagitis.  
ALSO CONSIDER: Dysphagia (difficulty swallowing). 

 
GASTROINTESTINAL 
Page 4 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 22 - 
March 31, 2003, Publish Date: August 9, 2006 
Fistula, GI 
– Select: 
Fistula, GI – Select  
– Abdomen NOS 
– Anus 
– Biliary tree  
– Colon/cecum/appendix 
– Duodenum 
– Esophagus 
– Gallbladder  
– Ileum 
– Jejunum 
– Oral cavity 
– Pancreas 
– Pharynx 
– Rectum 
– Salivary gland  
– Small bowel NOS 
– Stomach 
Asymptomatic, 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, diarrhea, 
or GI fluid loss); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered GI 
function (e.g., altered 
dietary habits, diarrhea, 
or GI fluid loss); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences  
Death 
REMARK: A fistula is defined as an abnormal communication between two body cavities, potential spaces, and/or the skin. The site indicated for a fistula should be the site from which 
the abnormal process is believed to have originated. For example, a tracheo-esophageal fistula arising in the context of a resected or irradiated esophageal cancer is graded as 
Fistula, GI – esophagus. 
Flatulence 
Flatulence 
Mild 
Moderate 
— 
— 
— 
Gastritis (including bile 
reflux gastritis) 
Gastritis 
Asymptomatic 
radiographic or 
endoscopic findings only 
Symptomatic; altered 
gastric function (e.g., 
inadequate oral caloric or 
fluid intake); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered gastric 
function (e.g., inadequate 
oral caloric or fluid 
intake); IV fluids, tube 
feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., gastrectomy)  
Death 
ALSO CONSIDER: Hemorrhage, GI – Select; Ulcer, GI – Select. 
NAVIGATION NOTE: Head and neck soft tissue necrosis is graded as Soft tissue necrosis – Select in the MUSCULOSKELETAL/SOFT TISSUE CATEGORY. 
Heartburn/dyspepsia 
Heartburn 
Mild 
Moderate 
Severe 
— 
— 
Hemorrhoids 
Hemorrhoids 
Asymptomatic 
Symptomatic; banding or 
medical intervention 
indicated 
Interfering with ADL; 
interventional radiology, 
endoscopic, or operative 
intervention indicated 
Life-threatening 
consequences 
Death 

 
GASTROINTESTINAL 
Page 5 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 23 - 
March 31, 2003, Publish Date: August 9, 2006 
Ileus, GI (functional 
obstruction of bowel, i.e., 
neuroconstipation) 
Ileus 
Asymptomatic, 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered GI 
function; IV fluids, tube 
feeding, or TPN indicated 
≥24 hrs 
Life-threatening 
consequences 
Death 
REMARK: Ileus, GI is to be used for altered upper or lower GI function (e.g., delayed gastric or colonic emptying). 
ALSO CONSIDER: Constipation; Nausea; Obstruction, GI – Select; Vomiting. 
Incontinence, anal 
Incontinence, anal 
Occasional use of pads 
required 
Daily use of pads 
required 
Interfering with ADL; 
operative intervention 
indicated 
Permanent bowel 
diversion indicated 
Death 
REMARK: Incontinence, anal is to be used for loss of sphincter control as sequelae of operative or therapeutic intervention. 
Leak (including 
anastomotic), GI 
– Select: 
– Biliary tree 
– Esophagus 
– Large bowel 
– Leak NOS 
– Pancreas 
– Pharynx 
– Rectum 
– Small bowel  
– Stoma 
– Stomach 
Leak, GI – Select  
Asymptomatic 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and 
interfering with GI 
function; invasive or 
endoscopic intervention 
indicated  
Life-threatening 
consequences 
Death 
REMARK: Leak (including anasomotic), GI – Select is to be used for clinical signs/symptoms or radiographic confirmation of anastomotic or conduit leak (e.g., biliary, esophageal, 
intestinal, pancreatic, pharyngeal, rectal), but without development of fistula. 
Malabsorption  
Malabsorption 
— 
Altered diet; oral 
therapies indicated (e.g., 
enzymes, medications, 
dietary supplements)  
Inability to aliment 
adequately via GI tract 
(i.e., TPN indicated) 
Life-threatening 
consequences 
Death 

 
GASTROINTESTINAL 
Page 6 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 24 - 
March 31, 2003, Publish Date: August 9, 2006 
Mucositis/stomatitis 
(clinical exam)  
– Select: 
– Anus 
– Esophagus 
– Large bowel 
– Larynx 
– Oral cavity 
– Pharynx 
– Rectum 
– Small bowel 
– Stomach 
– Trachea 
Mucositis (clinical exam) 
– Select  
Erythema of the mucosa 
Patchy ulcerations or 
pseudomembranes  
Confluent ulcerations or 
pseudomembranes; 
bleeding with minor 
trauma 
Tissue necrosis; 
significant spontaneous 
bleeding; life-threatening 
consequences 
Death 
REMARK: Mucositis/stomatitis (functional/symptomatic) may be used for mucositis of the upper aero-digestive tract caused by radiation, agents, or GVHD.  
Mucositis/stomatitis 
(functional/symptomatic)  
– Select: 
– Anus 
– Esophagus 
– Large bowel 
– Larynx 
– Oral cavity 
– Pharynx 
– Rectum 
– Small bowel 
– Stomach 
– Trachea 
Mucositis (functional/ 
symptomatic) – Select  
Upper aerodigestive tract 
sites: Minimal symptoms, 
normal diet; minimal 
respiratory symptoms but 
not interfering with 
function 
Lower GI sites: 
Minimal discomfort, 
intervention not indicated 
Upper aerodigestive tract 
sites: Symptomatic but 
can eat and swallow 
modified diet; respiratory 
symptoms interfering with 
function but not 
interfering with ADL 
Lower GI sites:  
Symptomatic, medical 
intervention indicated but 
not interfering with ADL 
Upper aerodigestive tract 
sites: Symptomatic and 
unable to adequately 
aliment or hydrate orally; 
respiratory symptoms 
interfering with ADL 
Lower GI sites: 
Stool incontinence or 
other symptoms 
interfering with ADL 
Symptoms associated 
with life-threatening 
consequences  
Death 
Nausea 
Nausea 
Loss of appetite without 
alteration in eating habits 
Oral intake decreased 
without significant weight 
loss, dehydration or 
malnutrition; IV fluids 
indicated <24 hrs 
Inadequate oral caloric or 
fluid intake; IV fluids, tube 
feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Anorexia; Vomiting. 

 
GASTROINTESTINAL 
Page 7 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 25 - 
March 31, 2003, Publish Date: August 9, 2006 
Necrosis, GI 
– Select:  
Necrosis, GI – Select  
– Anus 
– Colon/cecum/appendix 
– Duodenum 
– Esophagus 
– Gallbladder 
– Hepatic 
– Ileum 
– Jejunum 
– Oral 
– Pancreas 
– Peritoneal cavity 
– Pharynx  
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
— 
— 
Inability to aliment 
adequately by GI tract 
(e.g., requiring enteral or 
parenteral nutrition); 
interventional radiology, 
endoscopic, or operative 
intervention indicated  
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., total colectomy)  
Death 
ALSO CONSIDER: Visceral arterial ischemia (non-myocardial). 
Obstruction, GI 
– Select: 
– Cecum 
– Colon 
– Duodenum 
– Esophagus 
– Gallbladder 
– Ileum 
– Jejunum 
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
Obstruction, GI – Select 
Asymptomatic 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, vomiting, 
diarrhea, or GI fluid loss); 
IV fluids indicated <24 
hrs 
Symptomatic and 
severely altered GI 
function (e.g., altered 
dietary habits, vomiting, 
diarrhea, or GI fluid loss); 
IV fluids, tube feedings, 
or TPN indicated ≥24 hrs; 
operative intervention 
indicated 
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., total colectomy)  
Death 
NAVIGATION NOTE: Operative injury is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY CATEGORY. 
NAVIGATION NOTE: Pelvic pain is graded as Pain – Select in the PAIN CATEGORY. 

 
GASTROINTESTINAL 
Page 8 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 26 - 
March 31, 2003, Publish Date: August 9, 2006 
Perforation, GI 
– Select: 
– Appendix 
– Biliary tree 
– Cecum 
– Colon 
– Duodenum 
– Esophagus 
– Gallbladder 
– Ileum 
– Jejunum 
– Rectum 
– Small bowel NOS 
– Stomach 
Perforation, GI – Select 
Asymptomatic 
radiographic findings only 
Medical intervention 
indicated; IV fluids 
indicated <24 hrs 
IV fluids, tube feedings, 
or TPN indicated ≥24 hrs; 
operative intervention 
indicated 
Life-threatening 
consequences 
Death 
Proctitis  
Proctitis 
Rectal discomfort, 
intervention not indicated 
Symptoms not interfering 
with ADL; medical 
intervention indicated  
Stool incontinence or 
other symptoms 
interfering with ADL; 
operative intervention 
indicated 
Life-threatening 
consequences (e.g., 
perforation) 
Death 
Prolapse of stoma, GI 
Prolapse of stoma, GI 
Asymptomatic  
Extraordinary local care 
or maintenance; minor 
revision indicated 
Dysfunctional stoma; 
major revision indicated  
Life-threatening 
consequences 
Death 
REMARK: Other stoma complications may be graded as Fistula, GI – Select; Leak (including anastomotic), GI – Select; Obstruction, GI – Select; Perforation, GI – Select; 
Stricture/stenosis (including anastomotic), GI – Select. 
NAVIGATION NOTE: Rectal or perirectal pain (proctalgia) is graded as Pain – Select in the PAIN CATEGORY.  
Salivary gland 
changes/saliva 
Salivary gland changes 
Slightly thickened saliva; 
slightly altered taste (e.g., 
metallic) 
Thick, ropy, sticky saliva; 
markedly altered taste; 
alteration in diet 
indicated; secretion-
induced symptoms not 
interfering with ADL 
Acute salivary gland 
necrosis; severe 
secretion-induced 
symptoms interfering with 
ADL  
Disabling 
— 
ALSO CONSIDER: Dry mouth/salivary gland (xerostomia); Mucositis/stomatitis (clinical exam) – Select; Mucositis/stomatitis (functional/symptomatic) – Select; Taste alteration 
(dysgeusia). 
NAVIGATION NOTE: Splenic function is graded in the BLOOD/BONE MARROW CATEGORY. 

 
GASTROINTESTINAL 
Page 9 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 27 - 
March 31, 2003, Publish Date: August 9, 2006 
Stricture/stenosis 
(including anastomotic), 
GI 
– Select:  
Stricture, GI – Select  
– Anus 
– Biliary tree 
– Cecum 
– Colon  
– Duodenum  
– Esophagus 
– Ileum 
– Jejunum 
– Pancreas/pancreatic duct 
– Pharynx 
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
Asymptomatic 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, vomiting, 
bleeding, diarrhea); IV 
fluids indicated <24 hrs 
Symptomatic and 
severely altered GI 
function (e.g., altered 
dietary habits, diarrhea, 
or GI fluid loss); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs; 
operative intervention 
indicated 
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., total colectomy)  
Death 
Taste alteration 
(dysgeusia) 
Taste alteration 
Altered taste but no 
change in diet 
Altered taste with change 
in diet (e.g., oral 
supplements); noxious or 
unpleasant taste; loss of 
taste 
— 
— 
— 
Typhlitis 
(cecal inflammation) 
Typhlitis 
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain; mucus 
or blood in stool 
Abdominal pain, fever, 
change in bowel habits 
with ileus; peritoneal 
signs 
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis); 
operative intervention 
indicated 
Death 
ALSO CONSIDER: Colitis; Hemorrhage, GI – Select ; Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation).  

 
GASTROINTESTINAL 
Page 10 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 28 - 
March 31, 2003, Publish Date: August 9, 2006 
Ulcer, GI 
– Select: 
– Anus 
– Cecum 
– Colon 
– Duodenum 
– Esophagus 
– Ileum 
– Jejunum 
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
Ulcer, GI – Select 
Asymptomatic, 
radiographic or 
endoscopic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, oral 
supplements); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered GI 
function (e.g., inadequate 
oral caloric or fluid 
intake); IV fluids, tube 
feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select. 
Vomiting 
Vomiting 
1 episode in 24 hrs 
2 – 5 episodes in 24 hrs; 
IV fluids indicated  
<24 hrs 
≥6 episodes in 24 hrs; IV 
fluids, or TPN indicated 
≥24 hrs 
Life-threatening 
consequences  
Death 
ALSO CONSIDER: Dehydration. 
Gastrointestinal – Other 
(Specify, __) 
GI – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling 
Death 

 
GROWTH AND DEVELOPMENT 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 29 - 
March 31, 2003, Publish Date: August 9, 2006 
Bone age 
(alteration in bone age) 
Bone age 
— 
+2 SD (standard 
deviation) from normal 
— 
— 
— 
Bone growth: 
femoral head; slipped 
capital femoral epiphysis 
Femoral head growth 
Mild valgus/varus 
deformity 
Moderate valgus/varus 
deformity, symptomatic, 
interfering with function 
but not interfering with 
ADL 
Mild slipped capital 
femoral epiphysis; 
operative intervention 
(e.g., fixation) indicated; 
interfering with ADL 
Disabling; severe slipped 
capital femoral epiphysis 
>60%; avascular necrosis 
— 
Bone growth: 
limb length discrepancy 
Limb length  
Mild length discrepancy 
<2 cm 
Moderate length 
discrepancy 2 – 5 cm; 
shoe lift indicated 
Severe length 
discrepancy >5 cm; 
operative intervention 
indicated; interfering with 
ADL 
Disabling; epiphysiodesis 
— 
Bone growth: 
spine kyphosis/lordosis 
Kyphosis/lordosis 
Mild radiographic 
changes  
Moderate accentuation; 
interfering with function 
but not interfering with 
ADL 
Severe accentuation; 
operative intervention 
indicated; interfering with 
ADL 
Disabling (e.g., cannot lift 
head) 
— 
Growth velocity 
(reduction in growth 
velocity) 
Reduction in growth 
velocity 
10 – 29% reduction in 
growth from the baseline 
growth curve 
30 – 49% reduction in 
growth from the baseline 
growth curve 
≥50% reduction in growth 
from the baseline growth 
curve  
— 
— 
Puberty (delayed) 
Delayed puberty 
— 
No breast development 
by age 13 yrs for females; 
no Tanner Stage 2 
development by age 14.5 
yrs for males 
No sexual development 
by age 14 yrs for girls, 
age 16 yrs for boys; 
hormone replacement 
indicated 
— 
— 
REMARK: Do not use testicular size for Tanner Stage in male cancer survivors. 
Puberty (precocious)  
Precocious puberty 
— 
Physical signs of puberty 
<7 years for females,  
<9 years for males 
— 
— 
— 
Short stature 
Short stature 
Beyond two standard 
deviations of age and 
gender mean height 
Altered ADL 
— 
— 
— 
REMARK: Short stature is secondary to growth hormone deficiency. 
ALSO CONSIDER: Neuroendocrine: growth hormone secretion abnormality. 
Growth and Development 
– Other (Specify, __) 
Growth and Development 
– Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
HEMORRHAGE/BLEEDING 
Page 1 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 30 - 
March 31, 2003, Publish Date: August 9, 2006 
Hematoma  
Hematoma 
Minimal symptoms, 
invasive intervention not 
indicated  
Minimally invasive 
evacuation or aspiration 
indicated 
Transfusion, 
interventional radiology, 
or operative intervention 
indicated 
Life-threatening 
consequences; major 
urgent intervention 
indicated 
Death 
REMARK: Hematoma refers to extravasation at wound or operative site or secondary to other intervention. Transfusion implies pRBC.  
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Hemorrhage/bleeding 
associated with surgery, 
intra-operative or 
postoperative 
Hemorrhage with surgery 
— 
— 
Requiring transfusion of  
2 units non-autologous 
(10 cc/kg for pediatrics) 
pRBCs beyond protocol 
specification; 
postoperative 
interventional radiology, 
endoscopic, or operative 
intervention indicated 
Life-threatening 
consequences  
Death 
REMARK: Postoperative period is defined as ≤72 hours after surgery. Verify protocol-specific acceptable guidelines regarding pRBC transfusion. 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Hemorrhage, CNS 
CNS hemorrhage 
Asymptomatic, 
radiographic findings only 
Medical intervention 
indicated  
Ventriculostomy, ICP 
monitoring, 
intraventricular 
thrombolysis, or operative 
intervention indicated 
Life-threatening 
consequences; 
neurologic deficit or 
disability 
Death 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 

 
HEMORRHAGE/BLEEDING 
Page 2 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 31 - 
March 31, 2003, Publish Date: August 9, 2006 
Hemorrhage, GI  
– Select: 
– Abdomen NOS 
– Anus 
– Biliary tree  
– Cecum/appendix  
– Colon 
– Duodenum 
– Esophagus 
– Ileum 
– Jejunum 
– Liver 
– Lower GI NOS 
– Oral cavity 
– Pancreas 
– Peritoneal cavity 
– Rectum 
– Stoma 
– Stomach 
– Upper GI NOS 
– Varices (esophageal) 
– Varices (rectal) 
Hemorrhage, GI – Select 
Mild, intervention (other 
than iron supplements) 
not indicated 
Symptomatic and medical 
intervention or minor 
cauterization indicated 
Transfusion, 
interventional radiology, 
endoscopic, or operative 
intervention indicated; 
radiation therapy (i.e., 
hemostasis of bleeding 
site) 
Life-threatening 
consequences; major 
urgent intervention 
indicated  
Death 
REMARK: Transfusion implies pRBC. 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 

 
HEMORRHAGE/BLEEDING 
Page 3 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 32 - 
March 31, 2003, Publish Date: August 9, 2006 
Hemorrhage, GU  
– Select:  
– Bladder 
– Fallopian tube 
– Kidney 
– Ovary 
– Prostate  
– Retroperitoneum  
– Spermatic cord 
– Stoma 
– Testes 
– Ureter 
– Urethra 
– Urinary NOS 
– Uterus 
– Vagina 
– Vas deferens 
Hemorrhage, GU – Select 
Minimal or microscopic 
bleeding; intervention not 
indicated 
Gross bleeding, medical 
intervention, or urinary 
tract irrigation indicated 
Transfusion, 
interventional radiology, 
endoscopic, or operative 
intervention indicated; 
radiation therapy (i.e., 
hemostasis of bleeding 
site) 
Life-threatening 
consequences; major 
urgent intervention 
indicated 
Death 
REMARK: Transfusion implies pRBC. 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Hemorrhage, pulmonary/ 
upper respiratory  
– Select: 
Hemorrhage pulmonary  
– Select 
– Bronchopulmonary NOS 
– Bronchus  
– Larynx  
– Lung  
– Mediastinum 
– Nose 
– Pharynx 
– Pleura 
– Respiratory tract NOS 
– Stoma 
– Trachea 
Mild, intervention not 
indicated 
Symptomatic and 
medical intervention 
indicated 
Transfusion, 
interventional radiology, 
endoscopic, or operative 
intervention indicated; 
radiation therapy (i.e., 
hemostasis of bleeding 
site) 
Life-threatening 
consequences; major 
urgent intervention 
indicated 
Death 
REMARK: Transfusion implies pRBC.  
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Petechiae/purpura 
(hemorrhage/bleeding 
into skin or mucosa) 
Petechiae 
Few petechiae 
Moderate petechiae; 
purpura 
Generalized petechiae or 
purpura 
— 
— 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 

 
HEMORRHAGE/BLEEDING 
Page 4 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 33 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Vitreous hemorrhage is graded in the OCULAR/VISUAL CATEGORY. 
Hemorrhage/Bleeding – 
Other (Specify, __) 
Hemorrhage – Other 
(Specify) 
Mild without transfusion 
— 
Transfusion indicated 
Catastrophic bleeding, 
requiring major non-
elective intervention 
Death 

 
HEPATOBILIARY/PANCREAS 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 34 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Biliary tree damage is graded as Fistula, GI – Select; Leak (including anastomotic), GI – Select; Necrosis, GI – Select; Obstruction, GI – Select; Perforation, GI – 
Select; Stricture/stenosis (including anastomotic), GI – Select in the GASTROINTESTINAL CATEGORY. 
Cholecystitis 
Cholecystitis 
Asymptomatic, 
radiographic findings only 
Symptomatic, medical 
intervention indicated 
Interventional radiology, 
endoscopic, or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
sepsis or perforation)  
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection 
with unknown ANC – Select.  
Liver dysfunction/failure 
(clinical)  
Liver dysfunction  
— 
Jaundice  
Asterixis 
Encephalopathy or coma 
Death 
REMARK: Jaundice is not an AE, but occurs when the liver is not working properly or when a bile duct is blocked. It is graded as a result of liver dysfunction/failure or elevated bilirubin. 
ALSO CONSIDER: Bilirubin (hyperbilirubinemia). 
Pancreas, exocrine 
enzyme deficiency 
Pancreas, exocrine 
enzyme deficiency 
— 
Increase in stool 
frequency, bulk, or odor; 
steatorrhea 
Sequelae of absorption 
deficiency (e.g., weight 
loss)  
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Diarrhea. 
Pancreatitis  
Pancreatitis 
Asymptomatic, enzyme 
elevation and/or 
radiographic findings  
Symptomatic, medical 
intervention indicated 
Interventional radiology or 
operative intervention 
indicated 
Life-threatening 
consequences 
(e.g., circulatory failure, 
hemorrhage, sepsis) 
Death 
ALSO CONSIDER: Amylase. 
NAVIGATION NOTE: Stricture (biliary tree, hepatic or pancreatic) is graded as Stricture/stenosis (including anastomotic), GI – Select in the GASTROINTESTINAL CATEGORY. 
Hepatobiliary/Pancreas – 
Other (Specify, __) 
Hepatobiliary – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
INFECTION 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 35 - 
March 31, 2003, Publish Date: August 9, 2006 
Colitis, infectious 
(e.g., Clostridium difficile) 
Colitis, infectious  
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain with 
mucus and/or blood in 
stool 
IV antibiotics or TPN 
indicated  
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis or 
toxic megacolon); 
operative resection or 
diversion indicated 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select; Typhlitis (cecal inflammation).  
Febrile neutropenia 
(fever of unknown origin 
without clinically or 
microbiologically 
documented infection) 
(ANC <1.0 x 109/L, fever 
≥38.5°C) 
Febrile neutropenia 
— 
— 
Present 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
ALSO CONSIDER: Neutrophils/granulocytes (ANC/AGC). 
Infection  
(documented clinically or 
microbiologically) with 
Grade 3 or 4 neutrophils  
(ANC <1.0 x 109/L) 
– Select  
‘Select’ AEs appear at the 
end of the CATEGORY. 
Infection (documented 
clinically) with Grade 3 or 
4 ANC – Select 
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
REMARK: Fever with Grade 3 or 4 neutrophils in the absence of documented infection is graded as Febrile neutropenia (fever of unknown origin without clinically or microbiologically 
documented infection). 
ALSO CONSIDER: Neutrophils/granulocytes (ANC/AGC). 
Infection with normal 
ANC or Grade 1 or 2 
neutrophils  
– Select  
‘Select’ AEs appear at the 
end of the CATEGORY. 
Infection with normal 
ANC – Select 
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 

 
INFECTION 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 36 - 
March 31, 2003, Publish Date: August 9, 2006 
Infection with unknown 
ANC 
– Select  
‘Select’ AEs appear at the 
end of the CATEGORY. 
Infection with unknown 
ANC – Select 
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
REMARK: Infection with unknown ANC – Select is to be used in the rare case when ANC is unknown. 
Opportunistic infection 
associated with ≥Grade 2 
Lymphopenia 
Opportunistic infection  
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
ALSO CONSIDER: Lymphopenia. 
Viral hepatitis 
Viral hepatitis 
Present; transaminases 
and liver function normal 
Transaminases 
abnormal, liver function 
normal  
Symptomatic liver 
dysfunction; fibrosis by 
biopsy; compensated 
cirrhosis 
Decompensated liver 
function (e.g., ascites, 
coagulopathy, 
encephalopathy, coma) 
Death 
REMARK: Non-viral hepatitis is graded as Infection – Select. 
ALSO CONSIDER: Albumin, serum-low (hypoalbuminemia); ALT, SGPT (serum glutamic pyruvic transaminase); AST, SGOT (serum glutamic oxaloacetic transaminase); Bilirubin 
(hyperbilirubinemia); Encephalopathy. 
Infection – Other 
(Specify, __) 
Infection – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
INFECTION – SELECT 
Page 3 of 3 
CTCAE v3.0  
- 37 - 
March 31, 2003, Publish Date: August 9, 2006 
AUDITORY/EAR 
– External ear (otitis externa) 
– Middle ear (otitis media) 
CARDIOVASCULAR 
– Artery 
– Heart (endocarditis) 
– Spleen 
– Vein 
DERMATOLOGY/SKIN  
– Lip/perioral 
– Peristomal 
– Skin (cellulitis) 
– Ungual (nails) 
GASTROINTESTINAL  
– Abdomen NOS 
– Anal/perianal 
– Appendix 
– Cecum 
– Colon 
– Dental-tooth 
– Duodenum 
– Esophagus 
– Ileum 
– Jejunum 
– Oral cavity-gums (gingivitis) 
– Peritoneal cavity 
– Rectum 
– Salivary gland 
– Small bowel NOS 
– Stomach 
GENERAL 
– Blood 
– Catheter-related 
– Foreign body (e.g., graft, implant,  
prosthesis, stent) 
– Wound  
HEPATOBILIARY/PANCREAS 
– Biliary tree 
– Gallbladder (cholecystitis) 
– Liver 
– Pancreas 
LYMPHATIC 
– Lymphatic 
MUSCULOSKELETAL 
– Bone (osteomyelitis) 
– Joint 
– Muscle (infection myositis) 
– Soft tissue NOS 
NEUROLOGY 
– Brain (encephalitis, infectious) 
– Brain + Spinal cord (encephalomyelitis) 
– Meninges (meningitis) 
– Nerve-cranial 
– Nerve-peripheral 
– Spinal cord (myelitis) 
OCULAR 
– Conjunctiva 
– Cornea 
– Eye NOS 
– Lens 
PULMONARY/UPPER RESPIRATORY 
– Bronchus 
– Larynx 
– Lung (pneumonia) 
– Mediastinum NOS 
– Mucosa 
– Neck NOS 
– Nose 
– Paranasal 
– Pharynx 
– Pleura (empyema) 
– Sinus 
– Trachea 
– Upper aerodigestive NOS 
– Upper airway NOS  
RENAL/GENITOURINARY  
– Bladder (urinary) 
– Kidney 
– Prostate 
– Ureter 
– Urethra 
– Urinary tract NOS 
SEXUAL/REPRODUCTIVE FUNCTION 
– Cervix 
– Fallopian tube 
– Pelvis NOS 
– Penis 
– Scrotum 
– Uterus 
– Vagina 
– Vulva 
 

 
LYMPHATICS 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 38 - 
March 31, 2003, Publish Date: August 9, 2006 
Chyle or lymph leakage  
Chyle or lymph leakage 
Asymptomatic, clinical or 
radiographic findings 
Symptomatic, medical 
intervention indicated  
Interventional radiology 
or operative intervention 
indicated 
Life-threatening 
complications 
Death 
ALSO CONSIDER: Chylothorax. 
Dermal change 
lymphedema, 
phlebolymphedema  
Dermal change 
Trace thickening or faint 
discoloration 
Marked discoloration; 
leathery skin texture; 
papillary formation 
— 
— 
— 
REMARK: Dermal change lymphedema, phlebolymphedema refers to changes due to venous stasis. 
ALSO CONSIDER: Ulceration.  
Edema: 
head and neck 
Edema: head and neck 
Localized to dependent 
areas, no disability or 
functional impairment 
Localized facial or neck 
edema with functional 
impairment 
Generalized facial or 
neck edema with 
functional impairment 
(e.g., difficulty in turning 
neck or opening mouth 
compared to baseline) 
Severe with ulceration or 
cerebral edema; 
tracheotomy or feeding 
tube indicated 
Death 
Edema: 
limb 
Edema: limb 
5 – 10% inter-limb 
discrepancy in volume or 
circumference at point of 
greatest visible 
difference; swelling or 
obscuration of anatomic 
architecture on close 
inspection; pitting edema 
>10 – 30% inter-limb 
discrepancy in volume or 
circumference at point of 
greatest visible 
difference; readily 
apparent obscuration of 
anatomic architecture; 
obliteration of skin folds; 
readily apparent 
deviation from normal 
anatomic contour  
>30% inter-limb 
discrepancy in volume; 
lymphorrhea; gross 
deviation from normal 
anatomic contour; 
interfering with ADL 
Progression to 
malignancy (i.e., 
lymphangiosarcoma); 
amputation indicated; 
disabling 
Death 
Edema: 
trunk/genital 
Edema: trunk/genital 
Swelling or obscuration 
of anatomic architecture 
on close inspection; 
pitting edema 
Readily apparent 
obscuration of anatomic 
architecture; obliteration 
of skin folds; readily 
apparent deviation from 
normal anatomic contour 
Lymphorrhea; interfering 
with ADL; gross deviation 
from normal anatomic 
contour 
Progression to 
malignancy (i.e., 
lymphangiosarcoma); 
disabling  
Death 
Edema: 
viscera 
Edema: viscera 
Asymptomatic; clinical or 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and unable 
to aliment adequately 
orally; interventional 
radiology or operative 
intervention indicated  
Life-threatening 
consequences 
Death 

 
LYMPHATICS 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 39 - 
March 31, 2003, Publish Date: August 9, 2006 
Lymphedema-related 
fibrosis 
Lymphedema-related 
fibrosis 
Minimal to moderate 
redundant soft tissue, 
unresponsive to elevation 
or compression, with 
moderately firm texture or 
spongy feel 
Marked increase in 
density and firmness, 
with or without tethering 
Very marked density and 
firmness with tethering 
affecting ≥40% of the 
edematous area 
— 
— 
Lymphocele 
Lymphocele 
Asymptomatic, clinical or 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and 
interventional radiology 
or operative intervention 
indicated 
— 
— 
Phlebolymphatic cording  
Phlebolymphatic cording 
Asymptomatic, clinical 
findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and leading 
to contracture or reduced 
range of motion 
— 
— 
Lymphatics – Other  
(Specify, __) 
Lymphatics – Other  
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling 
Death 

 
METABOLIC/LABORATORY 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 40 - 
March 31, 2003, Publish Date: August 9, 2006 
Acidosis  
(metabolic or respiratory) 
Acidosis  
pH <normal, but ≥7.3 
— 
pH <7.3 
pH <7.3 with life-
threatening 
consequences 
Death 
Albumin, serum-low 
(hypoalbuminemia)  
Hypoalbuminemia 
<LLN – 3 g/dL  
<LLN – 30 g/L 
<3 – 2 g/dL 
<30 – 20 g/L  
<2 g/dL  
<20 g/L 
— 
Death 
Alkaline phosphatase 
Alkaline phosphatase 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Alkalosis  
(metabolic or respiratory) 
Alkalosis 
pH >normal, but ≤7.5 
— 
pH >7.5 
pH >7.5 with life-
threatening 
consequences 
Death 
ALT, SGPT  
(serum glutamic pyruvic 
transaminase) 
ALT 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Amylase 
Amylase 
>ULN – 1.5 x ULN 
>1.5 – 2.0 x ULN 
>2.0 – 5.0 x ULN 
>5.0 x ULN 
— 
AST, SGOT 
(serum glutamic 
oxaloacetic 
transaminase) 
AST 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Bicarbonate, serum-low  
Bicarbonate, serum-low 
<LLN – 16 mmol/L 
<16 – 11 mmol/L 
<11 – 8 mmol/L 
<8 mmol/L 
Death 
Bilirubin 
(hyperbilirubinemia) 
Bilirubin 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x ULN 
>3.0 – 10.0 x ULN 
>10.0 x ULN 
— 
REMARK: Jaundice is not an AE, but may be a manifestation of liver dysfunction/failure or elevated bilirubin. If jaundice is associated with elevated bilirubin, grade bilirubin. 
Calcium, serum-low 
(hypocalcemia) 
Hypocalcemia 
<LLN – 8.0 mg/dL 
<LLN – 2.0 mmol/L 
Ionized calcium: 
<LLN – 1.0 mmol/L 
<8.0 – 7.0 mg/dL 
<2.0 – 1.75 mmol/L 
Ionized calcium: 
<1.0 – 0.9 mmol/L 
<7.0 – 6.0 mg/dL 
<1.75 – 1.5 mmol/L 
Ionized calcium: 
<0.9 – 0.8 mmol/L 
<6.0 mg/dL 
<1.5 mmol/L 
Ionized calcium: 
<0.8 mmol/L 
Death 
REMARK: Calcium can be falsely low if hypoalbuminemia is present. Serum albumin is <4.0 g/dL, hypocalcemia is reported after the following corrective calculation has been 
performed: Corrected Calcium (mg/dL) = Total Calcium (mg/dL) – 0.8 [Albumin (g/dL) – 4] 4. Alternatively, direct measurement of ionized calcium is the definitive method to diagnose 
metabolically relevant alterations in serum calcium. 
                                            
4Crit Rev Clin Lab Sci 1984;21(1):51-97 

 
METABOLIC/LABORATORY 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 41 - 
March 31, 2003, Publish Date: August 9, 2006 
Calcium, serum-high 
(hypercalcemia) 
Hypercalcemia 
>ULN – 11.5 mg/dL 
>ULN – 2.9 mmol/L 
Ionized calcium: 
>ULN – 1.5 mmol/L 
>11.5 – 12.5 mg/dL 
>2.9 – 3.1 mmol/L 
Ionized calcium: 
>1.5 – 1.6 mmol/L 
>12.5 – 13.5 mg/dL 
>3.1 – 3.4 mmol/L 
Ionized calcium: 
>1.6 – 1.8 mmol/L 
>13.5 mg/dL 
>3.4 mmol/L 
Ionized calcium: 
>1.8 mmol/L 
Death 
Cholesterol, serum-high 
(hypercholesteremia) 
Cholesterol 
>ULN – 300 mg/dL 
>ULN – 7.75 mmol/L 
>300 – 400 mg/dL 
>7.75 – 10.34 mmol/L 
>400 – 500 mg/dL 
>10.34 – 12.92 mmol/L 
>500 mg/dL 
>12.92 mmol/L 
Death 
CPK (creatine 
phosphokinase) 
CPK 
>ULN – 2.5 x ULN 
>2.5 x ULN – 5 x ULN 
>5 x ULN – 10 x ULN 
>10 x ULN 
Death 
Creatinine 
Creatinine 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x ULN 
>3.0 – 6.0 x ULN 
>6.0 x ULN 
Death 
REMARK: Adjust to age-appropriate levels for pediatric patients.  
ALSO CONSIDER: Glomerular filtration rate. 
GGT (γ-Glutamyl 
transpeptidase) 
GGT 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Glomerular filtration rate  
GFR 
<75 – 50% LLN 
<50 – 25% LLN 
<25% LLN, chronic 
dialysis not indicated 
Chronic dialysis or renal 
transplant indicated 
Death 
ALSO CONSIDER: Creatinine. 
Glucose, serum-high 
(hyperglycemia)  
Hyperglycemia 
>ULN – 160 mg/dL 
>ULN – 8.9 mmol/L 
>160 – 250 mg/dL 
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL 
>13.9 – 27.8 mmol/L 
>500 mg/dL 
>27.8 mmol/L or acidosis 
Death 
REMARK: Hyperglycemia, in general, is defined as fasting unless otherwise specified in protocol. 
Glucose, serum-low 
(hypoglycemia) 
Hypoglycemia 
<LLN – 55 mg/dL 
<LLN – 3.0 mmol/L 
<55 – 40 mg/dL 
<3.0 – 2.2 mmol/L 
<40 – 30 mg/dL 
<2.2 – 1.7 mmol/L 
<30 mg/dL 
<1.7 mmol/L 
Death 
Hemoglobinuria 
Hemoglobinuria 
Present 
— 
— 
— 
Death 
Lipase 
Lipase 
>ULN – 1.5 x ULN 
>1.5 – 2.0 x ULN 
>2.0 – 5.0 x ULN 
>5.0 x ULN 
— 
Magnesium, serum-high 
(hypermagnesemia) 
Hypermagnesemia 
>ULN – 3.0 mg/dL 
>ULN – 1.23 mmol/L 
— 
>3.0 – 8.0 mg/dL 
>1.23 – 3.30 mmol/L 
>8.0 mg/dL 
>3.30 mmol/L 
Death 
Magnesium, serum-low 
(hypomagnesemia)  
Hypomagnesemia 
<LLN – 1.2 mg/dL 
<LLN – 0.5 mmol/L 
<1.2 – 0.9 mg/dL 
<0.5 – 0.4 mmol/L 
<0.9 – 0.7 mg/dL 
<0.4 – 0.3 mmol/L 
<0.7 mg/dL 
<0.3 mmol/L 
Death 
Phosphate, serum-low 
(hypophosphatemia)  
Hypophosphatemia 
<LLN – 2.5 mg/dL 
<LLN – 0.8 mmol/L 
<2.5 – 2.0 mg/dL  
<0.8 – 0.6 mmol/L 
<2.0 – 1.0 mg/dL 
<0.6 – 0.3 mmol/L 
<1.0 mg/dL 
<0.3 mmol/L 
Death 
Potassium, serum-high 
(hyperkalemia) 
Hyperkalemia 
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L 
>6.0 – 7.0 mmol/L 
>7.0 mmol/L 
Death 

 
METABOLIC/LABORATORY 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 42 - 
March 31, 2003, Publish Date: August 9, 2006 
Potassium, serum-low 
(hypokalemia)  
Hypokalemia 
<LLN – 3.0 mmol/L 
— 
<3.0 – 2.5 mmol/L 
<2.5 mmol/L 
Death 
Proteinuria 
Proteinuria 
1+ or 
0.15 – 1.0 g/24 hrs 
2+ to 3+ or 
>1.0 – 3.5 g/24 hrs  
4+ or 
>3.5 g/24 hrs 
Nephrotic syndrome 
Death 
Sodium, serum-high 
(hypernatremia) 
Hypernatremia 
>ULN – 150 mmol/L 
>150 – 155 mmol/L 
>155 – 160 mmol/L 
>160 mmol/L 
Death 
Sodium, serum-low 
(hyponatremia) 
Hyponatremia 
<LLN – 130 mmol/L 
— 
<130 – 120 mmol/L 
<120 mmol/L 
Death 
Triglyceride, serum-high 
(hypertriglyceridemia) 
Hypertriglyceridemia 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 10 x ULN 
>10 x ULN 
Death 
Uric acid, serum-high 
(hyperuricemia) 
Hyperuricemia 
>ULN – 10 mg/dL 
≤0.59 mmol/L without 
physiologic 
consequences 
— 
>ULN – 10 mg/dL 
≤0.59 mmol/L with 
physiologic 
consequences 
>10 mg/dL 
>0.59 mmol/L 
Death 
ALSO CONSIDER: Creatinine; Potassium, serum-high (hyperkalemia); Renal failure; Tumor lysis syndrome. 
Metabolic/Laboratory – 
Other (Specify, __) 
Metabolic/Lab – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
MUSCULOSKELETAL/SOFT TISSUE 
Page 1 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 43 - 
March 31, 2003, Publish Date: August 9, 2006 
Arthritis (non-septic) 
Arthritis 
Mild pain with 
inflammation, erythema, 
or joint swelling, but not 
interfering with function 
Moderate pain with 
inflammation, erythema, 
or joint swelling 
interfering with function, 
but not interfering with 
ADL 
Severe pain with 
inflammation, erythema, 
or joint swelling and 
interfering with ADL 
Disabling 
Death 
REMARK: Report only when the diagnosis of arthritis (e.g., inflammation of a joint or a state characterized by inflammation of joints) is made. Arthralgia (sign or symptom of pain in a 
joint, especially non-inflammatory in character) is graded as Pain – Select in the PAIN CATEGORY.  
Bone: 
spine-scoliosis 
Scoliosis  
≤20 degrees; clinically 
undetectable 
>20 – 45 degrees; visible 
by forward flexion; 
interfering with function 
but not interfering with 
ADL 
>45 degrees; scapular 
prominence in forward 
flexion; operative 
intervention indicated; 
interfering with ADL 
Disabling (e.g., interfering 
with cardiopulmonary 
function) 
Death 
Cervical spine-range of 
motion 
Cervical spine ROM 
Mild restriction of rotation 
or flexion between  
60 – 70 degrees 
Rotation <60 degrees to 
right or left; <60 degrees 
of flexion 
Ankylosed/fused over 
multiple segments with 
no C-spine rotation 
— 
— 
REMARK: 60 – 65 degrees of rotation is required for reversing a car; 60 – 65 degrees of flexion is required to tie shoes. 
Exostosis 
Exostosis 
Asymptomatic 
Involving multiple sites; 
pain or interfering with 
function  
Excision indicated 
Progression to 
malignancy (i.e., 
chondrosarcoma) 
Death 
Extremity-lower 
(gait/walking) 
Gait/walking 
Limp evident only to 
trained observer and able 
to walk ≥1 kilometer; 
cane indicated for 
walking 
Noticeable limp, or 
limitation of limb function, 
but able to walk ≥0.1 
kilometer (1 city block); 
quad cane indicated for 
walking 
Severe limp with stride 
modified to maintain 
balance (widened base of 
support, marked 
reduction in step length); 
ambulation limited to 
walker; crutches 
indicated 
Unable to walk 
— 
ALSO CONSIDER: Ataxia (incoordination); Muscle weakness, generalized or specific area (not due to neuropathy) – Select.  
Extremity-upper 
(function)  
Extremity-upper 
(function) 
Able to perform most 
household or work 
activities with affected 
limb 
Able to perform most 
household or work 
activities with 
compensation from 
unaffected limb 
Interfering with ADL  
Disabling; no function of 
affected limb 
— 
Fibrosis-cosmesis 
Fibrosis-cosmesis 
Visible only on close 
examination 
Readily apparent but not 
disfiguring 
Significant disfigurement; 
operative intervention 
indicated if patient 
chooses 
— 
— 

 
MUSCULOSKELETAL/SOFT TISSUE 
Page 2 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 44 - 
March 31, 2003, Publish Date: August 9, 2006 
Fibrosis-deep connective 
tissue 
Fibrosis-deep connective 
tissue  
Increased density, 
“spongy” feel 
Increased density with 
firmness or tethering 
Increased density with 
fixation of tissue; 
operative intervention 
indicated; interfering with 
ADL 
Life-threatening; 
disabling; loss of limb; 
interfering with vital organ 
function 
Death 
ALSO CONSIDER: Induration/fibrosis (skin and subcutaneous tissue); Muscle weakness, generalized or specific area (not due to neuropathy) – Select; Neuropathy: motor; Neuropathy: 
sensory. 
Fracture 
Fracture 
Asymptomatic, 
radiographic findings only 
(e.g., asymptomatic rib 
fracture on plain x-ray, 
pelvic insufficiency 
fracture on MRI, etc.) 
Symptomatic but non-
displaced; immobilization 
indicated 
Symptomatic and 
displaced or open wound 
with bone exposure; 
operative intervention 
indicated 
Disabling; amputation 
indicated 
Death 
Joint-effusion 
Joint-effusion 
Asymptomatic, clinical or 
radiographic findings only 
Symptomatic; interfering 
with function but not 
interfering with ADL 
Symptomatic and 
interfering with ADL 
Disabling 
Death 
ALSO CONSIDER: Arthritis (non-septic). 
Joint-function5 
Joint-function 
Stiffness interfering with 
athletic activity; ≤25% 
loss of range of motion 
(ROM) 
Stiffness interfering with 
function but not 
interfering with ADL;  
>25 – 50% decrease in 
ROM 
Stiffness interfering with 
ADL; >50 – 75% 
decrease in ROM  
Fixed or non-functional 
joint (arthrodesis); 
>75% decrease in ROM 
— 
ALSO CONSIDER: Arthritis (non-septic). 
Local complication –
device/prosthesis-related 
Device/prosthesis 
Asymptomatic  
Symptomatic, but not 
interfering with ADL; local 
wound care; medical 
intervention indicated 
Symptomatic, interfering 
with ADL; operative 
intervention indicated 
(e.g., hardware/device 
replacement or removal, 
reconstruction)  
Life-threatening; 
disabling; loss of limb or 
organ 
Death 
Lumbar spine-range of 
motion 
Lumbar spine ROM 
Stiffness and difficulty 
bending to the floor to 
pick up a very light object 
but able to do activity 
Some lumbar spine 
flexion but requires a 
reaching aid to pick up a 
very light object from the 
floor 
Ankylosed/fused over 
multiple segments with 
no L-spine flexion (i.e., 
unable to reach to floor to 
pick up a very light 
— 
— 
                                            
5 Adapted from the International SFTR Method of Measuring and Recording Joint Motion, International Standard Orthopedic Measurements (ISOM), Jon J. Gerhardt and Otto A. 
Russee, Bern, Switzerland, Han Huber 9 Publisher), 1975. 

 
MUSCULOSKELETAL/SOFT TISSUE 
Page 3 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 45 - 
March 31, 2003, Publish Date: August 9, 2006 
object) 
Muscle weakness, 
generalized or specific 
area (not due to 
neuropathy)  
– Select: 
Muscle weakness  
– Select  
– Extraocular 
– Extremity-lower  
– Extremity-upper 
– Facial 
– Left-sided 
– Ocular 
– Pelvic 
– Right-sided 
– Trunk 
– Whole body/generalized  
Asymptomatic, weakness 
on physical exam 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Life-threatening; disabling 
Death 
ALSO CONSIDER: Fatigue (asthenia, lethargy, malaise). 
Muscular/skeletal 
hypoplasia 
Muscular/skeletal 
hypoplasia 
Cosmetically and 
functionally insignificant 
hypoplasia  
Deformity, hypoplasia, or 
asymmetry able to be 
remediated by prosthesis 
(e.g., shoe insert) or 
covered by clothing  
Functionally significant 
deformity, hypoplasia, or 
asymmetry, unable to be 
remediated by prosthesis 
or covered by clothing  
Disabling 
— 
Myositis 
(inflammation/damage of 
muscle) 
Myositis 
Mild pain, not interfering 
with function 
Pain interfering with 
function, but not 
interfering with ADL 
Pain interfering with ADL 
Disabling 
Death 
REMARK: Myositis implies muscle damage (i.e., elevated CPK). 
ALSO CONSIDER: CPK (creatine phosphokinase); Pain – Select. 
Osteonecrosis  
(avascular necrosis) 
Osteonecrosis 
Asymptomatic, 
radiographic findings only 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL; minimal bone 
removal indicated (i.e., 
minor sequestrectomy)  
Symptomatic and 
interfering with ADL; 
operative intervention or 
hyperbaric oxygen 
indicated 
Disabling  
Death 

 
MUSCULOSKELETAL/SOFT TISSUE 
Page 4 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 46 - 
March 31, 2003, Publish Date: August 9, 2006 
Osteoporosis6 
Osteoporosis 
Radiographic evidence of 
osteoporosis or Bone 
Mineral Density (BMD) 
t-score –1 to –2.5 
(osteopenia) and no loss 
of height or therapy 
indicated 
BMD t-score < –2.5; loss 
of height <2 cm; anti-
osteoporotic therapy 
indicated 
Fractures; loss of height 
≥2 cm 
Disabling 
Death 
Seroma 
Seroma 
Asymptomatic 
Symptomatic; medical 
intervention or simple 
aspiration indicated 
Symptomatic, 
interventional radiology 
or operative intervention 
indicated 
— 
— 
Soft tissue necrosis 
– Select: 
– Abdomen 
– Extremity-lower 
– Extremity-upper  
– Head 
– Neck 
– Pelvic 
– Thorax 
Soft tissue necrosis 
– Select 
— 
Local wound care; 
medical intervention 
indicated 
Operative debridement or 
other invasive 
intervention indicated 
(e.g., hyperbaric oxygen)  
Life-threatening 
consequences; major 
invasive intervention 
indicated (e.g., tissue 
reconstruction, flap, or 
grafting) 
Death 
Trismus (difficulty, 
restriction or pain when 
opening mouth) 
Trismus 
Decreased range of 
motion without impaired 
eating  
Decreased range of 
motion requiring small 
bites, soft foods or 
purees 
Decreased range of 
motion with inability to 
adequately aliment or 
hydrate orally 
— 
— 
NAVIGATION NOTE: Wound-infectious is graded as Infection – Select in the INFECTION CATEGORY. 
NAVIGATION NOTE: Wound non-infectious is graded as Wound complication, non-infectious in the DERMATOLOGY/SKIN CATEGORY.  
Musculoskeletal/Soft 
Tissue – Other 
(Specify, __) 
Musculoskeletal – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
                                            
6 "Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis," Report of a WHO Study Group Technical Report Series, No. 843, 1994, v + 129 
pages [C*, E, F, R, S], ISBN 92 4 120843 0, Sw.fr. 22.-/US $19.80; in developing countries: Sw.fr. 15.40, Order no. 1100843 

 
NEUROLOGY 
Page 1 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 47 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: ADD (Attention Deficit Disorder) is graded as Cognitive disturbance. 
NAVIGATION NOTE: Aphasia, receptive and/or expressive, is graded as Speech impairment (e.g., dysphasia or aphasia). 
Apnea 
Apnea 
— 
— 
Present 
Intubation indicated  
Death 
Arachnoiditis/ 
meningismus/radiculitis 
Arachnoiditis 
Symptomatic, not 
interfering with function; 
medical intervention 
indicated 
Symptomatic (e.g., 
photophobia, nausea) 
interfering with function 
but not interfering with 
ADL  
Symptomatic, interfering 
with ADL 
Life-threatening; disabling 
(e.g., paraplegia) 
Death 
ALSO CONSIDER: Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 109/L); Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select; Pain – Select; Vomiting. 
Ataxia (incoordination) 
Ataxia 
Asymptomatic  
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL; mechanical 
assistance indicated  
Disabling 
Death 
REMARK: Ataxia (incoordination) refers to the consequence of medical or operative intervention. 
Brachial plexopathy 
Brachial plexopathy 
Asymptomatic 
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
Disabling 
Death 
CNS cerebrovascular 
ischemia 
CNS ischemia 
— 
Asymptomatic, 
radiographic findings only 
Transient ischemic event 
or attack (TIA) ≤24 hrs 
duration 
Cerebral vascular 
accident (CVA, stroke), 
neurologic deficit 
>24 hrs  
Death 
NAVIGATION NOTE: CNS hemorrhage/bleeding is graded as Hemorrhage, CNS in the HEMORRHAGE/BLEEDING CATEGORY.  
CNS necrosis/cystic 
progression 
CNS necrosis 
Asymptomatic, 
radiographic findings only 
Symptomatic, not 
interfering with ADL; 
medical intervention 
indicated 
Symptomatic and 
interfering with ADL; 
hyperbaric oxygen 
indicated 
Life-threatening; 
disabling; operative 
intervention indicated to 
prevent or treat CNS 
necrosis/cystic 
progression 
Death 
Cognitive disturbance 
Cognitive disturbance 
Mild cognitive disability; 
not interfering with 
work/school/life 
performance; specialized 
educational 
services/devices not 
indicated 
Moderate cognitive 
disability; interfering with 
work/school/life 
performance but capable 
of independent living; 
specialized resources on 
part-time basis indicated 
Severe cognitive 
disability; significant 
impairment of 
work/school/life 
performance 
Unable to perform ADL; 
full-time specialized 
resources or 
institutionalization 
indicated 
Death 
REMARK: Cognitive disturbance may be used for Attention Deficit Disorder (ADD). 

 
NEUROLOGY 
Page 2 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 48 - 
March 31, 2003, Publish Date: August 9, 2006 
Confusion 
Confusion 
Transient confusion, 
disorientation, or attention 
deficit 
Confusion, disorientation, 
or attention deficit 
interfering with function, 
but not interfering with 
ADL 
Confusion or delirium 
interfering with ADL 
Harmful to others or self; 
hospitalization indicated 
Death 
REMARK: Attention Deficit Disorder (ADD) is graded as Cognitive disturbance. 
NAVIGATION NOTE: Cranial neuropathy is graded as Neuropathy-cranial – Select. 
Dizziness  
Dizziness 
With head movements or 
nystagmus only; not 
interfering with function 
Interfering with function, 
but not interfering with 
ADL 
Interfering with ADL 
Disabling 
— 
REMARK: Dizziness includes disequilibrium, lightheadedness, and vertigo. 
ALSO CONSIDER: Neuropathy: cranial – Select; Syncope (fainting). 
NAVIGATION NOTE: Dysphasia, receptive and/or expressive, is graded as Speech impairment (e.g., dysphasia or aphasia). 
Encephalopathy 
Encephalopathy 
— 
Mild signs or symptoms; 
not interfering with ADL 
Signs or symptoms 
interfering with ADL; 
hospitalization indicated 
Life-threatening; disabling 
Death 
ALSO CONSIDER: Cognitive disturbance; Confusion; Dizziness; Memory impairment; Mental status; Mood alteration – Select; Psychosis (hallucinations/delusions); 
Somnolence/depressed level of consciousness. 
Extrapyramidal/ 
involuntary movement/ 
restlessness 
Involuntary movement 
Mild involuntary 
movements not 
interfering with function 
Moderate involuntary 
movements interfering 
with function, but not 
interfering with ADL 
Severe involuntary 
movements or torticollis 
interfering with ADL 
Disabling 
 
Death 
NAVIGATION NOTE: Headache/neuropathic pain (e.g., jaw pain, neurologic pain, phantom limb pain, post-infectious neuralgia, or painful neuropathies) is graded as Pain – Select in the 
PAIN CATEGORY. 
Hydrocephalus 
Hydrocephalus 
Asymptomatic, 
radiographic findings only 
Mild to moderate 
symptoms not interfering 
with ADL 
Severe symptoms or 
neurological deficit 
interfering with ADL 
Disabling  
Death 
Irritability (children <3 
years of age) 
Irritability 
Mild; easily consolable 
Moderate; requiring 
increased attention 
Severe; inconsolable 
— 
— 
Laryngeal nerve 
dysfunction  
Laryngeal nerve 
Asymptomatic, weakness 
on clinical 
examination/testing only 
Symptomatic, but not 
interfering with ADL; 
intervention not indicated 
Symptomatic, interfering 
with ADL; intervention 
indicated (e.g., 
thyroplasty, vocal cord 
injection) 
Life-threatening; 
tracheostomy indicated 
 
Death 

 
NEUROLOGY 
Page 3 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 49 - 
March 31, 2003, Publish Date: August 9, 2006 
Leak, cerebrospinal fluid 
(CSF) 
CSF leak 
Transient headache; 
postural care indicated 
Symptomatic, not 
interfering with ADL; 
blood patch indicated 
Symptomatic, interfering 
with ADL; operative 
intervention indicated 
Life-threatening; disabling 
Death 
REMARK: Leak, cerebrospinal fluid (CSF) may be used for CSF leak associated with operation and persisting >72 hours. 
Leukoencephalopathy 
(radiographic findings) 
Leukoencephalopathy  
Mild increase in 
subarachnoid space 
(SAS); mild 
ventriculomegaly; small 
(+/- multiple) focal T2 
hyperintensities, involving 
periventricular white 
matter or <1/3 of 
susceptible areas of 
cerebrum 
Moderate increase in 
SAS; moderate 
ventriculomegaly; focal 
T2 hyperintensities 
extending into centrum 
ovale or involving 1/3 to 
2/3 of susceptible areas 
of cerebrum 
Severe increase in SAS; 
severe ventriculomegaly; 
near total white matter T2 
hyperintensities or diffuse 
low attenuation (CT) 
— 
— 
REMARK: Leukoencephalopathy is a diffuse white matter process, specifically NOT associated with necrosis. Leukoencephalopathy (radiographic findings) does not include lacunas, 
which are areas that become void of neural tissue.  
Memory impairment 
Memory impairment 
Memory impairment not 
interfering with function 
Memory impairment 
interfering with function, 
but not interfering with 
ADL 
Memory impairment 
interfering with ADL 
Amnesia 
— 
Mental status7 
Mental status 
— 
1 – 3 point below age  
and educational norm in 
Folstein Mini-Mental 
Status Exam (MMSE) 
>3 point below age and 
educational norm in 
Folstein MMSE  
— 
— 
Mood alteration  
– Select: 
– Agitation 
– Anxiety 
– Depression 
– Euphoria 
Mood alteration – Select 
Mild mood alteration not 
interfering with function 
Moderate mood alteration 
interfering with function, 
but not interfering with 
ADL; medication 
indicated 
Severe mood alteration 
interfering with ADL 
Suicidal ideation; danger 
to self or others 
Death 
Myelitis 
Myelitis 
Asymptomatic, mild signs 
(e.g., Babinski’s or 
Lhermitte’s sign) 
Weakness or sensory 
loss not interfering with 
ADL 
Weakness or sensory 
loss interfering with ADL 
Disabling 
Death 
                                            
7 Folstein MF, Folstein, SE and McHugh PR (1975) "Mini-Mental State: A Practical Method for Grading the State of Patients for the Clinician," Journal of Psychiatric Research, 12: 
189-198 

 
NEUROLOGY 
Page 4 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 50 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Neuropathic pain is graded as Pain – Select in the PAIN CATEGORY.  
Neuropathy: 
cranial  
– Select: 
Neuropathy: cranial  
– Select 
Asymptomatic, detected 
on exam/testing only 
– CN I  
Smell 
– CN II  Vision 
– CN III  Pupil, upper eyelid, extra ocular movements 
– CN IV  Downward, inward movement of eye 
– CN V  Motor-jaw muscles; Sensory-facial 
– CN VI  Lateral deviation of eye 
– CN VII Motor-face; Sensory-taste 
– CN VIII Hearing and balance 
– CN IX Motor-pharynx; Sensory-ear, pharynx, tongue 
– CN X 
Motor-palate; pharynx, larynx 
– CN XI Motor-sternomastoid and trapezius 
– CN XII Motor-tongue 
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
Life-threatening; disabling 
Death 
Neuropathy: 
motor  
Neuropathy-motor 
Asymptomatic, weakness 
on exam/testing only 
Symptomatic weakness 
interfering with function, 
but not interfering with 
ADL 
Weakness interfering with 
ADL; bracing or 
assistance to walk (e.g., 
cane or walker) indicated 
Life-threatening; disabling 
(e.g., paralysis)  
Death 
REMARK: Cranial nerve motor neuropathy is graded as Neuropathy: cranial – Select. 
ALSO CONSIDER: Laryngeal nerve dysfunction; Phrenic nerve dysfunction.  
Neuropathy: 
sensory 
Neuropathy-sensory 
Asymptomatic; loss of 
deep tendon reflexes or 
paresthesia (including 
tingling) but not 
interfering with function 
Sensory alteration or 
paresthesia (including 
tingling), interfering with 
function, but not 
interfering with ADL 
Sensory alteration or 
paresthesia interfering 
with ADL  
Disabling  
Death 
REMARK: Cranial nerve sensory neuropathy is graded as Neuropathy: cranial – Select. 
Personality/behavioral 
Personality 
Change, but not 
adversely affecting 
patient or family 
Change, adversely 
affecting patient or family  
Mental health intervention 
indicated 
Change harmful to others 
or self; hospitalization 
indicated 
Death 
Phrenic nerve dysfunction  Phrenic nerve 
Asymptomatic weakness 
on exam/testing only 
Symptomatic but not 
interfering with ADL; 
intervention not indicated 
Significant dysfunction; 
intervention indicated 
(e.g., diaphragmatic 
plication) 
Life-threatening 
respiratory compromise; 
mechanical ventilation 
indicated 
Death 
Psychosis (hallucinations/ 
delusions) 
Psychosis 
— 
Transient episode 
Interfering with ADL; 
medication, supervision 
Harmful to others or self; 
life-threatening 
Death 

 
NEUROLOGY 
Page 5 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 51 - 
March 31, 2003, Publish Date: August 9, 2006 
or restraints indicated  
consequences 
Pyramidal tract 
dysfunction (e.g., ↑ tone, 
hyperreflexia, positive 
Babinski, ↓ fine motor 
coordination) 
Pyramidal tract 
dysfunction 
Asymptomatic, 
abnormality on exam or 
testing only  
Symptomatic; interfering 
with function but not 
interfering with ADL 
Interfering with ADL 
Disabling; paralysis 
Death 
Seizure 
Seizure 
— 
One brief generalized 
seizure; seizure(s) well 
controlled by 
anticonvulsants or 
infrequent focal motor 
seizures not interfering 
with ADL 
Seizures in which 
consciousness is altered; 
poorly controlled seizure 
disorder, with 
breakthrough generalized 
seizures despite medical 
intervention 
Seizures of any kind 
which are prolonged, 
repetitive, or difficult to 
control (e.g., status 
epilepticus, intractable 
epilepsy) 
Death 
Somnolence/depressed 
level of consciousness 
Somnolence 
— 
Somnolence or sedation 
interfering with function, 
but not interfering with 
ADL 
Obtundation or stupor; 
difficult to arouse; 
interfering with ADL 
Coma 
Death 
Speech impairment  
(e.g., dysphasia or 
aphasia)  
Speech impairment 
— 
Awareness of receptive 
or expressive dysphasia, 
not impairing ability to 
communicate 
Receptive or expressive 
dysphasia, impairing 
ability to communicate 
Inability to communicate 
— 
REMARK: Speech impairment refers to a primary CNS process, not neuropathy or end organ dysfunction. 
ALSO CONSIDER: Laryngeal nerve dysfunction; Voice changes/dysarthria (e.g., hoarseness, loss, or alteration in voice, laryngitis). 
Syncope (fainting) 
Syncope (fainting) 
— 
— 
Present 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: CNS cerebrovascular ischemia; Conduction abnormality/atrioventricular heart block – Select; Dizziness; Supraventricular and nodal arrhythmia – Select; Vasovagal 
episode; Ventricular arrhythmia – Select. 
NAVIGATION NOTE: Taste alteration (CN VII, IX) is graded as Taste alteration (dysgeusia) in the GASTROINTESTINAL CATEGORY. 
Tremor 
Tremor 
Mild and brief or 
intermittent but not 
interfering with function 
Moderate tremor 
interfering with function, 
but not interfering with 
ADL 
Severe tremor interfering 
with ADL 
Disabling 
— 
Neurology – Other 
(Specify, __) 
Neurology – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
OCULAR/VISUAL 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 52 - 
March 31, 2003, Publish Date: August 9, 2006 
Cataract 
Cataract 
Asymptomatic, detected 
on exam only  
Symptomatic, with 
moderate decrease in 
visual acuity  
(20/40 or better); 
decreased visual function 
correctable with glasses  
Symptomatic with marked 
decrease in visual acuity 
(worse than 20/40); 
operative intervention 
indicated (e.g., cataract 
surgery) 
— 
— 
Dry eye syndrome  
Dry eye 
Mild, intervention not 
indicated 
Symptomatic, interfering 
with function but not 
interfering with ADL; 
medical intervention 
indicated  
Symptomatic or decrease 
in visual acuity interfering 
with ADL; operative 
intervention indicated 
— 
— 
Eyelid dysfunction  
Eyelid dysfunction 
Asymptomatic  
Symptomatic, interfering 
with function but not ADL; 
requiring topical agents or 
epilation 
Symptomatic; interfering 
with ADL; surgical 
intervention indicated 
— 
— 
REMARK: Eyelid dysfunction includes canalicular stenosis, ectropion, entropion, erythema, madarosis, symblepharon, telangiectasis, thickening, and trichiasis. 
ALSO CONSIDER: Neuropathy: cranial – Select. 
Glaucoma  
Glaucoma 
Elevated intraocular 
pressure (EIOP) with 
single topical agent for 
intervention; no visual 
field deficit 
EIOP causing early visual 
field deficit (i.e., nasal 
step or arcuate deficit); 
multiple topical or oral 
agents indicated 
EIOP causing marked 
visual field deficits (i.e., 
involving both superior 
and inferior visual fields); 
operative intervention 
indicated 
EIOP resulting in 
blindness (20/200 or 
worse); enucleation 
indicated 
— 
Keratitis (corneal 
inflammation/corneal 
ulceration) 
Keratitis 
Abnormal ophthalmologic 
changes only; 
intervention not indicated 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL; 
operative intervention 
indicated 
Perforation or blindness 
(20/200 or worse)  
— 
NAVIGATION NOTE: Ocular muscle weakness is graded as Muscle weakness, generalized or specific area (not due to neuropathy) – Select in the MUSCULOSKELETAL/SOFT TISSUE 
CATEGORY.  
Night blindness 
(nyctalopia) 
Nyctalopia 
Symptomatic, not 
interfering with function 
Symptomatic and 
interfering with function 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL  
Disabling 
— 

 
OCULAR/VISUAL 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 53 - 
March 31, 2003, Publish Date: August 9, 2006 
Nystagmus 
Nystagmus 
Asymptomatic 
Symptomatic and 
interfering with function 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
ALSO CONSIDER: Neuropathy: cranial – Select; Ophthalmoplegia/diplopia (double vision). 
Ocular surface disease  
Ocular surface disease  
Asymptomatic or 
minimally symptomatic 
but not interfering with 
function 
Symptomatic, interfering 
with function but not 
interfering with ADL; 
topical antibiotics or other 
topical intervention 
indicated 
Symptomatic, interfering 
with ADL; operative 
intervention indicated 
— 
— 
REMARK: Ocular surface disease includes conjunctivitis, keratoconjunctivitis sicca, chemosis, keratinization, and palpebral conjunctival epithelial metaplasia. 
Ophthalmoplegia/ 
diplopia (double vision) 
Diplopia 
Intermittently 
symptomatic, intervention 
not indicated 
Symptomatic and 
interfering with function 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL; 
surgical intervention 
indicated 
Disabling 
— 
ALSO CONSIDER: Neuropathy: cranial – Select. 
Optic disc edema 
Optic disc edema 
Asymptomatic 
Decreased visual acuity 
(20/40 or better); visual 
field defect present 
Decreased visual acuity 
(worse than 20/40); 
marked visual field defect 
but sparing the central 20 
degrees 
Blindness  
(20/200 or worse) 
— 
ALSO CONSIDER: Neuropathy: cranial – Select.  
Proptosis/enophthalmos 
Proptosis/enophthalmos 
Asymptomatic, 
intervention not indicated 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
— 
— 
Retinal detachment 
Retinal detachment 
Exudative; no central 
vision loss; intervention 
not indicated 
Exudative and visual 
acuity 20/40 or better but 
intervention not indicated 
Rhegmatogenous or 
exudative detachment; 
operative intervention 
indicated 
Blindness 
(20/200 or worse) 
— 
Retinopathy  
Retinopathy 
Asymptomatic  
Symptomatic with 
moderate decrease in 
visual acuity 
(20/40 or better) 
Symptomatic with marked 
decrease in visual acuity 
(worse than 20/40) 
Blindness 
(20/200 or worse) 
— 

 
OCULAR/VISUAL 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 54 - 
March 31, 2003, Publish Date: August 9, 2006 
Scleral necrosis/melt 
Scleral necrosis 
Asymptomatic or 
symptomatic but not 
interfering with function 
Symptomatic, interfering 
with function but not 
interfering with ADL; 
moderate decrease in 
visual acuity (20/40 or 
better); medical 
intervention indicated 
Symptomatic, interfering 
with ADL; marked 
decrease in visual acuity 
(worse than 20/40); 
operative intervention 
indicated 
Blindness (20/200 or 
worse); painful eye with 
enucleation indicated 
— 
Uveitis  
Uveitis 
Asymptomatic 
Anterior uveitis; medical 
intervention indicated 
Posterior or pan-uveitis; 
operative intervention 
indicated 
Blindness 
(20/200 or worse) 
— 
Vision-blurred vision 
Blurred vision 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
Vision-flashing 
lights/floaters 
Flashing lights 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
Vision-photophobia 
Photophobia 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
Vitreous hemorrhage 
Vitreous hemorrhage 
Asymptomatic, clinical 
findings only 
Symptomatic, interfering 
with function, but not 
interfering with ADL; 
intervention not indicated 
Symptomatic, interfering 
with ADL; vitrectomy 
indicated  
— 
— 
Watery eye (epiphora, 
tearing) 
Watery eye 
Symptomatic, intervention 
not indicated 
Symptomatic, interfering 
with function but not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
— 
— 
Ocular/Visual – Other  
(Specify, __) 
Ocular – Other  
(Specify) 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Blindness 
(20/200 or worse) 
Death 

 
PAIN 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 55 - 
March 31, 2003, Publish Date: August 9, 2006 
Pain  
– Select: 
‘Select’ AEs appear at the 
end of the CATEGORY. 
Pain – Select  
Mild pain not interfering 
with function 
Moderate pain; pain or 
analgesics interfering with 
function, but not 
interfering with ADL 
Severe pain; pain or 
analgesics severely 
interfering with ADL 
Disabling 
— 
Pain – Other 
(Specify, __) 
Pain – Other (Specify) 
Mild pain not interfering 
with function 
Moderate pain; pain or 
analgesics interfering with 
function, but not 
interfering with ADL 
Severe pain; pain or 
analgesics severely 
interfering with ADL 
Disabling 
— 
PAIN – SELECT 
AUDITORY/EAR 
– External ear 
– Middle ear 
CARDIOVASCULAR 
– Cardiac/heart  
– Pericardium 
DERMATOLOGY/SKIN 
– Face 
– Lip 
– Oral-gums 
– Scalp 
– Skin 
GASTROINTESTINAL 
– Abdomen NOS 
– Anus 
– Dental/teeth/peridontal 
– Esophagus 
– Oral cavity 
– Peritoneum 
– Rectum 
– Stomach 
GENERAL 
– Pain NOS 
– Tumor pain  
HEPATOBILIARY/PANCREAS 
– Gallbladder 
– Liver  
LYMPHATIC 
– Lymph node 
MUSCULOSKELETAL 
– Back 
– Bone 
– Buttock 
– Extremity-limb 
– Intestine 
– Joint 
– Muscle 
– Neck 
– Phantom (pain associated with missing limb) 
NEUROLOGY 
– Head/headache 
– Neuralgia/peripheral nerve 
OCULAR 
– Eye 
PULMONARY/UPPER RESPIRATORY 
– Chest wall 
– Chest/thorax NOS 
PULMONARY/UPPER RESPIRATORY (continued) 
– Larynx 
– Pleura 
– Sinus 
– Throat/pharynx/larynx 
RENAL/GENITOURINARY 
– Bladder 
– Kidney 
SEXUAL/REPRODUCTIVE FUNCTION 
– Breast 
– Ovulatory 
– Pelvis 
– Penis 
– Perineum 
– Prostate 
– Scrotum 
– Testicle 
– Urethra 
– Uterus 
– Vagina 
 
 

 
PULMONARY/UPPER RESPIRATORY 
Page 1 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 56 - 
March 31, 2003, Publish Date: August 9, 2006 
Adult Respiratory 
Distress Syndrome 
(ARDS) 
ARDS 
— 
— 
Present, intubation not 
indicated  
Present, intubation 
indicated 
Death 
ALSO CONSIDER: Dyspnea (shortness of breath); Hypoxia; Pneumonitis/pulmonary infiltrates. 
Aspiration 
Aspiration 
Asymptomatic (“silent 
aspiration”); endoscopy 
or radiographic (e.g., 
barium swallow) findings  
Symptomatic (e.g., 
altered eating habits, 
coughing or choking 
episodes consistent with 
aspiration); medical 
intervention indicated 
(e.g., antibiotics, suction 
or oxygen) 
Clinical or radiographic 
signs of pneumonia or 
pneumonitis; unable to 
aliment orally 
Life-threatening (e.g., 
aspiration pneumonia or 
pneumonitis)  
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils 
– Select; Infection with unknown ANC – Select; Laryngeal nerve dysfunction; Neuropathy: cranial – Select; Pneumonitis/pulmonary infiltrates. 
Atelectasis  
Atelectasis  
Asymptomatic  
Symptomatic (e.g., 
dyspnea, cough), medical 
intervention indicated 
(e.g., bronchoscopic 
suctioning, chest 
physiotherapy, 
suctioning)  
Operative (e.g., stent, 
laser) intervention 
indicated  
Life-threatening 
respiratory compromise 
Death 
ALSO CONSIDER: Adult Respiratory Distress Syndrome (ARDS); Cough; Dyspnea (shortness of breath); Hypoxia; Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select; Obstruction/stenosis of airway – 
Select; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes). 
Bronchospasm, 
wheezing  
Bronchospasm 
Asymptomatic  
Symptomatic not 
interfering with function 
Symptomatic interfering 
with function 
Life-threatening 
Death 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever); Dyspnea (shortness of breath).  
Carbon monoxide 
diffusion capacity (DLCO) 
DLCO 
90 – 75% of predicted 
value 
<75 – 50% of predicted 
value 
<50 – 25% of predicted 
value 
<25% of predicted value 
Death 
ALSO CONSIDER: Hypoxia; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes). 
Chylothorax  
Chylothorax 
Asymptomatic 
Symptomatic; 
thoracentesis or tube 
drainage indicated  
Operative intervention 
indicated 
Life-threatening (e.g., 
hemodynamic instability 
or ventilatory support 
indicated) 
Death 
Cough 
Cough 
Symptomatic, non-
narcotic medication only 
indicated  
Symptomatic and 
narcotic medication 
indicated  
Symptomatic and 
significantly interfering 
with sleep or ADL 
— 
— 

 
PULMONARY/UPPER RESPIRATORY 
Page 2 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 57 - 
March 31, 2003, Publish Date: August 9, 2006 
Dyspnea (shortness of 
breath)  
Dyspnea  
Dyspnea on exertion, but 
can walk 1 flight of stairs 
without stopping 
Dyspnea on exertion but 
unable to walk 1 flight of 
stairs or 1 city block 
(0.1km) without stopping 
Dyspnea with ADL 
Dyspnea at rest; 
intubation/ventilator 
indicated  
Death 
ALSO CONSIDER: Hypoxia; Neuropathy: motor; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes). 
Edema, larynx  
Edema, larynx 
Asymptomatic edema by 
exam only 
Symptomatic edema, no 
respiratory distress  
Stridor; respiratory 
distress; interfering with 
ADL 
Life-threatening airway 
compromise; 
tracheotomy, intubation, 
or laryngectomy indicated 
Death 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever). 
FEV1  
FEV1 
90 – 75% of predicted 
value 
<75 – 50% of predicted 
value 
<50 – 25% of predicted 
value 
<25% of predicted 
Death 
Fistula, pulmonary/upper 
respiratory  
– Select: 
– Bronchus 
– Larynx 
– Lung 
– Oral cavity 
– Pharynx  
– Pleura 
– Trachea 
Fistula, pulmonary  
– Select  
Asymptomatic, 
radiographic findings only 
Symptomatic, tube 
thoracostomy or medical 
management indicated; 
associated with altered 
respiratory function but 
not interfering with ADL 
Symptomatic and 
associated with altered 
respiratory function 
interfering with ADL; or 
endoscopic (e.g., stent) 
or primary closure by 
operative intervention 
indicated 
Life-threatening 
consequences; operative 
intervention with 
thoracoplasty, chronic 
open drainage or multiple 
thoracotomies indicated 
Death 
REMARK: A fistula is defined as an abnormal communication between two body cavities, potential spaces, and/or the skin. The site indicated for a fistula should be the site from which 
the abnormal process is believed to have arisen. For example, a tracheo-esophageal fistula arising in the context of a resected or irradiated esophageal cancer should be graded as 
Fistula, GI – esophagus in the GASTROINTESTINAL CATEGORY. 
NAVIGATION NOTE: Hemoptysis is graded as Hemorrhage, pulmonary/upper respiratory – Select in the HEMORRHAGE/BLEEDING CATEGORY.  
Hiccoughs (hiccups, 
singultus) 
Hiccoughs 
Symptomatic, 
intervention not indicated 
Symptomatic, 
intervention indicated  
Symptomatic, 
significantly interfering 
with sleep or ADL 
— 
— 
Hypoxia 
Hypoxia 
— 
Decreased O2 saturation 
with exercise (e.g., pulse 
oximeter <88%); 
intermittent supplemental 
oxygen  
Decreased O2 saturation 
at rest; continuous 
oxygen indicated 
Life-threatening; 
intubation or ventilation 
indicated  
Death 

 
PULMONARY/UPPER RESPIRATORY 
Page 3 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 58 - 
March 31, 2003, Publish Date: August 9, 2006 
Nasal cavity/paranasal 
sinus reactions 
Nasal/paranasal 
reactions 
Asymptomatic mucosal 
crusting, blood-tinged 
secretions 
Symptomatic stenosis or 
edema/narrowing 
interfering with airflow 
Stenosis with significant 
nasal obstruction; 
interfering with ADL 
Necrosis of soft tissue or 
bone 
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils 
– Select; Infection with unknown ANC – Select. 
Obstruction/stenosis of 
airway 
– Select: 
– Bronchus 
– Larynx 
– Pharynx 
– Trachea 
Airway obstruction  
– Select  
Asymptomatic obstruction 
or stenosis on exam, 
endoscopy, or radiograph 
Symptomatic (e.g., noisy 
airway breathing), but 
causing no respiratory 
distress; medical 
management indicated 
(e.g., steroids)  
Interfering with ADL; 
stridor or endoscopic 
intervention indicated 
(e.g., stent, laser)  
Life-threatening airway 
compromise; tracheotomy 
or intubation indicated 
Death 
Pleural effusion 
(non-malignant)  
Pleural effusion 
Asymptomatic 
Symptomatic, 
intervention such as 
diuretics or up to 2 
therapeutic 
thoracenteses indicated 
Symptomatic and 
supplemental oxygen,  
>2 therapeutic 
thoracenteses, tube 
drainage, or pleurodesis 
indicated 
Life-threatening (e.g., 
causing hemodynamic 
instability or ventilatory 
support indicated)  
Death 
ALSO CONSIDER: Atelectasis; Cough; Dyspnea (shortness of breath); Hypoxia; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes).  
NAVIGATION NOTE: Pleuritic pain is graded as Pain – Select in the PAIN CATEGORY. 
Pneumonitis/pulmonary 
infiltrates  
Pneumonitis 
Asymptomatic, 
radiographic findings only 
Symptomatic, not 
interfering with ADL  
Symptomatic, interfering 
with ADL; O2 indicated  
Life-threatening; 
ventilatory support 
indicated 
Death 
ALSO CONSIDER: Adult Respiratory Distress Syndrome (ARDS); Cough; Dyspnea (shortness of breath); Hypoxia; Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select; Pneumonitis/pulmonary infiltrates; 
Pulmonary fibrosis (radiographic changes). 
Pneumothorax  
Pneumothorax  
Asymptomatic, 
radiographic findings only 
Symptomatic; 
intervention indicated 
(e.g., hospitalization for 
observation, tube 
placement without 
sclerosis) 
Sclerosis and/or 
operative intervention 
indicated 
Life-threatening, causing 
hemodynamic instability 
(e.g., tension 
pneumothorax); 
ventilatory support 
indicated 
Death 
Prolonged chest tube 
drainage or air leak after 
pulmonary resection 
Chest tube drainage or 
leak 
— 
Sclerosis or additional 
tube thoracostomy 
indicated 
Operative intervention 
indicated (e.g., 
thoracotomy with stapling 
or sealant application) 
Life-threatening; 
debilitating; organ 
resection indicated 
Death 

 
PULMONARY/UPPER RESPIRATORY 
Page 4 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 59 - 
March 31, 2003, Publish Date: August 9, 2006 
Prolonged intubation 
after pulmonary resection 
(>24 hrs after surgery)  
Prolonged intubation 
— 
Extubated within  
24 – 72 hrs 
postoperatively 
Extubated >72 hrs 
postoperatively, but 
before tracheostomy 
indicated 
Tracheostomy indicated 
Death 
NAVIGATION NOTE: Pulmonary embolism is graded as Grade 4 either as Thrombosis/embolism (vascular access-related) or Thrombosis/thrombus/embolism in the VASCULAR 
CATEGORY.  
Pulmonary fibrosis 
(radiographic changes)  
Pulmonary fibrosis 
Minimal radiographic 
findings (or patchy or bi-
basilar changes) with 
estimated radiographic 
proportion of total lung 
volume that is fibrotic of 
<25% 
Patchy or bi-basilar 
changes with estimated 
radiographic proportion of 
total lung volume that is 
fibrotic of 25 – <50% 
Dense or widespread 
infiltrates/consolidation 
with estimated 
radiographic proportion of 
total lung volume that is 
fibrotic of 50 – <75% 
Estimated radiographic 
proportion of total lung 
volume that is fibrotic is 
≥75%; honeycombing 
Death 
REMARK: Fibrosis is usually a “late effect” seen >3 months after radiation or combined modality therapy (including surgery). It is thought to represent scar/fibrotic lung tissue. It may be 
difficult to distinguish from pneumonitis that is generally seen within 3 months of radiation or combined modality therapy.  
ALSO CONSIDER: Adult Respiratory Distress Syndrome (ARDS); Cough; Dyspnea (shortness of breath); Hypoxia; Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select. 
NAVIGATION NOTE: Recurrent laryngeal nerve dysfunction is graded as Laryngeal nerve dysfunction in the NEUROLOGY CATEGORY. 
Vital capacity  
Vital capacity 
90 – 75% of predicted 
value 
<75 – 50% of predicted 
value 
<50 – 25% of predicted 
value 
<25% of predicted value 
Death 
Voice changes/dysarthria 
(e.g., hoarseness, loss or 
alteration in voice, 
laryngitis)  
Voice changes  
Mild or intermittent 
hoarseness or voice 
change, but fully 
understandable 
Moderate or persistent 
voice changes, may 
require occasional 
repetition but 
understandable on 
telephone 
Severe voice changes 
including predominantly 
whispered speech; may 
require frequent repetition 
or face-to-face contact for 
understandability; 
requires voice aid (e.g., 
electrolarynx) for ≤50% of 
communication 
Disabling; 
non-understandable voice 
or aphonic; requires voice 
aid (e.g., electrolarynx) 
for >50% of 
communication or 
requires >50% written 
communication 
Death 
ALSO CONSIDER: Laryngeal nerve dysfunction; Speech impairment (e.g., dysphasia or aphasia). 
Pulmonary/Upper 
Respiratory – Other 
(Specify, __) 
Pulmonary – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling 
Death 

 
RENAL/GENITOURINARY 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 60 - 
March 31, 2003, Publish Date: August 9, 2006 
Bladder spasms 
Bladder spasms 
Symptomatic, intervention 
not indicated 
Symptomatic, 
antispasmodics indicated 
Narcotics indicated 
Major surgical 
intervention indicated 
(e.g., cystectomy) 
— 
Cystitis 
Cystitis 
Asymptomatic 
Frequency with dysuria; 
macroscopic hematuria 
Transfusion; IV pain 
medications; bladder 
irrigation indicated 
Catastrophic bleeding; 
major non-elective 
intervention indicated 
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils 
– Select; Infection with unknown ANC – Select; Pain – Select. 
Fistula, GU 
– Select:  
– Bladder 
– Genital tract-female 
– Kidney 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
Fistula, GU – Select  
Asymptomatic, 
radiographic findings only 
Symptomatic; 
noninvasive intervention 
indicated  
Symptomatic interfering 
with ADL; invasive 
intervention indicated  
Life-threatening 
consequences; operative 
intervention requiring 
partial or full organ 
resection; permanent 
urinary diversion  
Death 
REMARK: A fistula is defined as an abnormal communication between two body cavities, potential spaces, and/or the skin. The site indicated for a fistula should be the site from which 
the abnormal process is believed to have originated. 
Incontinence, urinary  
Incontinence, urinary 
Occasional (e.g., with 
coughing, sneezing, etc.), 
pads not indicated 
Spontaneous, pads 
indicated  
Interfering with ADL; 
intervention indicated 
(e.g., clamp, collagen 
injections) 
Operative intervention 
indicated (e.g., 
cystectomy or permanent 
urinary diversion) 
— 
Leak (including 
anastomotic), GU 
– Select: 
– Bladder 
– Fallopian tube  
– Kidney 
– Spermatic cord 
– Stoma 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Leak, GU – Select  
Asymptomatic, 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic, interfering 
with GU function; invasive 
or endoscopic 
intervention indicated 
Life-threatening 
Death 
REMARK: Leak (including anastomotic), GU – Select refers to clinical signs and symptoms or radiographic confirmation of anastomotic leak but without development of fistula. 

 
RENAL/GENITOURINARY 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 61 - 
March 31, 2003, Publish Date: August 9, 2006 
Obstruction, GU  
– Select: 
– Bladder 
– Fallopian tube 
– Prostate 
– Spermatic cord 
– Stoma 
– Testes 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Obstruction, GU – Select  
Asymptomatic, 
radiographic or 
endoscopic findings only 
Symptomatic but no 
hydronephrosis, sepsis or 
renal dysfunction; dilation 
or endoscopic repair or 
stent placement indicated 
Symptomatic and altered 
organ function (e.g., 
sepsis or hydronephrosis, 
or renal dysfunction); 
operative intervention 
indicated  
Life-threatening 
consequences; organ 
failure or operative 
intervention requiring 
complete organ resection 
indicated  
Death 
NAVIGATION NOTE: Operative injury is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY CATEGORY.  
Perforation, GU  
– Select: 
– Bladder 
– Fallopian tube 
– Kidney  
– Ovary 
– Prostate 
– Spermatic cord 
– Stoma 
– Testes 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Perforation, GU – Select 
Asymptomatic 
radiographic findings only 
Symptomatic, associated 
with altered renal/GU 
function 
Symptomatic, operative 
intervention indicated 
Life-threatening 
consequences or organ 
failure; operative 
intervention requiring 
organ resection indicated 
Death 
Prolapse of stoma, GU 
Prolapse stoma, GU 
Asymptomatic; special 
intervention, 
extraordinary care not 
indicated 
Extraordinary local care 
or maintenance; minor 
revision under local 
anesthesia indicated 
Dysfunctional stoma; 
operative intervention or 
major stomal revision 
indicated 
Life-threatening 
consequences 
Death 
REMARK: Other stoma complications may be graded as Fistula, GU – Select; Leak (including anastomotic), GU – Select; Obstruction, GU – Select; Perforation, GU – Select; 
Stricture/stenosis (including anastomotic), GU – Select. 
Renal failure  
Renal failure 
— 
— 
Chronic dialysis not 
indicated 
Chronic dialysis or renal 
transplant indicated 
Death 
ALSO CONSIDER: Glomerular filtration rate. 

 
RENAL/GENITOURINARY 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 62 - 
March 31, 2003, Publish Date: August 9, 2006 
Stricture/stenosis 
(including anastomotic), 
GU 
– Select: 
– Bladder 
– Fallopian tube 
– Prostate 
– Spermatic cord 
– Stoma 
– Testes 
– Ureter  
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Stricture, anastomotic, 
GU – Select  
Asymptomatic, 
radiographic or 
endoscopic findings only 
Symptomatic but no 
hydronephrosis, sepsis or 
renal dysfunction; dilation 
or endoscopic repair or 
stent placement indicated 
Symptomatic and altered 
organ function (e.g., 
sepsis or hydronephrosis, 
or renal dysfunction); 
operative intervention 
indicated  
Life-threatening 
consequences; organ 
failure or operative 
intervention requiring 
organ resection indicated  
Death 
ALSO CONSIDER: Obstruction, GU – Select. 
Urinary electrolyte 
wasting (e.g., Fanconi’s 
syndrome, renal tubular 
acidosis) 
Urinary electrolyte 
wasting 
Asymptomatic, 
intervention not indicated 
Mild, reversible and 
manageable with 
replacement 
Irreversible, requiring 
continued replacement  
— 
— 
ALSO CONSIDER: Acidosis (metabolic or respiratory); Bicarbonate, serum-low; Calcium, serum-low (hypocalcemia); Phosphate, serum-low (hypophosphatemia). 
Urinary 
frequency/urgency 
Urinary frequency 
Increase in frequency or 
nocturia up to 2 x normal; 
enuresis 
Increase >2 x normal but 
<hourly 
≥1 x/hr; urgency; catheter 
indicated 
— 
— 
Urinary retention 
(including neurogenic 
bladder)  
Urinary retention 
Hesitancy or dribbling, no 
significant residual urine; 
retention occurring during 
the immediate 
postoperative period 
Hesitancy requiring 
medication; or operative 
bladder atony requiring 
indwelling catheter 
beyond immediate 
postoperative period but 
for <6 weeks 
More than daily 
catheterization indicated; 
urological intervention 
indicated (e.g., TURP, 
suprapubic tube, 
urethrotomy) 
Life-threatening 
consequences; organ 
failure (e.g., bladder 
rupture); operative 
intervention requiring 
organ resection indicated 
Death 
REMARK: The etiology of retention (if known) is graded as Obstruction, GU – Select; Stricture/stenosis (including anastomotic), GU – Select. 
ALSO CONSIDER: Obstruction, GU – Select; Stricture/stenosis (including anastomotic), GU – Select. 
Urine color change  
Urine color change 
Present 
— 
— 
— 
— 
REMARK: Urine color refers to change that is not related to other dietary or physiologic cause (e.g., bilirubin, concentrated urine, and hematuria). 
Renal/Genitourinary – 
Other (Specify, __) 
Renal – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
SECONDARY MALIGNANCY 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 63 - 
March 31, 2003, Publish Date: August 9, 2006 
Secondary Malignancy – 
possibly related to cancer 
treatment (Specify, __)  
Secondary Malignancy 
(possibly related to 
cancer treatment) 
— 
— 
Non-life-threatening basal 
or squamous cell 
carcinoma of the skin 
Solid tumor, leukemia or 
lymphoma  
Death 
REMARK: Secondary malignancy excludes metastasis from initial primary. Any malignancy possibly related to cancer treatment (including AML/MDS) should be reported via the routine 
reporting mechanisms outlined in each protocol. Important: Secondary Malignancy is an exception to NCI Expedited Adverse Event Reporting Guidelines. Secondary Malignancy is 
“Grade 4, present” but NCI does not require AdEERS Expedited Reporting for any (related or unrelated to treatment) Secondary Malignancy. A diagnosis of AML/MDS following 
treatment with an NCI-sponsored investigational agent is to be reported using the form available from the CTEP Web site at http://ctep.cancer.gov. Cancers not suspected of being 
treatment-related are not to be reported here. 

 
SEXUAL/REPRODUCTIVE FUNCTION 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 64 - 
March 31, 2003, Publish Date: August 9, 2006 
Breast function/lactation 
Breast function 
Mammary abnormality, 
not functionally significant 
Mammary abnormality, 
functionally significant 
— 
— 
— 
Breast nipple/areolar 
deformity  
Nipple/areolar 
Limited areolar 
asymmetry with no 
change in nipple/areolar 
projection 
Asymmetry of nipple 
areolar complex with 
slight deviation in nipple 
projection 
Marked deviation of 
nipple projection  
— 
— 
Breast volume/hypoplasia 
Breast 
Minimal asymmetry; 
minimal hypoplasia 
Asymmetry exists, ≤1/3 of 
the breast volume; 
moderate hypoplasia  
Asymmetry exists, >1/3 of 
the breast volume; severe 
hypoplasia 
— 
— 
REMARK: Breast volume is referenced with both arms straight overhead. 
NAVIGATION NOTE: Dysmenorrhea is graded as Pain – Select in the PAIN CATEGORY.  
NAVIGATION NOTE: Dyspareunia is graded as Pain – Select in the PAIN CATEGORY.  
NAVIGATION NOTE: Dysuria (painful urination) is graded as Pain – Select in the PAIN CATEGORY.  
Erectile dysfunction 
Erectile dysfunction 
Decrease in erectile 
function 
(frequency/rigidity of 
erections) but erectile 
aids not indicated 
Decrease in erectile 
function 
(frequency/rigidity of 
erections), erectile aids 
indicated 
Decrease in erectile 
function 
(frequency/rigidity of 
erections) but erectile 
aids not helpful; penile 
prosthesis indicated 
— 
— 
Ejaculatory dysfunction 
Ejaculatory dysfunction 
Diminished ejaculation 
Anejaculation or 
retrograde ejaculation 
— 
— 
— 
NAVIGATION NOTE: Feminization of male is graded in the ENDOCRINE CATEGORY. 
Gynecomastia 
Gynecomastia 
— 
Asymptomatic breast 
enlargement 
Symptomatic breast 
enlargement; intervention 
indicated 
— 
— 
ALSO CONSIDER: Pain – Select.  
Infertility/sterility 
Infertility/sterility 
— 
Male: oligospermia/low 
sperm count 
Female: diminished 
fertility/ovulation 
Male: sterile/azoospermia 
Female: infertile/ 
anovulatory 
— 
— 
Irregular menses  
(change from baseline) 
Irregular menses 
1 – 3 months without 
menses 
>3 – 6 months without 
menses but continuing 
menstrual cycles 
Persistent amenorrhea 
for >6 months 
— 
— 

 
SEXUAL/REPRODUCTIVE FUNCTION 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 65 - 
March 31, 2003, Publish Date: August 9, 2006 
Libido 
Libido 
Decrease in interest but 
not affecting relationship; 
intervention not indicated 
Decrease in interest and 
adversely affecting 
relationship; intervention 
indicated 
— 
— 
— 
NAVIGATION NOTE: Masculinization of female is graded in the ENDOCRINE CATEGORY. 
Orgasmic dysfunction 
Orgasmic function 
Transient decrease 
Decrease in orgasmic 
response requiring 
intervention 
Complete inability of 
orgasmic response; not 
responding to intervention 
— 
— 
NAVIGATION NOTE: Pelvic pain is graded as Pain – Select in the PAIN CATEGORY. 
NAVIGATION NOTE: Ulcers of the labia or perineum are graded as Ulceration in DERMATOLOGY/SKIN CATEGORY. 
Vaginal discharge  
(non-infectious) 
Vaginal discharge 
Mild 
Moderate to heavy; pad 
use indicated 
— 
— 
— 
Vaginal dryness 
Vaginal dryness 
Mild 
Interfering with sexual 
function; dyspareunia; 
intervention indicated 
— 
— 
— 
ALSO CONSIDER: Pain – Select. 
Vaginal mucositis 
Vaginal mucositis 
Erythema of the mucosa; 
minimal symptoms 
Patchy ulcerations; 
moderate symptoms or 
dyspareunia 
Confluent ulcerations; 
bleeding with trauma; 
unable to tolerate vaginal 
exam, sexual intercourse 
or tampon placement  
Tissue necrosis; 
significant spontaneous 
bleeding; life-threatening 
consequences 
— 
Vaginal stenosis/length 
Vaginal stenosis 
Vaginal narrowing and/or 
shortening not interfering 
with function  
Vaginal narrowing and/or 
shortening interfering with 
function  
Complete obliteration; not 
surgically correctable 
— 
— 
Vaginitis (not due to 
infection) 
Vaginitis 
Mild, intervention not 
indicated 
Moderate, intervention 
indicated 
Severe, not relieved with 
treatment; ulceration, but 
operative intervention not 
indicated 
Ulceration and operative 
intervention indicated 
— 
Sexual/Reproductive 
Function – Other 
(Specify, __) 
Sexual – Other (Specify) 
Mild 
Moderate 
Severe 
Disabling 
Death 

 
SURGERY/INTRA-OPERATIVE INJURY 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 66 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Intra-operative hemorrhage is graded as Hemorrhage/bleeding associated with surgery, intra-operative or postoperative in the HEMORRHAGE/BLEEDING 
CATEGORY.  
Intra-operative injury  
– Select Organ or 
Structure 
‘Select’ AEs appear at the 
end of the CATEGORY. 
Intraop injury – Select  
Primary repair of injured 
organ/structure indicated  
Partial resection of 
injured organ/structure 
indicated 
Complete resection or 
reconstruction of injured 
organ/structure indicated 
Life threatening 
consequences; disabling 
— 
REMARK: The ‘Select’ AEs are defined as significant, unanticipated injuries that are recognized at the time of surgery. These AEs do not refer to additional surgical procedures that 
must be performed because of a change in the operative plan based on intra-operative findings. Any sequelae resulting from the intra-operative injury that result in an adverse 
outcome for the patient must also be recorded and graded under the relevant CTCAE Term. 
Intra-operative Injury – 
Other (Specify, __) 
Intraop Injury – Other 
(Specify) 
Primary repair of injured 
organ/structure indicated  
Partial resection of 
injured organ/structure 
indicated 
Complete resection or 
reconstruction of injured 
organ/structure indicated 
Life threatening 
consequences; disabling 
— 
REMARK: Intra-operative Injury – Other (Specify, __) is to be used only to report an organ/structure not included in the ‘Select’ AEs found at the end of the CATEGORY. Any sequelae 
resulting from the intra-operative injury that result in an adverse outcome for the patient must also be recorded and graded under the relevant CTCAE Term. 

 
SURGERY/INTRA-OPERATIVE INJURY – SELECT  
Page 2 of 2 
CTCAE v3.0  
- 67 - 
March 31, 2003, Publish Date: August 9, 2006 
AUDITORY/EAR 
– Inner ear  
– Middle ear  
– Outer ear NOS  
– Outer ear-Pinna  
CARDIOVASCULAR 
– Artery-aorta  
– Artery-carotid  
– Artery-cerebral  
– Artery-extremity (lower)  
– Artery-extremity (upper)  
– Artery-hepatic  
– Artery-major visceral artery  
– Artery-pulmonary  
– Artery NOS 
– Heart  
– Spleen 
– Vein-extremity (lower)  
– Vein-extremity (upper)  
– Vein-hepatic  
– Vein-inferior vena cava  
– Vein-jugular  
– Vein-major visceral vein  
– Vein-portal vein  
– Vein-pulmonary  
– Vein-superior vena cava  
– Vein NOS 
DERMATOLOGY/SKIN 
– Breast  
– Nails  
– Skin 
ENDOCRINE 
– Adrenal gland 
– Parathyroid 
– Pituitary  
ENDOCRINE (continued) 
– Thyroid 
HEAD AND NECK 
– Gingiva  
– Larynx  
– Lip/perioral area  
– Face NOS  
– Nasal cavity  
– Nasopharynx  
– Neck NOS 
– Nose  
– Oral cavity NOS  
– Parotid gland  
– Pharynx  
– Salivary duct  
– Salivary gland  
– Sinus  
– Teeth  
– Tongue  
– Upper aerodigestive NOS 
GASTROINTESTINAL 
– Abdomen NOS  
– Anal sphincter  
– Anus 
– Appendix  
– Cecum  
– Colon  
– Duodenum  
– Esophagus  
– Ileum  
– Jejunum  
– Oral  
– Peritoneal cavity  
– Rectum 
– Small bowel NOS 
GASTROINTESTINAL (continued) 
– Stoma (GI)  
– Stomach  
HEPATOBILIARY/ PANCREAS 
– Biliary tree-common bile  
duct  
– Biliary tree-common hepatic 
duct  
– Biliary tree-left hepatic duct  
– Biliary tree-right hepatic duct  
– Biliary tree NOS  
– Gallbladder  
– Liver 
– Pancreas 
– Pancreatic duct 
MUSCULOSKELETAL 
– Bone  
– Cartilage  
– Extremity-lower 
– Extremity-upper 
– Joint  
– Ligament  
– Muscle  
– Soft tissue NOS 
– Tendon 
NEUROLOGY  
– Brain  
– Meninges  
– Spinal cord 
NERVES: 
– Brachial plexus 
– CN I (olfactory) 
– CN II (optic) 
– CN III (oculomotor) 
– CN IV (trochlear)  
NEUROLOGY (continued) 
NERVES: 
– CN V (trigeminal) motor  
– CN V (trigeminal) sensory  
– CN VI (abducens)  
– CN VII (facial) motor-face  
– CN VII (facial) sensory-
taste  
– CN VIII (vestibulocochlear)  
– CN IX (glossopharyngeal) 
motor pharynx  
– CN IX (glossopharyngeal) 
sensory ear-pharynx-
tongue  
– CN X (vagus)  
– CN XI (spinal accessory)  
– CN XII (hypoglossal)  
– Cranial nerve or branch 
NOS  
– Lingual  
– Lung thoracic  
– Peripheral motor NOS 
– Peripheral sensory NOS 
– Recurrent laryngeal  
– Sacral plexus  
– Sciatic 
– Thoracodorsal 
OCULAR 
– Conjunctiva  
– Cornea  
– Eye NOS 
– Lens 
– Retina 
PULMONARY/UPPER 
RESPIRATORY 
– Bronchus  
– Lung  
– Mediastinum  
– Pleura  
– Thoracic duct  
– Trachea 
– Upper airway NOS 
RENAL/GENITOURINARY 
– Bladder  
– Cervix  
– Fallopian tube  
– Kidney  
– Ovary  
– Pelvis NOS  
– Penis  
– Prostate  
– Scrotum  
– Testis  
– Ureter  
– Urethra  
– Urinary conduit  
– Urinary tract NOS  
– Uterus  
– Vagina  
– Vulva 
 
 

 
SYNDROMES 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 68 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Acute vascular leak syndrome is graded in the VASCULAR CATEGORY. 
NAVIGATION NOTE: Adrenal insufficiency is graded in the ENDOCRINE CATEGORY. 
NAVIGATION NOTE: Adult Respiratory Distress Syndrome (ARDS) is graded in the PULMONARY/UPPER RESPIRATORY CATEGORY. 
Alcohol intolerance 
syndrome (antabuse-like 
syndrome) 
Alcohol intolerance 
syndrome 
— 
— 
Present 
— 
Death 
REMARK: An antabuse-like syndrome occurs with some new anti-androgens (e.g., nilutamide) when patient also consumes alcohol. 
NAVIGATION NOTE: Autoimmune reaction is graded as Autoimmune reaction/hypersensitivity (including drug fever) in the ALLERGY/IMMUNOLOGY CATEGORY. 
Cytokine release 
syndrome/acute infusion 
reaction 
Cytokine release 
syndrome 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDS, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption of 
infusion); recurrence of 
symptoms following initial 
improvement; 
hospitalization indicated 
for other clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates) 
Life-threatening; pressor 
or ventilatory support 
indicated 
Death 
REMARK: Cytokine release syndromes/acute infusion reactions are different from Allergic/hypersensitive reactions, although some of the manifestations are common to both AEs. An 
acute infusion reaction may occur with an agent that causes cytokine release (e.g., monoclonal antibodies or other biological agents). Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hrs of completion of infusion. Signs/symptoms may include: Allergic reaction/hypersensitivity (including drug 
fever); Arthralgia (joint pain); Bronchospasm; Cough; Dizziness; Dyspnea (shortness of breath); Fatigue (asthenia, lethargy, malaise); Headache; Hypertension; Hypotension; Myalgia 
(muscle pain); Nausea; Pruritis/itching; Rash/desquamation; Rigors/chills; Sweating (diaphoresis); Tachycardia; Tumor pain (onset or exacerbation of tumor pain due to treatment); 
Urticaria (hives, welts, wheals); Vomiting.  
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever); Bronchospasm, wheezing; Dyspnea (shortness of breath); Hypertension; Hypotension; Hypoxia; Prolonged 
QTc interval; Supraventricular and nodal arrhythmia – Select; Ventricular arrhythmia – Select.  
NAVIGATION NOTE: Disseminated intravascular coagulation (DIC) is graded in the COAGULATION CATEGORY. 
NAVIGATION NOTE: Fanconi’s syndrome is graded as Urinary electrolyte wasting (e.g., Fanconi’s syndrome, renal tubular acidosis) in the RENAL/GENITOURINARY CATEGORY. 
Flu-like syndrome 
Flu-like syndrome 
Symptoms present but 
not interfering with 
function 
Moderate or causing 
difficulty performing some 
ADL 
Severe symptoms 
interfering with ADL 
Disabling 
Death 
REMARK: Flu-like syndrome represents a constellation of symptoms which may include cough with catarrhal symptoms, fever, headache, malaise, myalgia, prostration, and is to be 
used when the symptoms occur in a cluster consistent with one single pathophysiological process. 
NAVIGATION NOTE: Renal tubular acidosis is graded as Urinary electrolyte wasting (e.g., Fanconi’s syndrome, renal tubular acidosis) in the RENAL/GENITOURINARY CATEGORY. 

 
SYNDROMES 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 69 - 
March 31, 2003, Publish Date: August 9, 2006 
“Retinoic acid syndrome”  
“Retinoic acid syndrome” 
Fluid retention; less than 
3 kg of weight gain; 
intervention with fluid 
restriction and/or diuretics 
indicated 
Mild to moderate signs/ 
symptoms; steroids 
indicated 
Severe signs/symptoms; 
hospitalization indicated 
Life-threatening; 
ventilatory support 
indicated 
Death 
REMARK: Patients with acute promyelocytic leukemia may experience a syndrome similar to “retinoic acid syndrome” in association with other agents such as arsenic trioxide. The 
syndrome is usually manifested by otherwise unexplained fever, weight gain, respiratory distress, pulmonary infiltrates and/or pleural effusion, with or without leukocytosis.  
ALSO CONSIDER: Acute vascular leak syndrome; Pleural effusion (non-malignant); Pneumonitis/pulmonary infiltrates. 
NAVIGATION NOTE: SIADH is graded as Neuroendocrine: ADH secretion abnormality (e.g., SIADH or low ADH) in the ENDOCRINE CATEGORY.  
NAVIGATION NOTE: Stevens-Johnson syndrome is graded as Rash: erythema multiforme (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis) in the DERMATOLOGY/SKIN 
CATEGORY. 
NAVIGATION NOTE: Thrombotic microangiopathy is graded as Thrombotic microangiopathy (e.g., thrombotic thrombocytopenic purpura [TTP] or hemolytic uremic syndrome [HUS]) in 
the COAGULATION CATEGORY. 
Tumor flare 
Tumor flare 
Mild pain not interfering 
with function 
Moderate pain; pain or 
analgesics interfering with 
function, but not 
interfering with ADL 
Severe pain; pain or 
analgesics interfering with 
function and interfering 
with ADL 
Disabling 
Death 
REMARK: Tumor flare is characterized by a constellation of signs and symptoms in direct relation to initiation of therapy (e.g., anti-estrogens/androgens or additional hormones). The 
symptoms/signs include tumor pain, inflammation of visible tumor, hypercalcemia, diffuse bone pain, and other electrolyte disturbances.  
ALSO CONSIDER: Calcium, serum-high (hypercalcemia). 
Tumor lysis syndrome 
Tumor lysis syndrome 
— 
— 
Present 
— 
Death 
ALSO CONSIDER: Creatinine; Potassium, serum-high (hyperkalemia). 
Syndromes – Other 
(Specify, __) 
Syndromes – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
VASCULAR 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 70 - 
March 31, 2003, Publish Date: August 9, 2006 
Acute vascular leak 
syndrome 
Acute vascular leak 
syndrome 
— 
Symptomatic, fluid 
support not indicated 
Respiratory compromise 
or fluids indicated 
Life-threatening; pressor 
support or ventilatory 
support indicated  
Death 
Peripheral arterial 
ischemia 
Peripheral arterial 
ischemia 
— 
Brief (<24 hrs) episode of 
ischemia managed non-
surgically and without 
permanent deficit 
Recurring or prolonged 
(≥24 hrs) and/or invasive 
intervention indicated 
Life-threatening, disabling 
and/or associated with 
end organ damage 
(e.g., limb loss) 
Death 
Phlebitis (including 
superficial thrombosis) 
Phlebitis 
— 
Present 
— 
— 
— 
ALSO CONSIDER: Injection site reaction/extravasation changes. 
Portal vein flow 
Portal flow 
— 
Decreased portal vein 
flow 
Reversal/retrograde 
portal vein flow 
— 
— 
Thrombosis/embolism 
(vascular access-related) 
Thrombosis/embolism 
(vascular access) 
— 
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
not indicated 
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
indicated 
Embolic event including 
pulmonary embolism or 
life-threatening thrombus 
Death 
Thrombosis/thrombus/ 
embolism 
Thrombosis/thrombus/ 
embolism 
— 
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
not indicated  
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
indicated  
Embolic event including 
pulmonary embolism or 
life-threatening thrombus 
Death 
Vessel injury-artery  
– Select:  
– Aorta 
– Carotid 
– Extremity-lower 
– Extremity-upper  
– Other NOS 
– Visceral 
Artery injury – Select 
Asymptomatic diagnostic 
finding; intervention not 
indicated 
Symptomatic (e.g., 
claudication); not 
interfering with ADL; 
repair or revision not 
indicated 
Symptomatic interfering 
with ADL; repair or 
revision indicated 
Life-threatening; 
disabling; evidence of 
end organ damage (e.g., 
stroke, MI, organ or limb 
loss) 
Death 
NAVIGATION NOTE: Vessel injury to an artery intra-operatively is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY 
CATEGORY. 

 
VASCULAR 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 71 - 
March 31, 2003, Publish Date: August 9, 2006 
Vessel injury-vein  
– Select: 
– Extremity-lower  
– Extremity-upper 
– IVC 
– Jugular 
– Other NOS 
– SVC 
– Viscera 
Vein injury – Select 
Asymptomatic diagnostic 
finding; intervention not 
indicated 
Symptomatic (e.g., 
claudication); not 
interfering with ADL; 
repair or revision not 
indicated  
Symptomatic interfering 
with ADL; repair or 
revision indicated 
Life-threatening; 
disabling; evidence of 
end organ damage  
Death 
NAVIGATION NOTE: Vessel injury to a vein intra-operatively is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY CATEGORY. 
Visceral arterial ischemia 
(non-myocardial) 
Visceral arterial ischemia 
— 
Brief (<24 hrs) episode of 
ischemia managed 
medically and without 
permanent deficit 
Prolonged (≥24 hrs) or 
recurring symptoms 
and/or invasive 
intervention indicated 
Life-threatening; 
disabling; evidence of 
end organ damage  
Death 
ALSO CONSIDER: CNS cerebrovascular ischemia.  
Vascular – Other  
(Specify, __) 
Vascular – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
 

Clinical Trial Protocol:  HGT-SAN-067 
Study Title: 
An Open-Label Extension of Study HGT-SAN-055 Evaluating 
Long-Term Safety and Clinical Outcomes of Intrathecal Administration 
of rhHNS in Patients with Sanfilippo Syndrome Type A (MPS IIIA) 
Study Number: 
HGT-SAN-067 
Study Phase: 
I/II  
Product Name: 
Recombinant human heparan N-sulfatase (rhHNS) 
EudraCT Number: 2010-021348-16 
Indication: 
Sanfilippo Syndrome A 
Investigators: 
Multicenter 
 
 
Sponsor: 
Shire 
Medical Monitor: 
, MD 
 
Shire Human Genetic Therapies, Inc. 
700 Main Street  
Cambridge, MA 02139, USA 
Telephone:  
 
Fax:  
 (USA) 
 
 
Date 
Original Protocol: 
21 June 2010 
Amendment 1 
27 January 2011 
Confidentiality Statement 
This document is the proprietary and confidential property of Shire Human Genetic 
Therapies, Inc. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
2 
SYNOPSIS 
Sponsor: 
Shire 
Name of Finished Product: 
Recombinant human heparan N-sulfatase (rhHNS) 
Name of Active Ingredient: 
rhHNS 
Name of Inactive Ingredient: 
N/A 
Study Title: 
An Open-Label Extension of Study HGT-SAN-055 Evaluating Long-Term Safety and 
Clinical Outcomes of Intrathecal Administration of rhHNS in Patients with Sanfilippo 
Syndrome Type A (MPS IIIA)  
Study Number: 
HGT-SAN-067 
Study Phase:  I/II  
Primary Objective:  
To collect long-term safety and tolerability data in patients with Sanfilippo Syndrome Type A 
(MPS IIIA) who received rhHNS via a surgically implanted intrathecal drug delivery device 
(IDDD) in study HGT-SAN-055 and elected to continue therapy. 
Secondary Objectives: 
To collect as indications of drug efficacy, over an extended treatment period (as change from 
baseline), the following:  clinical, neurological, cognitive, behavioral, functional, and quality of 
life (QoL) assessments, together with potential imaging and biochemical biomarkers. 
Study Endpoints:  
The primary endpoint of this study is: 
To determine the long-term safety of intrathecal rhHNS administration, as measured by adverse 
events (by type and severity), changes in clinical laboratory testing (serum chemistry including 
liver function tests, hematology, and urinalysis), electrocardiograms, cerebrospinal fluid (CSF) 
chemistries (including cell counts and inflammatory markers), and anti-rhHNS antibodies (in 
CSF and serum). 
The secondary endpoints of this study are to collect over an extended treatment period (as 
change from baseline) clinical and potential surrogate biomarker efficacy data: 
• Standardized neurocognitive and behavioral assessments, Sanfilippo-specific behavioral 
rating scales, gross and fine motor assessments, functional adaptive rating scales, quality 
of life questionnaires, and Children’s Sleep Habits Rating Scale. 
• Concentration of rhHNS in cerebrospinal fluid (CSF) and serum. 
• Concentration of inflammatory cytokines in serum and CSF. 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
3 
• Concentration of safety and potential surrogate efficacy biomarkers in CSF, urine, and 
serum. 
• Concentration of heparan sulfate and heparan sulfate derivatives in urine and CSF  
• Brain magnetic resonance imaging (MRI) and auditory brainstem response (ABR), aka 
Brainstem Auditory Evoked Potentials. 
Study Design: 
This is a multicenter, multiple-dose, open-label extension of Study HGT-SAN-055 designed to 
evaluate the long-term safety and clinical activity and biomarker outcomes of intrathecal 
administration of 3 dose levels (10 mg and 45 mg once per month and 45 mg every other week 
[EOW]) of rhHNS via an IDDD in patients with MPS IIIA.   
Patients will continue in the treatment group as they participated in the HGT-SAN-055 study:  
• Group 1:  rhHNS administered by IT injection 10 mg once per month for a total of 6 months 
• Group 2:  rhHNS administered by IT injection 45 mg once per month for a total of 6 months 
• Group 3:  rhHNS administered by IT injection 45 mg EOW for a total of 6 months 
 
It is anticipated that all patients successfully completing the HGT-SAN-055 study will elect to 
continue to receive intrathecal (IT) rhHNS per their previous schedule in Study HGT-SAN-055 
by consenting to participate, without interruption, in the HGT-SAN-067 extension study.  Thus, 
for nomenclature of chronology purposes, the Baseline Visit for this extension study will be 
considered to be the first day the patient received his/her IT dose of rhHNS in Study 
HGT-SAN-055. 
Patients whose parents/legal guardians provide written informed consent/assent to participate in 
this study will check in with the study center 1 day prior to rhHNS dosing for safety assessments 
on each rhHNS treatment week.  If no safety concerns exist, the patient will subsequently receive 
IT administration of rhHNS on Day 2.  Patients will be discharged from the inpatient unit a 
minimum of 1 day following dosing with rhHNS and when deemed clinically stable by the 
Investigator.  The patient will have already received a standardized battery of 
neurodevelopmental assessments at the baseline and 6 month time points in the HGT-SAN-055 
study.  These same assessments and tests will also be performed at 12, 24, 36, and 48 months.  
Similarly, MRI of the head, ABR testing, CSF sampling via lumbar puncture and any other 
procedures requiring anesthesia will be performed at 12, 24, 36, and 48 months.   
All patients will undergo end of study procedures 30 (±7) days following their last administration 
of rhHNS.  End of study (EOS) procedures will include a standard battery of clinical laboratory 
tests (serum chemistry, hematology, and urinalysis) in CSF and blood, protocol specific 
laboratory testing (eg, anti-rhHNS antibody testing), neurodevelopmental testing, ABR, and 
MRI.  
All patients will be contacted by telephone for a Final Safety Follow-up, to be conducted at 
30 (±7) days after the EOS procedures to collect updated information on adverse events and 
concomitant medications, therapies, and procedures. 
It is anticipated that the IDDD will be used to obtain CSF samples and to deliver all 
administrations of rhHNS.  However, if a patient’s IDDD becomes nonfunctional or infected, it 
will be replaced so that the patient can remain on the study.   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
4 
 
If use of the IDDD is precluded on a scheduled day of dosing, the IDDD will be declared a 
failure; no study drug will be administered, nor CSF sample obtained on that visit.  Unlike the 
HGT-SAN-055 study, no study drug will be administered by lumbar puncture in this extension 
study.  Upon declaration of failure, the IDDD will be removed and the patient scheduled for 
re-implantation of a new IDDD at the earliest convenience, so that the patient may remain on, or 
remain as close as possible, to his/her original IT rhHNS dosing schedule.  Note:  Patients will 
require 1 week of recovery time from time of re-implantation, during which time the IDDD 
cannot be used, this may result in a delay in the next scheduled dose of rhHNS.  The patient will 
resume his or her original dosing schedule; no catch-up dosing will occur. 
 
If a patient discontinues or is withdrawn from the study or the study is stopped by the Sponsor, 
the IDDD will be removed as part of the End of Study Procedures.  
 
Study Population:  
A maximum of twelve patients are planned for this study.  To be eligible for participation, 
patients will have completed all study requirements in Study HGT-SAN-055 and will have 
elected to continue treatment with rhHNS. 
Diagnosis and Main Criteria for Inclusion 
Inclusion Criteria: 
Patients must meet all of the following criteria to be considered eligible for enrollment: 
1. Patients must have completed all study requirements and assessments for Study 
HGT-SAN-055 prior to enrolling in this extension study and must have no safety or medical 
issues that contraindicate participation. 
2. The patient, patient’s parent(s), or legally authorized guardian(s) must have voluntarily 
signed an Institutional Review Board / Independent Ethics Committee-approved informed 
consent form after all relevant aspects of the study have been explained and discussed with 
the patient.  The guardians’ consent and patient’s assent, as relevant, must be obtained. 
3. The patient has received and tolerated treatment with rhHNS, completed the End of Study 
visit, and has received at least 80% of the total planned infusions within the last 6 months in 
study HGT-SAN-055, (ie, at least 5/6 ([Group 1 or 2] or 10/12 infusions [Group 3]). 
4. Patients must be medically stable, in the opinion of the Investigator, to accommodate the 
protocol requirements, including travel, assessments, and IDDD surgery (if necessary for 
replacement purposes), without placing an undue burden on the patient/patient's family. 
 
Exclusion Criteria: 
Subjects will be excluded from the study if there is evidence of any of the following criteria at 
screening or at anytime during the study: 
1. The patient has experienced an adverse reaction to study drug in Study HGT-SAN-055 that 
contraindicates further treatment with rhHNS. 
2. The patient has a known hypersensitivity to the active ingredient or any excipients in rhHNS 
drug product. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
5 
3. The patient has significant non-MPS IIIA related central nervous system (CNS) impairment 
or behavioral disturbances that would confound the scientific integrity or interpretation of 
study assessments, as determined by the Investigator. 
4. The patient has significant MPS IIIA behavioral-related issues, as determined by the 
Investigator, which would preclude performance of study neurocognitive and developmental 
testing procedures. 
5. The patient is pregnant, breast feeding, or is a female patient of childbearing potential, who 
will not or cannot comply with the use of an acceptable method of birth control, such as 
condoms, barrier method, oral contraception, etc. 
6. The patient has any known or suspected hypersensitivity to anesthesia or is thought to have 
an unacceptably high risk for anesthesia due to airway compromise or other conditions. 
7. The patient has a history of poorly controlled seizure disorder. 
8. The patient is currently receiving psychotropic or other medications, which in the 
Investigator’s opinion, would be likely to substantially confound test results and the dose and 
regimen of which cannot be kept constant throughout the study. 
9. The patient cannot sustain absence from aspirin, non-steroidal medications, or medications 
that affect blood clotting within 1 week prior to a relevant study-related procedure (eg, 
device implantation if applicable), or has ingested such medications within 1 week before 
any procedures in which any change in clotting activity would be deleterious. 
10. The patient has received treatment with any investigational drug (other than rhHNS) intended 
as a treatment for MPS IIIA or used any other intrathecal delivery device other than what was 
used in Study HGT-SAN-055, within the 30 days prior to, or during the study, or is currently 
enrolled in another study that involves an investigational drug or device (screening through 
safety follow-up contact). 
11. The patient has received a hematopoietic stem cell or bone marrow transplant. 
12. The patient’s parent(s), or patient’s legal guardian(s) is/are unable to provide consent or the 
patient cannot provide assent, as appropriate, due to, but not limited to, the inability to 
understand the nature, scope, and possible consequences of the study, or do/does not agree to 
comply with the protocol defined schedule of assessments. 
Test Product; Dose; and Mode of Administration:  
Recombinant human heparan N-sulfatase (rhHNS) will be administered via an IDDD according 
to the same dosing regimen to which the patient was assigned in HGT-SAN-055 (ie, 10 mg 
monthly, 45 mg monthly, or 45 mg EOW).   
Reference Therapy; Dose; and Mode of Administration: Not Applicable 
Duration of Treatment:  
The study duration will be 4 years. 
Pharmacokinetic Variables: 
Pharmacokinetics will not be assessed in this study. 
Safety Assessments: 
Safety evaluations will include vital signs, physical examinations, adverse event (AE) 
assessments, and electrocardiograms (ECG); serum chemistry, hematology, and urine laboratory 
tests; and screening for antibodies to rhHNS (in CSF and serum).   
 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
6 
 
Statistical Methods:  
The statistical methodology supporting the trial will focus on descriptive rather than inferential 
approaches, given the early phase and objectives of the trial.   
Data will be plotted and the mean, standard deviation, median, minimum, and maximum for each 
variable will be tabulated by dose group to look for gross trends over time which may be 
attributed to treatment.  For continuous data, 95% confidence interval around the mean will be 
presented. 
The analysis population consists of all eligible patients from HGT-SAN-055, who have agreed to 
participate in the extension study.  Safety analyses will be performed using the above mentioned 
population.  The data will be presented by dose group. 
Date of Original Protocol:  21 June 2010 
Date of Amendment 1:  27 January 2011 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
7 
TABLE OF CONTENTS 
SYNOPSIS.................................................................................................................................2 
TABLE OF CONTENTS...........................................................................................................7 
LIST OF IN-TEXT TABLES..................................................................................................10 
LIST OF APPENDICES..........................................................................................................10 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..........................................12 
1 
INTRODUCTION ...........................................................................................................15 
1.1 
Disease Background...............................................................................................15 
1.2 
Nonclinical Overview............................................................................................17 
1.2.1 
Toxicology in Monkeys...............................................................................17 
1.2.2 
Efficacy in Murine and Canine Models of MPS IIIA..................................17 
1.3 
Clinical Development Program..............................................................................18 
1.4 
Extension Study Rationale.....................................................................................18 
2 
STUDY OBJECTIVES....................................................................................................20 
2.1 
Primary Objective..................................................................................................20 
2.2 
Secondary Objectives.............................................................................................20 
3 
STUDY ENDPOINTS.....................................................................................................21 
3.1 
Primary Endpoint...................................................................................................21 
3.2 
Secondary Endpoint...............................................................................................21 
4 
INVESTIGATIONAL PLAN..........................................................................................22 
4.1 
Overall Study Design and Plan..............................................................................22 
4.2 
Rationale for Study Design and Control Group.....................................................23 
4.3 
Study Duration and Dates......................................................................................23 
5 
STUDY POPULATION SELECTION ...........................................................................24 
5.1 
Study Population....................................................................................................24 
5.2 
Inclusion Criteria ...................................................................................................24 
5.3 
Exclusion Criteria ..................................................................................................24 
6 
STUDY TREATMENT(S)..............................................................................................26 
6.1 
Description of Treatment(s)...................................................................................26 
6.1.1 
Study Drug...................................................................................................26 
6.1.2 
Placebo or Control .......................................................................................26 
6.2 
Treatment(s) Administered....................................................................................26 
6.3 
Selection and Timing of Dose for Each Subject....................................................26 
6.4 
Cerebral Spinal Fluid Sample Procedure...............................................................26 
6.5 
Intrathecal Administration of rhHNS.....................................................................27 
6.6 
Method of Assigning Subjects to Treatment Groups.............................................27 
6.7 
Blinding..................................................................................................................27 
6.8 
Concomitant Therapy.............................................................................................27 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
8 
6.9 
Restrictions ............................................................................................................28 
6.9.1 
Prior Therapy ...............................................................................................28 
6.9.2 
Fluid and Food Intake..................................................................................28 
6.9.3 
Subject Activity Restrictions .......................................................................28 
6.10 
Treatment Compliance...........................................................................................28 
6.11 
Packaging and Labeling.........................................................................................28 
6.12 
Storage and Accountability....................................................................................29 
6.13 
Investigational Product Retention at Study Site ....................................................29 
7 
STUDY PROCEDURES .................................................................................................30 
7.1 
Informed Consent...................................................................................................30 
7.2 
Physical Examination.............................................................................................30 
7.3 
Height and Weight.................................................................................................31 
7.4 
Head Circumference ..............................................................................................31 
7.5 
Vital Signs..............................................................................................................31 
7.6 
Electrocardiography...............................................................................................31 
7.6.1 
Electrocardiograms ......................................................................................31 
7.7 
Clinical Laboratory Tests.......................................................................................31 
7.7.1 
Hematology..................................................................................................32 
7.7.2 
Serum Chemistry .........................................................................................32 
7.7.2.1 
Standard Serum Chemistry ................................................................32 
7.7.3 
Urinalysis.....................................................................................................32 
7.7.3.1 
Standard Urinalysis............................................................................33 
7.7.3.2 
Urine Heparan Sulfate and Heparan Sulfate Derivatives ..................33 
7.7.4 
Cerebrospinal Fluid Assessments ................................................................33 
7.7.4.1 
CSF Cell Counts ................................................................................33 
7.7.4.2 
CSF Heparan Sulfate Levels and Heparan Sulfate Derivatives.........33 
7.7.4.3 
Anti-rhHNS Antibodies .....................................................................34 
7.7.4.4 
CSF Biomarkers.................................................................................34 
7.7.5 
Sample Collection, Storage, and Shipping ..................................................34 
7.8 
Anesthesia..............................................................................................................34 
7.9 
Audiometry and Auditory Brainstem Response ....................................................34 
7.10 
MRI of the Head ....................................................................................................35 
7.11 
Surgical Re-implantation of the IDDD..................................................................35 
7.12 
Intracranial Pressure Measurement........................................................................35 
7.13 
Dispensing Study Drug..........................................................................................35 
7.14 
Pharmacokinetic Assessments ...............................................................................35 
7.15 
Neurological Examination .....................................................................................35 
7.16 
Serum Anti-rhHNS Antibody, Heparan Sulfate and Heparan Sulfate Derivative 
Determination ........................................................................................................36 
7.17 
Neurocognitive and Developmental Assessments.................................................36 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
9 
7.18 
Sleep Questionnaire:  Children’s Sleep Habits Rating Scale.................................37 
7.19 
Age-Dependent, Health-Related Quality of Life in Children................................37 
7.19.1 
Quality of Life Indicator:  CHQ-50 .............................................................37 
7.19.2 
Quality of Life Indicator:  CHQ-87 .............................................................38 
7.19.3 
Quality of Life Indicator:  ITQOL...............................................................38 
7.20 
Concomitant Medications, Therapies and Medical/Surgical Procedures ..............38 
7.21 
Adverse Events ......................................................................................................38 
7.21.1 
Adverse Events Assessments.......................................................................38 
7.21.2 
Definitions of Adverse Events and Serious Adverse Events.......................39 
7.21.2.1 
Adverse Event....................................................................................39 
7.21.2.2 
Serious Adverse Event.......................................................................40 
7.21.3 
Procedures for Recording and Reporting Adverse Events ..........................42 
7.21.3.1 
Reporting Serious Adverse Events ....................................................42 
7.21.3.2 
Eliciting Adverse Events....................................................................43 
7.21.3.3 
Protocol Deviations for Medical Emergency or Adverse Event........43 
7.22 
Pregnancy...............................................................................................................44 
7.23 
Removal of Subjects from the Trial or Study Drug...............................................44 
7.24 
Other Study Procedures .........................................................................................45 
7.25 
Appropriateness of Measurements.........................................................................45 
8 
STUDY ACTIVITIES .....................................................................................................46 
8.1 
Screening Visit/Baseline Visit...............................................................................46 
8.2 
Treatment:  Monthly, Weekly Assessments ..........................................................47 
8.2.1 
Week 1 (Groups 1 and 2); Week 1 and 3 (Group 3)....................................47 
8.2.1.1 
Day 1 (Pre-treatment) Assessments...................................................47 
8.2.1.2 
Day 2 (±2 days) Assessments and IDDD Injection of rhHNS...........48 
8.2.1.3 
Day 3 (Post IT Dose) Assessments....................................................48 
8.3 
End of Study/ Early Termination Procedures........................................................48 
8.4 
Safety Follow-up Visit (by Telephone) .................................................................49 
9 
QUALITY CONTROL AND ASSURANCE .................................................................50 
10 PLANNED STATISTICAL METHODS ........................................................................51 
10.1 
General Statistical Methodology............................................................................51 
10.2 
Determination of Sample Size ...............................................................................51 
10.3 
Analysis Populations..............................................................................................51 
10.4 
Demographics and Baseline Characteristics..........................................................52 
10.5 
Statistical Analysis of Pharmacokinetic Variables ................................................52 
10.6 
Efficacy, Safety, and Pharmacodynamic Evaluations ...........................................52 
10.6.1 
Primary Analyses.........................................................................................52 
10.6.1.1 
Safety Analysis ..................................................................................52 
10.6.1.2 
Clinical Laboratory Evaluations ........................................................53 
10.6.1.3 
Anti-rhHNS Antibody Formation......................................................53 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
10 
10.6.2 
Secondary Analysis......................................................................................54 
10.6.2.1 
Clinical Assessments .........................................................................54 
10.6.2.2 
Pharmacodynamic Analyses..............................................................54 
11 ADMINISTRATIVE CONSIDERATIONS....................................................................55 
11.1 
Investigators and Study Administrative Structure.................................................55 
11.2 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval ................................................................................................................55 
11.3 
Ethical Conduct of the Study.................................................................................55 
11.4 
Patient Information and Consent ...........................................................................55 
11.5 
Patient Confidentiality ...........................................................................................56 
11.6 
Study Monitoring...................................................................................................56 
11.7 
Case Report Forms and Study Records .................................................................57 
11.7.1 
Critical Documents ......................................................................................57 
11.8 
Data Monitoring Committee..................................................................................58 
11.9 
Protocol Violations/Deviations..............................................................................58 
11.10 Access to Source Documentation ..........................................................................58 
11.11 Data Generation and Analysis ...............................................................................58 
11.12 Premature Closure of the Study.............................................................................59 
11.12.1 Study Termination .......................................................................................59 
11.12.2 Site Termination...........................................................................................59 
11.13 Retention of Data...................................................................................................59 
11.14 Financial Disclosure...............................................................................................59 
11.15 Publication and Disclosure Policy .........................................................................59 
12 REFERENCE LIST .........................................................................................................61 
 
LIST OF IN-TEXT TABLES 
Table 7-1  
Approximate Total Sample Volumes Collected Over the Duration of the 
Study From Each Patient by Group and Assay............................................30 
Table 7-2  
Neurodevelopmental Assessments Tests.....................................................36 
Table 7-3  
Sanfilippo-Specific Disability Assessment And Behavior Rating Scales ...37 
Table 7-4  
Adverse Event Severity................................................................................41 
Table 7-5 
Adverse Event Relatedness..........................................................................41 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events.............................................................................63 
Appendix 2 
Sample Neurological Exam ...............................................................67 
Appendix 3 
Neurodevelopmental and Behavioral Assessments ...........................71 
Appendix 4 
Investigator’s Signature .....................................................................74 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
11 
Appendix 5 
Summary of Changes for Amendment 1 ...........................................75 
Appendix 6 
The National Cancer Institute Common Terminology Criteria for 
Adverse Events (CTCAE) Version 3.0..............................................76 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
12 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ABR 
Auditory Brainstem Response 
AE 
adverse event 
ALB 
albumin 
ALK-P 
alkaline phosphatase 
ALT 
alanine aminotransferase (SGPT) 
AP 
alkaline phosphatase 
AST 
aspartate aminotransferase (SGOT) 
BSID-III 
Bayley Scales of Infant Development, Third Edition 
BBB 
blood brain barrier 
BUN 
blood urea nitrogen 
Ca 
calcium 
CFR 
Code of Federal Regulations 
CNS 
central nervous system 
CHQ-50 
Child Health Questionnaire™ Parent Form 50 
CHQ-87 
Child Health Questionnaire™ Child Form 87 
CK 
creatine kinase 
Cl 
chloride 
CO2 
carbon dioxide 
CRO 
contract research organization 
CSF 
cerebrospinal fluid 
DDD 
drug delivery device 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ERT 
enzyme replacement therapy 
EOS 
end of study 
EOW 
every other week 
FDA 
Food and Drug Administration 
FG 
formylglycine 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
13 
FPSS/TDS 
Four-Point Scoring System/Total Disability Score 
GAG 
glycosaminoglycan 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
Hct 
hematocrit 
Hgb 
hemoglobin 
HS 
heparan sulfate 
ICH 
International Conference on Harmonisation  
ICP 
intracranial pressure  
IDDD 
intrathecal drug delivery device 
IEC 
Independent Ethics Committee 
IgG 
immunoglobulin G 
IgE 
immunoglobulin E 
IND 
Investigational New Drug  
IRB 
Institutional Review Board 
IT 
intrathecal 
ITQOL 
Infant Toddler Quality of Life Questionnaire™ 
IV 
intravenous 
K 
potassium 
KABC-II 
Kaufman Assessment Battery for Children, Second Edition 
LDH 
lactic dehydrogenase 
LP 
lumbar puncture  
LSD 
lysosomal storage disease 
M6P 
mannose-6-phosphate 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MABC-2 
Movement Assessment Battery for Children, Second Edition 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
14 
MPS IIIA 
Mucopolysaccharidosis IIIA or Sanfilippo syndrome Type A 
MRI 
magnetic resonance imaging 
Na 
sodium  
QoL 
quality of life 
PE 
pressure-equalization 
RBC 
red blood cell (count) 
rhHNS 
recombinant human heparan N-sulfatase 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SBRS 
The Sanfilippo Behavior Rating Scale 
SGOT 
serum glutamic oxaloacetic transaminase (AST) 
SGPT 
serum glutamic pyruvic transaminase (ALT) 
Shire HGT 
Shire Human Genetic Therapies, Inc. 
TMF 
Trial Master File 
TX 
treatment 
UK 
United Kingdom 
US 
United States 
VABS-II 
Vineland Adaptive Behavior Scales  
WBC 
white blood cell (count) 
WHODRL 
World Health Organization Drug Reference List 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
15 
1 
INTRODUCTION 
The progressive and irreversible nature of lysosomal storage diseases (LSDs) present a challenge 
in the interpretation of clinical benefit derived from treatment in studies using enzyme 
replacement therapy (ERT).  Any short-term improvement and/or stabilization of clinically 
important manifestations of the disease may be viewed as clinically meaningful.  However, the 
demonstration of the different aspects of a long-term, clinically-meaningful improvement may be 
limited by the short duration of treatment in clinical studies.  Extended access to treatment 
through extension studies provides an opportunity for further evaluation of long-term safety and 
clinical outcomes for treated patients.  In this extension study, patients who completed study 
HGT-SAN-055, a phase I/II safety and dose-escalation trial, and elected to continue to receive 
recombinant human heparan N-sulfatase (rhHNS), will receive treatment through this extension 
protocol.  The patient’s treatment group, dosing regimen, and the intrathecal drug delivery device 
(IDDD) will be the same as that employed in study HGT-SAN-055. 
1.1 
Disease Background 
Sanfilippo syndrome, or Mucopolysaccharidosis (MPS) III, is a lysosomal storage disease (LSD) 
caused by loss in activity of 1 of 4 enzymes necessary for degradation of the glycosaminoglycan 
(GAG) heparan sulfate (HS) in lysosomes.  Four different subtypes (A, B, C, and D) have been 
identified and are each due to a specific enzyme deficiency involved in the lysosomal catabolism 
of HS.  MPS IIIA results from deficiency of the enzyme heparan N-sulfatase (sulfamidase).  In 
the absence of this enzyme, intermediates of the HS degradation process accumulate in the 
lysosomes of neurons and glial cells, with lesser accumulation outside the brain.   
MPS III is the most prevalent of all mucopolysaccharidoses, with subtypes A and B similar in 
prevalence, accounting for approximately 90% of all cases of MPS III.1  The birth prevalence of 
MPS IIIA has been estimated as 1.28 in 100,000 in Australia, 1.16 in 100,000 in the Netherlands, 
and 0.88 in 100,000 in Germany.1, 2, 3  In summary, there is widespread geographic distribution 
of MPS IIIA, with an average global birth incidence of approximately 1 in 100,000.  
MPS IIIA symptoms arise on average at 7 months of age, with the average age of diagnosis at 
4.5 years for the majority of patients.4  Patients present a wide spectrum and severity of clinical 
symptoms.  The central nervous system (CNS) is the most severely affected organ system in 
patients with MPS IIIA, evidenced by deficits in language development, motor skills, and 
intellectual development.4  In addition, there are abnormal behaviors including, but not limited 
to, aggression and excess motor activity/hyperactivity that contribute to disturbances in sleep.4,5,6  
In contrast with other MPS types, the viscera are mildly affected, with transient enlargement of 
liver and spleen during childhood with no evidence of dysfunction.7  There are also reports of 
unexplained, recurrent and severe diarrhea.7  Overall, individuals with MPS IIIA have a marked 
developmental delay and significantly reduced lifespan of 15 years of age on average.7  A milder 
variant has recently been identified with slower progression and survival to later age in 
approximately 10% of German patients with MPS IIIA.8  
No effective, disease-modifying therapies are currently approved as treatments for this rare, 
devastating and disabling disease.   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
16 
A long-range goal of Shire Human Genetic Therapies, Inc. (Shire HGT) is to develop a 
recombinant human sulfamidase enzyme replacement therapy (ERT) for patients with MPS IIIA.  
A particular problem for lysosomal storage disorders that damage the brain such as MPS III is 
how to target ERT to the brain.9  In animal studies, ERT was administered into the cerebrospinal 
fluid (CSF) via an intrathecal (IT) route, because when administered intravenously (IV), it was 
shown to not cross the blood brain barrier (BBB) after the immediate postnatal period of life.10, 11 
  
As the CNS in patients with MPS IIIA is the most severely affected body system, the main focus 
of the rhHNS clinical development program has been the development of ERT specifically for 
delivery directly to the CNS.  Recombinant human heparan N-sulfatase (rhHNS) has been 
developed specifically for delivery into the CSF via an IDDD due to the acknowledged 
impermeability of the BBB to macromolecules.  
Heparan N-sulfatase is a highly purified recombinant form of the naturally occurring human 
lysosomal enzyme sulfamidase.  It is expressed from the well characterized continuous human 
HT-1080 cell line as a 482 amino acid peptide, following cleavage of the 20 amino acid 
N-terminal signal peptide.  The mature protein in solution is a homodimeric glycoprotein of 
approximately 122 kDa, which undergoes post-translational modifications by conversion of 
Cys50 to formylglycine (FG), required for enzyme activity, and glycosylation at 4 of the 
5 potential N-linked glycosylation sites.  The rhHNS glycans contain mannose-6-phosphate 
(M6P) residues which target the protein for cellular uptake and internalization in its lysosomal 
site of action via the membrane-bound M6P receptors. 12, 13, 14, 15 
The first precedent for intraspinal ERT was recently published and has been shown to be both 
safe and effective for spinal cord compression in MPS I.16  In this study, a patient with 
mucopolysaccharidosis Type I received 4 intrathecal doses of enzyme (Laronidase) at 1-month 
intervals.  Safety evaluations included CSF opening pressure, serum chemistry and CSF protein, 
glucose and cell count, in addition to clinical efficacy studies.  No changes in safety evaluations 
were observed. 
In another recent study, a patient with MPS VI and spinal cord compression received intrathecal 
injections of enzyme (Galsulfase) monthly, for 4 months.  CSF analysis revealed no 
inflammatory reaction; no other side effects were noted.17  
Several MPS I patients have been treated since 2005 with intrathecal Laronidase (recombinant 
α-L-Idurunonidase) in 2 ongoing clinical trials (clinicaltrials.gov identifiers NCT00215527 and 
NCT00786968) studying efficacy on spinal cord compression.  No results of these trials have yet 
been published.  However, in June 2009 a study further investigating the effectiveness of 
intrathecal ERT as a treatment for another neurological symptom in MPS I, cognitive decline, 
was initiated (clinicaltrials.gov identifier NCT00852358).  This study is a 24-month, open label, 
prospective, randomized trial in 16 patients with MPS I, 6 years of age or older, who have 
documented evidence of cognitive decline.  In this study, the clinical safety of the regimen will 
be assessed by adverse events monitoring, cerebrospinal fluid (CSF) laboratory assessments, and 
clinical evaluations.  This study is ongoing; no efficacy or safety data have yet been published as 
of April 2010.18  

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
17 
Finally, the Sponsor of this current study has initiated a Phase I/II clinical trial titled, “A Safety 
and Dose Ranging Study of Idursulfase (Intrathecal) Administration Via an Intrathecal Drug 
Delivery Device in Pediatric Patients With Hunter Syndrome Who Have Central Nervous 
System Involvement and Are Receiving Treatment With Elaprase®” (clinicaltrials.gov identifier 
NCT00920647), which is using a comparable (IDDD drug route of administration and dosing 
regimen) to the current protocol.  Given the similarity in dosing regimen any untoward safety 
signals from the idursulfase IT trial will be taken under careful consideration in this clinical trial. 
1.2 
Nonclinical Overview 
Nonclinical studies indicate that IT administration of recombinant human heparan N sulfatase 
(rhHNS) leads to uptake by target CNS tissues.  Preliminary PK and biodistribution results 
indicate that IT administration of rhHNS will provide the greatest chance of achieving a 
therapeutic effect in the Sanfilippo A population as compared to systemic administration.  
Likewise, CNS penetration from IV administration is unlikely to supply sufficient brain tissue 
levels to ameliorate the CNS manifestations of the disease.  Thus, the IT route of administration 
is hypothesized to be of benefit in stabilizing, improving, or preventing the CNS manifestations 
of MPS IIIA. 
1.2.1 
Toxicology in Monkeys 
In the pivotal, 6-month IT toxicity study in juvenile cynomolgus monkeys, the high dose of 
rhHNS was administered at 8.3 mg every other week (EOW).  This translates into a 138 mg/kg 
brain weight dose (ie, based on a 60 g juvenile monkey brain).  The CNS is considered a 
compartmentalized space, isolated by highly regulated flux mechanisms; thus, allometric scaling 
from animal to man is performed by normalizing doses to brain size.19  No rhHNS-related 
adverse effects were noted at the highest dose; thus, an ~13.8 × safety margin relative to the 
starting clinical dose (10 mg, given EOW) in study HGT-SAN-055, and a ~3 × safety margin 
relative to the highest anticipated clinical dose (45 mg, given EOW) was achieved.  
1.2.2 
Efficacy in Murine and Canine Models of MPS IIIA 
Efficacy has been demonstrated at a range of doses in nonclinical mouse and canine models.  In 
MPS IIIA mice, a dose-dependent reduction in the level of a heparan sulfate-derived monosulfate 
disaccharide was observed within the brain (up to 62% reduction compared with vehicle-treated 
mice) and spinal cord (up to 71% reduction).  An ultrastructural examination revealed a 
reduction in lysosomal vesicle formation in various cell types and fewer (ubiquitin-positive) 
axonal spheroids in several brain regions after repeated injections (5 to 20 µg) of rhHNS into the 
CSF of MPS III mutant mice via the cisterna magna (ie, IT).  The biochemical changes were 
accompanied by improved behavior, particularly in mice treated more frequently.20  
In the MPS IIIA mutant mouse model, intracisternal (ie, IT) injection of a single dose of 100 µg 
rhHNS resulted in a substantial (and sustained) reduction of biomarkers of disease activity 
(heparan sulfate-derived disaccharides, microgliosis, astrogliosis).21  Equally impressive was the 
improvement in neurobehavioral parameters (learning in the Morris water maze, normalization 
of aggression) in these mice post-dose.21  

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
18 
One-hundred ug rhHNS per mouse translates into 200 mg/kg brain weight (ie, based on a 0.5 g 
mutant mouse brain); this is ~4.5 times the top human dose (45 mg) (human brain = ~1 kg).  
Efficacy at lower doses of rhHNS (eg, 20 ug, given IT, EOW or monthly) has been 
demonstrated.10  A 20 ug injection translates into a 40 mg human dose (ie, 40 mg per kilogram of 
brain weight).  Thus, this data further suggests that efficacy will be seen at the highest clinical 
dose (45 mg, EOW) in the proposed Phase I/II study.  
In the tolerized Huntaway (San A) dogs, 3 mg rhHNS was initially given IT on a weekly basis, 
then EOW, and had a significant effect on biomarkers of disease activity.22  The 3 mg dose in the 
dog translates into a 33 mg (per kg brain weight) human dose (based on a 90 g Huntaway dog 
brain).   
1.3 
Clinical Development Program 
Study HGT-SAN-053 and Study HGT-SAN-055 comprise the current Shire HGT MPS IIIA 
clinical development program to registration.  Study HGT-SAN-053 (also known as the 
Surrogate Endpoint Trial or SET) is an ongoing natural history study of untreated patients with 
MPS IIIA disease.  The study endpoints in the SET study (neurocognitive and behavioral 
assessments; CSF, urine, and serum biomarkers; and brain MRI) have been chosen as direct 
comparators for the HGT-SAN-055 treatment study. 
Study HGT-SAN-055 is a Phase I/II safety and ascending dose ranging study of recombinant 
human rhHNS administration via an intrathecal drug delivery device (IDDD) in patients with 
Sanfilippo Syndrome Type A (MPS IIIA).  The Phase I/II study was designed to determine the 
safety, tolerability, and dose frequency via ascending IT dose regimens of rhHNS administered 
via an IDDD to patients age ≥3 years of age with MPS IIIA who have quantifiable evidence of 
CNS pathology early in the course of the disease.  Patients who complete study HGT-SAN-055 
and elect to continue to receive rhHNS IT treatment will comprise the patient population for 
HGT-SAN-067. 
1.4 
Extension Study Rationale 
This extension study (Study HGT-SAN-067) will continue the evaluation of the effects of 
rhHNS administration on long-term safety and clinical activity and biomarker outcomes for 
patients who completed Study HGT-SAN-055 and elected to continue therapy with rhHNS.  
Patients who were enrolled in Study HGT-SAN-055 through Week 26 (patients who were dosed 
monthly) or Week 28 (patients who were dosed every other week) and completed the End of 
Study evaluations will be eligible for enrollment in this open-label extension study.  All patients 
enrolled in the extension study will continue to receive rhHNS at the same dose and schedule as 
that received in Study HGT-SAN-055.  The dose for each group will remain unchanged during 
this study unless safety and/or efficacy analyses of HGT-SAN-055 data indicate otherwise.  
Meaningful composite analysis of the optimum dose and regimen will come only after all 3 dose 
groups complete the entire HGT-SAN-055 study. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
19 
Study HGT-SAN-055 will be initiated in 2010.  There is no clinical information available to date 
on the use of rhHNS.  Please refer to the current edition of the rhHNS Investigator’s Brochure 
for further information. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
20 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective  
The primary objective(s) of this study is: 
To collect long-term safety and tolerability data in patients with Sanfilippo Syndrome Type A 
(MPS IIIA) who received rhHNS via a surgically implanted intrathecal drug delivery device 
(IDDD) in study HGT-SAN-055 and elected to continue therapy. 
2.2 
Secondary Objectives  
The secondary objectives of this study are: 
To collect as indications of drug efficacy, over an extended treatment period (as change from 
baseline), the following:  clinical, neurological, cognitive, behavioral, functional, and QoL 
assessments, together with potential imaging and biochemical biomarkers. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
21 
3 
STUDY ENDPOINTS 
3.1 
Primary Endpoint 
The primary endpoint of this study is: 
To determine the long-term safety of intrathecal rhHNS administration, as measured by adverse 
events (by type and severity), changes in clinical laboratory testing (serum chemistry including 
liver function tests, hematology, and urinalysis), electrocardiograms, CSF chemistries (including 
cell counts and inflammatory markers), and anti-rhHNS antibodies (in CSF and serum). 
3.2 
Secondary Endpoint  
The secondary endpoints of this study are to collect over an extended treatment period (as 
change from baseline) clinical and potential surrogate biomarker efficacy data:  
• Standardized neurocognitive and behavioral assessments, Sanfilippo-specific behavioral 
rating scales, gross and fine motor assessments, functional adaptive rating scales, quality 
of life questionnaires, and Children’s Sleep Habits Rating Scale. 
• Concentration of rhHNS in cerebrospinal fluid (CSF) and serum. 
• Concentration of inflammatory cytokines in serum and CSF. 
• Concentration of safety and potential surrogate efficacy biomarkers in CSF, urine, and 
serum. 
• Concentration of heparan sulfate and heparan sulfate derivatives in urine and CSF. 
• Brain magnetic resonance imaging (MRI) and auditory brainstem response (ABR), aka 
Brainstem Auditory Evoked Potentials. 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
22 
4 
INVESTIGATIONAL PLAN 
4.1 
Overall Study Design and Plan 
This study, HGT-SAN-067, is an open-label, long term, multicenter, extension of 
Study HGT-SAN-055.  The study is designed to evaluate the long-term safety, clinical activity, 
and biomarker outcomes of intrathecal administration of 3 dose levels (10 mg and 45 mg once 
per month and 45 mg EOW) of rhHNS via an IDDD in patients with MPS IIIA who completed 
HGT-SAN-055 and elected to continue to receive rhHNS treatment.  Patients will continue in the 
treatment group as previously received in the HGT SAN 055 study:  
• Group 1:  rhHNS administered by IT injection 10 mg once per month  
• Group 2:  rhHNS administered by IT injection 45 mg once per month  
• Group 3:  rhHNS administered by IT injection 45 mg EOW  
 
It is anticipated that all patients successfully completing the HGT-SAN-055 study will elect to 
continue to receive IT rhHNS per their previous schedule in Study HGT-SAN-055 by consenting 
to participate, without interruption, in the HGT-SAN-067 extension study.  Thus, for 
nomenclature of chronology purposes, the Baseline Visit for this extension study will be 
considered to be the first day the patient received his/her IT dose of rhHNS in Study 
HGT-SAN-055. 
Patients who participated in Study HGT-SAN-055 through Week 26 (patients dosed monthly) or 
Week 28 (patients dosed every other week) and completed the End of Study (EOS) will be 
eligible for enrollment after completing the HGT-SAN-055 EOS evaluations.  Patients will be 
screened for entry into the study based on their completed participation in Study HGT-SAN-055.  
Once eligibility is confirmed, the Investigator will fully inform the patient’s parent(s) or 
guardians(s) of the nature and scope of the study, potential risks and benefits of participation, the 
study procedures involved, and will answer all questions prior to the signing of the informed 
consent form.  The informed consent must be obtained prior to performing any study-related 
procedures.  Informed consent will be provided by the patient’s parent/legal guardian(s) prior to 
the start of the extension study procedures. 
Patients whose parents/legal guardians provide written informed consent/assent to participate in 
this study will check in with the study center 1 day prior to rhHNS dosing for safety assessments 
on each rhHNS treatment week.  If no safety concerns exist, the patient will subsequently receive 
IT administration of rhHNS on Day 2 (±2 days).  Patients will be discharged from the inpatient 
unit a minimum of 1 day following dosing with rhHNS and when deemed clinically stable by the 
Investigator.   
The patient will have already received a standardized battery of neurodevelopmental assessments 
at the Baseline and 6-month time points in the HGT-SAN-055 study.  These same assessments 
and tests will be performed at 12, 24, 36, and 48 months.  Similarly, MRI of the head, ABR 
testing, CSF sampling by means of lumbar puncture and any other procedures requiring 
anesthesia will be performed at 12, 24, 36, and 48 months.   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
23 
All patients will undergo end of study procedures 30 (±7) days following their last administration 
of rhHNS.  End of study procedures will include a standard battery of clinical laboratory tests 
(serum chemistry, hematology, and urinalysis) in CSF and blood, protocol specific laboratory 
testing (eg, anti-rhHNS antibody testing), neurodevelopmental testing, ABR, child health 
questionnaires, MRI, and concomitant medications and AE monitoring.  
All patients will be contacted by telephone for a Final Safety Follow-up, to be conducted at 
30 (±7) days after the EOS procedures to collect updated information on adverse events and 
concomitant medications, therapies, and procedures. 
It is anticipated that the IDDD will be used to obtain CSF samples and to deliver all 
administrations of rhHNS.  However, if a patient’s IDDD becomes nonfunctional or infected, it 
will be replaced so that the patient can remain on study.  If use of the IDDD is precluded on a 
scheduled day of dosing, the IDDD will be declared a failure; no study drug will be 
administered, nor CSF sample obtained on that visit.  Unlike the HGT-SAN-055 study, no study 
drug will be administered by lumbar puncture in this extension study.  Upon declaration of 
failure, the IDDD will be removed and the patient scheduled for re-implantation of a new IDDD 
(see Section 7.11) at the earliest convenience, so that the patient may remain on, or remain as 
close as possible, to his/her original IT rhHNS dosing schedule.  Note:  Patients will require 
1 week of recovery time from time of re-implantation, during which time the IDDD cannot be 
used, this may result in a delay in the next scheduled dose of rhHNS.  The patient will resume his 
or her original dosing schedule; no catch-up dosing will occur. 
If a patient discontinues the study, is withdrawn from the study, or the study is stopped by the 
Sponsor, the IDDD will be removed as part of the End of Study Procedures.  
An overview of the study appears in Appendix 1 Schedule of Events. 
4.2 
Rationale for Study Design and Control Group 
Study HGT-SAN-055 is an ongoing Phase I/II safety and ascending dose ranging study of 
intrathecal administration of rhHNS via an IDDD, in patients 3 years of age and older with MPS 
IIIA and early cognitive impairment.  This extension study is proposed to continue evaluation of 
the effects of intrathecal rhHNS administration on long-term safety and clinical outcomes for 
patients who completed Study HGT-SAN-055 and elected to continue treatment with rhHNS.  
4.3 
Study Duration and Dates 
The study duration will be 4 years. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
24 
5 
STUDY POPULATION SELECTION 
5.1 
Study Population 
Patients who have completed all study requirements in Study-HGT-SAN-055 and who elected to 
continue rhHNS treatment will be eligible to participate; a maximum of twelve patients are 
planned for this study.  
5.2 
Inclusion Criteria 
Each patient must meet the following criteria to be considered eligible for enrollment in this 
study. 
1. Patients must have completed all study requirements and assessments for Study 
HGT-SAN-055 prior to enrolling in this extension study and must have no safety or medical 
issues that contraindicate participation. 
2. The patient, patient’s parent(s), or legally authorized guardian(s) must have voluntarily 
signed an Institutional Review Board / Independent Ethics Committee-approved informed 
consent form after all relevant aspects of the study have been explained and discussed with 
the patient.  The guardians’ consent and patient’s assent, as relevant, must be obtained. 
3. The patient has received and tolerated treatment with rhHNS, completed the End of Study 
visit, and has received at least 80% of the total planned infusions within the last 6 months in 
study HGT-SAN-055 (ie, at least 5/6 ([Group 1 or 2] or 10/12 infusions [Group 3]). 
4. Patients must be medically stable, in the opinion of the Investigator, to accommodate the 
protocol requirements, including travel, assessments, and IDDD surgery (if necessary for 
replacement purposes), without placing an undue burden on the patient/patient's family. 
 
5.3 
Exclusion Criteria 
Subjects will be excluded from the study if there is evidence of any of the following criteria at 
screening or at anytime during the study: 
1. The patient has experienced an adverse reaction to study drug in Study HGT-SAN-055 that 
contraindicates further treatment with rhHNS. 
2. The patient has a known hypersensitivity to the active ingredient or any excipients in rhHNS 
drug product. 
3. The patient has significant non-MPS IIIA related central nervous system (CNS) impairment 
or behavioral disturbances that would confound the scientific integrity or interpretation of 
study assessments, as determined by the Investigator. 
4. The patient has significant MPS IIIA behavioral-related issues, as determined by the 
Investigator, which would preclude performance of study neurocognitive and developmental 
testing procedures. 
5. The patient is pregnant, breast feeding, or is a female patient of childbearing potential who 
will not or cannot comply with the use of an acceptable method of birth control, such as 
condoms, barrier method, oral contraception, etc. 
6. The patient has any known or suspected hypersensitivity to anesthesia or is thought to have 
an unacceptably high risk for anesthesia due to airway compromise or other conditions. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
25 
7. The patient has a history of poorly controlled seizure disorder. 
8. The patient is currently receiving psychotropic or other medications, which in the 
Investigator’s opinion, would be likely to substantially confound test results and the dose and 
regimen of which cannot be kept constant throughout the study. 
9. The patient cannot sustain absence from aspirin, non-steroidal medications, or medications 
that affect blood clotting within 1 week prior to a relevant study-related procedure (eg, 
device implantation if applicable), or has ingested such medications within 1 week before 
any procedures in which any change in clotting activity would be deleterious. 
10. The patient has received treatment with any investigational drug (other than rhHNS) intended 
as a treatment for MPS IIIA or used any other intrathecal delivery device other than what was 
used in Study HGT-SAN-055, within the 30 days prior to, or during the study, or is currently 
enrolled in another study that involves an investigational drug or device (screening through 
safety follow-up contact). 
11. The patient has received a hematopoietic stem cell or bone marrow transplant. 
12. The patient’s parent(s), or patient’s legal guardian(s) is/are unable to provide consent or the 
patient cannot provide assent, as appropriate, due to, but not limited to, the inability to 
understand the nature, scope, and possible consequences of the study, or do/does not agree to 
comply with the protocol defined schedule of assessments. 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
26 
6 
STUDY TREATMENT(S) 
6.1 
Description of Treatment(s) 
6.1.1 
Study Drug 
Recombinant human heparin N-sulfatase (rhHNS) drug product formulation is a sterile solution 
for injection in single-use vials for intrathecal (IT) administration.  It is formulated in an aqueous 
isotonic solution containing 15.0 mg/mL rhHNS in 145 mM sodium chloride, 0.005% (v/v) 
polysorbate 20, 5 mM sodium phosphate at pH 7.0. 
6.1.2 
Placebo or Control 
This study will not employ a placebo or control.   
6.2 
Treatment(s) Administered 
rhHNS for IT administration will be provided by Shire HGT.  rhHNS will be administered by an 
IDDD.  Following the review and signing of informed consent, patients will receive the same 
dose of rhHNS they received in Study HGT-SAN-055: 
• Group 1:  rhHNS administered by IT injection 10 mg once per month  
• Group 2:  rhHNS administered by IT injection 45 mg once per month  
• Group 3:  rhHNS administered by IT injection 45 mg every other week (EOW) 
 
6.3 
Selection and Timing of Dose for Each Subject 
The patient’s dose of rhHNS will be the same dose (10 mg and 45 mg once per month and 45 mg 
EOW) they received in Study HGT-SAN-055.  Patients will check in to the study center 1 day 
prior to intrathecal rhHNS dosing for safety assessments on each rhHNS treatment week, and if 
no safety concerns exist, will subsequently receive IT administration of rhHNS on Day 2.  
Patients will be discharged from the inpatient unit a minimum of 1 day following dosing with 
rhHNS and when deemed clinically stable by the Investigator.   
The IT injections are to be administered 28 days (±7 days [groups 1 and 2]) and 14 days (±3 days 
[group 3]) apart.  If a patient’s IDDD becomes nonfunctional, it will be replaced so that the 
patient can remain on study.  See Section 6.5 for a description on the replacement of a 
nonfunctional IDDD. 
6.4 
Cerebral Spinal Fluid Sample Procedure 
A total of 10 mL of CSF will be obtained in two 5 mL aliquots prior to each injection for safety 
evaluation using the IDDD.  A topical anesthetic agent may be applied over the skin covering the 
IDDD reservoir prior to CSF sampling.  However, CSF will not be obtained if use of the IDDD 
is precluded, with the exception at the EOS visit, when it may be obtained by means of a lumbar 
puncture (LP).  The performance of LP is at the discretion of the Investigator.  An intracranial 
pressure (ICP) measurement will be obtained whenever a LP is performed. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
27 
If a lumbar puncture is to be performed, the patient will be anesthetized via general anesthesia 
with appropriate airway management.  Once the patient is anesthetized, a lumbar puncture will 
be performed and a CSF sample will be obtained. 
6.5 
Intrathecal Administration of rhHNS 
rhHNS will be administered using an IDDD.  After appropriate pre-procedure assessments are 
completed, anesthesia cream will be applied to the skin over the port.  Patients may receive mild 
sedation to alleviate anxiety and/or to facilitate drug delivery.     
Patients will then receive their appropriate dose of rhHNS via slow push/ injection over 2 to 
5 minutes.  Replacement of fluid, including drug, to the CSF will be an approximate equal 
volume to that removed.  The patient’s vital signs will be continuously monitored.  The patient 
will also be monitored closely during enzyme administration and through the next 24 hours for 
any adverse clinical reactions.  The patient will be encouraged to lie down comfortably for 1 to 
3 hours post injection, although this may be difficult for the most hyperactive patients. 
If use of the IDDD is precluded on a scheduled day of dosing, the IDDD will be declared a 
failure; no study drug will be administered, nor CSF sample obtained on that visit.  Unlike the 
HGT-SAN-055 study, no study drug will be administered by lumbar puncture in this extension 
study.  Upon declaration of failure, the IDDD will be removed and the patient scheduled for 
re-implantation of a new IDDD (see Section 7.11) at the earliest convenience, so that the patient 
may remain on, or remain as close as possible, to his/her original IT rhHNS dosing schedule.  
Note:  Patients will require 1 week of recovery time from time of re-implantation, during which 
time the IDDD cannot be used, this may result in a delay in the next scheduled dose of rhHNS.  
The patient will resume his or her original dosing schedule; no catch-up dosing will occur. 
6.6 
Method of Assigning Subjects to Treatment Groups 
This is an open-label, non-randomized study; all patients enrolled in this study will be treated 
with rhHNS.  Patients will remain in the groups (1, 2, or 3) they were assigned to in 
Study HGT-SAN-055.  
6.7 
Blinding 
Not applicable; this trial is not blinded. 
6.8 
Concomitant Therapy 
All non-protocol treatments and procedures that occur from the time of informed consent (or 
assent, if applicable) through the safety follow-up contact are regarded as concomitant and will 
be documented on the appropriate pages of the electronic case report form (eCRF).  Concomitant 
therapy includes medications, therapies/interventions administered to patients, and 
medical/surgical procedures performed on the patients.  
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
28 
Every effort should be made to keep the patient’s symptomatic Sanfilippo syndrome Type A 
treatment constant throughout the study.  However, changes in medications are acceptable if 
necessary according to clinical judgment.  All changes will be recorded on the appropriate eCRF.  
Concomitant medication will be coded using World Health Organization Drug Reference List 
(WHODRL). 
6.9 
Restrictions 
6.9.1 
Prior Therapy 
Prior therapy excluded for this study consists of the following: 
• Psychotropic or other medications, which in the Investigator’s opinion, would be likely to 
substantially confound test results and the dose and regimen of which cannot be kept constant 
throughout the study. 
• The patient cannot sustain absence from aspirin, non-steroidal medications, or medications 
that affect blood clotting within 1 week prior to a relevant study related procedure (eg, device 
implantation if applicable) or medications within 1 week before any procedures in which any 
change in clotting activity would be deleterious. 
• The patient has received any investigational drug or device intended as a treatment for MPS 
IIIA within the 30 days prior to the study other than rhHNS or is enrolled in another study 
that involves an investigational drug or device. 
• Hematopoietic stem cell or bone marrow transplant. 
 
6.9.2 
Fluid and Food Intake  
Oral food and fluid intake are not restricted over the course of the study, with the exception of 
hospital standard pre-anesthesia dietary restrictions. 
6.9.3 
Subject Activity Restrictions 
There are no restrictions on patient activities in this study. 
6.10 Treatment Compliance 
rhHNS is administered under controlled conditions by the Investigator; therefore, full patient 
compliance with study treatment is anticipated in this study.  
6.11 Packaging and Labeling 
Drug product will be supplied in a 3 mL clear, colorless glass (Type 1) vial.  Each vial holds an 
extractable volume of 1 mL of rhHNS.  The closure is a gray, 13 mm stopper composed of butyl 
rubber with a fluoro resin lamination.  The overseal is an aluminum seal with a flip-off, plastic, 
tamper evident cap.  

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
29 
6.12 Storage and Accountability 
Drug product should be stored refrigerated (2 to 8°C); drug product may not be stored beyond 
the expiration date on the vial. 
6.13 Investigational Product Retention at Study Site 
All rhHNS study drug delivered to an Investigator will be recorded and accounted for throughout 
the study.  All rhHNS study drug must be recorded on a patient-by-patient basis.  The lot number 
of the IDDD and the date and time of administration of the study medication will be documented 
on the appropriate eCRF. 
All unused study medication and other study materials are to be returned to the Sponsor or its 
designee or disposed after Sponsor approval per site policy after the study has been completed. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
30 
7 
STUDY PROCEDURES 
7.1 
Informed Consent 
Study procedures will be conducted only after written informed consent for the patient to 
participate in this study is provided by the parent(s) or legal guardian(s) and assent from the 
patient (if applicable).  Detailed descriptions of patient evaluations required for this protocol are 
described in this section.  These evaluations will be performed during the indicated days and 
weeks of each study month (see Appendix 1 Schedule of Events). 
All data collected are to be recorded on the appropriate eCRF.  The approximate maximum total 
blood, urine, and CSF volumes to be collected from each patient by the end of this study for 
safety assessments are presented in Table 7-1. 
Table 7-1 Approximate Total Sample Volumes Collected Over the Duration of the 
Study From Each Patient by Group and Assay 
 
Groups 1 and 2 
Group 3 
Blood  
290 mL 
555 mL 
Urine 
530 mL 
1,010 mL 
CSF 
480 mL 
960 mL 
 
 
Blood, urine and CSF volumes to be collected for each clinical laboratory measurement are 
described in detail in the Laboratory and/or Study Operations Manual. 
7.2 
Physical Examination 
A physical examination of each patient will be performed as detailed in Appendix 1 Schedule of 
Events. 
Note:  if the patient’s hearing cannot be assessed during the physical examination, the patient 
will have an Ears, Nose, and Throat Evaluation performed under anesthesia at the baseline visit.  
If is determined that the patient requires pressure-equalization (PE) tubes, they may be implanted 
during that same visit.  See Section 7.9 for details.  Note:  Pressure-equalization tubes may be 
re-implanted if they fall out during this study. 
 
 
 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
31 
The physical examination findings will be recorded on the eCRF and will include a review of the 
patient’s general appearance as well as the following evaluations: 
- 
Head and neck 
- 
Eyes, ears, nose and throat 
- 
Chest and lungs 
- 
Cardiovascular 
- 
Abdomen 
- 
Skin 
- 
Lymphatic 
- 
Musculoskeletal 
- 
Neurological 
- 
Endocrine 
- 
Genitourinary 
 
7.3 
Height and Weight 
Height or length (cm), and weight (kg) measurements will be taken once.  All data will be 
recorded on the eCRF. 
7.4 
Head Circumference 
Head circumference will be measured once.  The data will be recorded on the eCRF. 
7.5 
Vital Signs 
Vital signs (blood pressure, heart rate, respiratory rate, and temperature measurements) will be 
measured and recorded on the eCRF. 
7.6 
Electrocardiography 
7.6.1 
Electrocardiograms 
An ECG will be performed.  Each ECG will include assessment of heart rate, sinus rhythm, atrial 
or ventricular hypertrophy, PR, QRS, QT, and QTc intervals.  The ECGs will be conducted in 
accordance with the clinical site’s standard practice(s), and will be read locally at the clinical 
site.  Identification of any clinically significant findings and/or conduction abnormalities will be 
recorded on the eCRF.   
7.7 
Clinical Laboratory Tests 
Blood, urine, and CSF samples will be collected as described below for clinical laboratory 
testing.  Procedures for collection and handling of samples are included in the Laboratory and/or 
Study Operations Manual.  
Patients will be in a seated or supine position during blood collection.  Clinical laboratory tests 
will include hematology, serum chemistry, and urinalysis. 
Laboratory Parameters  
Clinical laboratory tests will be performed at a central laboratory include the following: 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
32 
7.7.1 
Hematology 
• Hematocrit (Hct) 
• Hemoglobin (Hgb) 
• Mean corpuscular hemoglobin (MCH) 
• Mean corpuscular hemoglobin concentration (MCHC) 
• Mean corpuscular volume (MCV) 
• Platelet count 
• Red blood cell (RBC) count  
• White blood cell (WBC) count with differential  
 
7.7.2 
Serum Chemistry 
7.7.2.1 
Standard Serum Chemistry 
• Albumin (ALB) 
• Alkaline phosphatase (ALK-P) 
• Alanine aminotransferase (ALT; SGPT) 
• Aspartate aminotransferase (AST; SGOT) 
• Blood urea nitrogen (BUN) 
• Calcium (Ca) 
• Carbon dioxide (CO2) 
• Chloride (Cl) 
• Creatinine 
• Creatine kinase (CK) and subtypes 
• Gamma-glutamyl transferase (GGT) 
• Globulin 
• Glucose 
• Lactate dehydrogenase (LDH) 
• Phosphorus 
• Potassium (K) 
• Sodium (Na) 
• Total bilirubin 
• Direct bilirubin 
• Total cholesterol 
• Total protein 
• Triglycerides 
• Uric acid 
 
7.7.3 
Urinalysis  
Patient catheterization may be required for obtaining urine samples (if deemed necessary by the 
Investigator).   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
33 
7.7.3.1 
Standard Urinalysis 
The following urinalysis parameters will be performed at a central laboratory on urine samples: 
• Macroscopic examination  
• Microscopic examination of sediment  
• pH 
 
7.7.3.2 
Urine Heparan Sulfate and Heparan Sulfate Derivatives 
A urine sample will be collected for the determination of heparan sulfate and heparan sulfate 
derivatives and the analysis will be performed at Shire HGT laboratories.  A urine sample from 
each visit will be reserved for possible, exploratory biomarker studies that may provide new 
indicators or markers of MPS IIIA disease severity or progression. 
7.7.4 
Cerebrospinal Fluid Assessments 
Cerebrospinal fluid (CSF) samples (10 ml in two 5 ml aliquots; labeled separately and processed 
according to the study operations manual) will be obtained from patients through an implanted 
IDDD.  Should the IDDD become blocked or undergo mechanical complications, the CSF 
sample will not be obtained via lumbar puncture (LP), except when part of the EOS visit.  The 
performance of LP is at the discretion of the Investigator.  See Section 6.4 for further details. 
CSF sample collection, processing, and shipping instructions will be provided in the Laboratory 
and/or Study Operations Manual.  A CSF sample will be reserved for possible exploratory 
biomarker studies for MPS IIIA disease. 
Each CSF sample collected will be assessed for appearance and will be analyzed using the assays 
listed in Sections 7.7.4.1, 7.7.4.2, and 7.7.4.4.  In addition, as more is learned about Sanfilippo 
CNS pathology and etiology, future exploratory assays of CSF metabolites or protein or RNA 
may become available in the future (the samples maybe analyzed, if the assays are found 
applicable) and are thus not presently listed within this protocol. 
7.7.4.1 
CSF Cell Counts 
An aliquot of each CSF sample collected will be evaluated for CSF standard chemistries, 
glucose, protein, and cell counts.  These assessments will be performed at the local laboratory. 
7.7.4.2 
CSF Heparan Sulfate Levels and Heparan Sulfate Derivatives 
An aliquot of each CSF sample collected will be quick frozen as per the Laboratory and/or Study 
Operations Manual for subsequent determination of CSF heparan sulfate and heparan sulfate 
derivatives at Shire HGT laboratories. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
34 
7.7.4.3 
Anti-rhHNS Antibodies 
An aliquot of each CSF sample collected will be quick frozen as per the Laboratory and/or Study 
Operations Manual for subsequent determination of anti-rhHNS antibodies at Shire HGT 
laboratories. 
7.7.4.4 
CSF Biomarkers  
An aliquot of each CSF sample collected will be quick frozen as per the Laboratory and/or Study 
Operations Manual for subsequent determination of MPS exploratory biomarkers at Shire HGT 
laboratories. 
7.7.5 
Sample Collection, Storage, and Shipping 
Sample collection, processing, and shipping instructions will be provided in the Laboratory 
and/or Study Operations Manual to be provided by Shire HGT. 
7.8 
Anesthesia 
Administration of anesthesia/sedation will be given prior to obtaining CSF (when the use of the 
IDDD is precluded – see Section 6.4), prior to performing the MRI of the head, the ABR, the 
intracranial pressure (ICP), and the re-implantation of the IDDD (if applicable).  See Appendix 1 
for the Schedule of Events. 
Note:  the neurologic exam and the neurocognitive and developmental assessments must be 
performed prior to the administration of anesthesia. 
7.9 
Audiometry and Auditory Brainstem Response 
The rare attenuated patients with MPS IIIA with high levels of cognitive functioning will have 
hearing tests via clinical audiometry measurement performed using age-appropriate testing 
methods based on the child’s developmental age at the time of the testing.  It is anticipated that 
most of the cognitively-impaired and/or behaviorally-deteriorated patients with Sanfilippo A will 
be unable to co-operate with a (conscious) hearing evaluation.  In these instances, the 
Investigator will utilize his best clinical judgement to initially estimate the extent of hearing loss 
(if any) during the initial physical examination.  In this situation, specific evaluation of hearing 
loss will await examination of waveforms in the ABR (see below).  If the patient has a history of 
multiple instances of otitis media or evidence of clinically-significant otitis media on physical 
examination, which the Investigator believes causes significant conductive hearing loss and 
impairment of daily living, the Investigator will ask and offer the parent or guardian placement 
of PE tubes as part of the scheduled anesthesia.  A patient’s PE tubes may be replaced if they fall 
out during the course of this study. 
The auditory brainstem response (ABR) will be conducted under anesthesia.  The ABR findings 
will be considered within normal limits if, after applying appropriate correction factors, the 
waveforms reveal normal morphology.  

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
35 
7.10 MRI of the Head 
The regional brain volume will be assessed through an MRI of the head.  The patient will be 
under general anesthesia for this assessment.  The central reading for MRI data, across all sites, 
will be completed at the University of Minnesota Medical Center.  Refer to the Study Operations 
Manual for specific procedures and precautions. 
7.11 Surgical Re-implantation of the IDDD 
If a patient’s IDDD becomes nonfunctional or infected, it will be replaced so that the patient can 
remain on study.  Procedures for implantation will be detailed in the device’s Instructions for 
Use manual.  The patient will be under general anesthesia for this procedure.  Standard hospital 
procedure for surgery will be followed and will include an X-ray to confirm device placement at 
the mid-thoracic level.  A post-operative check of the IDDD will be performed on Day 7 
following surgery.  X-rays may be performed to check placement of the device, as needed, 
throughout the study.  Drug can only be administered via the IDDD. 
7.12 Intracranial Pressure Measurement 
Intracranial pressure measurement (ICP) (centimeters of H2O) will be conducted per standard 
hospital practice.  The measurement will be obtained whenever a LP is performed. 
7.13 Dispensing Study Drug 
rhHNS will be administered IT by means of an IDDD to patients in Dose Groups 1 and 2 on 
Day 2 (±2 days) of Week 1 of each treatment month and to patients in Dose Group 3 on Day 2 
(±2 days) of Weeks 1 and 3 of each treatment month. 
The patient may be mildly sedated for this procedure; rhHNS will be administered over 2 to 
5 minutes.  Please see Section 6.5 if the IDDD is not functioning.   
The patient must not receive aspirin, non-steroidal anti-inflammatory medications, or 
medications that affect clotting within 1 week prior to each IT injection. 
7.14 Pharmacokinetic Assessments 
Pharmacokinetic assessments will not be included in this study. 
7.15 Neurological Examination 
A neurological examination to monitor CNS changes in patient’s neurological status will be 
conducted during this study.  See Appendix 2 for a complete list of the neurological 
examinations. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
36 
7.16 Serum Anti-rhHNS Antibody, Heparan Sulfate and Heparan Sulfate 
Derivative Determination 
Blood samples will be collected prior to rhHNS injection and evaluated at Shire HGT 
laboratories for the determination of anti-rhHNS antibodies, heparan sulfate and heparan sulfate 
derivatives.  Samples will be reserved for potential future MPS IIIA research that may determine 
biomarkers of disease severity and progression.  
Two 5 mL blood samples will be collected from each patient at each designated time point.  One 
5 mL sample will be collected in a tube intended for serum specimens, while the second sample 
will be collected in a tube intended for plasma specimens.  Blood sample collection, processing, 
and shipping instructions will be provided in the Laboratory and or Study Operations Manual. 
7.17 Neurocognitive and Developmental Assessments 
Patients will undergo neurocognitive and neurobehavioral development testing.  The assessments 
are estimated to last between 2 and 4 hours and must be conducted prior to sedation or 
anesthesia.  
A full neurodevelopmental assessment, including global development, cognition, adaptive 
behavior, receptive and expressive language, and gross motor function, will be evaluated using 
standardized developmental and behavioral tests to provide a surrogate and quantifiable measure 
of global CNS neurodevelopmental/neurobehavioral function.  
For this study, outcome measures will be computed for each patient enrolled.  The psychometric 
instruments and Sanfilippo-specific assessments are summarized below in Table 7-2 and 
Table 7-3, respectively.  See Appendix 3 for details on these assessments. 
Table 7-2 Neurodevelopmental Assessments Tests  
Developmental or Cognitive 
Domain(s) 
Patient Age:  Representative Cognitive Test or 
Scale 
COGNITIVE DEVELOPMENT ASSESSMENT 
Summary score and sub-domains: 
- Cognitive 
- Motor 
 
0 to 42 months:  Bayley Scales of Infant 
Development-III (BSID-III) 23 
 
- Cognitive  
- Processing skills 
 
3 to 18 years:  Kaufman Assessment Battery for 
Children, Second Edition (KABC-II) 24 
GROSS AND FINE MOTOR SKILLS ASSESSMENT AND VOLUNTARY MOVEMENT 
Motor 
3.0 to 16:11 years:  Movement Assessment Battery 
for Children II (MABC-2) 25 
- Cognitive 
- Motor 
0 to 5 ½ years:  Bayley Scales of Infant 
Development III (BSID-III) 23 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
37 
Table 7-2 Neurodevelopmental Assessments Tests  
Developmental or Cognitive 
Domain(s) 
Patient Age:  Representative Cognitive Test or 
Scale 
ADAPTIVE BEHAVIOR 
Communication 
Daily Living 
Socialization 
Motor Skills 
0 to 90 years:  Vineland Adaptive Behavior Scales 
(VABS-II)  Second Edition 26 
 
Table 7-3 Sanfilippo-Specific Disability Assessment And Behavior Rating Scales 
Developmental or Cognitive 
Domain(s) 
Sanfilippo Specific Assessments 
Parent-scored behavioral inventory 
- communication:  understanding 
- communication:  expression 
- tantrums 
- specific behaviors inventory 
- mood & emotions inventory 
 
Sanfilippo Behavior Rating Scale (SBRS) 
MPS-specific disability score  
- cognitive functioning 
- expressive language 
- motor score 
Four-Point Scoring System/Total Disability Score 
(FPSS/TDS)4  
 
7.18 Sleep Questionnaire:  Children’s Sleep Habits Rating Scale  
A sleep questionnaire, Children’s Sleep Habits Rating Scale, will be administered to the patient's 
patients/legal guardian. 
7.19 Age-Dependent, Health-Related Quality of Life in Children 
The Quality of Life questionnaires will be administered as outlined in Sections 7.19.1, 7.19.2, 
and 7.19.3. 
7.19.1 
Quality of Life Indicator:  CHQ-50 
The Child Health Questionnaire™ Parent Form 50 Questions (CHQ-50) will be administered 
during the study.   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
38 
The questionnaire is a generic quality of life instrument, measuring 14 unique physical and 
psychosocial concepts, which was developed for children from 5 to 18 years of age 
7.19.2 
Quality of Life Indicator:  CHQ-87 
The Child Health Questionnaire™ Child Form 87 (CHQ-87) will be administered during the 
study.  The CHQ-87 is a child and adolescent self-report, developed for ages 10 and older, which 
assesses the child’s self-perceived physical and psychosocial well-being 
7.19.3 
Quality of Life Indicator:  ITQOL 
The Infant Toddler Quality of Life Questionnaire™ (ITQOL) will be administered during the 
study.  The ITQOL was developed for children at least 2 months of age up to 5 years and 
assesses the physical, mental, and social well being of the child and assesses the quality of the 
parent/guardian’s life.   
7.20 Concomitant Medications, Therapies and Medical/Surgical Procedures 
All non-protocol treatments that occur from the time of informed consent (assent if applicable) 
through the safety follow-up contact are regarded as concomitant and will be documented on the 
appropriate pages of the eCRF.  Concomitant therapy includes medication, 
therapies/interventions administered to patients, and medical/surgical procedures performed on 
the patients. 
Every effort should be made to keep symptomatic Sanfilippo syndrome Type A treatment 
constant throughout the study.  However, changes in medications are acceptable if necessary 
according to clinical judgment.  All changes will be recorded on the appropriate eCRF.  
Concomitant medication will be coded using WHODRL. 
7.21 Adverse Events 
7.21.1 
Adverse Events Assessments 
Adverse events will be monitored continuously throughout the study from the time the patient, 
patient's parent/legal guardian signs the informed consent/assent (if applicable) until the safety 
follow-up contact or until the event has resolved or stabilized, or an outcome is reached, 
whichever comes first.  
If the Investigator considers it necessary to report an AE in a study patient after the end of the 
observation period, he or she should contact the Sponsor to determine how the AE should be 
documented and reported. 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
39 
7.21.2 
Definitions of Adverse Events and Serious Adverse Events 
7.21.2.1 
Adverse Event 
An adverse event (AE) is any noxious, pathologic, or unintended change in anatomical, 
physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory 
changes occurring in any phase of a clinical study, whether or not considered study drug-related.  
This includes an exacerbation of a pre-existing condition.  Once the informed consent is signed, 
any adverse event prior to the start of study drug must be reported.  
AEs include: 
• Worsening (change in nature, severity, or frequency) of conditions present at the onset of the 
study 
• Intercurrent illnesses 
• Drug interactions 
• Events related to or possibly related to concomitant medications 
• Abnormal laboratory values (this includes significant shifts from baseline  within the range 
of normal that the Investigator considers to be clinically important) 
• Clinically significant abnormalities in physical examination, vital signs, and weight 
 
Throughout the study, the Investigator must record all AEs on the AE case report form (eCRF), 
regardless of the severity or relationship to study drug.  The Investigator should treat patients 
with AEs appropriately and observe them at suitable intervals until the events stabilize or 
resolve.  AEs may be discovered through observation or examination of the patient, questioning 
of the patient, complaint by the patient, or by abnormal clinical laboratory values. 
In addition, AEs may also include laboratory values that become significantly out of range.  In 
the event of an out-of-range value, the laboratory test should be repeated until it returns to 
normal or can be explained and the patient’s safety is not at risk.   
All adverse events should be recorded with causality assessment. 
The information presented below is intended to provide issues to consider for adverse events 
associated with intrathecal injections of rhHNS.  In general, these adverse events can be 
classified as follows:  
• Adverse events due to systemic exposure to rhHNS caused by the drug diffusion from the 
CSF to the peripheral circulation;  
• Adverse events related to the direct delivery of rhHNS to the intrathecal CSF space and 
meninges, and subsequent diffusion into brain parenchyma, via an intrathecal route  
• IDDD–related adverse events.   
 
Note:  the classification of potential adverse events and the examples presented below are based 
on purely theoretical considerations and/or published literature as there is no human experience 
with intrathecal rhHNS therapy to date. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
40 
POTENTIAL ADVERSE EVENTS:  INTRATHECAL RHHNS 
Adverse Events Due To Systemic Exposure To rhHNS 
Although rhHNS is given intrathecally only, some proportion of the drug will diffuse from the 
CSF into the peripheral circulation.  The resulting systemic exposure may cause events that are 
typically seen in patients receiving ERT via an intravenous administration, known as 
infusion-related reactions.  An infusion-related reaction is defined as an adverse event that 
(1) begins either during or within 24 hours after the start of the infusion, and (2) is judged as 
possibly or probably related to study drug.  Other AEs that occur prior to the infusion, along with 
AEs associated with protocol-defined testing and assessments (laboratory testing and physical 
examinations) that were performed prior to the infusion will not be defined as infusion-related 
reactions.   
Adverse Events Related to the Direct Delivery of rhHNS to the CNS Through Intrathecal 
Administration 
Examples of adverse events observed in other published clinical trials with 
intrathecally-administered peptides or proteins, include, but are not limited to the following:  
headache, fever, feeling of warmth, sensory parathesias (including feelings of warmth, tingling, 
or pain) or autonomic symptoms such as dry mouth or gustatory abnormalities (including loss of 
smell and metallic taste).  Changes in mental cognitive status or level of consciousness that are 
not caused by pre-medication may either occur acutely or develop post-injection, over time. 
Potential Adverse Events:  IDDD -Related Adverse Events 
Examples of adverse events related to the insertion or use of an IDDD include, but are not 
limited to, the following:  catheter disconnection or fracture, erosion of portal/catheter through 
the skin, fibrin sheath formation around catheter tip, hematoma, implant rejection, malposition of 
catheter, migration of portal/catheter, occlusion of portal/catheter, portal site or subcutaneous 
tract infection, and sepsis.   
In addition, there are risks associated with intraspinal access, which include the following:  
cerebrospinal fluid leaks, dura mater or epidural vein perforation, epidural or intrathecal space 
infection (which could result in meningitis), inadvertent epidural placement, pain on injection, 
and spinal cord or nerve injury. 
7.21.2.2 
Serious Adverse Event 
A serious AE (SAE) is any AE occurring at any dose that results in any of the following 
outcomes: 
• Death 
• Is life-threatening 
• Requires inpatient hospitalization 
• Requires prolongation of existing hospitalization 
• A persistent or significant disability or incapacity  

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
41 
• A congenital anomaly or birth defect 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization. 
The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) 
Version 3.0 grading scale should be referenced when assessing the severity of an AE (see 
Appendix 5)  If an AE is not described in the NCI CTC, the severity should be recorded based on 
the scale provided in Table 7-4.  The severity of all AEs/SAEs should be recorded on the 
appropriate eCRF page as Grade 1, 2, 3, 4, or 5 corresponding, respectively, to a severity of mild, 
moderate, severe, life-threatening, or death. 
Table 7-4  Adverse Event Severity 
Severity 
Definition 
Grade 1 (Mild) 
No limitation of usual activities. 
Grade 2 (Moderate) 
Some limitation of usual activities. 
Grade 3 (Severe) 
Inability to carry out usual activities. 
Grade 4 (Life-threatening) 
Immediate risk of death. 
Grade 5 (Death related to an AE) 
Death 
 
Relationship of an adverse event or serious adverse event to study medication is to be determined 
by the Investigator based on the definitions in Table 7-5: 
Table 7-5 Adverse Event Relatedness 
Relationship to Product(s) 
Definition 
Not Related 
Unrelated to study drug. 
Possibly Related 
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of study drug, but which could also be 
explained by concurrent disease or other drugs or chemicals. 
Probably Related 
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of study drug, unlikely to be attributable to 
concurrent disease or other drugs and chemicals and which follows a 
clinically reasonable response on de-challenge.  The association of the 
clinical event or laboratory abnormality must also have some biologic 
plausibility, at least on theoretical grounds. 
Definitely related 
The event follows a reasonable temporal sequence from administration 
of the medication, follows a known or suspected response pattern to 
the medication, is confirmed by improvement upon stopping the 
medication (dechallenge) and reappears upon repeated exposure 
(rechallenge).   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
42 
Table 7-5 Adverse Event Relatedness 
Relationship to Product(s) 
Definition 
Note that this is not to be construed as requiring re-exposure of the 
patient to study drug; however, the determination of definitely related 
can only be used when recurrence of event is observed. 
 
7.21.3 
Procedures for Recording and Reporting Adverse Events 
7.21.3.1 
Reporting Serious Adverse Events 
Any SAE, regardless of relationship to study medication, which occurs in a patient after 
informed consent, should be recorded by the clinical site on an SAE form.  The SAE must be 
completely described on the patient’s eCRF, including the judgment of the Investigator as to the 
relationship of the SAE to the study drug or device.  The Investigator will promptly supply all 
information identified and requested by the Sponsor (or contract research organization [CRO]) 
regarding the SAE.  
The Investigator must report the SAE to the Shire Pharmacovigilance and Risk Management 
Department AND to the Shire HGT Medical Monitor on an SAE form.  This form must be 
completed and FAXED within 24 hours of the Investigator’s learning of the event to: 
Shire Pharmacovigilance and Risk Management Department: 
International FAX: 
(UK) OR United States FAX: 
AND 
Shire HGT Medical Monitor: 
 MD 
FAX: 
(USA) 
Any follow-up information must also be completed on an SAE form and faxed to the same 
numbers listed above. 
In the event of a severe and unexpected, fatal, or life-threatening SAE, the clinical site must 
contact the Shire HGT Medical Monitor by telephone; this is in addition to completing and 
transmitting the SAE form as stated above.  The following provides contact information for the 
Shire HGT Medical Monitor. 
 
 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
43 
If an SAE is assessed as severe and unexpected, or life-threatening, contact: 
, MD 
Shire Human Genetic Therapies, Inc. 
700 Main Street 
Cambridge, MA 02139, USA 
Telephone: 
Fax: 
(USA) 
Mobile: 
 
The Investigator must promptly report all required information to the Institutional Review Board 
(IRB)/ Independent Ethics Committee (IEC).  It is the responsibility of the Sponsor to ensure that 
each Investigator receives a copy of any CIOMS I/ MedWatch report that has been submitted to 
the appropriate regulatory agencies notifying them of an unexpected related SAE.  The 
Investigator or Sponsor must ensure that the IRB/IEC receives a copy of the report and that a 
copy is also filed within their study files.  
7.21.3.2 
Eliciting Adverse Events 
Patients should be asked non-leading questions (eg, “How do you feel?”) and further questions 
should be posed if there is indication of an AE.  The questioning should be conducted with due 
regard for objectivity and, in particular, the questioner should gather information regarding AEs 
from questioning the patient, the patient’s parent/guardian, spontaneous report by the patient or 
parent/guardian, laboratory reports, and any health care provider’s observations. 
The onset date, resolution date, treatment administered, and outcome of each AE must be 
recorded on the appropriate eCRF.  In addition, the relationship of each AE to study medication 
must be recorded. 
7.21.3.3 
Protocol Deviations for Medical Emergency or Adverse Event 
During and following a patient’s participation in the study, the Investigator should ensure that 
adequate medical care is provided to a patient for any AEs, including clinically significant 
laboratory test results.  The Investigator should inform the patient, the patient’s parent(s), or the 
patient’s legally authorized representative when medical care is needed for intercurrent 
illness(es) of which the Investigator becomes aware.  In an emergency situation, the Investigator 
should contact the Shire HGT Medical Monitor (see Section 7.21.3.1). 
Only when an emergency occurs that requires an immediate deviation from the protocol for the 
safety of a patient, will there be such a deviation and this will be only for that patient.  The 
Investigator or other physician in attendance in such an emergency must contact the Shire HGT 
Medical Monitor as soon as possible.   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
44 
The Investigator, along with the Shire HGT Medical Monitor, will make a decision as to whether 
or not the patient should continue in the study prior to the next scheduled dose.  The departure 
from the protocol and the grounds for it should be stated in the eCRF. 
7.22 Pregnancy 
Pregnancy and lactation are exclusion criteria.  The Sponsor must be notified in the event of a 
pregnancy occurring during the course of the study and through 30 days after the patient’s last 
dose of study drug.  Pregnancy is not to be reported as an AE; the pregnancy reporting form 
should be used to report the pregnancy.  The pregnancy will be followed up through delivery or 
final outcome. 
7.23 Removal of Subjects from the Trial or Study Drug 
The patient's parent or legal guardian acting on behalf of the patient is free to withdraw consent 
and discontinue participation in the study at any time without prejudice to further treatment.  
Since this is an extension trial, there will be no replacement of patients who discontinue the 
study for any reason. 
A patient’s participation in the study may be discontinued at any time at the discretion of the 
Investigator, Sponsor or Medical Monitor.  The following may be justifiable reasons for the 
Investigator, Sponsor or Medical Monitor to remove a patient from the study: 
• Adverse Event:  If a patient experiences an AE which, in the judgment of the investigator, the 
sponsor, or the medical monitor, presents an unacceptable consequence or risk to the patient. 
• Adverse Laboratory Experience:  If a patient has an adverse laboratory experience which, in 
the judgment of the investigator, the Sponsor, or the medical monitor, presents an 
unacceptable consequence or risk to the patient, the patient may be withdrawn from the 
study. 
• Comorbidity:  If a patient develops comorbidity during the course of the study that is 
independent of the study indication, and treatment is required that is not consistent with 
protocol requirements.  
• Intercurrent Illness:  If a patient develops an illness during the course of the study that is not 
associated with the condition under study, and which requires treatment that is not consistent 
with protocol requirements. 
• Refusal of Treatment:  If for any reason the patient refuses treatment during the study, the 
patient will be withdrawn from the study, and the reason for refusal will be documented on 
the eCRF.  Reasonable efforts will be made to monitor the patient for AEs following such 
discontinuation.  Such efforts will be documented in the eCRF. 
• Withdrawal of Informed Consent:  A patient’s parent or legally authorized guardian may 
withdraw his informed consent to participate in the study at any time. 
• Cerebrospinal fluid leukocyte count >100 cells per cubic millimeter for 2 consecutive 
months. 
• New onset seizure. 
• Anaphylactic reaction beyond reasonable management as described in the Investigator’s 
Brochure. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
45 
• Clinically problematic intubations or extubations which may preclude safe airway 
management and anesthesia. 
• Development of refractory spinal fluid leakage.  
• Clinically significant prolonged (eg greater than 24 to 48 hours) worsening in mental status, 
including development of new focal or non-focal neurological symptoms, or recurrence of a 
previously stable prior medical problem judged due to study drug or participation that is 
exclusive of effects from anesthesia. 
• Non-compliance, including failure to appear at 1 or more study visits. 
• The patient was erroneously included in the study. 
• The patient develops an exclusion criterion. 
• The study is terminated by the Sponsor. 
 
If a patient or the patient’s legal guardian(s), acting on behalf of the patient, discontinues 
participation in the study, or the patient is discontinued by the Investigator, the Patient 
Completion/Discontinuation Case Report Form (eCRF) describing the reason for discontinuation 
must be completed.  Any adverse events (AE’s) experienced up to the point of discontinuation 
must be documented on the AE eCRF.  If AEs are present when the patient withdraws from the 
study, the patient will be re-evaluated within 30 days of withdrawal.  All ongoing SAEs at the 
time of withdrawal will be followed until resolution. 
At the time of discontinuation or withdrawal, patients will be asked to participate in all safety 
and efficacy evaluations required for the end of study visit and for the safety follow-up visit.  
Participation in these EOS procedures will be strongly encouraged, but is voluntary for those 
patients electing to discontinue from the study.  The patient will be scheduled for the removal of 
the IDDD.  
7.24 Other Study Procedures 
This section is not applicable. 
7.25 Appropriateness of Measurements 
The neurocognitive and developmental assessments are intended to gauge which domains can be 
accurately measured, with which specific tools, despite the considerable behavioral and cognitive 
challenges in Sanfilippo syndrome.  The evaluation of these domains and the analysis of CSF, 
serum, and urine biomarkers will provide the pivotal data necessary to inform the clinical 
assessments and biomarkers used in possible future Sanfilippo syndrome ERT trials.  

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
46 
8 
STUDY ACTIVITIES 
Patients who participated in Study HGT-SAN-055 through Week 26 (patients who were dosed 
monthly) or Week 28 (patients who were dosed every other week) and completed the End of 
Study evaluations will be eligible for enrollment in this open-label extension study.  Informed 
consent will be provided by the patient’s parent(s)/legal guardian(s) prior to start of extension 
study procedures.   
If there are no safety concerns, patients who were previously treated with intrathecal rhHNS in 
Study HGT-SAN-055 and elect to continue rhHNS treatment will continue receiving monthly 
(Groups 1 and 2) or EOW (Group 3) intrathecal rhHNS in this extension study, as described in 
Appendix 1 Schedule of Events. 
8.1 
Screening Visit/Baseline Visit  
All Screening assessments for this study are to have been performed during the Week 26 
(Groups 1 and 2) or Week 28 (Group 3) (30 [±7] days after the last rhHNS administration) EOS 
procedures in HGT-SAN-055.  If less than 60 days have elapsed since completion of the EOS 
assessments for HGT-SAN-055, the assessments detailed in this Screening visit are not required 
to be repeated.  The Baseline Visit for this study will be the first day the patient received his/her 
IT dose of rhHNS in Study HGT-SAN-055.   
If more than 60 days have elapsed following the HGT-SAN-055 EOS procedures, patients will 
be evaluated for enrollment in HGT-SAN-067on a case-by-case basis by the Investigator.  A 
decision about enrollment will be made following discussion with the Medical Monitor.  If the 
patient is enrolled, the following assessments are to be repeated within 30 days prior to the first 
scheduled intrathecal rhHNS dose: 
• Physical examination 
• Height and weight 
• Head circumference 
• ECG 
• Vital signs 
• Hematology 
• Serum chemistry 
• Urinalysis 
• Neurological examination (performed prior to the administration of anesthesia) 
• Neurodevelopmental assessments (performed prior to the administration of anesthesia 
• General anesthesia:  administration of anesthesia will be given prior to the following 
assessments: 
• ABR 
• MRI of the head 
• CSF sample collection (chemistry, cell count, heparan sulfate and heparan sulfate derivatives, 
and other MPS exploratory biomarkers) via the IDDD 
• Urine heparan sulfate and heparan sulfate derivatives 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
47 
• Serum heparan sulfate and heparan sulfate derivatives 
• Anti-rhHNS antibody testing 
• Children’s Sleep Habits Rating Scale  
• CHQ-50 
• CHQ-87 
• ITQOL 
• Concomitant medications, therapies, and procedures 
• AE assessments 
 
8.2 
Treatment:  Monthly, Weekly Assessments 
Patients in Dose Groups 1 and 2 will receive rhHNS IDDD monthly, on Week 1, Day 2 
(±2 days).  Patients in dose Group 3 will receive rhHNS EOW, on Weeks 1 and 3, Day 2 
(±2 days).   
8.2.1 
Week 1 (Groups 1 and 2); Week 1 and 3 (Group 3) 
8.2.1.1 
Day 1 (Pre-treatment) Assessments 
• Informed consent (Week 1, Month 1 only) prior to study HGT-SAN-067 study procedures 
• Physical examination 
• Height and weight 
• Vital signs 
• Hematology 
• Serum Chemistry 
• Urinalysis 
• Neurological Examination (performed prior to the administration of anesthesia and the 
rhHNS IT injection) 
• Concomitant Medications, Therapies, and Procedures 
• AE assessments 
 
Note:  If the HGT-SAN-055 EOS (or Screening) assessments were performed within 7 days of 
first intrathecal rhHNS treatment in this study, the pre-treatment assessments described in this 
section do not need to be completed prior to the first treatment 
DAY 1 (PRE-TREATMENT) ADDITIONAL ASSESSMENTS PERFORMED ONLY AT MONTHS 12, 24, 36, 
AND 48 
• Head circumference 
• Visual and hearing assessments  
• Urine Heparan Sulfate and Heparan Sulfate Derivatives (Group 3:  obtained only at first 
week of each treatment month) 
• Serum Heparan Sulfate and Heparan Sulfate Derivatives (Group 3:  obtained only at first 
week of each treatment month) 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
48 
• Anti-rhHNS antibody testing 
• Auditory Brainstem Response (ABR) 
• MRI of the head  
• Full neurodevelopmental testing (performed prior to the administration of anesthesia and the 
rhHNS IT injection) 
• Children’s Sleep Habits Rating Scale  
• Child health questionnaire-50  
• Child health questionnaire-87  
• Infant toddler QOL Questionnaire  
 
8.2.1.2 
Day 2 (±2 days) Assessments and IDDD Injection of rhHNS 
• Physical examination 
• ECG (performed following IT study drug injection) 
• Vital signs 
• CSF sample collection (obtained prior to IT study drug injection) 
• rhHNS IT injection (Day 2 ±2 days) 
• neurological examination 
• Concomitant medications, therapies, and procedures 
• AE assessments 
 
8.2.1.3 
Day 3 (Post IT Dose) Assessments 
Patients will be discharged when deemed clinically stable by the Investigator. 
• Vital signs 
• Neurological examination  
• Concomitant medications, therapies, and procedures 
• AE assessments 
 
8.3 
End of Study/ Early Termination Procedures 
Patients who complete the study or who discontinue prior to the end of the study, will have EOS 
assessments performed 30 (±7 days) after their last dose of rhHNS.  Patients who discontinue or 
are withdrawn prior to study completion will be asked to participate in the end of study 
procedures at time of discontinuation.  Participation in these EOS procedures will be strongly 
encouraged, but is voluntary for those patients electing to discontinue from the study.  Note:  
scheduled removal of the IDDD will be required at study completion with sedation or anesthesia, 
as required. 
• Physical examination 
• Height and weight 
• Head circumference 
• Visual and hearing  

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
49 
• ECG 
• Vital signs 
• Hematology 
• Serum Chemistries 
• Urinalysis 
• Urine Heparan Sulfate and Heparan Sulfate Derivatives  
• Serum Heparan Sulfate and Heparan Sulfate Derivatives  
• Anti-rhHNS antibody testing 
• Auditory Brainstem Response (ABR) 
• MRI of the head  
• CSF sample collection  
• Neurological examination 
• Full neurodevelopmental testing  
• Children’s Sleep Habits Rating Scale  
• Child health questionnaire-50  
• Child health questionnaire-87  
• Infant toddler QOL Questionnaire  
• Concomitant medications, therapies, and procedures 
• AE assessments 
 
8.4 
Safety Follow-up Visit (by Telephone) 
Patients who complete the study will have a safety follow-up visit 30 Days (±7 days) 
Patients who discontinue or are withdrawn prior to study completion will be asked to participate 
in the safety follow-up visit at the time of discontinuation.  Participation in these procedures will 
be strongly encouraged, but is voluntary for those patients electing to discontinue from the study. 
• Concomitant medications, therapies, and procedures 
• AE assessments 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
50 
9 
QUALITY CONTROL AND ASSURANCE 
Training will occur at an investigator meeting or at the site initiation visit or both, and instruction 
manuals (eg, laboratory manuals and pharmacy manuals) will be provided to aid consistency in 
data collection and reporting across sites. 
Clinical sites will be monitored by Shire HGT or its designee to ensure the accuracy of data 
against source documents.  The required data will be captured in a validated clinical data 
management system that is compliant with the Food and Drug Administration (FDA) 21 Code of 
Federal Regulations (CFR) Part 11 Guidance.  The clinical trial database will include an audit 
trail to document any evidence of data processing or activity on each data field by each user.  
Users will be trained and given restricted access, based on their role in the study, through a 
password protected environment.   
Data entered in the system will be reviewed manually for validity and completeness against the 
source documents by a clinical monitor from Shire HGT or its designee.  If necessary, the study 
site will be contacted for corrections or clarifications; all missing data will be accounted for. 
SAE information captured in the clinical trial database will be reconciled with the information 
captured in the Pharmacovigilance database. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
51 
10 PLANNED STATISTICAL METHODS 
10.1 General Statistical Methodology 
This is an open-label extension of study HGT-SAN-055 to evaluate the long-term safety and 
clinical outcomes of intrathecal administration of rhHNS in patients with Sanfilippo syndrome 
type A (MPS IIIA).  The statistical methodology supporting the trial will focus on descriptive 
rather than inferential approaches, given the early phase and objectives of this trial.  
Data will be summarized by dose group (10 mg per month, 45 mg per month and 45 mg every 
other week) with respect to demographic and baseline characteristics, efficacy variables and 
safety variables.  Summary statistics for continuous variables will include the n, mean, standard 
deviation, median, minimum and maximum.  Categorical variables will be summarized in a 
contingency table by the frequency and percentage of patients in each category.  Data will be 
plotted to assess trends across time.  
All hypothesis tests will be 2-sided and will be performed at the 0.05 level.  Hypothesis testing 
will be viewed as exploratory.  Any resulting p-values will not be regarded as a firm support for 
conclusions, but rather suggestive of areas of examination in future studies.  In general, variables 
will be quantified as a change from the baseline value.  The null hypothesis will be that there is 
no difference in the change from baseline between dose groups.  Note that the baseline visit for 
this study will be the first day the patient received his/her IT dose of rhHNS in study 
HGT-SAN-055.  
The primary objective of this trial is to assess the long term safety of rhHNS administration via a 
surgically implanted intrathecal drug delivery device (IDDD).  Hence an extensive safety 
assessment will be performed.  The safety analyses will consist of all enrolled patients.  To 
evaluate safety, adverse experiences will be tabulated by dose group.  Vital signs, 
electrocardiograms, serum and CSF components and chemistries, hematology, and urinalysis 
safety monitoring will be listed for each patient and abnormal values will be flagged.  In 
addition, anti-rhHNS antibodies (in CSF and serum) will also be listed.  No formal statistical 
tests will be performed on the safety parameters. 
10.2 Determination of Sample Size 
Since this is an extension study, sample size is determined by the number of patients who 
completed HGT-SAN-055 (maximum of 12 patients) and enrolled in this study 
10.3 Analysis Populations 
The analysis population consists of all eligible patients from HGT-SAN-055 who have agreed to 
participate in the extension study.  Both safety and efficacy analyses would be performed using 
the above mentioned population.  

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
52 
10.4 Demographics and Baseline Characteristics 
Patient disposition for those enrolled will be presented in a summary table using number and 
percentage of patients enrolled, completed or discontinued/withdrew, by dose group.  The 
reasons for discontinuation/withdrawal will also be presented. 
Demographic and baseline characteristics (eg, age, race, ethnicity, medical history, and surgical 
history) will be reported in summary tables. 
10.5 Statistical Analysis of Pharmacokinetic Variables 
Not applicable 
10.6 Efficacy, Safety, and Pharmacodynamic Evaluations     
10.6.1 
Primary Analyses 
10.6.1.1 
Safety Analysis 
In general, safety assessments will be based on all assessments post-baseline.  The assessment of 
safety will be based primarily on the frequency of treatment-emergent adverse events, due to 
study drug and on the frequency of clinically notable abnormal vital sign and laboratory values.  
Changes from baseline will be calculated by subtracting the baseline value from the 
post-baseline value. 
All enrolled patients will be included in the safety analysis.  Patients will be grouped according 
to the actual dose received.   
No formal statistical test will be performed in the safety evaluations.  Vital sign measurements, 
clinical chemistry, and hematology safety monitoring will be listed for each patient, and 
abnormal values will be flagged.  These will also be summarized at each time point, including 
change from baseline. 
Adverse events will be recorded throughout the study and at early termination.  Adverse events 
and medical conditions will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 9.0 or later.  In all cases (with the exception of device-related events), 
adverse event summaries will be based on all adverse event recorded beginning on Study Day 1 
(treatment-emergent AEs). 
Adverse events will be summarized by presenting, for each treatment group, the number and 
percentage of patients having any adverse event, having an adverse event in system organ class, 
and having each individual adverse event.  Note that in any given category (eg, system organ 
class) a patient will only be counted once.  In addition, those events which resulted in death or 
were otherwise classified as serious will be presented in a separate listing.  The incidence of 
treatment-emergent adverse events (new or worsened from baseline) will be summarized by 
system organ class, severity, type of adverse event and relationship to trial medication.   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
53 
Adverse events that occur up to 30 days after the last dose of study drug will be considered 
“on-treatment”.  Adverse events which are deemed probably or possibly related to the device 
will be summarized by dose group and overall. 
Laboratory data will be listed by patient and dose group.  Patients with newly occurring 
abnormalities outside the normal range will be flagged and listed separately and summarized.  
Mean change from baseline values or shift tables will also be provided by dose group at each 
visit. 
Vital signs data will be listed by patient and dose group.  Furthermore, mean changes from 
baseline for vital sign data will be summarized for each dose group.  Shift tables may be 
presented, utilizing reference ranges.  Patients with notably abnormal values will be identified 
and listed separately along with their values. 
ECG assessments will be listed by patient and dose group.  Mean changes from baseline for ECG 
data will be summarized for each dose group.  Patients with any clinically significant findings 
and/or conduction abnormalities will be listed separately along with their values.   
For those patients who fail to complete the study, the reason for discontinuation will be listed by 
patient and dose group.   
Listings of all study safety data will be presented. 
10.6.1.2 
Clinical Laboratory Evaluations 
Descriptive summaries of clinical laboratory evaluations (hematology, serum chemistry, 
urinalysis) results will be presented in summary tables by evaluation visit using number of 
patients (n), mean, median, standard deviation, minimum, and maximum.  Changes from 
baseline will be summarized for each post-baseline visit.  The number of patients with clinically 
significant laboratory results or abnormal results during the study period will be presented in 
shift tables. 
For the laboratory measurements, shift tables will be presented in terms of Low (L), Normal (N), 
High (H), Missing (M).  High and Low measurements will be based on reference ranges 
provided by the laboratory at the study site. 
Clinical laboratory results will also be presented in data listings. 
10.6.1.3 
Anti-rhHNS Antibody Formation 
Anti-rhHNS antibody formation will be monitored throughout the study.  Results will be 
presented in summary tables by assay methodology used to identify antibodies, number and 
percentage of positive and negative specimens by evaluation visit and/or study week, and 
number and percentage of positive and negative specimens overall.  These results will also be 
presented in data listings.   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
54 
10.6.2 
Secondary Analysis 
10.6.2.1 
Clinical Assessments 
The change from baseline in neurocognitive assessment based scores will be examined by dose 
group.  Furthermore, the effect of rhHNS administration on QoL measures will be examined by 
presenting mean change from baseline across dose groups.  Other relevant assessments which 
might help in the understanding of clinical activity will also be analyzed.  
10.6.2.2 
Pharmacodynamic Analyses 
To determine the effects of rhHNS administration on biomarkers, mean change from baseline 
will be assessed at selected time points.  The heparin sulfate reduction (in CSF and urine) will be 
examined using mean change and the corresponding 95% confidence interval.  The concentration 
of inflammatory cytokines in serum and CSF will also be examined.  Other exploratory 
biomarkers in CSF, serum, and urine may also be examined. 
The effect of anti- rhHNS antibodies on the changes in CSF biomarkers may also be examined 
by presenting summary tables by antibody status. 
The planned analyses and presentations will be defined in the Statistical Analysis Plan (SAP). 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
55 
11 ADMINISTRATIVE CONSIDERATIONS 
11.1 Investigators and Study Administrative Structure 
Before initiation of the study, the Investigators must provide the Sponsor with a completed Form 
FDA 1572.  Study medications may be administered only under the supervision of the 
Investigators listed on this form.  Curriculum vitae must be provided for the Investigators and 
sub-investigators listed on Form FDA 1572. 
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, any amendments to the protocol, the study treatments, and their study related 
duties and functions.  The Investigator must maintain a list of sub-investigators and other 
appropriately qualified persons to whom he or she has delegated significant study related duties. 
11.2 Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval 
Before initiation of the study, the Investigator must provide the Sponsor with a copy of the 
written IRB/IEC approval of the protocol and the informed consent form.  This approval must 
refer to the informed consent form and to the study title, study number, and version and date of 
issue of the study protocol, as given by the Sponsor on the cover page of the protocol. 
Status reports must be submitted to the IRB/IEC at least once per year.  The IRB/IEC must be 
notified of completion of the study.  Within 3 months of study completion or termination, a final 
report must be provided to the IRB/IEC.  A copy of these reports will be sent to the study clinical 
monitor.  The Investigators must maintain an accurate and complete record of all submissions 
made to the IRB/IEC, including a list of all reports and documents submitted.  AEs which are 
reported to the U.S. Food and Drug Administration (FDA) or other Regulatory agencies 
(Investigational New Drug [IND] Safety Reports) must be submitted promptly to the IRB/IEC. 
11.3 Ethical Conduct of the Study 
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor and Investigators abide by 
good clinical practice (GCP) as described in the 21 CFR Parts 50, 56, and 312 and the 
International Conference on Harmonisation (ICH) GCP Guidelines.  Compliance with these 
regulations and guidelines also constitutes compliance with the ethical principles described in the 
Declaration of Helsinki (2008). 
11.4 Patient Information and Consent 
Before enrolling in the clinical study, the patient’s parent(s), or the patient’s legally authorized 
representative(s) must consent to participate after the nature, scope, and possible consequences 
of the clinical study have been explained in a form understandable to him or her.  An informed 
consent form that includes information about the study will be prepared and given to the 
patient’s parent(s), or the patient’s legally authorized representative(s).  This document will 
contain all FDA and ICH-required elements.   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
56 
The informed consent form must be in a language understandable to the patient’s parent(s), or 
the patient’s legally authorized representative(s) and must specify who informed the patient’s 
parent(s), or the patient’s legally authorized representative. 
After reading the informed consent document, the patient, patient’s parent(s), or the patient’s 
legally authorized representative(s) must give consent in writing.  The patient’s consent must be 
confirmed at the time of consent by the personally dated signature of the patient, patient’s 
parent(s) or the patient’s legally authorized representative(s) and by the personally dated 
signature of the person conducting the informed consent discussions.  If the patient, patient’s 
parent(s), or the patient’s legally authorized representative(s) is unable to read, oral presentation 
and explanation of the written informed consent form and information to be supplied must take 
place in the presence of an impartial witness.  Consent (or assent) must be confirmed at the time 
of consent orally and by the personally dated signature of the patient, patient’s parent(s) or by the 
patient’s legally authorized representative(s).  The witness and the person conducting the 
informed consent discussions must also sign and personally date the informed consent document.  
It should also be recorded and dated in the source document that consent was given. 
A copy of the signed and dated consent document(s) must be given to the patient’s parent(s), or 
the patient’s legally authorized representative(s).  The original signed and dated consent 
document will be retained by the Investigator. 
The Investigator will not undertake any measures specifically required solely for the clinical 
study until valid consent has been obtained. 
A model of the informed consent form to be used in this study will be provided to the sites 
separately from this protocol.  Where applicable, signed assent(s) to participate in the study must 
be obtained. 
11.5 Patient Confidentiality 
Patient names will not be supplied to the Sponsor.  Only the patient number and patient initials 
will be recorded in the eCRF, and if the patient name appears on any other document, it must be 
obliterated before a copy of the document is supplied to the Sponsor.  Study findings stored on a 
computer will be stored in accordance with local data protection laws.  The patients will be told 
that representatives of the Sponsor, a designated CRO, the IRB/IEC, or regulatory authorities 
may inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws.  The Investigator will maintain a personal patient 
identification list (patient numbers with the corresponding patient names) to enable records to be 
identified. 
11.6 Study Monitoring 
Monitoring procedures that comply with current Good Clinical Practice (GCP) guidelines will be 
followed.  On-site review of the eCRF's for completeness and clarity, cross-checking with source 
documents, and clarification of administrative matters will be performed. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
57 
The study will be monitored by the Sponsor or its designee.  On site monitoring will be 
performed by a representative of the Sponsor (Clinical Study Monitor) who will review the CRFs 
and source documents.  The site monitor will ensure that the investigation is conducted 
according to protocol design and regulatory requirements by frequent site visits and 
communications (letter, telephone, and facsimile). 
11.7 Case Report Forms and Study Records 
Case report forms are provided for each patient in electronic format.  Electronic Data Capture 
(EDC) will be used for this study.  The study data will be recorded from the source documents 
into the electronic clinical report form (eCRF).  The electronic files will be considered as the 
CRFs.  
All forms must be filled out by authorized study personnel.  All corrections to the original eCRF 
entry must indicate the reason for change.  The Investigator is required to sign the eCRF after all 
data have been captured for each patient.  If corrections are made after review and signature by 
the Investigator, he or she must be made aware of the changes, and his or her awareness 
documented by re-signing the eCRF.    
11.7.1 
Critical Documents 
Before Shire HGT initiates the trial (ie, obtains informed consent from the first patient), it is the 
responsibility of the Investigator to ensure that the following documents are available to Shire 
HGT or their designee: 
• Curricula vitae of Investigator and sub-investigator(s) (current, dated and signed or supported 
by an official regulatory document) 
• Current medical license of Investigator and sub investigator(s) 
• Signed and dated agreement of the final protocol 
• Signed and dated agreement of any amendment(s), if applicable 
• Approval/favorable opinion from the IRB/IEC clearly identifying the documents reviewed:  
protocol, any amendments, Patient Information/Informed Consent Form (Assent form if 
applicable), and any other written information to be provided regarding patients recruitment 
procedures 
• Copy of IRB/IEC approved Patient Information/Informed Consent Form (Assent Form if 
applicable)/any other written information/advertisement 
• Any additional regulatory approvals, ie national regulatory approvals 
• List of IRB/IEC Committee members/constitution 
• Financial agreement(s) 
• Documentation from central or local laboratory as applicable 
• 
Reference ranges 
• 
Certification/QA scheme/other documentation 
 
Regulatory approval and notification as required must also be available; these are the 
responsibility of Shire HGT.  All trial documents will be available in a Trial Master File (TMF) 
at the Investigator/trial site and at Shire HGT.      

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
58 
11.8 Data Monitoring Committee 
There will be no data monitoring committee for this study. 
11.9 Protocol Violations/Deviations 
The Investigator will conduct the study in compliance with the protocol.  The protocol will not 
be initiated until the IRB/IEC and the appropriate regulatory authorities have given 
approval/favorable opinion.  Modifications to the protocol will not be made without agreement 
of the Sponsor.  Changes to the protocol will require written IRB/IEC approval/favorable opinion 
prior to implementation, except when the modification is needed to eliminate an immediate 
hazard(s) to patients.  The IRB/IEC may provide, if applicable regulatory authorities permit, 
expedited review and approval/favorable opinion for minor change(s) in ongoing studies that 
have the approval/favorable opinion of the IRB/IEC.  The Sponsor will submit all protocol 
modifications to the regulatory authorities in accordance with the governing regulations.  A 
record of patients screened, but not entered into the study, is also to be maintained.   
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
patients, the Investigator will contact the Sponsor or its designee, if circumstances permit, to 
discuss the planned course of action.  Any departures from the protocol must be fully 
documented as a protocol deviation.  Protocol deviations will need to be reviewed by the medical 
monitor and may also be required to be submitted to the IRB/IEC 
Protocol modifications will only be initiated by the Sponsor and must be approved by the 
IRB/IEC and submitted to the FDA or other applicable international regulatory authority before 
initiation. 
11.10 Access to Source Documentation 
Regulatory authorities, the IEC/IRB, or the Sponsor may request access to all source documents, 
CRFs, and other study documentation for on-site audit or inspection.  Direct access to these 
documents must be guaranteed by the Investigator, who must provide support at all times for 
these activities.  Monitoring and auditing procedures that comply with current GCP guidelines 
will be followed.  On-site review of the CRFs for completeness and clarity, cross-checking with 
source documents, and clarification of administrative matters will be performed. 
11.11 Data Generation and Analysis 
The clinical database will be developed and maintained by a contract research organization or an 
electronic data capture technology provider as designated by Shire HGT.  Shire HGT or its 
designee will be responsible for performing study data management activities.  
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
Version 9.0 or later.  Concomitant medication will be coded using WHODRL.  Centralized 
laboratories will be employed as described in the study manual to aid in consistent measurement 
of efficacy and safety parameters. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
59 
11.12 Premature Closure of the Study 
11.12.1 Study Termination 
If the Sponsor or an Investigator discovers conditions arising during the study which indicate that 
the clinical investigation should be halted due to an unacceptable patient risk, the study may be 
terminated after appropriate consultation between Shire HGT and the Investigators.  In addition, 
a decision on the part of Shire HGT to suspend or discontinue development of the study material 
may be made at any time. 
11.12.2 Site Termination 
A specific site may be terminated separate from the general study for, but not limited to, the 
following conditions: 
• The discovery of an unexpected, significant, or unacceptable risk to the patients enrolled at 
the site. 
• Failure of the Investigator to enter patients at an acceptable rate. 
• Insufficient adherence by the Investigator to protocol requirements. 
 
11.13 Retention of Data 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application and until there are no pending or contemplated marketing applications or 
at least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product.  The Sponsor will notify the Investigator if these documents must be 
retained for a longer period of time.  It is the responsibility of the Sponsor to inform the 
Investigator or institution as to when these documents no longer need to be retained. 
11.14 Financial Disclosure 
The Investigator should disclose any financial interests in the Sponsor as described in 21 CFR 
Part 54 prior to beginning this study.  The appropriate form will be provided to the Investigator 
by the Sponsor, which will be signed and dated by the Investigator, prior to the start of the study.  
11.15 Publication and Disclosure Policy 
All information concerning the study material, such as patent applications, manufacturing 
processes, basic scientific data, and formulation information supplied by the Sponsor and not 
previously published are considered confidential and will remain the sole property of the 
Sponsor.  The Investigator agrees to use this information only in accomplishing this study and 
will not use it for other purposes. 
It is understood by the Investigator that the information developed in the clinical study may be 
disclosed as required to the authorized regulatory authorities and governmental agencies.   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
60 
In order to allow for the use of the information derived from the clinical studies, it is understood 
that there is an obligation to provide the Sponsor with complete test results and all data 
developed in the study in a timely manner. 
The Investigator and any other clinical personnel associated with this study will not publish the 
results of the study, in whole or in part, at any time, unless they have consulted with Shire HGT, 
provided Shire HGT a copy of the draft document intended for publication, and obtained Shire 
HGT’s written consent for such publication.  All information obtained during the conduct of this 
study will be regarded as confidential.  Shire HGT will use the information for registration 
purposes and for the general development of the drug. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
61 
12 REFERENCE LIST 
1. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. 
JAMA 1999;281:249-54. 
2. Poorthuis BJ, Wevers RA, Kleijer WJ, et al. The frequency of lysosomal storage diseases in 
The Netherlands. Hum Genet 1999;105:151-6. 
3. Baehner F, Schmiedeskamp C, Krummenauer F, et al. Cumulative incidence rates of the 
mucopolysaccharidoses in Germany. J Inherit Metab Dis 2005;28:1011-7. 
4. Meyer A, Kossow K, Gal A, et al. Scoring evaluation of the natural course of 
mucopolysaccharidosis type IIIA (Sanfilippo syndrome type A). Pediatrics 
2007;120:e1255-61. 
5. Cleary MA, Wraith JE. Management of mucopolysaccharidosis type III. Arch Dis Child 
1993;69:403-6. 
6. Fraser J, Wraith JE, Delatycki MB. Sleep disturbance in mucopolysaccharidosis type III 
(Sanfilippo syndrome): a survey of managing clinicians. Clin Genet 2002;62:418-21. 
7. Neufeld E, Muenzer J. The Mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, 
Valle D, eds. The metabolic and molecular bases of inherited disease. 8th ed. New York: 
McGraw-Hill; 2001:4 v. (xivii, 6338, I-104 p.). 
8. Meyer A, Kossow K, Gal A, et al. The mutation p.Ser298Pro in the sulphamidase gene 
(SGSH) is associated with a slowly progressive clinical phenotype in mucopolysaccharidosis 
type IIIA (Sanfilippo A syndrome). Hum Mutat 2008;29:770. 
9. Vellodi A. Lysosomal storage disorders. Br J Haematol 2005;128:413-31. 
10. Hemsley KM, Beard H, King BM, Hopwood JJ. Effect of high dose, repeated intra-CSF 
injection of sulphamidase on neuropathology in MPS IIIA mice. Genes Brain Behav 2008, 
7:740-753. 
11. Urayama A, Grubb JH, Sly WS, Banks WA. Mannose 6-phosphate receptor-mediated 
transport of sulfamidase across the blood-brain barrier in the newborn mouse. Mol Ther 
2008;16:1261-6. 
12. Bielicki J, Hopwood JJ, Melville EL, Anson DS. Recombinant human sulphamidase: 
expression, amplification, purification and characterization. Biochem J 1998;329 
( Pt 1):145-50. 
13. Di Natale P, Vanacore B, Daniele A, Esposito S. Heparan N-sulfatase: in vitro mutagenesis 
of potential N-glycosylation sites. Biochem Biophys Res Commun 2001;280:1251-7. 
14. Daniele A, Di Natale P. Heparan N-sulfatase: cysteine 70 plays a role in the enzyme catalysis 
and processing. FEBS Lett 2001;505:445-8. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
62 
15. Perkins KJ, Byers S, Yogalingam G, Weber B, Hopwood JJ. Expression and characterization 
of wild type and mutant recombinant human sulfamidase. Implications for Sanfilippo 
(Mucopolysaccharidosis IIIA) syndrome. J Biol Chem 1999;274:37193-9. 
16. Munoz-Rojas MV, Vieira T, Costa R, et al. Intrathecal enzyme replacement therapy in a 
patient with mucopolysaccharidosis type I and symptomatic spinal cord compression. Am J 
Med Genet A 2008;146A:2538-44. 
17. Munoz-Rojas MV, Horovitz DD, Jardim LB, et al. Intrathecal administration of recombinant 
human N-acetylgalactosamine 4-sulfatase to a MPS VI patient with pachymeningitis 
cervicalis. Mol Genet Metab 2010;99:346-50. 
18. Chen A, Dickson P, Shapiro E, Lyons B, S-H K, Guillaume D. A study of intrathecal enzyme 
replacement for cognitive decline in mucopolysaccharidosis 1. In. Abstracts for the 
Lysosomal Disease Network's WORLD Symposium Molecular Genetics and Metabolism; 
2010:S13-S4. 
19. Estimating the Maximum Safe Starting Dose in Clinical Trials for Therapeutics in Adult 
Healthy Volunteers. In. United States Food and Drug Administration, Center for Drug 
Evaluation and Research (CDER): July; 2005, Pharmacology and Toxicology. 
20. Hemsley KM, King B, Hopwood JJ. Injection of recombinant human sulfamidase into the 
CSF via the cerebellomedullary cistern in MPS IIIA mice. Mol Genet Metab 
2007;90:313-328. 
21. Hemsley KM, Luck AJ, Crawley AC, et al. Examination of intravenous and intra-CSF 
protein delivery for treatment of neurological disease. Eur J Neurosci 2009; 29:1389-96. 
22. Hemsley KM, Norman EJ, Crawley AC, et al. Effect of cisternal sulfamidase delivery in 
MPS IIIA Huntaway dogs-A proof of principle study. Mol Genet Metab 2009, doi: 
10.1016/j.ymgme.2009.07.013. 
23. Bayley N. Bayley Scales of Infant and Toddler Development: Third Edition. San Antonio, 
TX The Psychological Corporation; 2005. 
24. Kaufman S, Kaufman N. Kaufman Assessment Battery for Children, Second Edition 
(KABC-II). 
25. Henderson S, Sugden D, Barnett A. Movement Assessment Battery for Children (second 
ed.). London: Harcourt Assessment; 2007. 
26. Sparrow S, Balla D, Cicchetti D. Vineland Adaptive Behavior Scales (Second Edition). 4201 
Woodland Road Circle Pines, MN 55014-1796: American Guidance Service, Inc; 2005. 

Recombinant human heparan N-sulfatase (rhHNS) 
 
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
 
27 January 2011 
Shire 
Confidential 
63 
Appendix 1 
Schedule of Events 
Table 1  Study Assessments for Patients Who Have Received 6 Months of Treatment With rhHNS (Study HGT-SAN-055) 
(Dose Groups 1 and 2) 
 
 
Week 1 Each Treatment Month 
 
Assessment 
Screening/
Baseline 
Visiti 
Pre-Tx
Day 1a, l 
IT administration
Day 2 
Day  
3d 
12, 24, 36, and 48 
months  
End of Studyf 
Safety 
Follow-uph 
Informed Consent/Enrollment 
 
● 
 
 
 
 
 
Physical Examination 
● 
● 
● 
 
 
● 
 
Height and Weight 
● 
● 
 
 
 
● 
 
Head Circumference 
● 
 
 
 
● 
● 
 
Visual and Hearing Assessment 
 
 
 
 
● 
● 
 
ECG 
● 
 
●b 
 
 
● 
 
Vital Signs 
● 
● 
● 
● 
 
● 
 
Hematology 
● 
● 
 
 
 
● 
 
Serum Chemistry 
● 
● 
 
 
 
● 
 
Urinalysis 
● 
● 
 
 
 
● 
 
Urine Heparan Sulfate and Heparan 
Sulfate Derivatives  
● 
 
 
 
●e 
● 
 
Serum Heparan Sulfate and Heparan 
Sulfate Derivatives 
● 
 
 
 
●e 
● 
 
Anti-rhHNS antibody testing (serum and 
CSF)j 
● 
 
 
 
● 
● 
 
Auditory Brainstem Response (ABR) 
● 
 
 
 
● 
● 
 
MRI of the Head 
● 
 
 
 
● 
● 
 
CSF Sample Collectionk 
● 
 
●c 
 
 
●c 
 
rhHNS administrationg 
 
 
● 
 
 
 
 
Neurological Examination 
● 
● 
● 
● 
 
● 
 
Full Neurodevelopmental Testing 
● 
 
 
 
● 
● 
 
Children’s Sleep Habits Rating Scale 
● 
 
 
 
● 
● 
 
Child Health Questionnaire-50 
● 
 
 
 
● 
● 
 
Child Health Questionnaire-87 
● 
 
 
 
● 
● 
 
Infant Toddler QOL Questionnaire 
● 
 
 
 
● 
● 
 

Recombinant human heparan N-sulfatase (rhHNS) 
 
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
 
27 January 2011 
Shire 
Confidential 
64 
Table 1  Study Assessments for Patients Who Have Received 6 Months of Treatment With rhHNS (Study HGT-SAN-055) 
(Dose Groups 1 and 2) 
 
 
Week 1 Each Treatment Month 
 
Assessment 
Screening/
Baseline 
Visiti 
Pre-Tx
Day 1a, l 
IT administration
Day 2 
Day  
3d 
12, 24, 36, and 48 
months  
End of Studyf 
Safety 
Follow-uph 
Concomitant Medications, Therapies, 
and 
Procedures 
● 
● 
● 
● 
 
● 
● 
Adverse Event Monitoring 
● 
● 
● 
● 
 
● 
● 
Abbreviations:  ABR = Auditory brainstem response; CSF = cerebrospinal fluid; ECG = electrocardiogram; MRI = Magnetic resonance imaging; 
TX = treatment; 
a 
Week 1 only, and only performed if >7 days have elapsed since  HGT-SAN-055 EOS visit assessments. 
b 
ECG to be performed following administration of study drug. 
c 
A total of 10 mLs of CSF will be obtained in two 5 mL aliquots (labeled separately – process according to study operations manual).  An attempt will 
be made to obtain CSF sample via the IDDD prior to each administration of rhHNS and at the End of Study visit.  If it is not possible to obtain CSF 
using the IDDD, the IDDD will be replaced.  See Section 6.4 for details.  
d 
Patients will be discharged when deemed clinically stable by the Investigator. 
e 
Specimens collected once a month, at Day 1 of the first treatment week. 
f 
All patients who complete the study will have end of study assessments performed 30 (±7 days) after their last dose of study drug. 
g  
If a patient’s IDDD becomes nonfunctional or infected; it will be replaced so that the patient can remain on study.  See Section 6.5.  
h 
A safety follow up telephone call will be made 30 (±7 days) after End of Study Procedures. 
i 
Assessments will be required only if more than 60 days have elapsed following the HGT-SAN-055 procedures.  These assessments would be repeated 
within 30 days prior to the first scheduled rhHNS IT dose. 
j 
Blood sample drawn before IT injection of rhHNS. 
k 
CSF will be tested for standard chemistries, heparan sulfate and heparan sulfate derivatives, anti-rhHNS antibodies, and MPS exploratory biomarkers. 
 
 
 
 
 
 

Recombinant human heparan N-sulfatase (rhHNS) 
 
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
 
27 January 2011 
Shire 
Confidential 
65 
Table 2  Study Assessments for Patients Who Have Received 6 Months of Treatment With rhHNS (Study HGT-SAN-055) 
(Dose Group 3) 
 
 
Week 1 and 3 Each Treatment Month 
 
Assessment 
Screening/Basel
ine Visiti 
Pre-Tx
Day 1a 
IT administration
Day 2 
Day  
3d, 
12, 24, 36, and 48 
months  
End of Studyf 
Safety 
Follow-uph 
Informed Consent/Enrollment 
 
● 
 
 
 
 
 
Physical Examination 
● 
● 
● 
 
 
● 
 
Height and Weight 
● 
● 
 
 
 
● 
 
Head Circumference 
● 
 
 
 
● 
● 
 
Visual and Hearing Assessment 
 
 
 
 
● 
● 
 
ECG 
● 
 
●b 
 
 
● 
 
Vital Signs 
● 
● 
● 
● 
 
● 
 
Hematology 
● 
● 
 
 
 
● 
 
Serum Chemistry 
● 
● 
 
 
 
● 
 
Urinalysis 
● 
● 
 
 
 
● 
 
Urine Heparan Sulfate and Heparan 
Sulfate Derivatives  
● 
 
 
 
●e 
● 
 
Serum Heparan Sulfate and Heparan 
Sulfate Derivatives 
● 
 
 
 
●e 
● 
 
Anti-rhHNS antibody testing (serum 
and CSF)j 
● 
 
 
 
● 
● 
 
Auditory Brainstem Response (ABR) 
● 
 
 
 
● 
● 
 
MRI of the Head 
● 
 
 
 
● 
● 
 
CSF Sample Collectionk 
● 
 
●c 
 
 
●c 
 
rhHNS administrationg 
 
 
● 
 
 
 
 
Neurological Examination 
● 
● 
● 
●j 
 
● 
 
Full Neurodevelopmental Testing 
● 
 
 
 
● 
● 
 
Children’s Sleep Habits Rating Scale 
● 
 
 
 
● 
● 
 
Child Health Questionnaire-50 
● 
 
 
 
● 
● 
 
Child Health Questionnaire-87 
● 
 
 
 
● 
● 
 
Infant Toddler QOL Questionnaire 
● 
 
 
 
● 
● 
 

Recombinant human heparan N-sulfatase (rhHNS) 
 
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
 
27 January 2011 
Shire 
Confidential 
66 
Table 2  Study Assessments for Patients Who Have Received 6 Months of Treatment With rhHNS (Study HGT-SAN-055) 
(Dose Group 3) 
 
 
Week 1 and 3 Each Treatment Month 
 
Assessment 
Screening/Basel
ine Visiti 
Pre-Tx
Day 1a 
IT administration
Day 2 
Day  
3d, 
12, 24, 36, and 48 
months  
End of Studyf 
Safety 
Follow-uph 
Concomitant Medications, Therapies, 
and Procedures 
● 
● 
● 
● 
 
● 
● 
Adverse Event Monitoring 
● 
● 
● 
● 
 
● 
● 
Abbreviations:  ABR = Auditory brainstem response; CSF = cerebrospinal fluid; ECG = electrocardiogram; MRI = Magnetic resonance imaging ; 
TX = treatment; 
a 
Week 1 only, and only performed if >7 days have elapsed since  HGT-SAN-055 EOS visit assessments. 
b 
ECG to be performed following administration of study drug. 
c 
A total of 10 mLs of CSF will be obtained in two 5 mL aliquots (labeled separately – process according to study operations manual).  An attempt will 
be made to obtain CSF sample via the IDDD prior to each administration of rhHNS and at the End of Study visit.  If it is not possible to obtain CSF 
using the IDDD, the IDDD will be replaced.  See Section 6.4 for details.  
d 
Patients will be discharged when deemed clinically stable by the Investigator. 
e 
Specimens collected once a month, at Day 1 of the first treatment week. 
f 
All patients who complete the study will have end of study assessments performed 30 (±7 days) after their last dose of study drug. 
g  
If a patient’s IDDD becomes nonfunctional or infected; it will be replaced so that the patient can remain on study.  See Section 6.5. 
h 
A safety follow up telephone call will be made 30 (±7 days) after End of Study Procedures. 
i 
Assessments will be required only if more than 60 days have elapsed following the HGT-SAN-055 procedures.  These assessments would be repeated 
within 30 days prior to the first scheduled rhHNS IT dose. 
j 
Blood sample drawn before IT injection of rhHNS. 
k 
CSF will be tested for standard chemistries, heparan sulfate and heparan sulfate derivatives, anti-rhHNS antibodies, and MPS exploratory biomarkers. 
 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
67 
Appendix 2 
Sample Neurological Exam 
□ Not Done, Please provide reason:  ________________________________________ 
Exam date:  _____________ (Day/Mon/Year)    Name of Examiner:  _________________ 
Overall neurological impression 
□ Normal  
□ Abnormal 
 
Please mark normal, abnormal, or unable to determine for each item listed.  If any abnormalities 
are found, please specify the findings in the space provided. 
Items 
Status 
Please describe abnormalities 
Observation and mental status 
Alertness 
□ Normal  
□ Abnormal   
□ Not Done 
 
Interaction with care taker 
□ Normal  
□ Abnormal   
□ Not Done 
 
Activity level 
□ Normal  
□ Abnormal   
□ Not Done 
 
Involuntary movements 
□ Absent  
□ Present   
□ Not Done 
 
Cranial nerves 
Pupillary reaction to light 
□ Normal  
□ Abnormal   
□ Not Done 
 
Extra ocular movements 
□ Normal  
□ Abnormal   
□ Not Done 
 
Eye closure 
□ Normal  
□ Abnormal   
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
68 
Items 
Status 
Please describe abnormalities 
□ Not Done 
Facial symmetry 
□ Normal  
□ Abnormal   
□ Not Done 
 
Coordination/Sensory 
Rapid finger tapping 
□ Normal  
□ Abnormal   
□ Unable to Perform   
□ Not Done 
 
Finger to nose 
□ Normal  
□ Abnormal   
□ Unable to Perform   
□ Not Done 
 
Stand on one foot 
□ Normal  
□ Abnormal   
□ Unable to Perform   
□ Not Done 
 
Hop on one foot 
□ Normal  
□ Abnormal   
□ Unable to Perform   
□ Not Done 
 
Romberg 
□ Normal  
□ Abnormal   
□ Unable to Perform   
□ Not Done 
 
Deep tendon reflexes 
Biceps 
□ Normal  
□ Abnormal   
□ Not Done 
 
Patellar 
□ Normal  
□ Abnormal   
□ Not Done 
 
Ankle 
□ Normal  
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
69 
Items 
Status 
Please describe abnormalities 
□ Abnormal   
□ Not Done 
Deep tendon reflexes (continue) 
Ankle clonus 
□ Absent  
□ Present   
□ Not done 
 
Gait 
Natural walking 
□ Normal  
□ Abnormal   
□ Unable to Perform   
□ Not Done 
 
Straight line walking 
□ Normal  
□ Abnormal   
□ Unable to Perform   
□ Not Done 
 
Tandem walking 
□ Normal  
□ Abnormal   
□ Unable to Perform   
□ Not Done 
 
Other 
Specify:  ___________________ 
□ Normal  
□ Abnormal   
 
Specify:  ___________________ 
□ Normal  
□ Abnormal   
 
Specify:  ___________________ 
□ Normal  
□ Abnormal   
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
70 
Items 
Status 
Please describe abnormalities 
Specify:  ___________________ 
□ Normal  
□ Abnormal   
 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
71 
Appendix 3 
Neurodevelopmental and Behavioral Assessments 
Table 3-1 and Table 3-2 detail the specific psychometric instruments that will be used to provide 
measures of each of relevant neurobehavioral or developmental domain assessed.  The tables 
also summarize the rules used to select a test for a patient, the subtests included in each test, and 
the subscales generated by the test battery. 
Table 3-1 Summary of Neurodevelopmental Outcome Measures 
Domain 
Age 
Test 
Summary score and 
subdomains: 
- Cognitive 
- Motor 
0 to 42 months Bayley Scales of Infant Development, Third 
Edition (BSID-III)23  
- Cognitive  
- Processing skills 
3 to 18 years 
Kaufman Assessment Battery for Children, 
Second Edition (KABC-II)24  
Motor 
3.0 to 16:11 
years 
Movement Assessment Battery for Children, 
Second Edition (MABC-2)25  
Communication 
Daily Living 
Socialization 
Motor Skills 
0 to 90 years 
Vineland Adaptive Behavior Scales, Second 
Edition (VABS-II)26  
 
Table 3-2 Summary of Sanfilippo-specific Assessments 
Domain 
Assessment 
Parent-scored behavioral inventory 
- communication:  understanding 
- communication:  expression 
- tantrums 
- specific behaviors inventory 
- mood & emotions inventory 
Sanfilippo Behavior Rating Scale 
MPS-specific four-point scoring 
system/total disability score 
- cognition 
- expressive language 
- motor score 
Four-Point Scoring System/Total Disability 
Score (FPSS/TDS)4  
 
The term “neurodevelopmental” refers to the process by which the neurological system matures 
and changes over time.  Assessing these changes in a population of children whose neurological 
system is progressively more affected can be very challenging.   
Typically, neurodevelopmental progress is reflected by the child’s abilities to perform certain 
skills (sitting, walking, and talking).  However, a child with a neurological disorder may be able 
to perform age appropriate skills, but with atypical patterns.   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
72 
For example, the child may be able to walk, but his gait is not normal.  Most assessments will 
therefore measure the skills, but are not designed to capture the abnormalities in pattern or 
quality of the skill.   
These qualitative differences will be evident to the skilled test administrator/clinician who is 
familiar with the disorder.  However, only longitudinal tracking and repeated measures will 
reveal the significance of these abnormalities in overall function to the less experienced clinician.    
The rate at which different skills develop or regress over time will give insight into the disease 
process.  The next step is to determine how the learned skills are used for daily functional 
activities so that as the children grow up they become independent from caregivers.  These 
functional skills can be tracked to reflect quality of life issues for both parents and children.  
Neurodevelopmental assessments described below will be scheduled for administration in the 
morning and estimated to last between 2 and 4 hours. 
The list of assessments is discussed in detail in the Study Operations Manual and includes: 
Bayley Scales of Infant Development, Third Edition (BSID-III)23  
The Bayley Scales of Infant Development is a standard series of measurements used primarily to 
assess the motor (fine and gross), language (receptive and expressive), and cognitive 
development of infants and toddlers, ages 0 to 42 months.  This measure consists of a series of 
developmental play tasks and takes between 45 and 60 minutes to administer.  Raw scores of 
successfully completed items are converted to scale scores and to composite scores.  These 
scores are used to determine the child's performance compared with norms taken from typically 
developing children of their age (in months).  The assessment is often used in conjunction with 
the Social-Emotional Adaptive Behavior Questionnaire.  Completed by the parent or caregiver, 
this questionnaire establishes the range of adaptive behaviors that the child can currently achieve 
and enables comparison with age norms. 
Kaufman Assessment Battery for Children, Second Edition (KABC-II)24  
Purpose: 
The KABC-II measures a child’s cognitive ability and processing skills and was designed to 
minimize verbal instructions and responses.  In addition, the assessment contains little cultural 
content to provide a more accurate assessment of children from diverse backgrounds.  Thus 
language difficulties or cultural differences are minimized in the test battery’s results. 
Description: 
Investigators may choose either the Cattell-Horn-Carroll or the Luria model for a patient’s 
assessment.   
The Cattell-Horn-Carroll model is used with children from a mainstream cultural and language 
background and the Luria model is used for children with significantly limited verbal ability.  
Subtests are administered on four or five ability scales and interpreted using the chosen model.  

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
73 
Movement Assessment Battery for Children, Second Edition (MABC-2)25  
Purpose: 
The Movement Assessment Battery for Children, Second Edition identifies, describes and guides 
treatment of motor impairment in children from 3.0 to 16:11 years of age. 
Description: 
The MABC-2 checklist is administered individually over approximately 30 minutes.  It yields 
both normative and qualitative measures of movement competence, manual dexterity, ball skills, 
static and dynamic balance. 
Vineland Adaptive Behavior Scales, Second Edition (VABS-II)26  
Purpose: 
The test measures adaptive behaviors, including the ability to cope with environmental changes, 
to learn new everyday skills and to demonstrate independence.  It is an instrument that supports 
the diagnosis of intellectual and developmental disabilities.  It encompasses ages from birth to 
90 years.  
Description: 
Adaptive behavior is a composite of various dimensions.  This test measures 5 domains:  
communication, daily living skills, socialization, motor skills, and maladaptive behavior 
(optional) and is administered in a semi-structured interview in through a questionnaire.  The 
scales of the VABS-II were organized within a 3-domain structure:  Communication, Daily 
Living, and Socialization.  This structure corresponds to the 3 broad domains of adaptive 
functioning by the American Association of Intellectual and Developmental Disabilities:  
Conceptual, Practical, and Social.  In addition, VABS-II offers a Motor Skills Domain and an 
optional Maladaptive Behavior Index.  The scores are interpreted by means of score equivalents 
for the raw scores in each domain, percentile ranks, age equivalents, adaptive levels, and 
maladaptive levels. 
Sanfilippo Behavior Rating Scale (SBRS) 
The Sanfilippo Behavior Rating Scale (SBRS) is a newly-developed scale designed by Drs. Elsa 
Shapiro and Michael Potegal to measure a cluster of behaviors known to occur in Sanfilippo 
syndrome.  The SBRS is a parent-scored behavioral inventory measuring (1) comprehensive 
language skills, (2) expressive language skills, (3) tantrums, (4) mood and emotions, and 
(5) other behaviors not otherwise classified. 
Four-Point Scoring System/Total Disability Score (FPSS/TDS)5 
The FPSS assesses motor function, expressive language, and cognitive function on a 0 to 3 point 
scale and can be used for individuals of all ages.  The total disability score is the average of the 
motor function, speech, and cognitive function scores. 

Recombinant human heparan N-su)fatase (rhHNS) 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Appendix 4 
Investigator's Signature 
Study Title: 
An Open-Label Extension of Study IIGT-SAN-055 Evaluating 
Long-Term Safety and Clinical Outcomes of Intrathecal 
Administration of rhllNS in Patients with Sanfilippo Syndrome 
Type A (MPS IliA) 
Study Number: 
HGT-SAN-067 
Final Date: 
21 June 2010 
Amendment 1 Date: 
27 January 2011 
I have read the protocol described above. I agree to comply with all applicable regulations and 
to conduct the study 
in the protocol.
Signed: 
Dr.
 
The Netberlands 
Date: 
Signed: 
-------
Date: --'r
__ _ 
Shire 
 MD 
SbireHGT 
700 Main Street 
Cambridge, MA 01239 
Confidential 
74 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
75 
Appendix 5 
Summary of Changes for Amendment 1 
Clinical protocol HGT-SAN-067 has been revised from the previous version (original protocol, 
21 June 2010) to clarify that the study duration will be 4 years.   
In addition, one administrative change was made to the protocol; the title of the National Cancer 
Institute grading scale version 3.0 title was corrected: The National Cancer Institute Common 
Toxicity Criteria (NCI CTC) Version 3.0 was modified to correctly state The National Cancer 
Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0.   
The amendment number is 1. 
The change relative to the original protocol (21 June 2010) has been made in the protocol and is 
summarized below by section number; new or additional text is indicated in bold and deleted text 
is indicated as strikethrough below.  Other sections affected by the same change are listed below 
each change. 
Change: The text was modified to clarify that the study duration will be 4 years. 
Section impacted by this change: Section 4.3 Study Duration and Dates 
Modified Text: 
The study duration will be a maximum duration of 4 years of rhHNS treatment or until rhHNS is 
commercially available, the patient discontinues from the study, the Sponsor stops the study, or 
the Sponsor discontinues the development of rhHNS.  Study completion will be defined as the 
time at which a patient completes 4 years of rhHNS treatment (including participation in study 
HGT-SAN-055), or transitions to commercially available rhHNS or discontinues from this study 
for other reasons. 
Other sections affected by the same change: Synopsis 
 
 
 
 
 
 
 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 1 
27 January 2011 
Shire 
Confidential 
76 
Appendix 6 
The National Cancer Institute Common Terminology Criteria 
for Adverse Events (CTCAE) Version 3.0 
 
 
 
 

Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, Version 3.0, DCTD, NCI, NIH, DHHS 
 
March 31, 2003 (http://ctep.cancer.gov), Publish Date: August 9, 2006 
Common Terminology Criteria for Adverse Events v3.0 (CTCAE) 
Publish Date: August 9, 2006 
Quick Reference 
The NCI Common Terminology Criteria for Adverse Events 
v3.0 is a descriptive terminology which can be utilized for 
Adverse Event (AE) reporting. A grading (severity) scale is 
provided for each AE term. 
Components and Organization  
CATEGORY 
A CATEGORY is a broad classification of AEs based on 
anatomy and/or pathophysiology. Within each CATEGORY, 
AEs are listed accompanied by their descriptions of severity 
(Grade). 
Adverse Event Terms 
An AE is any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medical treatment or procedure 
that may or may not be considered related to the medical 
treatment or procedure. An AE is a term that is a unique 
representation of a specific event used for medical 
documentation and scientific analyses. Each AE term is 
mapped to a MedDRA term and code. AEs are listed 
alphabetically within CATEGORIES. 
Short AE Name 
The ‘SHORT NAME’ column is new and it is used to simplify 
documentation of AE names on Case Report Forms.   
Supra-ordinate Terms  
A supra-ordinate term is located within a CATEGORY and is a 
grouping term based on disease process, signs, symptoms, 
or diagnosis. A supra-ordinate term is followed by the word 
‘Select’ and is accompanied by specific AEs that are all 
related to the supra-ordinate term. Supra-ordinate terms 
provide clustering and consistent representation of Grade for 
related AEs. Supra-ordinate terms are not AEs, are not 
mapped to a MedDRA term and code, cannot be graded and 
cannot be used for reporting. 
REMARK 
A ‘REMARK’ is a clarification of an AE. 
ALSO CONSIDER 
An ‘ALSO CONSIDER’ indicates additional AEs that are to be 
graded if they are clinically significant. 
NAVIGATION NOTE 
A ‘NAVIGATION NOTE’ indicates the location of an AE term 
within the CTCAE document. It lists signs/symptoms 
alphabetically and the CTCAE term will appear in the same 
CATEGORY unless the ‘NAVIGATION NOTE’ states differently. 
Grades 
Grade refers to the severity of the AE. The CTCAE v3.0 
displays Grades 1 through 5 with unique clinical descriptions 
of severity for each AE based on this general guideline: 
Grade 1 
Mild AE  
Grade 2 
Moderate AE 
Grade 3 
Severe AE 
Grade 4 
Life-threatening or disabling AE 
Grade 5 
Death related to AE 
A Semi-colon indicates ‘or’ within the description of the grade. 
An ‘Em dash’ (—) indicates a grade not available. 
Not all Grades are appropriate for all AEs. Therefore, some 
AEs are listed with fewer than five options for Grade 
selection. 
Grade 5 
Grade 5 (Death) is not appropriate for some AEs and 
therefore is not an option. 
The DEATH CATEGORY is new. Only one Supra-ordinate 
term is listed in this CATEGORY: ‘Death not associated with 
CTCAE term – Select’ with 4 AE options: Death NOS; 
Disease progression NOS; Multi-organ failure; Sudden death. 
Important: 
• 
Grade 5 is the only appropriate Grade 
• 
This AE is to be used in the situation where 
a death  
1. cannot be reported using a CTCAE v3.0 
term associated with Grade 5, or 
2. cannot be reported within a CTCAE 
CATEGORY as ‘Other (Specify)’ 
 
 
 
 
 
Contents 
ALLERGY/IMMUNOLOGY ............................................1 
AUDITORY/EAR............................................................2 
BLOOD/BONE MARROW .............................................4 
CARDIAC ARRHYTHMIA..............................................5 
CARDIAC GENERAL ....................................................7 
COAGULATION ..........................................................10 
CONSTITUTIONAL SYMPTOMS................................11 
DEATH ........................................................................13 
DERMATOLOGY/SKIN ...............................................14 
ENDOCRINE...............................................................17 
GASTROINTESTINAL.................................................19 
GROWTH AND DEVELOPMENT................................29 
HEMORRHAGE/BLEEDING ....................................... 30 
HEPATOBILIARY/PANCREAS ................................... 34 
INFECTION................................................................. 35 
LYMPHATICS ............................................................. 38 
METABOLIC/LABORATORY ...................................... 40 
MUSCULOSKELETAL/SOFT TISSUE........................ 43 
NEUROLOGY ............................................................. 47 
OCULAR/VISUAL........................................................ 52 
PAIN............................................................................ 55 
PULMONARY/UPPER RESPIRATORY...................... 56 
RENAL/GENITOURINARY.......................................... 60 
SECONDARY MALIGNANCY..................................... 63 
SEXUAL/REPRODUCTIVE FUNCTION ..................... 64 
SURGERY/INTRA-OPERATIVE INJURY ................... 66 
SYNDROMES............................................................. 68 
VASCULAR................................................................. 70 
 

 
ALLERGY/IMMUNOLOGY 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 1 - 
March 31, 2003, Publish Date: August 9, 2006 
Allergic reaction/ 
hypersensitivity  
(including drug fever) 
Allergic reaction 
Transient flushing or 
rash; drug fever <38°C 
(<100.4°F) 
Rash; flushing; urticaria; 
dyspnea; drug fever 
≥38°C (≥100.4°F) 
Symptomatic 
bronchospasm, with or 
without urticaria; 
parenteral medication(s) 
indicated; allergy-related 
edema/angioedema; 
hypotension 
Anaphylaxis 
Death 
REMARK: Urticaria with manifestations of allergic or hypersensitivity reaction is graded as Allergic reaction/hypersensitivity (including drug fever). 
ALSO CONSIDER: Cytokine release syndrome/acute infusion reaction. 
Allergic rhinitis  
(including sneezing, 
nasal stuffiness, 
postnasal drip) 
Rhinitis 
Mild, intervention not 
indicated  
Moderate, intervention 
indicated 
— 
— 
— 
REMARK: Rhinitis associated with obstruction or stenosis is graded as Obstruction/stenosis of airway – Select in the PULMONARY/UPPER RESPIRATORY CATEGORY. 
Autoimmune reaction 
Autoimmune reaction 
Asymptomatic and 
serologic or other 
evidence of autoimmune 
reaction, with normal 
organ function and 
intervention not indicated 
Evidence of autoimmune 
reaction involving a non-
essential organ or 
function (e.g., 
hypothyroidism) 
Reversible autoimmune 
reaction involving function 
of a major organ or other 
adverse event (e.g., 
transient colitis or 
anemia)  
Autoimmune reaction with 
life-threatening 
consequences 
Death 
ALSO CONSIDER: Colitis; Hemoglobin; Hemolysis (e.g., immune hemolytic anemia, drug-related hemolysis); Thyroid function, low (hypothyroidism). 
Serum sickness 
Serum sickness 
— 
— 
Present 
— 
Death 
NAVIGATION NOTE: Splenic function is graded in the BLOOD/BONE MARROW CATEGORY. 
NAVIGATION NOTE: Urticaria as an isolated symptom is graded as Urticaria (hives, welts, wheals) in the DERMATOLOGY/SKIN CATEGORY. 
Vasculitis 
Vasculitis 
Mild, intervention not 
indicated 
Symptomatic, non-
steroidal medical 
intervention indicated 
Steroids indicated 
Ischemic changes; 
amputation indicated 
Death 
Allergy/Immunology – 
Other (Specify, __) 
Allergy – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
AUDITORY/EAR 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 2 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Earache (otalgia) is graded as Pain – Select in the PAIN CATEGORY. 
Hearing:  
patients with/without 
baseline audiogram and 
enrolled in a monitoring 
program1 
Hearing (monitoring 
program) 
Threshold shift or loss of 
15 – 25 dB relative to 
baseline, averaged at 2 
or more contiguous test 
frequencies in at least 
one ear; or subjective 
change in the absence of 
a Grade 1 threshold shift 
Threshold shift or loss of 
>25 – 90 dB, averaged at 
2 contiguous test 
frequencies in at least 
one ear 
Adult only: Threshold shift 
of >25 – 90 dB, averaged 
at 3 contiguous test 
frequencies in at least 
one ear  
Pediatric:  
Hearing loss sufficient to 
indicate therapeutic 
intervention, including 
hearing aids (e.g., ≥20 dB 
bilateral HL in the speech 
frequencies; ≥30 dB 
unilateral HL; and 
requiring additional 
speech-language related 
services) 
Adult only: Profound 
bilateral hearing loss 
(>90 dB) 
Pediatric:  
Audiologic indication for 
cochlear implant and 
requiring additional 
speech-language related 
services  
— 
REMARK: Pediatric recommendations are identical to those for adults, unless specified. For children and adolescents (≤18 years of age) without a baseline test, pre-exposure/pre-
treatment hearing should be considered to be <5 dB loss. 
Hearing: 
patients without baseline 
audiogram and not 
enrolled in a monitoring 
program1  
Hearing (without 
monitoring program) 
— 
Hearing loss not requiring 
hearing aid or 
intervention (i.e., not 
interfering with ADL) 
Hearing loss requiring 
hearing aid or 
intervention (i.e., 
interfering with ADL) 
Profound bilateral hearing 
loss (>90 dB) 
— 
REMARK: Pediatric recommendations are identical to those for adults, unless specified. For children and adolescents (≤18 years of age) without a baseline test, pre-exposure/pre-
treatment hearing should be considered to be <5 dB loss. 
Otitis, external ear 
(non-infectious) 
Otitis, external  
External otitis with 
erythema or dry 
desquamation  
External otitis with moist 
desquamation, edema, 
enhanced cerumen or 
discharge; tympanic 
membrane perforation; 
tympanostomy 
External otitis with 
mastoiditis; stenosis or 
osteomyelitis 
Necrosis of soft tissue or 
bone 
Death 
ALSO CONSIDER: Hearing: patients with/without baseline audiogram and enrolled in a monitoring program1; Hearing: patients without baseline audiogram and not enrolled in a 
monitoring program1.  
Otitis, middle ear  
(non-infectious) 
Otitis, middle 
Serous otitis  
Serous otitis, medical 
intervention indicated 
Otitis with discharge; 
mastoiditis  
Necrosis of the canal soft 
tissue or bone 
Death 

 
AUDITORY/EAR 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 3 - 
March 31, 2003, Publish Date: August 9, 2006 
Tinnitus 
Tinnitus 
— 
Tinnitus not interfering 
with ADL 
Tinnitus interfering with 
ADL 
Disabling 
— 
ALSO CONSIDER: Hearing: patients with/without baseline audiogram and enrolled in a monitoring program1; Hearing: patients without baseline audiogram and not enrolled in a 
monitoring program1. 
Auditory/Ear – Other 
(Specify, __) 
Auditory/Ear – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
 
 
 
 
 
 
                                            
1 Drug-induced ototoxicity should be distinguished from age-related threshold decrements or unrelated cochlear insult. When considering whether an adverse event has occurred, it is 
first necessary to classify the patient into one of two groups. (1) The patient is under standard treatment/enrolled in a clinical trial <2.5 years, and has a 15 dB or greater threshold 
shift averaged across two contiguous frequencies; or (2) The patient is under standard treatment/enrolled in a clinical trial >2.5 years, and the difference between the expected age-
related and the observed threshold shifts is 15 dB or greater averaged across two contiguous frequencies. Consult standard references for appropriate age- and gender-specific 
hearing norms, e.g., Morrell, et al. Age- and gender-specific reference ranges for hearing level and longitudinal changes in hearing level. Journal of the Acoustical Society of America 
100:1949-1967, 1996; or Shotland, et al. Recommendations for cancer prevention trials using potentially ototoxic test agents. Journal of Clinical Oncology 19:1658-1663, 2001.  
In the absence of a baseline prior to initial treatment, subsequent audiograms should be referenced to an appropriate database of normals. ANSI. (1996) 
American National Standard: Determination of occupational noise exposure and estimation of noise-induced hearing impairment, ANSI S 3.44-1996. (Standard S 3.44). New York: 
American National Standards Institute. The recommended ANSI S3.44 database is Annex B. 

 
BLOOD/BONE MARROW 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 4 - 
March 31, 2003, Publish Date: August 9, 2006 
Bone marrow cellularity 
Bone marrow cellularity 
Mildly hypocellular or  
≤25% reduction from 
normal cellularity for age 
Moderately hypocellular 
or >25 – ≤50% reduction 
from normal cellularity for 
age  
Severely hypocellular or 
>50 – ≤75% reduction 
cellularity from normal for 
age  
— 
Death 
CD4 count  
CD4 count 
<LLN – 500/mm3 
<LLN – 0.5 x 109 /L 
<500 – 200/mm3  
<0.5 – 0.2 x 109 /L 
<200 – 50/mm3  
<0.2 x 0.05 – 109 /L 
<50/mm3  
<0.05 x 109 /L 
Death 
Haptoglobin  
Haptoglobin 
<LLN  
— 
Absent 
— 
Death 
Hemoglobin  
Hemoglobin 
<LLN – 10.0 g/dL  
<LLN – 6.2 mmol/L  
<LLN – 100 g/L 
<10.0 – 8.0 g/dL 
<6.2 – 4.9 mmol/L  
<100 – 80g/L 
<8.0 – 6.5 g/dL 
<4.9 – 4.0 mmol/L 
<80 – 65 g/L 
<6.5 g/dL 
<4.0 mmol/L  
<65 g/L 
Death 
Hemolysis (e.g., immune 
hemolytic anemia, drug-
related hemolysis) 
Hemolysis 
Laboratory evidence of 
hemolysis only (e.g., 
direct antiglobulin test 
[DAT, Coombs’] 
schistocytes) 
Evidence of red cell 
destruction and ≥2 gm 
decrease in hemoglobin, 
no transfusion 
Transfusion or medical 
intervention (e.g., 
steroids) indicated 
Catastrophic 
consequences of 
hemolysis (e.g., renal 
failure, hypotension, 
bronchospasm, 
emergency splenectomy) 
Death 
ALSO CONSIDER: Haptoglobin; Hemoglobin. 
Iron overload 
Iron overload 
— 
Asymptomatic iron 
overload, intervention not 
indicated  
Iron overload, 
intervention indicated  
Organ impairment (e.g., 
endocrinopathy, 
cardiopathy) 
Death 
Leukocytes (total WBC) 
Leukocytes 
<LLN – 3000/mm3 
<LLN – 3.0 x 109 /L  
<3000 – 2000/mm3 
<3.0 – 2.0 x 109 /L 
<2000 – 1000/mm3 
<2.0 – 1.0 x 109 /L 
<1000/mm3  
<1.0 x 109 /L 
Death 
Lymphopenia  
Lymphopenia 
<LLN – 800/mm3 
<LLN x 0.8 – 109 /L 
<800 – 500/mm3 
<0.8 – 0.5 x 109 /L 
<500 – 200 mm3 
<0.5 – 0.2 x 109 /L 
<200/mm3 
<0.2 x 109 /L 
Death 
Myelodysplasia 
Myelodysplasia 
— 
— 
Abnormal marrow 
cytogenetics (marrow 
blasts ≤5%)  
RAEB or RAEB-T 
(marrow blasts >5%) 
Death 
Neutrophils/granulocytes 
(ANC/AGC) 
Neutrophils 
<LLN – 1500/mm3  
<LLN – 1.5 x 109 /L 
<1500 – 1000/mm3 
<1.5 – 1.0 x 109 /L  
<1000 – 500/mm3 
<1.0 – 0.5 x 109 /L 
<500/mm3 
<0.5 x 109 /L 
Death 
Platelets 
Platelets 
<LLN – 75,000/mm3 
<LLN – 75.0 x 109 /L 
<75,000 – 50,000/mm3 
<75.0 – 50.0 x 109 /L 
<50,000 – 25,000/mm3  
<50.0 – 25.0 x 109 /L 
<25,000/mm3  
<25.0 x 109 /L 
Death 
Splenic function 
Splenic function 
Incidental findings (e.g., 
Howell-Jolly bodies) 
Prophylactic antibiotics 
indicated 
—  
Life-threatening 
consequences 
Death 
Blood/Bone Marrow – 
Other (Specify, __) 
Blood – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
CARDIAC ARRHYTHMIA 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 5 - 
March 31, 2003, Publish Date: August 9, 2006 
Conduction abnormality/ 
atrioventricular heart 
block  
– Select:  
Conduction abnormality 
– Select 
Asymptomatic, 
intervention not indicated 
– Asystole 
– AV Block-First degree 
– AV Block-Second degree Mobitz Type I (Wenckebach)  
– AV Block-Second degree Mobitz Type II 
– AV Block-Third degree (Complete AV block) 
– Conduction abnormality NOS 
– Sick Sinus Syndrome  
– Stokes-Adams Syndrome 
– Wolff-Parkinson-White Syndrome 
Non-urgent medical 
intervention indicated 
Incompletely controlled 
medically or controlled  
with device (e.g., 
pacemaker) 
Life-threatening (e.g., 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
Death 
Palpitations 
Palpitations 
Present 
Present with associated 
symptoms (e.g., 
lightheadedness, 
shortness of breath) 
— 
— 
— 
REMARK: Grade palpitations only in the absence of a documented arrhythmia. 
Prolonged QTc interval 
Prolonged QTc 
QTc >0.45 – 0.47 second 
 QTc >0.47 – 0.50 
second; ≥0.06 second 
above baseline 
QTc >0.50 second 
QTc >0.50 second; life-
threatening signs or 
symptoms (e.g., 
arrhythmia, CHF, 
hypotension, shock 
syncope); Torsade de 
pointes 
Death 
Supraventricular and 
nodal arrhythmia  
– Select: 
Supraventricular 
arrhythmia – Select 
Asymptomatic, 
intervention not indicated 
Non-urgent medical 
intervention indicated 
– Atrial fibrillation 
– Atrial flutter  
– Atrial tachycardia/Paroxysmal Atrial Tachycardia 
– Nodal/Junctional 
– Sinus arrhythmia  
– Sinus bradycardia 
– Sinus tachycardia  
– Supraventricular arrhythmia NOS 
– Supraventricular extrasystoles (Premature Atrial Contractions; Premature Nodal/Junctional Contractions) 
– Supraventricular tachycardia 
Symptomatic and 
incompletely controlled 
medically, or controlled 
with device (e.g., 
pacemaker) 
Life-threatening (e.g., 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
Death 
NAVIGATION NOTE: Syncope is graded as Syncope (fainting) in the NEUROLOGY CATEGORY. 

 
CARDIAC ARRHYTHMIA 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 6 - 
March 31, 2003, Publish Date: August 9, 2006 
Vasovagal episode 
Vasovagal episode 
— 
Present without loss of 
consciousness 
Present with loss of 
consciousness 
Life-threatening 
consequences  
Death 
Ventricular arrhythmia 
– Select: 
Ventricular arrhythmia 
– Select 
– Bigeminy 
– Idioventricular rhythm 
– PVCs 
– Torsade de pointes 
– Trigeminy 
– Ventricular arrhythmia NOS 
– Ventricular fibrillation  
– Ventricular flutter 
– Ventricular tachycardia 
Asymptomatic, no 
intervention indicated 
Non-urgent medical 
intervention indicated 
Symptomatic and 
incompletely controlled 
medically or controlled 
with device (e.g., 
defibrillator) 
Life-threatening (e.g., 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
Death 
Cardiac Arrhythmia  
– Other (Specify, __) 
Cardiac Arrhythmia – 
Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling  
Death 

 
CARDIAC GENERAL 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 7 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Angina is graded as Cardiac ischemia/infarction in the CARDIAC GENERAL CATEGORY. 
Cardiac 
ischemia/infarction 
Cardiac 
ischemia/infarction 
Asymptomatic arterial 
narrowing without 
ischemia 
Asymptomatic and testing 
suggesting ischemia; 
stable angina  
Symptomatic and testing 
consistent with ischemia; 
unstable angina; 
intervention indicated 
Acute myocardial 
infarction 
Death 
Cardiac troponin I (cTnI) 
cTnI 
— 
— 
Levels consistent with 
unstable angina as 
defined by the 
manufacturer 
Levels consistent with 
myocardial infarction as 
defined by the 
manufacturer 
Death 
Cardiac troponin T (cTnT) 
cTnT 
0.03 – <0.05 ng/mL 
0.05 – <0.1 ng/mL 
0.1 – <0.2 ng/mL 
0.2 ng/mL 
Death 
Cardiopulmonary arrest, 
cause unknown 
(non-fatal) 
Cardiopulmonary arrest 
— 
— 
— 
Life-threatening  
— 
REMARK: Grade 4 (non-fatal) is the only appropriate grade. CTCAE provides three alternatives for reporting Death: 
1. A CTCAE term associated with Grade 5.  
2. A CTCAE 'Other (Specify, __)’ within any CATEGORY. 
3. Death not associated with CTCAE term – Select in the DEATH CATEGORY. 
NAVIGATION NOTE: Chest pain (non-cardiac and non-pleuritic) is graded as Pain – Select in the PAIN CATEGORY. 
NAVIGATION NOTE: CNS ischemia is graded as CNS cerebrovascular ischemia in the NEUROLOGY CATEGORY. 
Hypertension 
Hypertension 
Asymptomatic, transient 
(<24 hrs) increase by >20 
mmHg (diastolic) or to 
>150/100 if previously 
WNL; intervention not 
indicated  
Pediatric: 
Asymptomatic, transient 
(<24 hrs) BP increase 
>ULN; intervention not 
indicated 
Recurrent or persistent 
(≥24 hrs) or symptomatic 
increase by >20 mmHg 
(diastolic) or to >150/100 
if previously WNL; 
monotherapy may be 
indicated  
Pediatric: 
Recurrent or persistent 
(≥24 hrs) BP >ULN; 
monotherapy may be 
indicated 
Requiring more than one 
drug or more intensive 
therapy than previously 
Pediatric: 
Same as adult 
Life-threatening 
consequences (e.g., 
hypertensive crisis) 
Pediatric: 
Same as adult 
Death 
REMARK: Use age and gender-appropriate normal values >95th percentile ULN for pediatric patients. 

 
CARDIAC GENERAL 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 8 - 
March 31, 2003, Publish Date: August 9, 2006 
Hypotension 
Hypotension 
Changes, intervention not 
indicated 
Brief (<24 hrs) fluid 
replacement or other 
therapy; no physiologic 
consequences 
Sustained (≥24 hrs) 
therapy, resolves without 
persisting physiologic 
consequences 
Shock (e.g., acidemia; 
impairment of vital organ 
function)  
Death 
ALSO CONSIDER: Syncope (fainting). 
Left ventricular diastolic 
dysfunction 
Left ventricular diastolic 
dysfunction 
Asymptomatic diagnostic 
finding; intervention not 
indicated 
Asymptomatic, 
intervention indicated 
Symptomatic CHF 
responsive to intervention 
Refractory CHF, poorly 
controlled; intervention 
such as ventricular assist 
device or heart transplant 
indicated  
Death 
Left ventricular systolic 
dysfunction 
Left ventricular systolic 
dysfunction 
Asymptomatic, resting 
ejection fraction (EF)  
<60 – 50%; shortening 
fraction (SF) <30 – 24% 
Asymptomatic, resting  
EF <50 – 40%; 
SF <24 – 15% 
Symptomatic CHF 
responsive to 
intervention; 
EF <40 – 20% 
SF <15% 
Refractory CHF or poorly 
controlled; EF <20%; 
intervention such as 
ventricular assist device, 
ventricular reduction 
surgery, or heart 
transplant indicated 
Death 
NAVIGATION NOTE: Myocardial infarction is graded as Cardiac ischemia/infarction in the CARDIAC GENERAL CATEGORY. 
Myocarditis 
Myocarditis 
— 
— 
CHF responsive to 
intervention 
Severe or refractory CHF 
Death 
Pericardial effusion 
(non-malignant) 
Pericardial effusion 
Asymptomatic effusion  
—  
Effusion with physiologic 
consequences 
Life-threatening 
consequences (e.g., 
tamponade); emergency 
intervention indicated 
Death 
Pericarditis 
Pericarditis 
Asymptomatic, ECG or 
physical exam (rub) 
changes consistent with 
pericarditis 
Symptomatic pericarditis 
(e.g., chest pain) 
Pericarditis with 
physiologic 
consequences (e.g., 
pericardial constriction) 
Life-threatening 
consequences; 
emergency intervention 
indicated 
Death 
NAVIGATION NOTE: Pleuritic pain is graded as Pain – Select in the PAIN CATEGORY. 
Pulmonary hypertension 
Pulmonary hypertension 
Asymptomatic without 
therapy 
Asymptomatic, therapy 
indicated 
Symptomatic 
hypertension, responsive 
to therapy 
Symptomatic 
hypertension, poorly 
controlled 
Death 
Restrictive 
cardiomyopathy  
Restrictive 
cardiomyopathy  
Asymptomatic, therapy 
not indicated 
Asymptomatic, therapy 
indicated 
Symptomatic CHF 
responsive to intervention 
Refractory CHF, poorly 
controlled; intervention 
such as ventricular assist 
device, or heart 
transplant indicated  
Death 

 
CARDIAC GENERAL 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 9 - 
March 31, 2003, Publish Date: August 9, 2006 
Right ventricular 
dysfunction 
(cor pulmonale) 
Right ventricular 
dysfunction 
Asymptomatic without 
therapy 
Asymptomatic, therapy 
indicated 
Symptomatic cor 
pulmonale, responsive to 
intervention 
Symptomatic cor 
pulmonale poorly 
controlled; intervention 
such as ventricular assist 
device, or heart 
transplant indicated  
Death 
Valvular heart disease 
Valvular heart disease 
Asymptomatic valvular 
thickening with or without 
mild valvular regurgitation 
or stenosis; treatment 
other than endocarditis 
prophylaxis not indicated 
Asymptomatic; moderate 
regurgitation or stenosis 
by imaging 
Symptomatic; severe 
regurgitation or stenosis; 
symptoms controlled with 
medical therapy 
Life-threatening; 
disabling; intervention 
(e.g., valve replacement, 
valvuloplasty) indicated 
Death 
Cardiac General – Other 
(Specify, __) 
Cardiac General – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
COAGULATION 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 10 - 
March 31, 2003, Publish Date: August 9, 2006 
DIC (disseminated 
intravascular coagulation) 
DIC 
— 
Laboratory findings with 
no bleeding 
Laboratory findings and 
bleeding 
Laboratory findings, life-
threatening or disabling 
consequences (e.g., CNS 
hemorrhage, organ 
damage, or 
hemodynamically 
significant blood loss) 
Death 
REMARK: DIC (disseminated intravascular coagulation) must have increased fibrin split products or D-dimer.  
ALSO CONSIDER: Platelets. 
 
Fibrinogen  
Fibrinogen 
<1.0 – 0.75 x LLN 
or <25% decrease from 
baseline 
<0.75 – 0.5 x LLN 
or 25 – <50% decrease 
from baseline 
<0.5 – 0.25 x LLN 
or 50 – <75% decrease 
from baseline 
<0.25 x LLN  
or 75% decrease from 
baseline or absolute 
value <50 mg/dL  
Death 
REMARK: Use % decrease only when baseline is <LLN (local laboratory value). 
INR (International 
Normalized Ratio of 
prothrombin time) 
INR 
 
>1 – 1.5 x ULN 
>1.5 – 2 x ULN 
>2 x ULN 
— 
— 
ALSO CONSIDER: Hemorrhage, CNS; Hemorrhage, GI – Select; Hemorrhage, GU – Select; Hemorrhage, pulmonary/upper respiratory – Select. 
PTT (Partial 
Thromboplastin Time)  
PTT 
>1 – 1.5 x ULN 
>1.5 – 2 x ULN 
>2 x ULN 
— 
— 
ALSO CONSIDER: Hemorrhage, CNS; Hemorrhage, GI – Select; Hemorrhage, GU – Select; Hemorrhage, pulmonary/upper respiratory – Select. 
Thrombotic 
microangiopathy (e.g., 
thrombotic 
thrombocytopenic 
purpura [TTP] or 
hemolytic uremic 
syndrome [HUS]) 
Thrombotic 
microangiopathy 
Evidence of RBC 
destruction 
(schistocytosis) without 
clinical consequences 
— 
Laboratory findings 
present with clinical 
consequences (e.g., renal 
insufficiency, petechiae) 
Laboratory findings and 
life-threatening or 
disabling consequences, 
(e.g., CNS hemorrhage/ 
bleeding or thrombosis/ 
embolism or renal failure) 
Death 
REMARK: Must have microangiopathic changes on blood smear (e.g., schistocytes, helmet cells, red cell fragments). 
ALSO CONSIDER: Creatinine; Hemoglobin; Platelets. 
Coagulation – Other 
(Specify, __) 
Coagulation – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
CONSTITUTIONAL SYMPTOMS 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 11 - 
March 31, 2003, Publish Date: August 9, 2006 
Fatigue  
(asthenia, lethargy, 
malaise) 
Fatigue 
Mild fatigue over baseline 
Moderate or causing 
difficulty performing some 
ADL 
Severe fatigue interfering 
with ADL 
Disabling 
— 
Fever  
(in the absence of 
neutropenia, where 
neutropenia is defined as 
ANC <1.0 x 109/L) 
Fever 
38.0 – 39.0°C  
(100.4 – 102.2°F) 
>39.0 – 40.0°C 
(102.3 – 104.0°F)  
>40.0°C 
(>104.0°F) for ≤24 hrs  
>40.0°C 
(>104.0°F) for >24 hrs 
Death 
REMARK: The temperature measurements listed are oral or tympanic. 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever).  
NAVIGATION NOTE: Hot flashes are graded as Hot flashes/flushes in the ENDOCRINE CATEGORY. 
Hypothermia 
Hypothermia 
— 
35 – >32°C 
95 – >89.6°F 
32 – >28°C  
89.6 – >82.4° F 
≤28 °C  
82.4°F or life-threatening 
consequences (e.g., 
coma, hypotension, 
pulmonary edema, 
acidemia, ventricular 
fibrillation) 
Death 
Insomnia 
Insomnia 
Occasional difficulty 
sleeping, not interfering 
with function 
Difficulty sleeping, 
interfering with function 
but not interfering with 
ADL 
Frequent difficulty 
sleeping, interfering with 
ADL 
Disabling 
— 
REMARK: If pain or other symptoms interfere with sleep, do NOT grade as insomnia. Grade primary event(s) causing insomnia. 
Obesity2 
Obesity 
— 
BMI 25 – 29.9 kg/m2 
BMI 30 – 39.99 kg/m2 
BMI ≥40 kg/m2 
— 
REMARK: BMI = (weight [kg]) / (height [m])2 
Odor  
(patient odor) 
Patient odor 
Mild odor 
Pronounced odor 
— 
— 
— 
Rigors/chills 
Rigors/chills 
Mild 
Moderate, narcotics 
indicated 
Severe or prolonged, not 
responsive to narcotics 
— 
— 
                                            
2 NHLBI Obesity Task Force. "Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults," The Evidence Report, Obes Res 6:51S-
209S, 1998.  

 
CONSTITUTIONAL SYMPTOMS 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 12 - 
March 31, 2003, Publish Date: August 9, 2006 
Sweating  
(diaphoresis) 
Sweating  
Mild and occasional 
Frequent or drenching 
— 
— 
— 
ALSO CONSIDER: Hot flashes/flushes.  
Weight gain  
Weight gain 
5 – <10% of baseline 
10 – <20% of baseline 
≥20% of baseline 
— 
— 
REMARK: Edema, depending on etiology, is graded in the CARDIAC GENERAL or LYMPHATICS CATEGORIES. 
ALSO CONSIDER: Ascites (non-malignant); Pleural effusion (non-malignant). 
Weight loss 
Weight loss 
5 to <10% from baseline; 
intervention not indicated 
10 – <20% from baseline; 
nutritional support 
indicated 
≥20% from baseline; tube 
feeding or TPN indicated 
— 
— 
Constitutional Symptoms 
– Other (Specify, __) 
Constitutional Symptoms 
– Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
DEATH 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 13 - 
March 31, 2003, Publish Date: August 9, 2006 
Death not associated with 
CTCAE term  
– Select: 
Death not associated with 
CTCAE term – Select 
– Death NOS 
– Disease progression NOS 
– Multi-organ failure 
– Sudden death 
— 
— 
— 
— 
Death 
REMARK: Grade 5 is the only appropriate grade. 'Death not associated with CTCAE term – Select' is to be used where a death: 
1. Cannot be attributed to a CTCAE term associated with Grade 5. 
2. Cannot be reported within any CATEGORY using a CTCAE 'Other (Specify, __)’.  

 
DERMATOLOGY/SKIN 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 14 - 
March 31, 2003, Publish Date: August 9, 2006 
Atrophy, skin 
Atrophy, skin 
Detectable 
Marked 
— 
— 
— 
Atrophy, subcutaneous 
fat 
Atrophy, subcutaneous 
fat 
Detectable 
Marked 
— 
— 
— 
ALSO CONSIDER: Induration/fibrosis (skin and subcutaneous tissue). 
Bruising  
(in absence of Grade 3 or 
4 thrombocytopenia) 
Bruising  
Localized or in a 
dependent area 
Generalized 
— 
— 
— 
Burn 
Burn 
Minimal symptoms; 
intervention not indicated  
Medical intervention; 
minimal debridement 
indicated  
Moderate to major 
debridement or 
reconstruction indicated  
Life-threatening 
consequences 
Death 
REMARK: Burn refers to all burns including radiation, chemical, etc. 
Cheilitis 
Cheilitis 
Asymptomatic 
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
— 
— 
Dry skin 
Dry skin 
Asymptomatic 
Symptomatic, not 
interfering with ADL 
Interfering with ADL 
— 
— 
Flushing 
Flushing 
Asymptomatic 
Symptomatic 
— 
— 
— 
Hair loss/alopecia 
(scalp or body) 
Alopecia 
Thinning or patchy 
Complete 
— 
— 
— 
Hyperpigmentation 
Hyperpigmentation 
Slight or localized 
Marked or generalized 
— 
— 
— 
Hypopigmentation 
Hypopigmentation 
Slight or localized 
Marked or generalized 
— 
— 
— 
Induration/fibrosis 
(skin and subcutaneous 
tissue) 
Induration  
Increased density on 
palpation 
Moderate impairment of 
function not interfering 
with ADL; marked 
increase in density and 
firmness on palpation 
with or without minimal 
retraction 
Dysfunction interfering 
with ADL; very marked 
density, retraction or 
fixation 
— 
— 
ALSO CONSIDER: Fibrosis-cosmesis; Fibrosis-deep connective tissue.  
Injection site reaction/ 
extravasation changes 
Injection site reaction 
Pain; itching; erythema 
Pain or swelling, with 
inflammation or phlebitis 
Ulceration or necrosis 
that is severe; operative 
intervention indicated  
— 
— 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever); Ulceration. 

 
DERMATOLOGY/SKIN 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 15 - 
March 31, 2003, Publish Date: August 9, 2006 
Nail changes 
Nail changes 
Discoloration; ridging 
(koilonychias); pitting 
Partial or complete loss of 
nail(s); pain in nailbed(s) 
Interfering with ADL  
— 
— 
NAVIGATION NOTE: Petechiae is graded as Petechiae/purpura (hemorrhage/bleeding into skin or mucosa) in the HEMORRHAGE/BLEEDING CATEGORY. 
Photosensitivity 
Photosensitivity 
Painless erythema 
Painful erythema 
Erythema with 
desquamation 
Life-threatening; disabling 
Death 
Pruritus/itching 
Pruritus 
Mild or localized 
Intense or widespread 
Intense or widespread 
and interfering with ADL  
— 
— 
ALSO CONSIDER: Rash/desquamation. 
Rash/desquamation  
Rash 
Macular or papular 
eruption or erythema 
without associated 
symptoms 
Macular or papular 
eruption or erythema with 
pruritus or other 
associated symptoms; 
localized desquamation 
or other lesions covering 
<50% of body surface 
area (BSA) 
Severe, generalized 
erythroderma or macular, 
papular or vesicular 
eruption; desquamation 
covering ≥50% BSA 
Generalized exfoliative, 
ulcerative, or bullous 
dermatitis 
Death 
REMARK: Rash/desquamation may be used for GVHD. 
Rash:  
acne/acneiform 
Acne 
Intervention not indicated  
Intervention indicated 
Associated with pain, 
disfigurement, ulceration, 
or desquamation 
— 
Death 
Rash:  
dermatitis associated with 
radiation  
– Select: 
– Chemoradiation 
– Radiation 
Dermatitis – Select  
Faint erythema or dry 
desquamation 
Moderate to brisk 
erythema; patchy moist 
desquamation, mostly 
confined to skin folds and 
creases; moderate 
edema 
Moist desquamation other 
than skin folds and 
creases; bleeding 
induced by minor trauma 
or abrasion 
Skin necrosis or 
ulceration of full thickness 
dermis; spontaneous 
bleeding from involved 
site  
Death 
Rash:  
erythema multiforme 
(e.g., Stevens-Johnson 
syndrome, toxic 
epidermal necrolysis) 
Erythema multiforme 
— 
Scattered, but not 
generalized eruption 
Severe (e.g., generalized 
rash or painful stomatitis); 
IV fluids, tube feedings, 
or TPN indicated 
Life-threatening; disabling 
Death 
Rash:  
hand-foot skin reaction 
Hand-foot 
Minimal skin changes or 
dermatitis (e.g., 
erythema) without pain  
Skin changes (e.g., 
peeling, blisters, 
bleeding, edema) or pain, 
not interfering with 
function  
Ulcerative dermatitis or 
skin changes with pain 
interfering with function  
— 
— 

 
DERMATOLOGY/SKIN 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 16 - 
March 31, 2003, Publish Date: August 9, 2006 
Skin breakdown/ 
decubitus ulcer 
Decubitus  
— 
Local wound care; 
medical intervention 
indicated 
Operative debridement or 
other invasive 
intervention indicated 
(e.g., hyperbaric oxygen)  
Life-threatening 
consequences; major 
invasive intervention 
indicated (e.g., tissue 
reconstruction, flap, or 
grafting) 
Death 
REMARK: Skin breakdown/decubitus ulcer is to be used for loss of skin integrity or decubitus ulcer from pressure or as the result of operative or medical intervention. 
Striae 
Striae 
Mild 
Cosmetically significant 
— 
— 
— 
Telangiectasia 
Telangiectasia 
Few 
Moderate number 
Many and confluent 
— 
— 
Ulceration 
Ulceration 
— 
Superficial ulceration  
<2 cm size; local wound 
care; medical intervention 
indicated 
Ulceration ≥2 cm size; 
operative debridement, 
primary closure or other 
invasive intervention 
indicated (e.g., hyperbaric 
oxygen)  
Life-threatening 
consequences; major 
invasive intervention 
indicated (e.g., complete 
resection, tissue 
reconstruction, flap, or 
grafting) 
Death 
Urticaria  
(hives, welts, wheals) 
Urticaria 
Intervention not indicated 
Intervention indicated for 
<24 hrs 
Intervention indicated for 
≥24 hrs 
— 
— 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever). 
Wound complication, 
non-infectious  
Wound complication, 
non-infectious 
Incisional separation of  
≤25% of wound, no 
deeper than superficial 
fascia 
Incisional separation 
>25% of wound with local 
care; asymptomatic 
hernia 
Symptomatic hernia 
without evidence of 
strangulation; fascial 
disruption/dehiscence 
without evisceration; 
primary wound closure or 
revision by operative 
intervention indicated; 
hospitalization or 
hyperbaric oxygen 
indicated 
Symptomatic hernia with 
evidence of strangulation; 
fascial disruption with 
evisceration; major 
reconstruction flap, 
grafting, resection, or 
amputation indicated 
Death 
REMARK: Wound complication, non-infectious is to be used for separation of incision, hernia, dehiscence, evisceration, or second surgery for wound revision. 
Dermatology/Skin – Other 
(Specify, __) 
Dermatology – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
ENDOCRINE 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 17 - 
March 31, 2003, Publish Date: August 9, 2006 
Adrenal insufficiency 
Adrenal insufficiency 
Asymptomatic, 
intervention not indicated 
Symptomatic, intervention 
indicated 
Hospitalization  
Life-threatening; disabling 
Death 
REMARK: Adrenal insufficiency includes any of the following signs and symptoms: abdominal pain, anorexia, constipation, diarrhea, hypotension, pigmentation of mucous membranes, 
pigmentation of skin, salt craving, syncope (fainting), vitiligo, vomiting, weakness, weight loss. Adrenal insufficiency must be confirmed by laboratory studies (low cortisol frequently 
accompanied by low aldosterone). 
ALSO CONSIDER: Potassium, serum-high (hyperkalemia); Thyroid function, low (hypothyroidism). 
Cushingoid appearance 
(e.g., moon face, buffalo 
hump, centripetal obesity, 
cutaneous striae) 
Cushingoid  
— 
Present 
— 
— 
— 
ALSO CONSIDER: Glucose, serum-high (hyperglycemia); Potassium, serum-low (hypokalemia). 
Feminization of male 
Feminization of male 
— 
— 
Present 
— 
— 
NAVIGATION NOTE: Gynecomastia is graded in the SEXUAL/REPRODUCTIVE FUNCTION CATEGORY. 
Hot flashes/flushes3 
Hot flashes 
Mild  
Moderate  
Interfering with ADL 
— 
— 
Masculinization of female 
Masculinization of female 
— 
— 
Present 
— 
— 
Neuroendocrine: 
ACTH deficiency 
ACTH  
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL; hospitalization 
indicated 
Life-threatening 
consequences (e.g., 
severe hypotension) 
Death 
Neuroendocrine: 
ADH secretion 
abnormality (e.g., SIADH 
or low ADH) 
ADH 
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL 
Life-threatening 
consequences 
Death 
Neuroendocrine: 
gonadotropin secretion 
abnormality 
Gonadotropin 
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL; osteopenia; 
fracture; infertility 
— 
— 
Neuroendocrine:  
growth hormone 
secretion abnormality 
Growth hormone  
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
— 
— 
— 
Neuroendocrine:  
prolactin hormone 
secretion abnormality 
Prolactin  
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL; amenorrhea; 
galactorrhea 
— 
Death 
                                            
3 Sloan JA, Loprinzi CL, Novotny PJ, Barton DL, Lavasseur BI, Windschitl HJ, "Methodologic Lessons Learned from Hot Flash Studies," J Clin Oncol 2001 Dec 1;19(23):4280-90 

 
ENDOCRINE 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 18 - 
March 31, 2003, Publish Date: August 9, 2006 
Pancreatic endocrine:  
glucose intolerance 
Diabetes 
Asymptomatic, 
intervention not indicated 
Symptomatic; dietary 
modification or oral agent 
indicated 
Symptoms interfering with 
ADL; insulin indicated 
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar non-ketotic 
coma)  
Death 
Parathyroid function, low 
(hypoparathyroidism) 
Hypoparathyroidism 
Asymptomatic, 
intervention not indicated 
Symptomatic; intervention 
indicated 
— 
— 
— 
Thyroid function, high 
(hyperthyroidism, 
thyrotoxicosis) 
Hyperthyroidism  
Asymptomatic, 
intervention not indicated 
Symptomatic, not 
interfering with ADL; 
thyroid suppression 
therapy indicated 
Symptoms interfering with 
ADL; hospitalization 
indicated  
Life-threatening 
consequences (e.g., 
thyroid storm) 
Death 
Thyroid function, low 
(hypothyroidism) 
Hypothyroidism 
Asymptomatic, 
intervention not indicated 
Symptomatic, not 
interfering with ADL; 
thyroid replacement 
indicated 
Symptoms interfering with 
ADL; hospitalization 
indicated  
Life-threatening 
myxedema coma 
Death 
Endocrine – Other  
(Specify, __) 
Endocrine – Other  
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
GASTROINTESTINAL 
Page 1 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 19 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Abdominal pain or cramping is graded as Pain – Select in the PAIN CATEGORY. 
Anorexia 
Anorexia 
Loss of appetite without 
alteration in eating habits 
Oral intake altered 
without significant weight 
loss or malnutrition; oral 
nutritional supplements 
indicated 
Associated with 
significant weight loss or 
malnutrition (e.g., 
inadequate oral caloric 
and/or fluid intake); IV 
fluids, tube feedings or 
TPN indicated 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Weight loss. 
Ascites (non-malignant) 
Ascites 
Asymptomatic 
Symptomatic, medical 
intervention indicated 
Symptomatic, invasive 
procedure indicated 
Life-threatening 
consequences 
Death 
REMARK: Ascites (non-malignant) refers to documented non-malignant ascites or unknown etiology, but unlikely malignant, and includes chylous ascites. 
Colitis 
Colitis 
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain; mucus 
or blood in stool 
Abdominal pain, fever, 
change in bowel habits 
with ileus; peritoneal 
signs 
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis, toxic 
megacolon) 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select.  
Constipation 
Constipation 
Occasional or intermittent 
symptoms; occasional 
use of stool softeners, 
laxatives, dietary 
modification, or enema 
Persistent symptoms with 
regular use of laxatives 
or enemas indicated 
Symptoms interfering 
with ADL; obstipation 
with manual evacuation 
indicated  
Life-threatening 
consequences (e.g., 
obstruction, toxic 
megacolon) 
Death 
ALSO CONSIDER: Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation); Obstruction, GI – Select. 
Dehydration 
Dehydration 
Increased oral fluids 
indicated; dry mucous 
membranes; diminished 
skin turgor 
IV fluids indicated <24 
hrs 
IV fluids indicated ≥24 hrs 
Life-threatening 
consequences (e.g., 
hemodynamic collapse) 
Death 
ALSO CONSIDER: Diarrhea; Hypotension; Vomiting. 
Dental:  
dentures or prosthesis 
Dentures  
Minimal discomfort, no 
restriction in activities  
Discomfort preventing 
use in some activities 
(e.g., eating), but not 
others (e.g., speaking) 
Unable to use dentures 
or prosthesis at any time 
— 
— 

 
GASTROINTESTINAL 
Page 2 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 20 - 
March 31, 2003, Publish Date: August 9, 2006 
Dental:  
periodontal disease  
Periodontal  
Gingival recession or 
gingivitis; limited bleeding 
on probing; mild local 
bone loss 
Moderate gingival 
recession or gingivitis; 
multiple sites of bleeding 
on probing; moderate 
bone loss 
Spontaneous bleeding; 
severe bone loss with or 
without tooth loss; 
osteonecrosis of maxilla 
or mandible  
— 
— 
REMARK: Severe periodontal disease leading to osteonecrosis is graded as Osteonecrosis (avascular necrosis) in the MUSCULOSKELETAL CATEGORY. 
Dental: 
teeth  
Teeth 
Surface stains; dental 
caries; restorable, without 
extractions 
Less than full mouth 
extractions; tooth fracture 
or crown amputation or 
repair indicated 
Full mouth extractions 
indicated 
— 
— 
Dental:  
teeth development 
Teeth development 
Hypoplasia of tooth or 
enamel not interfering 
with function 
Functional impairment 
correctable with oral 
surgery 
Maldevelopment with 
functional impairment not 
surgically correctable 
— 
— 
Diarrhea 
Diarrhea 
Increase of <4 stools per 
day over baseline; mild 
increase in ostomy output 
compared to baseline 
Increase of 4 – 6 stools 
per day over baseline; IV 
fluids indicated <24hrs; 
moderate increase in 
ostomy output compared 
to baseline; not 
interfering with ADL 
Increase of ≥7 stools per 
day over baseline; 
incontinence; IV fluids 
≥24 hrs; hospitalization; 
severe increase in 
ostomy output compared 
to baseline; interfering 
with ADL 
Life-threatening 
consequences (e.g., 
hemodynamic collapse) 
Death 
REMARK: Diarrhea includes diarrhea of small bowel or colonic origin, and/or ostomy diarrhea. 
ALSO CONSIDER: Dehydration; Hypotension. 
Distension/bloating, 
abdominal 
Distension 
Asymptomatic  
Symptomatic, but not 
interfering with GI 
function 
Symptomatic, interfering 
with GI function 
— 
— 
ALSO CONSIDER: Ascites (non-malignant); Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation); Obstruction, GI – Select.  

 
GASTROINTESTINAL 
Page 3 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 21 - 
March 31, 2003, Publish Date: August 9, 2006 
Dry mouth/salivary gland 
(xerostomia) 
Dry mouth 
Symptomatic (dry or thick 
saliva) without significant 
dietary alteration; 
unstimulated saliva flow 
>0.2 ml/min 
Symptomatic and 
significant oral intake 
alteration (e.g., copious 
water, other lubricants, 
diet limited to purees 
and/or soft, moist foods); 
unstimulated saliva 
0.1 to 0.2 ml/min 
Symptoms leading to 
inability to adequately 
aliment orally; IV fluids, 
tube feedings, or TPN 
indicated; unstimulated 
saliva <0.1 ml/min 
— 
— 
REMARK: Dry mouth/salivary gland (xerostomia) includes descriptions of grade using both subjective and objective assessment parameters. Record this event consistently throughout 
a patient’s participation on study. If salivary flow measurements are used for initial assessment, subsequent assessments must use salivary flow. 
ALSO CONSIDER: Salivary gland changes/saliva.  
Dysphagia 
(difficulty swallowing) 
Dysphagia 
Symptomatic, able to eat 
regular diet  
Symptomatic and altered 
eating/swallowing (e.g., 
altered dietary habits, 
oral supplements); IV 
fluids indicated <24 hrs 
Symptomatic and 
severely altered 
eating/swallowing (e.g., 
inadequate oral caloric or 
fluid intake); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences (e.g., 
obstruction, perforation) 
 
Death 
REMARK: Dysphagia (difficulty swallowing) is to be used for swallowing difficulty from oral, pharyngeal, esophageal, or neurologic origin. Dysphagia requiring dilation is graded as 
Stricture/stenosis (including anastomotic), GI – Select. 
ALSO CONSIDER: Dehydration; Esophagitis. 
Enteritis  
(inflammation of the small 
bowel) 
Enteritis 
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain; mucus 
or blood in stool 
Abdominal pain, fever, 
change in bowel habits 
with ileus; peritoneal 
signs 
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis) 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select; Typhlitis (cecal inflammation).  
Esophagitis 
Esophagitis 
Asymptomatic pathologic, 
radiographic, or 
endoscopic findings only 
Symptomatic; altered 
eating/swallowing (e.g., 
altered dietary habits, 
oral supplements); IV 
fluids indicated <24 hrs 
Symptomatic and 
severely altered 
eating/swallowing (e.g., 
inadequate oral caloric or 
fluid intake); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences 
Death 
REMARK: Esophagitis includes reflux esophagitis.  
ALSO CONSIDER: Dysphagia (difficulty swallowing). 

 
GASTROINTESTINAL 
Page 4 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 22 - 
March 31, 2003, Publish Date: August 9, 2006 
Fistula, GI 
– Select: 
Fistula, GI – Select  
– Abdomen NOS 
– Anus 
– Biliary tree  
– Colon/cecum/appendix 
– Duodenum 
– Esophagus 
– Gallbladder  
– Ileum 
– Jejunum 
– Oral cavity 
– Pancreas 
– Pharynx 
– Rectum 
– Salivary gland  
– Small bowel NOS 
– Stomach 
Asymptomatic, 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, diarrhea, 
or GI fluid loss); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered GI 
function (e.g., altered 
dietary habits, diarrhea, 
or GI fluid loss); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences  
Death 
REMARK: A fistula is defined as an abnormal communication between two body cavities, potential spaces, and/or the skin. The site indicated for a fistula should be the site from which 
the abnormal process is believed to have originated. For example, a tracheo-esophageal fistula arising in the context of a resected or irradiated esophageal cancer is graded as 
Fistula, GI – esophagus. 
Flatulence 
Flatulence 
Mild 
Moderate 
— 
— 
— 
Gastritis (including bile 
reflux gastritis) 
Gastritis 
Asymptomatic 
radiographic or 
endoscopic findings only 
Symptomatic; altered 
gastric function (e.g., 
inadequate oral caloric or 
fluid intake); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered gastric 
function (e.g., inadequate 
oral caloric or fluid 
intake); IV fluids, tube 
feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., gastrectomy)  
Death 
ALSO CONSIDER: Hemorrhage, GI – Select; Ulcer, GI – Select. 
NAVIGATION NOTE: Head and neck soft tissue necrosis is graded as Soft tissue necrosis – Select in the MUSCULOSKELETAL/SOFT TISSUE CATEGORY. 
Heartburn/dyspepsia 
Heartburn 
Mild 
Moderate 
Severe 
— 
— 
Hemorrhoids 
Hemorrhoids 
Asymptomatic 
Symptomatic; banding or 
medical intervention 
indicated 
Interfering with ADL; 
interventional radiology, 
endoscopic, or operative 
intervention indicated 
Life-threatening 
consequences 
Death 

 
GASTROINTESTINAL 
Page 5 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 23 - 
March 31, 2003, Publish Date: August 9, 2006 
Ileus, GI (functional 
obstruction of bowel, i.e., 
neuroconstipation) 
Ileus 
Asymptomatic, 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered GI 
function; IV fluids, tube 
feeding, or TPN indicated 
≥24 hrs 
Life-threatening 
consequences 
Death 
REMARK: Ileus, GI is to be used for altered upper or lower GI function (e.g., delayed gastric or colonic emptying). 
ALSO CONSIDER: Constipation; Nausea; Obstruction, GI – Select; Vomiting. 
Incontinence, anal 
Incontinence, anal 
Occasional use of pads 
required 
Daily use of pads 
required 
Interfering with ADL; 
operative intervention 
indicated 
Permanent bowel 
diversion indicated 
Death 
REMARK: Incontinence, anal is to be used for loss of sphincter control as sequelae of operative or therapeutic intervention. 
Leak (including 
anastomotic), GI 
– Select: 
– Biliary tree 
– Esophagus 
– Large bowel 
– Leak NOS 
– Pancreas 
– Pharynx 
– Rectum 
– Small bowel  
– Stoma 
– Stomach 
Leak, GI – Select  
Asymptomatic 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and 
interfering with GI 
function; invasive or 
endoscopic intervention 
indicated  
Life-threatening 
consequences 
Death 
REMARK: Leak (including anasomotic), GI – Select is to be used for clinical signs/symptoms or radiographic confirmation of anastomotic or conduit leak (e.g., biliary, esophageal, 
intestinal, pancreatic, pharyngeal, rectal), but without development of fistula. 
Malabsorption  
Malabsorption 
— 
Altered diet; oral 
therapies indicated (e.g., 
enzymes, medications, 
dietary supplements)  
Inability to aliment 
adequately via GI tract 
(i.e., TPN indicated) 
Life-threatening 
consequences 
Death 

 
GASTROINTESTINAL 
Page 6 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 24 - 
March 31, 2003, Publish Date: August 9, 2006 
Mucositis/stomatitis 
(clinical exam)  
– Select: 
– Anus 
– Esophagus 
– Large bowel 
– Larynx 
– Oral cavity 
– Pharynx 
– Rectum 
– Small bowel 
– Stomach 
– Trachea 
Mucositis (clinical exam) 
– Select  
Erythema of the mucosa 
Patchy ulcerations or 
pseudomembranes  
Confluent ulcerations or 
pseudomembranes; 
bleeding with minor 
trauma 
Tissue necrosis; 
significant spontaneous 
bleeding; life-threatening 
consequences 
Death 
REMARK: Mucositis/stomatitis (functional/symptomatic) may be used for mucositis of the upper aero-digestive tract caused by radiation, agents, or GVHD.  
Mucositis/stomatitis 
(functional/symptomatic)  
– Select: 
– Anus 
– Esophagus 
– Large bowel 
– Larynx 
– Oral cavity 
– Pharynx 
– Rectum 
– Small bowel 
– Stomach 
– Trachea 
Mucositis (functional/ 
symptomatic) – Select  
Upper aerodigestive tract 
sites: Minimal symptoms, 
normal diet; minimal 
respiratory symptoms but 
not interfering with 
function 
Lower GI sites: 
Minimal discomfort, 
intervention not indicated 
Upper aerodigestive tract 
sites: Symptomatic but 
can eat and swallow 
modified diet; respiratory 
symptoms interfering with 
function but not 
interfering with ADL 
Lower GI sites:  
Symptomatic, medical 
intervention indicated but 
not interfering with ADL 
Upper aerodigestive tract 
sites: Symptomatic and 
unable to adequately 
aliment or hydrate orally; 
respiratory symptoms 
interfering with ADL 
Lower GI sites: 
Stool incontinence or 
other symptoms 
interfering with ADL 
Symptoms associated 
with life-threatening 
consequences  
Death 
Nausea 
Nausea 
Loss of appetite without 
alteration in eating habits 
Oral intake decreased 
without significant weight 
loss, dehydration or 
malnutrition; IV fluids 
indicated <24 hrs 
Inadequate oral caloric or 
fluid intake; IV fluids, tube 
feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Anorexia; Vomiting. 

 
GASTROINTESTINAL 
Page 7 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 25 - 
March 31, 2003, Publish Date: August 9, 2006 
Necrosis, GI 
– Select:  
Necrosis, GI – Select  
– Anus 
– Colon/cecum/appendix 
– Duodenum 
– Esophagus 
– Gallbladder 
– Hepatic 
– Ileum 
– Jejunum 
– Oral 
– Pancreas 
– Peritoneal cavity 
– Pharynx  
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
— 
— 
Inability to aliment 
adequately by GI tract 
(e.g., requiring enteral or 
parenteral nutrition); 
interventional radiology, 
endoscopic, or operative 
intervention indicated  
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., total colectomy)  
Death 
ALSO CONSIDER: Visceral arterial ischemia (non-myocardial). 
Obstruction, GI 
– Select: 
– Cecum 
– Colon 
– Duodenum 
– Esophagus 
– Gallbladder 
– Ileum 
– Jejunum 
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
Obstruction, GI – Select 
Asymptomatic 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, vomiting, 
diarrhea, or GI fluid loss); 
IV fluids indicated <24 
hrs 
Symptomatic and 
severely altered GI 
function (e.g., altered 
dietary habits, vomiting, 
diarrhea, or GI fluid loss); 
IV fluids, tube feedings, 
or TPN indicated ≥24 hrs; 
operative intervention 
indicated 
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., total colectomy)  
Death 
NAVIGATION NOTE: Operative injury is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY CATEGORY. 
NAVIGATION NOTE: Pelvic pain is graded as Pain – Select in the PAIN CATEGORY. 

 
GASTROINTESTINAL 
Page 8 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 26 - 
March 31, 2003, Publish Date: August 9, 2006 
Perforation, GI 
– Select: 
– Appendix 
– Biliary tree 
– Cecum 
– Colon 
– Duodenum 
– Esophagus 
– Gallbladder 
– Ileum 
– Jejunum 
– Rectum 
– Small bowel NOS 
– Stomach 
Perforation, GI – Select 
Asymptomatic 
radiographic findings only 
Medical intervention 
indicated; IV fluids 
indicated <24 hrs 
IV fluids, tube feedings, 
or TPN indicated ≥24 hrs; 
operative intervention 
indicated 
Life-threatening 
consequences 
Death 
Proctitis  
Proctitis 
Rectal discomfort, 
intervention not indicated 
Symptoms not interfering 
with ADL; medical 
intervention indicated  
Stool incontinence or 
other symptoms 
interfering with ADL; 
operative intervention 
indicated 
Life-threatening 
consequences (e.g., 
perforation) 
Death 
Prolapse of stoma, GI 
Prolapse of stoma, GI 
Asymptomatic  
Extraordinary local care 
or maintenance; minor 
revision indicated 
Dysfunctional stoma; 
major revision indicated  
Life-threatening 
consequences 
Death 
REMARK: Other stoma complications may be graded as Fistula, GI – Select; Leak (including anastomotic), GI – Select; Obstruction, GI – Select; Perforation, GI – Select; 
Stricture/stenosis (including anastomotic), GI – Select. 
NAVIGATION NOTE: Rectal or perirectal pain (proctalgia) is graded as Pain – Select in the PAIN CATEGORY.  
Salivary gland 
changes/saliva 
Salivary gland changes 
Slightly thickened saliva; 
slightly altered taste (e.g., 
metallic) 
Thick, ropy, sticky saliva; 
markedly altered taste; 
alteration in diet 
indicated; secretion-
induced symptoms not 
interfering with ADL 
Acute salivary gland 
necrosis; severe 
secretion-induced 
symptoms interfering with 
ADL  
Disabling 
— 
ALSO CONSIDER: Dry mouth/salivary gland (xerostomia); Mucositis/stomatitis (clinical exam) – Select; Mucositis/stomatitis (functional/symptomatic) – Select; Taste alteration 
(dysgeusia). 
NAVIGATION NOTE: Splenic function is graded in the BLOOD/BONE MARROW CATEGORY. 

 
GASTROINTESTINAL 
Page 9 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 27 - 
March 31, 2003, Publish Date: August 9, 2006 
Stricture/stenosis 
(including anastomotic), 
GI 
– Select:  
Stricture, GI – Select  
– Anus 
– Biliary tree 
– Cecum 
– Colon  
– Duodenum  
– Esophagus 
– Ileum 
– Jejunum 
– Pancreas/pancreatic duct 
– Pharynx 
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
Asymptomatic 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, vomiting, 
bleeding, diarrhea); IV 
fluids indicated <24 hrs 
Symptomatic and 
severely altered GI 
function (e.g., altered 
dietary habits, diarrhea, 
or GI fluid loss); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs; 
operative intervention 
indicated 
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., total colectomy)  
Death 
Taste alteration 
(dysgeusia) 
Taste alteration 
Altered taste but no 
change in diet 
Altered taste with change 
in diet (e.g., oral 
supplements); noxious or 
unpleasant taste; loss of 
taste 
— 
— 
— 
Typhlitis 
(cecal inflammation) 
Typhlitis 
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain; mucus 
or blood in stool 
Abdominal pain, fever, 
change in bowel habits 
with ileus; peritoneal 
signs 
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis); 
operative intervention 
indicated 
Death 
ALSO CONSIDER: Colitis; Hemorrhage, GI – Select ; Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation).  

 
GASTROINTESTINAL 
Page 10 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 28 - 
March 31, 2003, Publish Date: August 9, 2006 
Ulcer, GI 
– Select: 
– Anus 
– Cecum 
– Colon 
– Duodenum 
– Esophagus 
– Ileum 
– Jejunum 
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
Ulcer, GI – Select 
Asymptomatic, 
radiographic or 
endoscopic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, oral 
supplements); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered GI 
function (e.g., inadequate 
oral caloric or fluid 
intake); IV fluids, tube 
feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select. 
Vomiting 
Vomiting 
1 episode in 24 hrs 
2 – 5 episodes in 24 hrs; 
IV fluids indicated  
<24 hrs 
≥6 episodes in 24 hrs; IV 
fluids, or TPN indicated 
≥24 hrs 
Life-threatening 
consequences  
Death 
ALSO CONSIDER: Dehydration. 
Gastrointestinal – Other 
(Specify, __) 
GI – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling 
Death 

 
GROWTH AND DEVELOPMENT 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 29 - 
March 31, 2003, Publish Date: August 9, 2006 
Bone age 
(alteration in bone age) 
Bone age 
— 
+2 SD (standard 
deviation) from normal 
— 
— 
— 
Bone growth: 
femoral head; slipped 
capital femoral epiphysis 
Femoral head growth 
Mild valgus/varus 
deformity 
Moderate valgus/varus 
deformity, symptomatic, 
interfering with function 
but not interfering with 
ADL 
Mild slipped capital 
femoral epiphysis; 
operative intervention 
(e.g., fixation) indicated; 
interfering with ADL 
Disabling; severe slipped 
capital femoral epiphysis 
>60%; avascular necrosis 
— 
Bone growth: 
limb length discrepancy 
Limb length  
Mild length discrepancy 
<2 cm 
Moderate length 
discrepancy 2 – 5 cm; 
shoe lift indicated 
Severe length 
discrepancy >5 cm; 
operative intervention 
indicated; interfering with 
ADL 
Disabling; epiphysiodesis 
— 
Bone growth: 
spine kyphosis/lordosis 
Kyphosis/lordosis 
Mild radiographic 
changes  
Moderate accentuation; 
interfering with function 
but not interfering with 
ADL 
Severe accentuation; 
operative intervention 
indicated; interfering with 
ADL 
Disabling (e.g., cannot lift 
head) 
— 
Growth velocity 
(reduction in growth 
velocity) 
Reduction in growth 
velocity 
10 – 29% reduction in 
growth from the baseline 
growth curve 
30 – 49% reduction in 
growth from the baseline 
growth curve 
≥50% reduction in growth 
from the baseline growth 
curve  
— 
— 
Puberty (delayed) 
Delayed puberty 
— 
No breast development 
by age 13 yrs for females; 
no Tanner Stage 2 
development by age 14.5 
yrs for males 
No sexual development 
by age 14 yrs for girls, 
age 16 yrs for boys; 
hormone replacement 
indicated 
— 
— 
REMARK: Do not use testicular size for Tanner Stage in male cancer survivors. 
Puberty (precocious)  
Precocious puberty 
— 
Physical signs of puberty 
<7 years for females,  
<9 years for males 
— 
— 
— 
Short stature 
Short stature 
Beyond two standard 
deviations of age and 
gender mean height 
Altered ADL 
— 
— 
— 
REMARK: Short stature is secondary to growth hormone deficiency. 
ALSO CONSIDER: Neuroendocrine: growth hormone secretion abnormality. 
Growth and Development 
– Other (Specify, __) 
Growth and Development 
– Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
HEMORRHAGE/BLEEDING 
Page 1 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 30 - 
March 31, 2003, Publish Date: August 9, 2006 
Hematoma  
Hematoma 
Minimal symptoms, 
invasive intervention not 
indicated  
Minimally invasive 
evacuation or aspiration 
indicated 
Transfusion, 
interventional radiology, 
or operative intervention 
indicated 
Life-threatening 
consequences; major 
urgent intervention 
indicated 
Death 
REMARK: Hematoma refers to extravasation at wound or operative site or secondary to other intervention. Transfusion implies pRBC.  
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Hemorrhage/bleeding 
associated with surgery, 
intra-operative or 
postoperative 
Hemorrhage with surgery 
— 
— 
Requiring transfusion of  
2 units non-autologous 
(10 cc/kg for pediatrics) 
pRBCs beyond protocol 
specification; 
postoperative 
interventional radiology, 
endoscopic, or operative 
intervention indicated 
Life-threatening 
consequences  
Death 
REMARK: Postoperative period is defined as ≤72 hours after surgery. Verify protocol-specific acceptable guidelines regarding pRBC transfusion. 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Hemorrhage, CNS 
CNS hemorrhage 
Asymptomatic, 
radiographic findings only 
Medical intervention 
indicated  
Ventriculostomy, ICP 
monitoring, 
intraventricular 
thrombolysis, or operative 
intervention indicated 
Life-threatening 
consequences; 
neurologic deficit or 
disability 
Death 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 

 
HEMORRHAGE/BLEEDING 
Page 2 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 31 - 
March 31, 2003, Publish Date: August 9, 2006 
Hemorrhage, GI  
– Select: 
– Abdomen NOS 
– Anus 
– Biliary tree  
– Cecum/appendix  
– Colon 
– Duodenum 
– Esophagus 
– Ileum 
– Jejunum 
– Liver 
– Lower GI NOS 
– Oral cavity 
– Pancreas 
– Peritoneal cavity 
– Rectum 
– Stoma 
– Stomach 
– Upper GI NOS 
– Varices (esophageal) 
– Varices (rectal) 
Hemorrhage, GI – Select 
Mild, intervention (other 
than iron supplements) 
not indicated 
Symptomatic and medical 
intervention or minor 
cauterization indicated 
Transfusion, 
interventional radiology, 
endoscopic, or operative 
intervention indicated; 
radiation therapy (i.e., 
hemostasis of bleeding 
site) 
Life-threatening 
consequences; major 
urgent intervention 
indicated  
Death 
REMARK: Transfusion implies pRBC. 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 

 
HEMORRHAGE/BLEEDING 
Page 3 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 32 - 
March 31, 2003, Publish Date: August 9, 2006 
Hemorrhage, GU  
– Select:  
– Bladder 
– Fallopian tube 
– Kidney 
– Ovary 
– Prostate  
– Retroperitoneum  
– Spermatic cord 
– Stoma 
– Testes 
– Ureter 
– Urethra 
– Urinary NOS 
– Uterus 
– Vagina 
– Vas deferens 
Hemorrhage, GU – Select 
Minimal or microscopic 
bleeding; intervention not 
indicated 
Gross bleeding, medical 
intervention, or urinary 
tract irrigation indicated 
Transfusion, 
interventional radiology, 
endoscopic, or operative 
intervention indicated; 
radiation therapy (i.e., 
hemostasis of bleeding 
site) 
Life-threatening 
consequences; major 
urgent intervention 
indicated 
Death 
REMARK: Transfusion implies pRBC. 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Hemorrhage, pulmonary/ 
upper respiratory  
– Select: 
Hemorrhage pulmonary  
– Select 
– Bronchopulmonary NOS 
– Bronchus  
– Larynx  
– Lung  
– Mediastinum 
– Nose 
– Pharynx 
– Pleura 
– Respiratory tract NOS 
– Stoma 
– Trachea 
Mild, intervention not 
indicated 
Symptomatic and 
medical intervention 
indicated 
Transfusion, 
interventional radiology, 
endoscopic, or operative 
intervention indicated; 
radiation therapy (i.e., 
hemostasis of bleeding 
site) 
Life-threatening 
consequences; major 
urgent intervention 
indicated 
Death 
REMARK: Transfusion implies pRBC.  
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Petechiae/purpura 
(hemorrhage/bleeding 
into skin or mucosa) 
Petechiae 
Few petechiae 
Moderate petechiae; 
purpura 
Generalized petechiae or 
purpura 
— 
— 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 

 
HEMORRHAGE/BLEEDING 
Page 4 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 33 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Vitreous hemorrhage is graded in the OCULAR/VISUAL CATEGORY. 
Hemorrhage/Bleeding – 
Other (Specify, __) 
Hemorrhage – Other 
(Specify) 
Mild without transfusion 
— 
Transfusion indicated 
Catastrophic bleeding, 
requiring major non-
elective intervention 
Death 

 
HEPATOBILIARY/PANCREAS 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 34 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Biliary tree damage is graded as Fistula, GI – Select; Leak (including anastomotic), GI – Select; Necrosis, GI – Select; Obstruction, GI – Select; Perforation, GI – 
Select; Stricture/stenosis (including anastomotic), GI – Select in the GASTROINTESTINAL CATEGORY. 
Cholecystitis 
Cholecystitis 
Asymptomatic, 
radiographic findings only 
Symptomatic, medical 
intervention indicated 
Interventional radiology, 
endoscopic, or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
sepsis or perforation)  
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection 
with unknown ANC – Select.  
Liver dysfunction/failure 
(clinical)  
Liver dysfunction  
— 
Jaundice  
Asterixis 
Encephalopathy or coma 
Death 
REMARK: Jaundice is not an AE, but occurs when the liver is not working properly or when a bile duct is blocked. It is graded as a result of liver dysfunction/failure or elevated bilirubin. 
ALSO CONSIDER: Bilirubin (hyperbilirubinemia). 
Pancreas, exocrine 
enzyme deficiency 
Pancreas, exocrine 
enzyme deficiency 
— 
Increase in stool 
frequency, bulk, or odor; 
steatorrhea 
Sequelae of absorption 
deficiency (e.g., weight 
loss)  
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Diarrhea. 
Pancreatitis  
Pancreatitis 
Asymptomatic, enzyme 
elevation and/or 
radiographic findings  
Symptomatic, medical 
intervention indicated 
Interventional radiology or 
operative intervention 
indicated 
Life-threatening 
consequences 
(e.g., circulatory failure, 
hemorrhage, sepsis) 
Death 
ALSO CONSIDER: Amylase. 
NAVIGATION NOTE: Stricture (biliary tree, hepatic or pancreatic) is graded as Stricture/stenosis (including anastomotic), GI – Select in the GASTROINTESTINAL CATEGORY. 
Hepatobiliary/Pancreas – 
Other (Specify, __) 
Hepatobiliary – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
INFECTION 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 35 - 
March 31, 2003, Publish Date: August 9, 2006 
Colitis, infectious 
(e.g., Clostridium difficile) 
Colitis, infectious  
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain with 
mucus and/or blood in 
stool 
IV antibiotics or TPN 
indicated  
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis or 
toxic megacolon); 
operative resection or 
diversion indicated 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select; Typhlitis (cecal inflammation).  
Febrile neutropenia 
(fever of unknown origin 
without clinically or 
microbiologically 
documented infection) 
(ANC <1.0 x 109/L, fever 
≥38.5°C) 
Febrile neutropenia 
— 
— 
Present 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
ALSO CONSIDER: Neutrophils/granulocytes (ANC/AGC). 
Infection  
(documented clinically or 
microbiologically) with 
Grade 3 or 4 neutrophils  
(ANC <1.0 x 109/L) 
– Select  
‘Select’ AEs appear at the 
end of the CATEGORY. 
Infection (documented 
clinically) with Grade 3 or 
4 ANC – Select 
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
REMARK: Fever with Grade 3 or 4 neutrophils in the absence of documented infection is graded as Febrile neutropenia (fever of unknown origin without clinically or microbiologically 
documented infection). 
ALSO CONSIDER: Neutrophils/granulocytes (ANC/AGC). 
Infection with normal 
ANC or Grade 1 or 2 
neutrophils  
– Select  
‘Select’ AEs appear at the 
end of the CATEGORY. 
Infection with normal 
ANC – Select 
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 

 
INFECTION 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 36 - 
March 31, 2003, Publish Date: August 9, 2006 
Infection with unknown 
ANC 
– Select  
‘Select’ AEs appear at the 
end of the CATEGORY. 
Infection with unknown 
ANC – Select 
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
REMARK: Infection with unknown ANC – Select is to be used in the rare case when ANC is unknown. 
Opportunistic infection 
associated with ≥Grade 2 
Lymphopenia 
Opportunistic infection  
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
ALSO CONSIDER: Lymphopenia. 
Viral hepatitis 
Viral hepatitis 
Present; transaminases 
and liver function normal 
Transaminases 
abnormal, liver function 
normal  
Symptomatic liver 
dysfunction; fibrosis by 
biopsy; compensated 
cirrhosis 
Decompensated liver 
function (e.g., ascites, 
coagulopathy, 
encephalopathy, coma) 
Death 
REMARK: Non-viral hepatitis is graded as Infection – Select. 
ALSO CONSIDER: Albumin, serum-low (hypoalbuminemia); ALT, SGPT (serum glutamic pyruvic transaminase); AST, SGOT (serum glutamic oxaloacetic transaminase); Bilirubin 
(hyperbilirubinemia); Encephalopathy. 
Infection – Other 
(Specify, __) 
Infection – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
INFECTION – SELECT 
Page 3 of 3 
CTCAE v3.0  
- 37 - 
March 31, 2003, Publish Date: August 9, 2006 
AUDITORY/EAR 
– External ear (otitis externa) 
– Middle ear (otitis media) 
CARDIOVASCULAR 
– Artery 
– Heart (endocarditis) 
– Spleen 
– Vein 
DERMATOLOGY/SKIN  
– Lip/perioral 
– Peristomal 
– Skin (cellulitis) 
– Ungual (nails) 
GASTROINTESTINAL  
– Abdomen NOS 
– Anal/perianal 
– Appendix 
– Cecum 
– Colon 
– Dental-tooth 
– Duodenum 
– Esophagus 
– Ileum 
– Jejunum 
– Oral cavity-gums (gingivitis) 
– Peritoneal cavity 
– Rectum 
– Salivary gland 
– Small bowel NOS 
– Stomach 
GENERAL 
– Blood 
– Catheter-related 
– Foreign body (e.g., graft, implant,  
prosthesis, stent) 
– Wound  
HEPATOBILIARY/PANCREAS 
– Biliary tree 
– Gallbladder (cholecystitis) 
– Liver 
– Pancreas 
LYMPHATIC 
– Lymphatic 
MUSCULOSKELETAL 
– Bone (osteomyelitis) 
– Joint 
– Muscle (infection myositis) 
– Soft tissue NOS 
NEUROLOGY 
– Brain (encephalitis, infectious) 
– Brain + Spinal cord (encephalomyelitis) 
– Meninges (meningitis) 
– Nerve-cranial 
– Nerve-peripheral 
– Spinal cord (myelitis) 
OCULAR 
– Conjunctiva 
– Cornea 
– Eye NOS 
– Lens 
PULMONARY/UPPER RESPIRATORY 
– Bronchus 
– Larynx 
– Lung (pneumonia) 
– Mediastinum NOS 
– Mucosa 
– Neck NOS 
– Nose 
– Paranasal 
– Pharynx 
– Pleura (empyema) 
– Sinus 
– Trachea 
– Upper aerodigestive NOS 
– Upper airway NOS  
RENAL/GENITOURINARY  
– Bladder (urinary) 
– Kidney 
– Prostate 
– Ureter 
– Urethra 
– Urinary tract NOS 
SEXUAL/REPRODUCTIVE FUNCTION 
– Cervix 
– Fallopian tube 
– Pelvis NOS 
– Penis 
– Scrotum 
– Uterus 
– Vagina 
– Vulva 
 

 
LYMPHATICS 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 38 - 
March 31, 2003, Publish Date: August 9, 2006 
Chyle or lymph leakage  
Chyle or lymph leakage 
Asymptomatic, clinical or 
radiographic findings 
Symptomatic, medical 
intervention indicated  
Interventional radiology 
or operative intervention 
indicated 
Life-threatening 
complications 
Death 
ALSO CONSIDER: Chylothorax. 
Dermal change 
lymphedema, 
phlebolymphedema  
Dermal change 
Trace thickening or faint 
discoloration 
Marked discoloration; 
leathery skin texture; 
papillary formation 
— 
— 
— 
REMARK: Dermal change lymphedema, phlebolymphedema refers to changes due to venous stasis. 
ALSO CONSIDER: Ulceration.  
Edema: 
head and neck 
Edema: head and neck 
Localized to dependent 
areas, no disability or 
functional impairment 
Localized facial or neck 
edema with functional 
impairment 
Generalized facial or 
neck edema with 
functional impairment 
(e.g., difficulty in turning 
neck or opening mouth 
compared to baseline) 
Severe with ulceration or 
cerebral edema; 
tracheotomy or feeding 
tube indicated 
Death 
Edema: 
limb 
Edema: limb 
5 – 10% inter-limb 
discrepancy in volume or 
circumference at point of 
greatest visible 
difference; swelling or 
obscuration of anatomic 
architecture on close 
inspection; pitting edema 
>10 – 30% inter-limb 
discrepancy in volume or 
circumference at point of 
greatest visible 
difference; readily 
apparent obscuration of 
anatomic architecture; 
obliteration of skin folds; 
readily apparent 
deviation from normal 
anatomic contour  
>30% inter-limb 
discrepancy in volume; 
lymphorrhea; gross 
deviation from normal 
anatomic contour; 
interfering with ADL 
Progression to 
malignancy (i.e., 
lymphangiosarcoma); 
amputation indicated; 
disabling 
Death 
Edema: 
trunk/genital 
Edema: trunk/genital 
Swelling or obscuration 
of anatomic architecture 
on close inspection; 
pitting edema 
Readily apparent 
obscuration of anatomic 
architecture; obliteration 
of skin folds; readily 
apparent deviation from 
normal anatomic contour 
Lymphorrhea; interfering 
with ADL; gross deviation 
from normal anatomic 
contour 
Progression to 
malignancy (i.e., 
lymphangiosarcoma); 
disabling  
Death 
Edema: 
viscera 
Edema: viscera 
Asymptomatic; clinical or 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and unable 
to aliment adequately 
orally; interventional 
radiology or operative 
intervention indicated  
Life-threatening 
consequences 
Death 

 
LYMPHATICS 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 39 - 
March 31, 2003, Publish Date: August 9, 2006 
Lymphedema-related 
fibrosis 
Lymphedema-related 
fibrosis 
Minimal to moderate 
redundant soft tissue, 
unresponsive to elevation 
or compression, with 
moderately firm texture or 
spongy feel 
Marked increase in 
density and firmness, 
with or without tethering 
Very marked density and 
firmness with tethering 
affecting ≥40% of the 
edematous area 
— 
— 
Lymphocele 
Lymphocele 
Asymptomatic, clinical or 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and 
interventional radiology 
or operative intervention 
indicated 
— 
— 
Phlebolymphatic cording  
Phlebolymphatic cording 
Asymptomatic, clinical 
findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and leading 
to contracture or reduced 
range of motion 
— 
— 
Lymphatics – Other  
(Specify, __) 
Lymphatics – Other  
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling 
Death 

 
METABOLIC/LABORATORY 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 40 - 
March 31, 2003, Publish Date: August 9, 2006 
Acidosis  
(metabolic or respiratory) 
Acidosis  
pH <normal, but ≥7.3 
— 
pH <7.3 
pH <7.3 with life-
threatening 
consequences 
Death 
Albumin, serum-low 
(hypoalbuminemia)  
Hypoalbuminemia 
<LLN – 3 g/dL  
<LLN – 30 g/L 
<3 – 2 g/dL 
<30 – 20 g/L  
<2 g/dL  
<20 g/L 
— 
Death 
Alkaline phosphatase 
Alkaline phosphatase 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Alkalosis  
(metabolic or respiratory) 
Alkalosis 
pH >normal, but ≤7.5 
— 
pH >7.5 
pH >7.5 with life-
threatening 
consequences 
Death 
ALT, SGPT  
(serum glutamic pyruvic 
transaminase) 
ALT 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Amylase 
Amylase 
>ULN – 1.5 x ULN 
>1.5 – 2.0 x ULN 
>2.0 – 5.0 x ULN 
>5.0 x ULN 
— 
AST, SGOT 
(serum glutamic 
oxaloacetic 
transaminase) 
AST 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Bicarbonate, serum-low  
Bicarbonate, serum-low 
<LLN – 16 mmol/L 
<16 – 11 mmol/L 
<11 – 8 mmol/L 
<8 mmol/L 
Death 
Bilirubin 
(hyperbilirubinemia) 
Bilirubin 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x ULN 
>3.0 – 10.0 x ULN 
>10.0 x ULN 
— 
REMARK: Jaundice is not an AE, but may be a manifestation of liver dysfunction/failure or elevated bilirubin. If jaundice is associated with elevated bilirubin, grade bilirubin. 
Calcium, serum-low 
(hypocalcemia) 
Hypocalcemia 
<LLN – 8.0 mg/dL 
<LLN – 2.0 mmol/L 
Ionized calcium: 
<LLN – 1.0 mmol/L 
<8.0 – 7.0 mg/dL 
<2.0 – 1.75 mmol/L 
Ionized calcium: 
<1.0 – 0.9 mmol/L 
<7.0 – 6.0 mg/dL 
<1.75 – 1.5 mmol/L 
Ionized calcium: 
<0.9 – 0.8 mmol/L 
<6.0 mg/dL 
<1.5 mmol/L 
Ionized calcium: 
<0.8 mmol/L 
Death 
REMARK: Calcium can be falsely low if hypoalbuminemia is present. Serum albumin is <4.0 g/dL, hypocalcemia is reported after the following corrective calculation has been 
performed: Corrected Calcium (mg/dL) = Total Calcium (mg/dL) – 0.8 [Albumin (g/dL) – 4] 4. Alternatively, direct measurement of ionized calcium is the definitive method to diagnose 
metabolically relevant alterations in serum calcium. 
                                            
4Crit Rev Clin Lab Sci 1984;21(1):51-97 

 
METABOLIC/LABORATORY 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 41 - 
March 31, 2003, Publish Date: August 9, 2006 
Calcium, serum-high 
(hypercalcemia) 
Hypercalcemia 
>ULN – 11.5 mg/dL 
>ULN – 2.9 mmol/L 
Ionized calcium: 
>ULN – 1.5 mmol/L 
>11.5 – 12.5 mg/dL 
>2.9 – 3.1 mmol/L 
Ionized calcium: 
>1.5 – 1.6 mmol/L 
>12.5 – 13.5 mg/dL 
>3.1 – 3.4 mmol/L 
Ionized calcium: 
>1.6 – 1.8 mmol/L 
>13.5 mg/dL 
>3.4 mmol/L 
Ionized calcium: 
>1.8 mmol/L 
Death 
Cholesterol, serum-high 
(hypercholesteremia) 
Cholesterol 
>ULN – 300 mg/dL 
>ULN – 7.75 mmol/L 
>300 – 400 mg/dL 
>7.75 – 10.34 mmol/L 
>400 – 500 mg/dL 
>10.34 – 12.92 mmol/L 
>500 mg/dL 
>12.92 mmol/L 
Death 
CPK (creatine 
phosphokinase) 
CPK 
>ULN – 2.5 x ULN 
>2.5 x ULN – 5 x ULN 
>5 x ULN – 10 x ULN 
>10 x ULN 
Death 
Creatinine 
Creatinine 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x ULN 
>3.0 – 6.0 x ULN 
>6.0 x ULN 
Death 
REMARK: Adjust to age-appropriate levels for pediatric patients.  
ALSO CONSIDER: Glomerular filtration rate. 
GGT (γ-Glutamyl 
transpeptidase) 
GGT 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Glomerular filtration rate  
GFR 
<75 – 50% LLN 
<50 – 25% LLN 
<25% LLN, chronic 
dialysis not indicated 
Chronic dialysis or renal 
transplant indicated 
Death 
ALSO CONSIDER: Creatinine. 
Glucose, serum-high 
(hyperglycemia)  
Hyperglycemia 
>ULN – 160 mg/dL 
>ULN – 8.9 mmol/L 
>160 – 250 mg/dL 
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL 
>13.9 – 27.8 mmol/L 
>500 mg/dL 
>27.8 mmol/L or acidosis 
Death 
REMARK: Hyperglycemia, in general, is defined as fasting unless otherwise specified in protocol. 
Glucose, serum-low 
(hypoglycemia) 
Hypoglycemia 
<LLN – 55 mg/dL 
<LLN – 3.0 mmol/L 
<55 – 40 mg/dL 
<3.0 – 2.2 mmol/L 
<40 – 30 mg/dL 
<2.2 – 1.7 mmol/L 
<30 mg/dL 
<1.7 mmol/L 
Death 
Hemoglobinuria 
Hemoglobinuria 
Present 
— 
— 
— 
Death 
Lipase 
Lipase 
>ULN – 1.5 x ULN 
>1.5 – 2.0 x ULN 
>2.0 – 5.0 x ULN 
>5.0 x ULN 
— 
Magnesium, serum-high 
(hypermagnesemia) 
Hypermagnesemia 
>ULN – 3.0 mg/dL 
>ULN – 1.23 mmol/L 
— 
>3.0 – 8.0 mg/dL 
>1.23 – 3.30 mmol/L 
>8.0 mg/dL 
>3.30 mmol/L 
Death 
Magnesium, serum-low 
(hypomagnesemia)  
Hypomagnesemia 
<LLN – 1.2 mg/dL 
<LLN – 0.5 mmol/L 
<1.2 – 0.9 mg/dL 
<0.5 – 0.4 mmol/L 
<0.9 – 0.7 mg/dL 
<0.4 – 0.3 mmol/L 
<0.7 mg/dL 
<0.3 mmol/L 
Death 
Phosphate, serum-low 
(hypophosphatemia)  
Hypophosphatemia 
<LLN – 2.5 mg/dL 
<LLN – 0.8 mmol/L 
<2.5 – 2.0 mg/dL  
<0.8 – 0.6 mmol/L 
<2.0 – 1.0 mg/dL 
<0.6 – 0.3 mmol/L 
<1.0 mg/dL 
<0.3 mmol/L 
Death 
Potassium, serum-high 
(hyperkalemia) 
Hyperkalemia 
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L 
>6.0 – 7.0 mmol/L 
>7.0 mmol/L 
Death 

 
METABOLIC/LABORATORY 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 42 - 
March 31, 2003, Publish Date: August 9, 2006 
Potassium, serum-low 
(hypokalemia)  
Hypokalemia 
<LLN – 3.0 mmol/L 
— 
<3.0 – 2.5 mmol/L 
<2.5 mmol/L 
Death 
Proteinuria 
Proteinuria 
1+ or 
0.15 – 1.0 g/24 hrs 
2+ to 3+ or 
>1.0 – 3.5 g/24 hrs  
4+ or 
>3.5 g/24 hrs 
Nephrotic syndrome 
Death 
Sodium, serum-high 
(hypernatremia) 
Hypernatremia 
>ULN – 150 mmol/L 
>150 – 155 mmol/L 
>155 – 160 mmol/L 
>160 mmol/L 
Death 
Sodium, serum-low 
(hyponatremia) 
Hyponatremia 
<LLN – 130 mmol/L 
— 
<130 – 120 mmol/L 
<120 mmol/L 
Death 
Triglyceride, serum-high 
(hypertriglyceridemia) 
Hypertriglyceridemia 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 10 x ULN 
>10 x ULN 
Death 
Uric acid, serum-high 
(hyperuricemia) 
Hyperuricemia 
>ULN – 10 mg/dL 
≤0.59 mmol/L without 
physiologic 
consequences 
— 
>ULN – 10 mg/dL 
≤0.59 mmol/L with 
physiologic 
consequences 
>10 mg/dL 
>0.59 mmol/L 
Death 
ALSO CONSIDER: Creatinine; Potassium, serum-high (hyperkalemia); Renal failure; Tumor lysis syndrome. 
Metabolic/Laboratory – 
Other (Specify, __) 
Metabolic/Lab – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
MUSCULOSKELETAL/SOFT TISSUE 
Page 1 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 43 - 
March 31, 2003, Publish Date: August 9, 2006 
Arthritis (non-septic) 
Arthritis 
Mild pain with 
inflammation, erythema, 
or joint swelling, but not 
interfering with function 
Moderate pain with 
inflammation, erythema, 
or joint swelling 
interfering with function, 
but not interfering with 
ADL 
Severe pain with 
inflammation, erythema, 
or joint swelling and 
interfering with ADL 
Disabling 
Death 
REMARK: Report only when the diagnosis of arthritis (e.g., inflammation of a joint or a state characterized by inflammation of joints) is made. Arthralgia (sign or symptom of pain in a 
joint, especially non-inflammatory in character) is graded as Pain – Select in the PAIN CATEGORY.  
Bone: 
spine-scoliosis 
Scoliosis  
≤20 degrees; clinically 
undetectable 
>20 – 45 degrees; visible 
by forward flexion; 
interfering with function 
but not interfering with 
ADL 
>45 degrees; scapular 
prominence in forward 
flexion; operative 
intervention indicated; 
interfering with ADL 
Disabling (e.g., interfering 
with cardiopulmonary 
function) 
Death 
Cervical spine-range of 
motion 
Cervical spine ROM 
Mild restriction of rotation 
or flexion between  
60 – 70 degrees 
Rotation <60 degrees to 
right or left; <60 degrees 
of flexion 
Ankylosed/fused over 
multiple segments with 
no C-spine rotation 
— 
— 
REMARK: 60 – 65 degrees of rotation is required for reversing a car; 60 – 65 degrees of flexion is required to tie shoes. 
Exostosis 
Exostosis 
Asymptomatic 
Involving multiple sites; 
pain or interfering with 
function  
Excision indicated 
Progression to 
malignancy (i.e., 
chondrosarcoma) 
Death 
Extremity-lower 
(gait/walking) 
Gait/walking 
Limp evident only to 
trained observer and able 
to walk ≥1 kilometer; 
cane indicated for 
walking 
Noticeable limp, or 
limitation of limb function, 
but able to walk ≥0.1 
kilometer (1 city block); 
quad cane indicated for 
walking 
Severe limp with stride 
modified to maintain 
balance (widened base of 
support, marked 
reduction in step length); 
ambulation limited to 
walker; crutches 
indicated 
Unable to walk 
— 
ALSO CONSIDER: Ataxia (incoordination); Muscle weakness, generalized or specific area (not due to neuropathy) – Select.  
Extremity-upper 
(function)  
Extremity-upper 
(function) 
Able to perform most 
household or work 
activities with affected 
limb 
Able to perform most 
household or work 
activities with 
compensation from 
unaffected limb 
Interfering with ADL  
Disabling; no function of 
affected limb 
— 
Fibrosis-cosmesis 
Fibrosis-cosmesis 
Visible only on close 
examination 
Readily apparent but not 
disfiguring 
Significant disfigurement; 
operative intervention 
indicated if patient 
chooses 
— 
— 

 
MUSCULOSKELETAL/SOFT TISSUE 
Page 2 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 44 - 
March 31, 2003, Publish Date: August 9, 2006 
Fibrosis-deep connective 
tissue 
Fibrosis-deep connective 
tissue  
Increased density, 
“spongy” feel 
Increased density with 
firmness or tethering 
Increased density with 
fixation of tissue; 
operative intervention 
indicated; interfering with 
ADL 
Life-threatening; 
disabling; loss of limb; 
interfering with vital organ 
function 
Death 
ALSO CONSIDER: Induration/fibrosis (skin and subcutaneous tissue); Muscle weakness, generalized or specific area (not due to neuropathy) – Select; Neuropathy: motor; Neuropathy: 
sensory. 
Fracture 
Fracture 
Asymptomatic, 
radiographic findings only 
(e.g., asymptomatic rib 
fracture on plain x-ray, 
pelvic insufficiency 
fracture on MRI, etc.) 
Symptomatic but non-
displaced; immobilization 
indicated 
Symptomatic and 
displaced or open wound 
with bone exposure; 
operative intervention 
indicated 
Disabling; amputation 
indicated 
Death 
Joint-effusion 
Joint-effusion 
Asymptomatic, clinical or 
radiographic findings only 
Symptomatic; interfering 
with function but not 
interfering with ADL 
Symptomatic and 
interfering with ADL 
Disabling 
Death 
ALSO CONSIDER: Arthritis (non-septic). 
Joint-function5 
Joint-function 
Stiffness interfering with 
athletic activity; ≤25% 
loss of range of motion 
(ROM) 
Stiffness interfering with 
function but not 
interfering with ADL;  
>25 – 50% decrease in 
ROM 
Stiffness interfering with 
ADL; >50 – 75% 
decrease in ROM  
Fixed or non-functional 
joint (arthrodesis); 
>75% decrease in ROM 
— 
ALSO CONSIDER: Arthritis (non-septic). 
Local complication –
device/prosthesis-related 
Device/prosthesis 
Asymptomatic  
Symptomatic, but not 
interfering with ADL; local 
wound care; medical 
intervention indicated 
Symptomatic, interfering 
with ADL; operative 
intervention indicated 
(e.g., hardware/device 
replacement or removal, 
reconstruction)  
Life-threatening; 
disabling; loss of limb or 
organ 
Death 
Lumbar spine-range of 
motion 
Lumbar spine ROM 
Stiffness and difficulty 
bending to the floor to 
pick up a very light object 
but able to do activity 
Some lumbar spine 
flexion but requires a 
reaching aid to pick up a 
very light object from the 
floor 
Ankylosed/fused over 
multiple segments with 
no L-spine flexion (i.e., 
unable to reach to floor to 
pick up a very light 
— 
— 
                                            
5 Adapted from the International SFTR Method of Measuring and Recording Joint Motion, International Standard Orthopedic Measurements (ISOM), Jon J. Gerhardt and Otto A. 
Russee, Bern, Switzerland, Han Huber 9 Publisher), 1975. 

 
MUSCULOSKELETAL/SOFT TISSUE 
Page 3 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 45 - 
March 31, 2003, Publish Date: August 9, 2006 
object) 
Muscle weakness, 
generalized or specific 
area (not due to 
neuropathy)  
– Select: 
Muscle weakness  
– Select  
– Extraocular 
– Extremity-lower  
– Extremity-upper 
– Facial 
– Left-sided 
– Ocular 
– Pelvic 
– Right-sided 
– Trunk 
– Whole body/generalized  
Asymptomatic, weakness 
on physical exam 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Life-threatening; disabling 
Death 
ALSO CONSIDER: Fatigue (asthenia, lethargy, malaise). 
Muscular/skeletal 
hypoplasia 
Muscular/skeletal 
hypoplasia 
Cosmetically and 
functionally insignificant 
hypoplasia  
Deformity, hypoplasia, or 
asymmetry able to be 
remediated by prosthesis 
(e.g., shoe insert) or 
covered by clothing  
Functionally significant 
deformity, hypoplasia, or 
asymmetry, unable to be 
remediated by prosthesis 
or covered by clothing  
Disabling 
— 
Myositis 
(inflammation/damage of 
muscle) 
Myositis 
Mild pain, not interfering 
with function 
Pain interfering with 
function, but not 
interfering with ADL 
Pain interfering with ADL 
Disabling 
Death 
REMARK: Myositis implies muscle damage (i.e., elevated CPK). 
ALSO CONSIDER: CPK (creatine phosphokinase); Pain – Select. 
Osteonecrosis  
(avascular necrosis) 
Osteonecrosis 
Asymptomatic, 
radiographic findings only 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL; minimal bone 
removal indicated (i.e., 
minor sequestrectomy)  
Symptomatic and 
interfering with ADL; 
operative intervention or 
hyperbaric oxygen 
indicated 
Disabling  
Death 

 
MUSCULOSKELETAL/SOFT TISSUE 
Page 4 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 46 - 
March 31, 2003, Publish Date: August 9, 2006 
Osteoporosis6 
Osteoporosis 
Radiographic evidence of 
osteoporosis or Bone 
Mineral Density (BMD) 
t-score –1 to –2.5 
(osteopenia) and no loss 
of height or therapy 
indicated 
BMD t-score < –2.5; loss 
of height <2 cm; anti-
osteoporotic therapy 
indicated 
Fractures; loss of height 
≥2 cm 
Disabling 
Death 
Seroma 
Seroma 
Asymptomatic 
Symptomatic; medical 
intervention or simple 
aspiration indicated 
Symptomatic, 
interventional radiology 
or operative intervention 
indicated 
— 
— 
Soft tissue necrosis 
– Select: 
– Abdomen 
– Extremity-lower 
– Extremity-upper  
– Head 
– Neck 
– Pelvic 
– Thorax 
Soft tissue necrosis 
– Select 
— 
Local wound care; 
medical intervention 
indicated 
Operative debridement or 
other invasive 
intervention indicated 
(e.g., hyperbaric oxygen)  
Life-threatening 
consequences; major 
invasive intervention 
indicated (e.g., tissue 
reconstruction, flap, or 
grafting) 
Death 
Trismus (difficulty, 
restriction or pain when 
opening mouth) 
Trismus 
Decreased range of 
motion without impaired 
eating  
Decreased range of 
motion requiring small 
bites, soft foods or 
purees 
Decreased range of 
motion with inability to 
adequately aliment or 
hydrate orally 
— 
— 
NAVIGATION NOTE: Wound-infectious is graded as Infection – Select in the INFECTION CATEGORY. 
NAVIGATION NOTE: Wound non-infectious is graded as Wound complication, non-infectious in the DERMATOLOGY/SKIN CATEGORY.  
Musculoskeletal/Soft 
Tissue – Other 
(Specify, __) 
Musculoskeletal – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
                                            
6 "Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis," Report of a WHO Study Group Technical Report Series, No. 843, 1994, v + 129 
pages [C*, E, F, R, S], ISBN 92 4 120843 0, Sw.fr. 22.-/US $19.80; in developing countries: Sw.fr. 15.40, Order no. 1100843 

 
NEUROLOGY 
Page 1 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 47 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: ADD (Attention Deficit Disorder) is graded as Cognitive disturbance. 
NAVIGATION NOTE: Aphasia, receptive and/or expressive, is graded as Speech impairment (e.g., dysphasia or aphasia). 
Apnea 
Apnea 
— 
— 
Present 
Intubation indicated  
Death 
Arachnoiditis/ 
meningismus/radiculitis 
Arachnoiditis 
Symptomatic, not 
interfering with function; 
medical intervention 
indicated 
Symptomatic (e.g., 
photophobia, nausea) 
interfering with function 
but not interfering with 
ADL  
Symptomatic, interfering 
with ADL 
Life-threatening; disabling 
(e.g., paraplegia) 
Death 
ALSO CONSIDER: Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 109/L); Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select; Pain – Select; Vomiting. 
Ataxia (incoordination) 
Ataxia 
Asymptomatic  
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL; mechanical 
assistance indicated  
Disabling 
Death 
REMARK: Ataxia (incoordination) refers to the consequence of medical or operative intervention. 
Brachial plexopathy 
Brachial plexopathy 
Asymptomatic 
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
Disabling 
Death 
CNS cerebrovascular 
ischemia 
CNS ischemia 
— 
Asymptomatic, 
radiographic findings only 
Transient ischemic event 
or attack (TIA) ≤24 hrs 
duration 
Cerebral vascular 
accident (CVA, stroke), 
neurologic deficit 
>24 hrs  
Death 
NAVIGATION NOTE: CNS hemorrhage/bleeding is graded as Hemorrhage, CNS in the HEMORRHAGE/BLEEDING CATEGORY.  
CNS necrosis/cystic 
progression 
CNS necrosis 
Asymptomatic, 
radiographic findings only 
Symptomatic, not 
interfering with ADL; 
medical intervention 
indicated 
Symptomatic and 
interfering with ADL; 
hyperbaric oxygen 
indicated 
Life-threatening; 
disabling; operative 
intervention indicated to 
prevent or treat CNS 
necrosis/cystic 
progression 
Death 
Cognitive disturbance 
Cognitive disturbance 
Mild cognitive disability; 
not interfering with 
work/school/life 
performance; specialized 
educational 
services/devices not 
indicated 
Moderate cognitive 
disability; interfering with 
work/school/life 
performance but capable 
of independent living; 
specialized resources on 
part-time basis indicated 
Severe cognitive 
disability; significant 
impairment of 
work/school/life 
performance 
Unable to perform ADL; 
full-time specialized 
resources or 
institutionalization 
indicated 
Death 
REMARK: Cognitive disturbance may be used for Attention Deficit Disorder (ADD). 

 
NEUROLOGY 
Page 2 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 48 - 
March 31, 2003, Publish Date: August 9, 2006 
Confusion 
Confusion 
Transient confusion, 
disorientation, or attention 
deficit 
Confusion, disorientation, 
or attention deficit 
interfering with function, 
but not interfering with 
ADL 
Confusion or delirium 
interfering with ADL 
Harmful to others or self; 
hospitalization indicated 
Death 
REMARK: Attention Deficit Disorder (ADD) is graded as Cognitive disturbance. 
NAVIGATION NOTE: Cranial neuropathy is graded as Neuropathy-cranial – Select. 
Dizziness  
Dizziness 
With head movements or 
nystagmus only; not 
interfering with function 
Interfering with function, 
but not interfering with 
ADL 
Interfering with ADL 
Disabling 
— 
REMARK: Dizziness includes disequilibrium, lightheadedness, and vertigo. 
ALSO CONSIDER: Neuropathy: cranial – Select; Syncope (fainting). 
NAVIGATION NOTE: Dysphasia, receptive and/or expressive, is graded as Speech impairment (e.g., dysphasia or aphasia). 
Encephalopathy 
Encephalopathy 
— 
Mild signs or symptoms; 
not interfering with ADL 
Signs or symptoms 
interfering with ADL; 
hospitalization indicated 
Life-threatening; disabling 
Death 
ALSO CONSIDER: Cognitive disturbance; Confusion; Dizziness; Memory impairment; Mental status; Mood alteration – Select; Psychosis (hallucinations/delusions); 
Somnolence/depressed level of consciousness. 
Extrapyramidal/ 
involuntary movement/ 
restlessness 
Involuntary movement 
Mild involuntary 
movements not 
interfering with function 
Moderate involuntary 
movements interfering 
with function, but not 
interfering with ADL 
Severe involuntary 
movements or torticollis 
interfering with ADL 
Disabling 
 
Death 
NAVIGATION NOTE: Headache/neuropathic pain (e.g., jaw pain, neurologic pain, phantom limb pain, post-infectious neuralgia, or painful neuropathies) is graded as Pain – Select in the 
PAIN CATEGORY. 
Hydrocephalus 
Hydrocephalus 
Asymptomatic, 
radiographic findings only 
Mild to moderate 
symptoms not interfering 
with ADL 
Severe symptoms or 
neurological deficit 
interfering with ADL 
Disabling  
Death 
Irritability (children <3 
years of age) 
Irritability 
Mild; easily consolable 
Moderate; requiring 
increased attention 
Severe; inconsolable 
— 
— 
Laryngeal nerve 
dysfunction  
Laryngeal nerve 
Asymptomatic, weakness 
on clinical 
examination/testing only 
Symptomatic, but not 
interfering with ADL; 
intervention not indicated 
Symptomatic, interfering 
with ADL; intervention 
indicated (e.g., 
thyroplasty, vocal cord 
injection) 
Life-threatening; 
tracheostomy indicated 
 
Death 

 
NEUROLOGY 
Page 3 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 49 - 
March 31, 2003, Publish Date: August 9, 2006 
Leak, cerebrospinal fluid 
(CSF) 
CSF leak 
Transient headache; 
postural care indicated 
Symptomatic, not 
interfering with ADL; 
blood patch indicated 
Symptomatic, interfering 
with ADL; operative 
intervention indicated 
Life-threatening; disabling 
Death 
REMARK: Leak, cerebrospinal fluid (CSF) may be used for CSF leak associated with operation and persisting >72 hours. 
Leukoencephalopathy 
(radiographic findings) 
Leukoencephalopathy  
Mild increase in 
subarachnoid space 
(SAS); mild 
ventriculomegaly; small 
(+/- multiple) focal T2 
hyperintensities, involving 
periventricular white 
matter or <1/3 of 
susceptible areas of 
cerebrum 
Moderate increase in 
SAS; moderate 
ventriculomegaly; focal 
T2 hyperintensities 
extending into centrum 
ovale or involving 1/3 to 
2/3 of susceptible areas 
of cerebrum 
Severe increase in SAS; 
severe ventriculomegaly; 
near total white matter T2 
hyperintensities or diffuse 
low attenuation (CT) 
— 
— 
REMARK: Leukoencephalopathy is a diffuse white matter process, specifically NOT associated with necrosis. Leukoencephalopathy (radiographic findings) does not include lacunas, 
which are areas that become void of neural tissue.  
Memory impairment 
Memory impairment 
Memory impairment not 
interfering with function 
Memory impairment 
interfering with function, 
but not interfering with 
ADL 
Memory impairment 
interfering with ADL 
Amnesia 
— 
Mental status7 
Mental status 
— 
1 – 3 point below age  
and educational norm in 
Folstein Mini-Mental 
Status Exam (MMSE) 
>3 point below age and 
educational norm in 
Folstein MMSE  
— 
— 
Mood alteration  
– Select: 
– Agitation 
– Anxiety 
– Depression 
– Euphoria 
Mood alteration – Select 
Mild mood alteration not 
interfering with function 
Moderate mood alteration 
interfering with function, 
but not interfering with 
ADL; medication 
indicated 
Severe mood alteration 
interfering with ADL 
Suicidal ideation; danger 
to self or others 
Death 
Myelitis 
Myelitis 
Asymptomatic, mild signs 
(e.g., Babinski’s or 
Lhermitte’s sign) 
Weakness or sensory 
loss not interfering with 
ADL 
Weakness or sensory 
loss interfering with ADL 
Disabling 
Death 
                                            
7 Folstein MF, Folstein, SE and McHugh PR (1975) "Mini-Mental State: A Practical Method for Grading the State of Patients for the Clinician," Journal of Psychiatric Research, 12: 
189-198 

 
NEUROLOGY 
Page 4 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 50 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Neuropathic pain is graded as Pain – Select in the PAIN CATEGORY.  
Neuropathy: 
cranial  
– Select: 
Neuropathy: cranial  
– Select 
Asymptomatic, detected 
on exam/testing only 
– CN I  
Smell 
– CN II  Vision 
– CN III  Pupil, upper eyelid, extra ocular movements 
– CN IV  Downward, inward movement of eye 
– CN V  Motor-jaw muscles; Sensory-facial 
– CN VI  Lateral deviation of eye 
– CN VII Motor-face; Sensory-taste 
– CN VIII Hearing and balance 
– CN IX Motor-pharynx; Sensory-ear, pharynx, tongue 
– CN X 
Motor-palate; pharynx, larynx 
– CN XI Motor-sternomastoid and trapezius 
– CN XII Motor-tongue 
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
Life-threatening; disabling 
Death 
Neuropathy: 
motor  
Neuropathy-motor 
Asymptomatic, weakness 
on exam/testing only 
Symptomatic weakness 
interfering with function, 
but not interfering with 
ADL 
Weakness interfering with 
ADL; bracing or 
assistance to walk (e.g., 
cane or walker) indicated 
Life-threatening; disabling 
(e.g., paralysis)  
Death 
REMARK: Cranial nerve motor neuropathy is graded as Neuropathy: cranial – Select. 
ALSO CONSIDER: Laryngeal nerve dysfunction; Phrenic nerve dysfunction.  
Neuropathy: 
sensory 
Neuropathy-sensory 
Asymptomatic; loss of 
deep tendon reflexes or 
paresthesia (including 
tingling) but not 
interfering with function 
Sensory alteration or 
paresthesia (including 
tingling), interfering with 
function, but not 
interfering with ADL 
Sensory alteration or 
paresthesia interfering 
with ADL  
Disabling  
Death 
REMARK: Cranial nerve sensory neuropathy is graded as Neuropathy: cranial – Select. 
Personality/behavioral 
Personality 
Change, but not 
adversely affecting 
patient or family 
Change, adversely 
affecting patient or family  
Mental health intervention 
indicated 
Change harmful to others 
or self; hospitalization 
indicated 
Death 
Phrenic nerve dysfunction  Phrenic nerve 
Asymptomatic weakness 
on exam/testing only 
Symptomatic but not 
interfering with ADL; 
intervention not indicated 
Significant dysfunction; 
intervention indicated 
(e.g., diaphragmatic 
plication) 
Life-threatening 
respiratory compromise; 
mechanical ventilation 
indicated 
Death 
Psychosis (hallucinations/ 
delusions) 
Psychosis 
— 
Transient episode 
Interfering with ADL; 
medication, supervision 
Harmful to others or self; 
life-threatening 
Death 

 
NEUROLOGY 
Page 5 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 51 - 
March 31, 2003, Publish Date: August 9, 2006 
or restraints indicated  
consequences 
Pyramidal tract 
dysfunction (e.g., ↑ tone, 
hyperreflexia, positive 
Babinski, ↓ fine motor 
coordination) 
Pyramidal tract 
dysfunction 
Asymptomatic, 
abnormality on exam or 
testing only  
Symptomatic; interfering 
with function but not 
interfering with ADL 
Interfering with ADL 
Disabling; paralysis 
Death 
Seizure 
Seizure 
— 
One brief generalized 
seizure; seizure(s) well 
controlled by 
anticonvulsants or 
infrequent focal motor 
seizures not interfering 
with ADL 
Seizures in which 
consciousness is altered; 
poorly controlled seizure 
disorder, with 
breakthrough generalized 
seizures despite medical 
intervention 
Seizures of any kind 
which are prolonged, 
repetitive, or difficult to 
control (e.g., status 
epilepticus, intractable 
epilepsy) 
Death 
Somnolence/depressed 
level of consciousness 
Somnolence 
— 
Somnolence or sedation 
interfering with function, 
but not interfering with 
ADL 
Obtundation or stupor; 
difficult to arouse; 
interfering with ADL 
Coma 
Death 
Speech impairment  
(e.g., dysphasia or 
aphasia)  
Speech impairment 
— 
Awareness of receptive 
or expressive dysphasia, 
not impairing ability to 
communicate 
Receptive or expressive 
dysphasia, impairing 
ability to communicate 
Inability to communicate 
— 
REMARK: Speech impairment refers to a primary CNS process, not neuropathy or end organ dysfunction. 
ALSO CONSIDER: Laryngeal nerve dysfunction; Voice changes/dysarthria (e.g., hoarseness, loss, or alteration in voice, laryngitis). 
Syncope (fainting) 
Syncope (fainting) 
— 
— 
Present 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: CNS cerebrovascular ischemia; Conduction abnormality/atrioventricular heart block – Select; Dizziness; Supraventricular and nodal arrhythmia – Select; Vasovagal 
episode; Ventricular arrhythmia – Select. 
NAVIGATION NOTE: Taste alteration (CN VII, IX) is graded as Taste alteration (dysgeusia) in the GASTROINTESTINAL CATEGORY. 
Tremor 
Tremor 
Mild and brief or 
intermittent but not 
interfering with function 
Moderate tremor 
interfering with function, 
but not interfering with 
ADL 
Severe tremor interfering 
with ADL 
Disabling 
— 
Neurology – Other 
(Specify, __) 
Neurology – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
OCULAR/VISUAL 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 52 - 
March 31, 2003, Publish Date: August 9, 2006 
Cataract 
Cataract 
Asymptomatic, detected 
on exam only  
Symptomatic, with 
moderate decrease in 
visual acuity  
(20/40 or better); 
decreased visual function 
correctable with glasses  
Symptomatic with marked 
decrease in visual acuity 
(worse than 20/40); 
operative intervention 
indicated (e.g., cataract 
surgery) 
— 
— 
Dry eye syndrome  
Dry eye 
Mild, intervention not 
indicated 
Symptomatic, interfering 
with function but not 
interfering with ADL; 
medical intervention 
indicated  
Symptomatic or decrease 
in visual acuity interfering 
with ADL; operative 
intervention indicated 
— 
— 
Eyelid dysfunction  
Eyelid dysfunction 
Asymptomatic  
Symptomatic, interfering 
with function but not ADL; 
requiring topical agents or 
epilation 
Symptomatic; interfering 
with ADL; surgical 
intervention indicated 
— 
— 
REMARK: Eyelid dysfunction includes canalicular stenosis, ectropion, entropion, erythema, madarosis, symblepharon, telangiectasis, thickening, and trichiasis. 
ALSO CONSIDER: Neuropathy: cranial – Select. 
Glaucoma  
Glaucoma 
Elevated intraocular 
pressure (EIOP) with 
single topical agent for 
intervention; no visual 
field deficit 
EIOP causing early visual 
field deficit (i.e., nasal 
step or arcuate deficit); 
multiple topical or oral 
agents indicated 
EIOP causing marked 
visual field deficits (i.e., 
involving both superior 
and inferior visual fields); 
operative intervention 
indicated 
EIOP resulting in 
blindness (20/200 or 
worse); enucleation 
indicated 
— 
Keratitis (corneal 
inflammation/corneal 
ulceration) 
Keratitis 
Abnormal ophthalmologic 
changes only; 
intervention not indicated 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL; 
operative intervention 
indicated 
Perforation or blindness 
(20/200 or worse)  
— 
NAVIGATION NOTE: Ocular muscle weakness is graded as Muscle weakness, generalized or specific area (not due to neuropathy) – Select in the MUSCULOSKELETAL/SOFT TISSUE 
CATEGORY.  
Night blindness 
(nyctalopia) 
Nyctalopia 
Symptomatic, not 
interfering with function 
Symptomatic and 
interfering with function 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL  
Disabling 
— 

 
OCULAR/VISUAL 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 53 - 
March 31, 2003, Publish Date: August 9, 2006 
Nystagmus 
Nystagmus 
Asymptomatic 
Symptomatic and 
interfering with function 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
ALSO CONSIDER: Neuropathy: cranial – Select; Ophthalmoplegia/diplopia (double vision). 
Ocular surface disease  
Ocular surface disease  
Asymptomatic or 
minimally symptomatic 
but not interfering with 
function 
Symptomatic, interfering 
with function but not 
interfering with ADL; 
topical antibiotics or other 
topical intervention 
indicated 
Symptomatic, interfering 
with ADL; operative 
intervention indicated 
— 
— 
REMARK: Ocular surface disease includes conjunctivitis, keratoconjunctivitis sicca, chemosis, keratinization, and palpebral conjunctival epithelial metaplasia. 
Ophthalmoplegia/ 
diplopia (double vision) 
Diplopia 
Intermittently 
symptomatic, intervention 
not indicated 
Symptomatic and 
interfering with function 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL; 
surgical intervention 
indicated 
Disabling 
— 
ALSO CONSIDER: Neuropathy: cranial – Select. 
Optic disc edema 
Optic disc edema 
Asymptomatic 
Decreased visual acuity 
(20/40 or better); visual 
field defect present 
Decreased visual acuity 
(worse than 20/40); 
marked visual field defect 
but sparing the central 20 
degrees 
Blindness  
(20/200 or worse) 
— 
ALSO CONSIDER: Neuropathy: cranial – Select.  
Proptosis/enophthalmos 
Proptosis/enophthalmos 
Asymptomatic, 
intervention not indicated 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
— 
— 
Retinal detachment 
Retinal detachment 
Exudative; no central 
vision loss; intervention 
not indicated 
Exudative and visual 
acuity 20/40 or better but 
intervention not indicated 
Rhegmatogenous or 
exudative detachment; 
operative intervention 
indicated 
Blindness 
(20/200 or worse) 
— 
Retinopathy  
Retinopathy 
Asymptomatic  
Symptomatic with 
moderate decrease in 
visual acuity 
(20/40 or better) 
Symptomatic with marked 
decrease in visual acuity 
(worse than 20/40) 
Blindness 
(20/200 or worse) 
— 

 
OCULAR/VISUAL 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 54 - 
March 31, 2003, Publish Date: August 9, 2006 
Scleral necrosis/melt 
Scleral necrosis 
Asymptomatic or 
symptomatic but not 
interfering with function 
Symptomatic, interfering 
with function but not 
interfering with ADL; 
moderate decrease in 
visual acuity (20/40 or 
better); medical 
intervention indicated 
Symptomatic, interfering 
with ADL; marked 
decrease in visual acuity 
(worse than 20/40); 
operative intervention 
indicated 
Blindness (20/200 or 
worse); painful eye with 
enucleation indicated 
— 
Uveitis  
Uveitis 
Asymptomatic 
Anterior uveitis; medical 
intervention indicated 
Posterior or pan-uveitis; 
operative intervention 
indicated 
Blindness 
(20/200 or worse) 
— 
Vision-blurred vision 
Blurred vision 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
Vision-flashing 
lights/floaters 
Flashing lights 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
Vision-photophobia 
Photophobia 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
Vitreous hemorrhage 
Vitreous hemorrhage 
Asymptomatic, clinical 
findings only 
Symptomatic, interfering 
with function, but not 
interfering with ADL; 
intervention not indicated 
Symptomatic, interfering 
with ADL; vitrectomy 
indicated  
— 
— 
Watery eye (epiphora, 
tearing) 
Watery eye 
Symptomatic, intervention 
not indicated 
Symptomatic, interfering 
with function but not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
— 
— 
Ocular/Visual – Other  
(Specify, __) 
Ocular – Other  
(Specify) 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Blindness 
(20/200 or worse) 
Death 

 
PAIN 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 55 - 
March 31, 2003, Publish Date: August 9, 2006 
Pain  
– Select: 
‘Select’ AEs appear at the 
end of the CATEGORY. 
Pain – Select  
Mild pain not interfering 
with function 
Moderate pain; pain or 
analgesics interfering with 
function, but not 
interfering with ADL 
Severe pain; pain or 
analgesics severely 
interfering with ADL 
Disabling 
— 
Pain – Other 
(Specify, __) 
Pain – Other (Specify) 
Mild pain not interfering 
with function 
Moderate pain; pain or 
analgesics interfering with 
function, but not 
interfering with ADL 
Severe pain; pain or 
analgesics severely 
interfering with ADL 
Disabling 
— 
PAIN – SELECT 
AUDITORY/EAR 
– External ear 
– Middle ear 
CARDIOVASCULAR 
– Cardiac/heart  
– Pericardium 
DERMATOLOGY/SKIN 
– Face 
– Lip 
– Oral-gums 
– Scalp 
– Skin 
GASTROINTESTINAL 
– Abdomen NOS 
– Anus 
– Dental/teeth/peridontal 
– Esophagus 
– Oral cavity 
– Peritoneum 
– Rectum 
– Stomach 
GENERAL 
– Pain NOS 
– Tumor pain  
HEPATOBILIARY/PANCREAS 
– Gallbladder 
– Liver  
LYMPHATIC 
– Lymph node 
MUSCULOSKELETAL 
– Back 
– Bone 
– Buttock 
– Extremity-limb 
– Intestine 
– Joint 
– Muscle 
– Neck 
– Phantom (pain associated with missing limb) 
NEUROLOGY 
– Head/headache 
– Neuralgia/peripheral nerve 
OCULAR 
– Eye 
PULMONARY/UPPER RESPIRATORY 
– Chest wall 
– Chest/thorax NOS 
PULMONARY/UPPER RESPIRATORY (continued) 
– Larynx 
– Pleura 
– Sinus 
– Throat/pharynx/larynx 
RENAL/GENITOURINARY 
– Bladder 
– Kidney 
SEXUAL/REPRODUCTIVE FUNCTION 
– Breast 
– Ovulatory 
– Pelvis 
– Penis 
– Perineum 
– Prostate 
– Scrotum 
– Testicle 
– Urethra 
– Uterus 
– Vagina 
 
 

 
PULMONARY/UPPER RESPIRATORY 
Page 1 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 56 - 
March 31, 2003, Publish Date: August 9, 2006 
Adult Respiratory 
Distress Syndrome 
(ARDS) 
ARDS 
— 
— 
Present, intubation not 
indicated  
Present, intubation 
indicated 
Death 
ALSO CONSIDER: Dyspnea (shortness of breath); Hypoxia; Pneumonitis/pulmonary infiltrates. 
Aspiration 
Aspiration 
Asymptomatic (“silent 
aspiration”); endoscopy 
or radiographic (e.g., 
barium swallow) findings  
Symptomatic (e.g., 
altered eating habits, 
coughing or choking 
episodes consistent with 
aspiration); medical 
intervention indicated 
(e.g., antibiotics, suction 
or oxygen) 
Clinical or radiographic 
signs of pneumonia or 
pneumonitis; unable to 
aliment orally 
Life-threatening (e.g., 
aspiration pneumonia or 
pneumonitis)  
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils 
– Select; Infection with unknown ANC – Select; Laryngeal nerve dysfunction; Neuropathy: cranial – Select; Pneumonitis/pulmonary infiltrates. 
Atelectasis  
Atelectasis  
Asymptomatic  
Symptomatic (e.g., 
dyspnea, cough), medical 
intervention indicated 
(e.g., bronchoscopic 
suctioning, chest 
physiotherapy, 
suctioning)  
Operative (e.g., stent, 
laser) intervention 
indicated  
Life-threatening 
respiratory compromise 
Death 
ALSO CONSIDER: Adult Respiratory Distress Syndrome (ARDS); Cough; Dyspnea (shortness of breath); Hypoxia; Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select; Obstruction/stenosis of airway – 
Select; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes). 
Bronchospasm, 
wheezing  
Bronchospasm 
Asymptomatic  
Symptomatic not 
interfering with function 
Symptomatic interfering 
with function 
Life-threatening 
Death 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever); Dyspnea (shortness of breath).  
Carbon monoxide 
diffusion capacity (DLCO) 
DLCO 
90 – 75% of predicted 
value 
<75 – 50% of predicted 
value 
<50 – 25% of predicted 
value 
<25% of predicted value 
Death 
ALSO CONSIDER: Hypoxia; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes). 
Chylothorax  
Chylothorax 
Asymptomatic 
Symptomatic; 
thoracentesis or tube 
drainage indicated  
Operative intervention 
indicated 
Life-threatening (e.g., 
hemodynamic instability 
or ventilatory support 
indicated) 
Death 
Cough 
Cough 
Symptomatic, non-
narcotic medication only 
indicated  
Symptomatic and 
narcotic medication 
indicated  
Symptomatic and 
significantly interfering 
with sleep or ADL 
— 
— 

 
PULMONARY/UPPER RESPIRATORY 
Page 2 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 57 - 
March 31, 2003, Publish Date: August 9, 2006 
Dyspnea (shortness of 
breath)  
Dyspnea  
Dyspnea on exertion, but 
can walk 1 flight of stairs 
without stopping 
Dyspnea on exertion but 
unable to walk 1 flight of 
stairs or 1 city block 
(0.1km) without stopping 
Dyspnea with ADL 
Dyspnea at rest; 
intubation/ventilator 
indicated  
Death 
ALSO CONSIDER: Hypoxia; Neuropathy: motor; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes). 
Edema, larynx  
Edema, larynx 
Asymptomatic edema by 
exam only 
Symptomatic edema, no 
respiratory distress  
Stridor; respiratory 
distress; interfering with 
ADL 
Life-threatening airway 
compromise; 
tracheotomy, intubation, 
or laryngectomy indicated 
Death 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever). 
FEV1  
FEV1 
90 – 75% of predicted 
value 
<75 – 50% of predicted 
value 
<50 – 25% of predicted 
value 
<25% of predicted 
Death 
Fistula, pulmonary/upper 
respiratory  
– Select: 
– Bronchus 
– Larynx 
– Lung 
– Oral cavity 
– Pharynx  
– Pleura 
– Trachea 
Fistula, pulmonary  
– Select  
Asymptomatic, 
radiographic findings only 
Symptomatic, tube 
thoracostomy or medical 
management indicated; 
associated with altered 
respiratory function but 
not interfering with ADL 
Symptomatic and 
associated with altered 
respiratory function 
interfering with ADL; or 
endoscopic (e.g., stent) 
or primary closure by 
operative intervention 
indicated 
Life-threatening 
consequences; operative 
intervention with 
thoracoplasty, chronic 
open drainage or multiple 
thoracotomies indicated 
Death 
REMARK: A fistula is defined as an abnormal communication between two body cavities, potential spaces, and/or the skin. The site indicated for a fistula should be the site from which 
the abnormal process is believed to have arisen. For example, a tracheo-esophageal fistula arising in the context of a resected or irradiated esophageal cancer should be graded as 
Fistula, GI – esophagus in the GASTROINTESTINAL CATEGORY. 
NAVIGATION NOTE: Hemoptysis is graded as Hemorrhage, pulmonary/upper respiratory – Select in the HEMORRHAGE/BLEEDING CATEGORY.  
Hiccoughs (hiccups, 
singultus) 
Hiccoughs 
Symptomatic, 
intervention not indicated 
Symptomatic, 
intervention indicated  
Symptomatic, 
significantly interfering 
with sleep or ADL 
— 
— 
Hypoxia 
Hypoxia 
— 
Decreased O2 saturation 
with exercise (e.g., pulse 
oximeter <88%); 
intermittent supplemental 
oxygen  
Decreased O2 saturation 
at rest; continuous 
oxygen indicated 
Life-threatening; 
intubation or ventilation 
indicated  
Death 

 
PULMONARY/UPPER RESPIRATORY 
Page 3 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 58 - 
March 31, 2003, Publish Date: August 9, 2006 
Nasal cavity/paranasal 
sinus reactions 
Nasal/paranasal 
reactions 
Asymptomatic mucosal 
crusting, blood-tinged 
secretions 
Symptomatic stenosis or 
edema/narrowing 
interfering with airflow 
Stenosis with significant 
nasal obstruction; 
interfering with ADL 
Necrosis of soft tissue or 
bone 
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils 
– Select; Infection with unknown ANC – Select. 
Obstruction/stenosis of 
airway 
– Select: 
– Bronchus 
– Larynx 
– Pharynx 
– Trachea 
Airway obstruction  
– Select  
Asymptomatic obstruction 
or stenosis on exam, 
endoscopy, or radiograph 
Symptomatic (e.g., noisy 
airway breathing), but 
causing no respiratory 
distress; medical 
management indicated 
(e.g., steroids)  
Interfering with ADL; 
stridor or endoscopic 
intervention indicated 
(e.g., stent, laser)  
Life-threatening airway 
compromise; tracheotomy 
or intubation indicated 
Death 
Pleural effusion 
(non-malignant)  
Pleural effusion 
Asymptomatic 
Symptomatic, 
intervention such as 
diuretics or up to 2 
therapeutic 
thoracenteses indicated 
Symptomatic and 
supplemental oxygen,  
>2 therapeutic 
thoracenteses, tube 
drainage, or pleurodesis 
indicated 
Life-threatening (e.g., 
causing hemodynamic 
instability or ventilatory 
support indicated)  
Death 
ALSO CONSIDER: Atelectasis; Cough; Dyspnea (shortness of breath); Hypoxia; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes).  
NAVIGATION NOTE: Pleuritic pain is graded as Pain – Select in the PAIN CATEGORY. 
Pneumonitis/pulmonary 
infiltrates  
Pneumonitis 
Asymptomatic, 
radiographic findings only 
Symptomatic, not 
interfering with ADL  
Symptomatic, interfering 
with ADL; O2 indicated  
Life-threatening; 
ventilatory support 
indicated 
Death 
ALSO CONSIDER: Adult Respiratory Distress Syndrome (ARDS); Cough; Dyspnea (shortness of breath); Hypoxia; Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select; Pneumonitis/pulmonary infiltrates; 
Pulmonary fibrosis (radiographic changes). 
Pneumothorax  
Pneumothorax  
Asymptomatic, 
radiographic findings only 
Symptomatic; 
intervention indicated 
(e.g., hospitalization for 
observation, tube 
placement without 
sclerosis) 
Sclerosis and/or 
operative intervention 
indicated 
Life-threatening, causing 
hemodynamic instability 
(e.g., tension 
pneumothorax); 
ventilatory support 
indicated 
Death 
Prolonged chest tube 
drainage or air leak after 
pulmonary resection 
Chest tube drainage or 
leak 
— 
Sclerosis or additional 
tube thoracostomy 
indicated 
Operative intervention 
indicated (e.g., 
thoracotomy with stapling 
or sealant application) 
Life-threatening; 
debilitating; organ 
resection indicated 
Death 

 
PULMONARY/UPPER RESPIRATORY 
Page 4 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 59 - 
March 31, 2003, Publish Date: August 9, 2006 
Prolonged intubation 
after pulmonary resection 
(>24 hrs after surgery)  
Prolonged intubation 
— 
Extubated within  
24 – 72 hrs 
postoperatively 
Extubated >72 hrs 
postoperatively, but 
before tracheostomy 
indicated 
Tracheostomy indicated 
Death 
NAVIGATION NOTE: Pulmonary embolism is graded as Grade 4 either as Thrombosis/embolism (vascular access-related) or Thrombosis/thrombus/embolism in the VASCULAR 
CATEGORY.  
Pulmonary fibrosis 
(radiographic changes)  
Pulmonary fibrosis 
Minimal radiographic 
findings (or patchy or bi-
basilar changes) with 
estimated radiographic 
proportion of total lung 
volume that is fibrotic of 
<25% 
Patchy or bi-basilar 
changes with estimated 
radiographic proportion of 
total lung volume that is 
fibrotic of 25 – <50% 
Dense or widespread 
infiltrates/consolidation 
with estimated 
radiographic proportion of 
total lung volume that is 
fibrotic of 50 – <75% 
Estimated radiographic 
proportion of total lung 
volume that is fibrotic is 
≥75%; honeycombing 
Death 
REMARK: Fibrosis is usually a “late effect” seen >3 months after radiation or combined modality therapy (including surgery). It is thought to represent scar/fibrotic lung tissue. It may be 
difficult to distinguish from pneumonitis that is generally seen within 3 months of radiation or combined modality therapy.  
ALSO CONSIDER: Adult Respiratory Distress Syndrome (ARDS); Cough; Dyspnea (shortness of breath); Hypoxia; Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select. 
NAVIGATION NOTE: Recurrent laryngeal nerve dysfunction is graded as Laryngeal nerve dysfunction in the NEUROLOGY CATEGORY. 
Vital capacity  
Vital capacity 
90 – 75% of predicted 
value 
<75 – 50% of predicted 
value 
<50 – 25% of predicted 
value 
<25% of predicted value 
Death 
Voice changes/dysarthria 
(e.g., hoarseness, loss or 
alteration in voice, 
laryngitis)  
Voice changes  
Mild or intermittent 
hoarseness or voice 
change, but fully 
understandable 
Moderate or persistent 
voice changes, may 
require occasional 
repetition but 
understandable on 
telephone 
Severe voice changes 
including predominantly 
whispered speech; may 
require frequent repetition 
or face-to-face contact for 
understandability; 
requires voice aid (e.g., 
electrolarynx) for ≤50% of 
communication 
Disabling; 
non-understandable voice 
or aphonic; requires voice 
aid (e.g., electrolarynx) 
for >50% of 
communication or 
requires >50% written 
communication 
Death 
ALSO CONSIDER: Laryngeal nerve dysfunction; Speech impairment (e.g., dysphasia or aphasia). 
Pulmonary/Upper 
Respiratory – Other 
(Specify, __) 
Pulmonary – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling 
Death 

 
RENAL/GENITOURINARY 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 60 - 
March 31, 2003, Publish Date: August 9, 2006 
Bladder spasms 
Bladder spasms 
Symptomatic, intervention 
not indicated 
Symptomatic, 
antispasmodics indicated 
Narcotics indicated 
Major surgical 
intervention indicated 
(e.g., cystectomy) 
— 
Cystitis 
Cystitis 
Asymptomatic 
Frequency with dysuria; 
macroscopic hematuria 
Transfusion; IV pain 
medications; bladder 
irrigation indicated 
Catastrophic bleeding; 
major non-elective 
intervention indicated 
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils 
– Select; Infection with unknown ANC – Select; Pain – Select. 
Fistula, GU 
– Select:  
– Bladder 
– Genital tract-female 
– Kidney 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
Fistula, GU – Select  
Asymptomatic, 
radiographic findings only 
Symptomatic; 
noninvasive intervention 
indicated  
Symptomatic interfering 
with ADL; invasive 
intervention indicated  
Life-threatening 
consequences; operative 
intervention requiring 
partial or full organ 
resection; permanent 
urinary diversion  
Death 
REMARK: A fistula is defined as an abnormal communication between two body cavities, potential spaces, and/or the skin. The site indicated for a fistula should be the site from which 
the abnormal process is believed to have originated. 
Incontinence, urinary  
Incontinence, urinary 
Occasional (e.g., with 
coughing, sneezing, etc.), 
pads not indicated 
Spontaneous, pads 
indicated  
Interfering with ADL; 
intervention indicated 
(e.g., clamp, collagen 
injections) 
Operative intervention 
indicated (e.g., 
cystectomy or permanent 
urinary diversion) 
— 
Leak (including 
anastomotic), GU 
– Select: 
– Bladder 
– Fallopian tube  
– Kidney 
– Spermatic cord 
– Stoma 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Leak, GU – Select  
Asymptomatic, 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic, interfering 
with GU function; invasive 
or endoscopic 
intervention indicated 
Life-threatening 
Death 
REMARK: Leak (including anastomotic), GU – Select refers to clinical signs and symptoms or radiographic confirmation of anastomotic leak but without development of fistula. 

 
RENAL/GENITOURINARY 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 61 - 
March 31, 2003, Publish Date: August 9, 2006 
Obstruction, GU  
– Select: 
– Bladder 
– Fallopian tube 
– Prostate 
– Spermatic cord 
– Stoma 
– Testes 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Obstruction, GU – Select  
Asymptomatic, 
radiographic or 
endoscopic findings only 
Symptomatic but no 
hydronephrosis, sepsis or 
renal dysfunction; dilation 
or endoscopic repair or 
stent placement indicated 
Symptomatic and altered 
organ function (e.g., 
sepsis or hydronephrosis, 
or renal dysfunction); 
operative intervention 
indicated  
Life-threatening 
consequences; organ 
failure or operative 
intervention requiring 
complete organ resection 
indicated  
Death 
NAVIGATION NOTE: Operative injury is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY CATEGORY.  
Perforation, GU  
– Select: 
– Bladder 
– Fallopian tube 
– Kidney  
– Ovary 
– Prostate 
– Spermatic cord 
– Stoma 
– Testes 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Perforation, GU – Select 
Asymptomatic 
radiographic findings only 
Symptomatic, associated 
with altered renal/GU 
function 
Symptomatic, operative 
intervention indicated 
Life-threatening 
consequences or organ 
failure; operative 
intervention requiring 
organ resection indicated 
Death 
Prolapse of stoma, GU 
Prolapse stoma, GU 
Asymptomatic; special 
intervention, 
extraordinary care not 
indicated 
Extraordinary local care 
or maintenance; minor 
revision under local 
anesthesia indicated 
Dysfunctional stoma; 
operative intervention or 
major stomal revision 
indicated 
Life-threatening 
consequences 
Death 
REMARK: Other stoma complications may be graded as Fistula, GU – Select; Leak (including anastomotic), GU – Select; Obstruction, GU – Select; Perforation, GU – Select; 
Stricture/stenosis (including anastomotic), GU – Select. 
Renal failure  
Renal failure 
— 
— 
Chronic dialysis not 
indicated 
Chronic dialysis or renal 
transplant indicated 
Death 
ALSO CONSIDER: Glomerular filtration rate. 

 
RENAL/GENITOURINARY 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 62 - 
March 31, 2003, Publish Date: August 9, 2006 
Stricture/stenosis 
(including anastomotic), 
GU 
– Select: 
– Bladder 
– Fallopian tube 
– Prostate 
– Spermatic cord 
– Stoma 
– Testes 
– Ureter  
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Stricture, anastomotic, 
GU – Select  
Asymptomatic, 
radiographic or 
endoscopic findings only 
Symptomatic but no 
hydronephrosis, sepsis or 
renal dysfunction; dilation 
or endoscopic repair or 
stent placement indicated 
Symptomatic and altered 
organ function (e.g., 
sepsis or hydronephrosis, 
or renal dysfunction); 
operative intervention 
indicated  
Life-threatening 
consequences; organ 
failure or operative 
intervention requiring 
organ resection indicated  
Death 
ALSO CONSIDER: Obstruction, GU – Select. 
Urinary electrolyte 
wasting (e.g., Fanconi’s 
syndrome, renal tubular 
acidosis) 
Urinary electrolyte 
wasting 
Asymptomatic, 
intervention not indicated 
Mild, reversible and 
manageable with 
replacement 
Irreversible, requiring 
continued replacement  
— 
— 
ALSO CONSIDER: Acidosis (metabolic or respiratory); Bicarbonate, serum-low; Calcium, serum-low (hypocalcemia); Phosphate, serum-low (hypophosphatemia). 
Urinary 
frequency/urgency 
Urinary frequency 
Increase in frequency or 
nocturia up to 2 x normal; 
enuresis 
Increase >2 x normal but 
<hourly 
≥1 x/hr; urgency; catheter 
indicated 
— 
— 
Urinary retention 
(including neurogenic 
bladder)  
Urinary retention 
Hesitancy or dribbling, no 
significant residual urine; 
retention occurring during 
the immediate 
postoperative period 
Hesitancy requiring 
medication; or operative 
bladder atony requiring 
indwelling catheter 
beyond immediate 
postoperative period but 
for <6 weeks 
More than daily 
catheterization indicated; 
urological intervention 
indicated (e.g., TURP, 
suprapubic tube, 
urethrotomy) 
Life-threatening 
consequences; organ 
failure (e.g., bladder 
rupture); operative 
intervention requiring 
organ resection indicated 
Death 
REMARK: The etiology of retention (if known) is graded as Obstruction, GU – Select; Stricture/stenosis (including anastomotic), GU – Select. 
ALSO CONSIDER: Obstruction, GU – Select; Stricture/stenosis (including anastomotic), GU – Select. 
Urine color change  
Urine color change 
Present 
— 
— 
— 
— 
REMARK: Urine color refers to change that is not related to other dietary or physiologic cause (e.g., bilirubin, concentrated urine, and hematuria). 
Renal/Genitourinary – 
Other (Specify, __) 
Renal – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
SECONDARY MALIGNANCY 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 63 - 
March 31, 2003, Publish Date: August 9, 2006 
Secondary Malignancy – 
possibly related to cancer 
treatment (Specify, __)  
Secondary Malignancy 
(possibly related to 
cancer treatment) 
— 
— 
Non-life-threatening basal 
or squamous cell 
carcinoma of the skin 
Solid tumor, leukemia or 
lymphoma  
Death 
REMARK: Secondary malignancy excludes metastasis from initial primary. Any malignancy possibly related to cancer treatment (including AML/MDS) should be reported via the routine 
reporting mechanisms outlined in each protocol. Important: Secondary Malignancy is an exception to NCI Expedited Adverse Event Reporting Guidelines. Secondary Malignancy is 
“Grade 4, present” but NCI does not require AdEERS Expedited Reporting for any (related or unrelated to treatment) Secondary Malignancy. A diagnosis of AML/MDS following 
treatment with an NCI-sponsored investigational agent is to be reported using the form available from the CTEP Web site at http://ctep.cancer.gov. Cancers not suspected of being 
treatment-related are not to be reported here. 

 
SEXUAL/REPRODUCTIVE FUNCTION 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 64 - 
March 31, 2003, Publish Date: August 9, 2006 
Breast function/lactation 
Breast function 
Mammary abnormality, 
not functionally significant 
Mammary abnormality, 
functionally significant 
— 
— 
— 
Breast nipple/areolar 
deformity  
Nipple/areolar 
Limited areolar 
asymmetry with no 
change in nipple/areolar 
projection 
Asymmetry of nipple 
areolar complex with 
slight deviation in nipple 
projection 
Marked deviation of 
nipple projection  
— 
— 
Breast volume/hypoplasia 
Breast 
Minimal asymmetry; 
minimal hypoplasia 
Asymmetry exists, ≤1/3 of 
the breast volume; 
moderate hypoplasia  
Asymmetry exists, >1/3 of 
the breast volume; severe 
hypoplasia 
— 
— 
REMARK: Breast volume is referenced with both arms straight overhead. 
NAVIGATION NOTE: Dysmenorrhea is graded as Pain – Select in the PAIN CATEGORY.  
NAVIGATION NOTE: Dyspareunia is graded as Pain – Select in the PAIN CATEGORY.  
NAVIGATION NOTE: Dysuria (painful urination) is graded as Pain – Select in the PAIN CATEGORY.  
Erectile dysfunction 
Erectile dysfunction 
Decrease in erectile 
function 
(frequency/rigidity of 
erections) but erectile 
aids not indicated 
Decrease in erectile 
function 
(frequency/rigidity of 
erections), erectile aids 
indicated 
Decrease in erectile 
function 
(frequency/rigidity of 
erections) but erectile 
aids not helpful; penile 
prosthesis indicated 
— 
— 
Ejaculatory dysfunction 
Ejaculatory dysfunction 
Diminished ejaculation 
Anejaculation or 
retrograde ejaculation 
— 
— 
— 
NAVIGATION NOTE: Feminization of male is graded in the ENDOCRINE CATEGORY. 
Gynecomastia 
Gynecomastia 
— 
Asymptomatic breast 
enlargement 
Symptomatic breast 
enlargement; intervention 
indicated 
— 
— 
ALSO CONSIDER: Pain – Select.  
Infertility/sterility 
Infertility/sterility 
— 
Male: oligospermia/low 
sperm count 
Female: diminished 
fertility/ovulation 
Male: sterile/azoospermia 
Female: infertile/ 
anovulatory 
— 
— 
Irregular menses  
(change from baseline) 
Irregular menses 
1 – 3 months without 
menses 
>3 – 6 months without 
menses but continuing 
menstrual cycles 
Persistent amenorrhea 
for >6 months 
— 
— 

 
SEXUAL/REPRODUCTIVE FUNCTION 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 65 - 
March 31, 2003, Publish Date: August 9, 2006 
Libido 
Libido 
Decrease in interest but 
not affecting relationship; 
intervention not indicated 
Decrease in interest and 
adversely affecting 
relationship; intervention 
indicated 
— 
— 
— 
NAVIGATION NOTE: Masculinization of female is graded in the ENDOCRINE CATEGORY. 
Orgasmic dysfunction 
Orgasmic function 
Transient decrease 
Decrease in orgasmic 
response requiring 
intervention 
Complete inability of 
orgasmic response; not 
responding to intervention 
— 
— 
NAVIGATION NOTE: Pelvic pain is graded as Pain – Select in the PAIN CATEGORY. 
NAVIGATION NOTE: Ulcers of the labia or perineum are graded as Ulceration in DERMATOLOGY/SKIN CATEGORY. 
Vaginal discharge  
(non-infectious) 
Vaginal discharge 
Mild 
Moderate to heavy; pad 
use indicated 
— 
— 
— 
Vaginal dryness 
Vaginal dryness 
Mild 
Interfering with sexual 
function; dyspareunia; 
intervention indicated 
— 
— 
— 
ALSO CONSIDER: Pain – Select. 
Vaginal mucositis 
Vaginal mucositis 
Erythema of the mucosa; 
minimal symptoms 
Patchy ulcerations; 
moderate symptoms or 
dyspareunia 
Confluent ulcerations; 
bleeding with trauma; 
unable to tolerate vaginal 
exam, sexual intercourse 
or tampon placement  
Tissue necrosis; 
significant spontaneous 
bleeding; life-threatening 
consequences 
— 
Vaginal stenosis/length 
Vaginal stenosis 
Vaginal narrowing and/or 
shortening not interfering 
with function  
Vaginal narrowing and/or 
shortening interfering with 
function  
Complete obliteration; not 
surgically correctable 
— 
— 
Vaginitis (not due to 
infection) 
Vaginitis 
Mild, intervention not 
indicated 
Moderate, intervention 
indicated 
Severe, not relieved with 
treatment; ulceration, but 
operative intervention not 
indicated 
Ulceration and operative 
intervention indicated 
— 
Sexual/Reproductive 
Function – Other 
(Specify, __) 
Sexual – Other (Specify) 
Mild 
Moderate 
Severe 
Disabling 
Death 

 
SURGERY/INTRA-OPERATIVE INJURY 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 66 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Intra-operative hemorrhage is graded as Hemorrhage/bleeding associated with surgery, intra-operative or postoperative in the HEMORRHAGE/BLEEDING 
CATEGORY.  
Intra-operative injury  
– Select Organ or 
Structure 
‘Select’ AEs appear at the 
end of the CATEGORY. 
Intraop injury – Select  
Primary repair of injured 
organ/structure indicated  
Partial resection of 
injured organ/structure 
indicated 
Complete resection or 
reconstruction of injured 
organ/structure indicated 
Life threatening 
consequences; disabling 
— 
REMARK: The ‘Select’ AEs are defined as significant, unanticipated injuries that are recognized at the time of surgery. These AEs do not refer to additional surgical procedures that 
must be performed because of a change in the operative plan based on intra-operative findings. Any sequelae resulting from the intra-operative injury that result in an adverse 
outcome for the patient must also be recorded and graded under the relevant CTCAE Term. 
Intra-operative Injury – 
Other (Specify, __) 
Intraop Injury – Other 
(Specify) 
Primary repair of injured 
organ/structure indicated  
Partial resection of 
injured organ/structure 
indicated 
Complete resection or 
reconstruction of injured 
organ/structure indicated 
Life threatening 
consequences; disabling 
— 
REMARK: Intra-operative Injury – Other (Specify, __) is to be used only to report an organ/structure not included in the ‘Select’ AEs found at the end of the CATEGORY. Any sequelae 
resulting from the intra-operative injury that result in an adverse outcome for the patient must also be recorded and graded under the relevant CTCAE Term. 

 
SURGERY/INTRA-OPERATIVE INJURY – SELECT  
Page 2 of 2 
CTCAE v3.0  
- 67 - 
March 31, 2003, Publish Date: August 9, 2006 
AUDITORY/EAR 
– Inner ear  
– Middle ear  
– Outer ear NOS  
– Outer ear-Pinna  
CARDIOVASCULAR 
– Artery-aorta  
– Artery-carotid  
– Artery-cerebral  
– Artery-extremity (lower)  
– Artery-extremity (upper)  
– Artery-hepatic  
– Artery-major visceral artery  
– Artery-pulmonary  
– Artery NOS 
– Heart  
– Spleen 
– Vein-extremity (lower)  
– Vein-extremity (upper)  
– Vein-hepatic  
– Vein-inferior vena cava  
– Vein-jugular  
– Vein-major visceral vein  
– Vein-portal vein  
– Vein-pulmonary  
– Vein-superior vena cava  
– Vein NOS 
DERMATOLOGY/SKIN 
– Breast  
– Nails  
– Skin 
ENDOCRINE 
– Adrenal gland 
– Parathyroid 
– Pituitary  
ENDOCRINE (continued) 
– Thyroid 
HEAD AND NECK 
– Gingiva  
– Larynx  
– Lip/perioral area  
– Face NOS  
– Nasal cavity  
– Nasopharynx  
– Neck NOS 
– Nose  
– Oral cavity NOS  
– Parotid gland  
– Pharynx  
– Salivary duct  
– Salivary gland  
– Sinus  
– Teeth  
– Tongue  
– Upper aerodigestive NOS 
GASTROINTESTINAL 
– Abdomen NOS  
– Anal sphincter  
– Anus 
– Appendix  
– Cecum  
– Colon  
– Duodenum  
– Esophagus  
– Ileum  
– Jejunum  
– Oral  
– Peritoneal cavity  
– Rectum 
– Small bowel NOS 
GASTROINTESTINAL (continued) 
– Stoma (GI)  
– Stomach  
HEPATOBILIARY/ PANCREAS 
– Biliary tree-common bile  
duct  
– Biliary tree-common hepatic 
duct  
– Biliary tree-left hepatic duct  
– Biliary tree-right hepatic duct  
– Biliary tree NOS  
– Gallbladder  
– Liver 
– Pancreas 
– Pancreatic duct 
MUSCULOSKELETAL 
– Bone  
– Cartilage  
– Extremity-lower 
– Extremity-upper 
– Joint  
– Ligament  
– Muscle  
– Soft tissue NOS 
– Tendon 
NEUROLOGY  
– Brain  
– Meninges  
– Spinal cord 
NERVES: 
– Brachial plexus 
– CN I (olfactory) 
– CN II (optic) 
– CN III (oculomotor) 
– CN IV (trochlear)  
NEUROLOGY (continued) 
NERVES: 
– CN V (trigeminal) motor  
– CN V (trigeminal) sensory  
– CN VI (abducens)  
– CN VII (facial) motor-face  
– CN VII (facial) sensory-
taste  
– CN VIII (vestibulocochlear)  
– CN IX (glossopharyngeal) 
motor pharynx  
– CN IX (glossopharyngeal) 
sensory ear-pharynx-
tongue  
– CN X (vagus)  
– CN XI (spinal accessory)  
– CN XII (hypoglossal)  
– Cranial nerve or branch 
NOS  
– Lingual  
– Lung thoracic  
– Peripheral motor NOS 
– Peripheral sensory NOS 
– Recurrent laryngeal  
– Sacral plexus  
– Sciatic 
– Thoracodorsal 
OCULAR 
– Conjunctiva  
– Cornea  
– Eye NOS 
– Lens 
– Retina 
PULMONARY/UPPER 
RESPIRATORY 
– Bronchus  
– Lung  
– Mediastinum  
– Pleura  
– Thoracic duct  
– Trachea 
– Upper airway NOS 
RENAL/GENITOURINARY 
– Bladder  
– Cervix  
– Fallopian tube  
– Kidney  
– Ovary  
– Pelvis NOS  
– Penis  
– Prostate  
– Scrotum  
– Testis  
– Ureter  
– Urethra  
– Urinary conduit  
– Urinary tract NOS  
– Uterus  
– Vagina  
– Vulva 
 
 

 
SYNDROMES 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 68 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Acute vascular leak syndrome is graded in the VASCULAR CATEGORY. 
NAVIGATION NOTE: Adrenal insufficiency is graded in the ENDOCRINE CATEGORY. 
NAVIGATION NOTE: Adult Respiratory Distress Syndrome (ARDS) is graded in the PULMONARY/UPPER RESPIRATORY CATEGORY. 
Alcohol intolerance 
syndrome (antabuse-like 
syndrome) 
Alcohol intolerance 
syndrome 
— 
— 
Present 
— 
Death 
REMARK: An antabuse-like syndrome occurs with some new anti-androgens (e.g., nilutamide) when patient also consumes alcohol. 
NAVIGATION NOTE: Autoimmune reaction is graded as Autoimmune reaction/hypersensitivity (including drug fever) in the ALLERGY/IMMUNOLOGY CATEGORY. 
Cytokine release 
syndrome/acute infusion 
reaction 
Cytokine release 
syndrome 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDS, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption of 
infusion); recurrence of 
symptoms following initial 
improvement; 
hospitalization indicated 
for other clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates) 
Life-threatening; pressor 
or ventilatory support 
indicated 
Death 
REMARK: Cytokine release syndromes/acute infusion reactions are different from Allergic/hypersensitive reactions, although some of the manifestations are common to both AEs. An 
acute infusion reaction may occur with an agent that causes cytokine release (e.g., monoclonal antibodies or other biological agents). Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hrs of completion of infusion. Signs/symptoms may include: Allergic reaction/hypersensitivity (including drug 
fever); Arthralgia (joint pain); Bronchospasm; Cough; Dizziness; Dyspnea (shortness of breath); Fatigue (asthenia, lethargy, malaise); Headache; Hypertension; Hypotension; Myalgia 
(muscle pain); Nausea; Pruritis/itching; Rash/desquamation; Rigors/chills; Sweating (diaphoresis); Tachycardia; Tumor pain (onset or exacerbation of tumor pain due to treatment); 
Urticaria (hives, welts, wheals); Vomiting.  
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever); Bronchospasm, wheezing; Dyspnea (shortness of breath); Hypertension; Hypotension; Hypoxia; Prolonged 
QTc interval; Supraventricular and nodal arrhythmia – Select; Ventricular arrhythmia – Select.  
NAVIGATION NOTE: Disseminated intravascular coagulation (DIC) is graded in the COAGULATION CATEGORY. 
NAVIGATION NOTE: Fanconi’s syndrome is graded as Urinary electrolyte wasting (e.g., Fanconi’s syndrome, renal tubular acidosis) in the RENAL/GENITOURINARY CATEGORY. 
Flu-like syndrome 
Flu-like syndrome 
Symptoms present but 
not interfering with 
function 
Moderate or causing 
difficulty performing some 
ADL 
Severe symptoms 
interfering with ADL 
Disabling 
Death 
REMARK: Flu-like syndrome represents a constellation of symptoms which may include cough with catarrhal symptoms, fever, headache, malaise, myalgia, prostration, and is to be 
used when the symptoms occur in a cluster consistent with one single pathophysiological process. 
NAVIGATION NOTE: Renal tubular acidosis is graded as Urinary electrolyte wasting (e.g., Fanconi’s syndrome, renal tubular acidosis) in the RENAL/GENITOURINARY CATEGORY. 

 
SYNDROMES 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 69 - 
March 31, 2003, Publish Date: August 9, 2006 
“Retinoic acid syndrome”  
“Retinoic acid syndrome” 
Fluid retention; less than 
3 kg of weight gain; 
intervention with fluid 
restriction and/or diuretics 
indicated 
Mild to moderate signs/ 
symptoms; steroids 
indicated 
Severe signs/symptoms; 
hospitalization indicated 
Life-threatening; 
ventilatory support 
indicated 
Death 
REMARK: Patients with acute promyelocytic leukemia may experience a syndrome similar to “retinoic acid syndrome” in association with other agents such as arsenic trioxide. The 
syndrome is usually manifested by otherwise unexplained fever, weight gain, respiratory distress, pulmonary infiltrates and/or pleural effusion, with or without leukocytosis.  
ALSO CONSIDER: Acute vascular leak syndrome; Pleural effusion (non-malignant); Pneumonitis/pulmonary infiltrates. 
NAVIGATION NOTE: SIADH is graded as Neuroendocrine: ADH secretion abnormality (e.g., SIADH or low ADH) in the ENDOCRINE CATEGORY.  
NAVIGATION NOTE: Stevens-Johnson syndrome is graded as Rash: erythema multiforme (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis) in the DERMATOLOGY/SKIN 
CATEGORY. 
NAVIGATION NOTE: Thrombotic microangiopathy is graded as Thrombotic microangiopathy (e.g., thrombotic thrombocytopenic purpura [TTP] or hemolytic uremic syndrome [HUS]) in 
the COAGULATION CATEGORY. 
Tumor flare 
Tumor flare 
Mild pain not interfering 
with function 
Moderate pain; pain or 
analgesics interfering with 
function, but not 
interfering with ADL 
Severe pain; pain or 
analgesics interfering with 
function and interfering 
with ADL 
Disabling 
Death 
REMARK: Tumor flare is characterized by a constellation of signs and symptoms in direct relation to initiation of therapy (e.g., anti-estrogens/androgens or additional hormones). The 
symptoms/signs include tumor pain, inflammation of visible tumor, hypercalcemia, diffuse bone pain, and other electrolyte disturbances.  
ALSO CONSIDER: Calcium, serum-high (hypercalcemia). 
Tumor lysis syndrome 
Tumor lysis syndrome 
— 
— 
Present 
— 
Death 
ALSO CONSIDER: Creatinine; Potassium, serum-high (hyperkalemia). 
Syndromes – Other 
(Specify, __) 
Syndromes – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
VASCULAR 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 70 - 
March 31, 2003, Publish Date: August 9, 2006 
Acute vascular leak 
syndrome 
Acute vascular leak 
syndrome 
— 
Symptomatic, fluid 
support not indicated 
Respiratory compromise 
or fluids indicated 
Life-threatening; pressor 
support or ventilatory 
support indicated  
Death 
Peripheral arterial 
ischemia 
Peripheral arterial 
ischemia 
— 
Brief (<24 hrs) episode of 
ischemia managed non-
surgically and without 
permanent deficit 
Recurring or prolonged 
(≥24 hrs) and/or invasive 
intervention indicated 
Life-threatening, disabling 
and/or associated with 
end organ damage 
(e.g., limb loss) 
Death 
Phlebitis (including 
superficial thrombosis) 
Phlebitis 
— 
Present 
— 
— 
— 
ALSO CONSIDER: Injection site reaction/extravasation changes. 
Portal vein flow 
Portal flow 
— 
Decreased portal vein 
flow 
Reversal/retrograde 
portal vein flow 
— 
— 
Thrombosis/embolism 
(vascular access-related) 
Thrombosis/embolism 
(vascular access) 
— 
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
not indicated 
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
indicated 
Embolic event including 
pulmonary embolism or 
life-threatening thrombus 
Death 
Thrombosis/thrombus/ 
embolism 
Thrombosis/thrombus/ 
embolism 
— 
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
not indicated  
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
indicated  
Embolic event including 
pulmonary embolism or 
life-threatening thrombus 
Death 
Vessel injury-artery  
– Select:  
– Aorta 
– Carotid 
– Extremity-lower 
– Extremity-upper  
– Other NOS 
– Visceral 
Artery injury – Select 
Asymptomatic diagnostic 
finding; intervention not 
indicated 
Symptomatic (e.g., 
claudication); not 
interfering with ADL; 
repair or revision not 
indicated 
Symptomatic interfering 
with ADL; repair or 
revision indicated 
Life-threatening; 
disabling; evidence of 
end organ damage (e.g., 
stroke, MI, organ or limb 
loss) 
Death 
NAVIGATION NOTE: Vessel injury to an artery intra-operatively is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY 
CATEGORY. 

 
VASCULAR 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 71 - 
March 31, 2003, Publish Date: August 9, 2006 
Vessel injury-vein  
– Select: 
– Extremity-lower  
– Extremity-upper 
– IVC 
– Jugular 
– Other NOS 
– SVC 
– Viscera 
Vein injury – Select 
Asymptomatic diagnostic 
finding; intervention not 
indicated 
Symptomatic (e.g., 
claudication); not 
interfering with ADL; 
repair or revision not 
indicated  
Symptomatic interfering 
with ADL; repair or 
revision indicated 
Life-threatening; 
disabling; evidence of 
end organ damage  
Death 
NAVIGATION NOTE: Vessel injury to a vein intra-operatively is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY CATEGORY. 
Visceral arterial ischemia 
(non-myocardial) 
Visceral arterial ischemia 
— 
Brief (<24 hrs) episode of 
ischemia managed 
medically and without 
permanent deficit 
Prolonged (≥24 hrs) or 
recurring symptoms 
and/or invasive 
intervention indicated 
Life-threatening; 
disabling; evidence of 
end organ damage  
Death 
ALSO CONSIDER: CNS cerebrovascular ischemia.  
Vascular – Other  
(Specify, __) 
Vascular – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
 

Clinical Trial Protocol:  HGT-SAN-067 
 
Study Title: 
An Open-Label Extension of Study HGT-SAN-055 Evaluating 
Long-Term Safety and Clinical Outcomes of Intrathecal 
Administration of rhHNS in Patients with Sanfilippo Syndrome 
Type A (MPS IIIA) 
Study Number: 
HGT-SAN-067 
Study Phase: 
I/II 
Product Name: 
Recombinant human heparan N-sulfatase (rhHNS) 
EudraCT 
Number: 
2010-021348-16 
Indication: 
Sanfilippo Syndrome A 
Investigators: 
Multicenter 
 
 
Sponsor: 
Shire Human Genetic Therapies, Inc.  
300 Shire Way 
Lexington, MA  02421 USA 
 
Medical Monitor: 
 MD, 
 
 
 
Date 
Original Protocol: 
21 June 2010 
Amendment 1: 
27 January 2011 
Amendment 2: 
13 January 2012 
 
Confidentiality Statement 
This document is the proprietary and confidential property of  
Shire Human Genetic Therapies, Inc. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
2 
SYNOPSIS 
Sponsor: 
Shire Human Genetic Therapies, Inc.  
300 Shire Way 
Lexington, MA  02421 USA 
 
Name of Finished Product: 
Recombinant human heparan N-sulfatase (rhHNS) 
Name of Active Ingredient: 
rhHNS 
Name of Inactive Ingredient: 
N/A 
Study Title: 
An Open-Label Extension of Study HGT-SAN-055 Evaluating Long-Term Safety and 
Clinical Outcomes of Intrathecal Administration of rhHNS in Patients with Sanfilippo 
Syndrome Type A (MPS IIIA)  
Study Number: 
HGT-SAN-067 
Study Phase:  I/II 
Study Objectives: 
Primary Objective:  
The primary objective of this study is: 
• To collect long-term safety and tolerability data in patients with Sanfilippo Syndrome 
Type A (MPS IIIA) who received rhHNS via a surgically implanted intrathecal drug 
delivery device (IDDD) in study HGT-SAN-055 and elected to continue therapy in 
study HGT-SAN-067. 
Secondary Objectives: 
The secondary objectives of this study are: 
• To collect as measures of drug efficacy, over an extended treatment period (as change 
from baseline), the following:  clinical, neurological, cognitive, behavioral, 
functional, and quality of life (QoL) assessments, together with potential imaging and 
biochemical biomarkers. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
3 
Study Endpoints:  
Primary Endpoints: 
The primary endpoint of this study is: 
• To determine the long-term safety of intrathecal rhHNS administration, as measured 
by the adverse events (type and severity), changes in clinical laboratory testing 
(serum chemistry including liver function tests, hematology, and urinalysis), 
electrocardiograms (ECG), cerebrospinal fluid (CSF), chemistries (including cell 
counts and inflammatory markers), and anti-rhHNS antibodies (in CSF and serum). 
Secondary Endpoints: 
The secondary endpoints of this study are to collect over an extended treatment period (as 
change from baseline) clinical and potential surrogate biomarker efficacy data: 
• Standardized neurocognitive and behavioral assessments, Sanfilippo-specific 
behavioral rating scales, gross and fine motor assessments, functional adaptive 
rating scales, quality of life questionnaires, and Children’s Sleep Habits Rating 
Scale. 
• Concentration of rhHNS in CSF and serum. 
• Concentration of inflammatory cytokines in serum and CSF. 
• Concentration of safety and potential surrogate efficacy biomarkers in CSF, urine, 
and serum. 
• Concentration of heparan sulfate and heparan sulfate derivatives in urine and/or 
CSF, and if possible, in serum and/or plasma. 
• Brain magnetic resonance imaging (MRI) and auditory brainstem response (ABR, 
Brainstem Auditory Evoked Potentials). 
 
Study Design: 
This study, HGT-SAN-067, is an open-label, long term, multicenter, extension of 
Study HGT-SAN-055.  The study is designed to evaluate the long-term safety, clinical 
activity, and biomarker outcomes of intrathecal (IT) administration of 3 dose levels 
(10 mg, 45 mg, and 90 mg once per month [Q4W]) of rhHNS via an IDDD in patients 
with MPS IIIA who successfully complete the Phase I/II study HGT-SAN-055 (including 
end of study [EOS] assessments) and elect to continue to receive rhHNS treatment.  
Patients will continue in the same treatment group they were assigned to in the 
HGT-SAN-055 study.  
For nomenclature of chronology purposes, the Baseline Visit for this extension study will 
be considered to be the first day the patient received his/her IT dose of rhHNS in 
Study HGT-SAN-055.  The HGT-SAN-055 EOS assessment information will provide the 
screening/start of study information for patients who continue into the HGT-SAN-067 
extension study.  Note:  HGT-SAN-055 EOS data must be recorded in the context of the 
HGT-SAN-055 trial, and a copy of those data can be used for HGT-SAN-067 screening.  
Once eligibility is confirmed, informed consent must be obtained prior to performing any 
study-related procedures that are specific to HGT-SAN-067.   
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
4 
Informed consent will be provided by the patient’s parent(s)/legally authorized 
representative(s) prior to the start of the extension study procedures.  Informed consent 
may be obtained anytime from week 20 in HGT-SAN-055.  This would allow a patient to 
have a nonfunctional IDDD replaced or revised prior to the first rhHNS dose in 
HGT-SAN-067. 
Enrolled patients will check in to the study center 1 day before each of the scheduled 
rhHNS dosing days for safety assessments (designated Day 1).  If no safety concerns 
exist, the patient will subsequently receive IT administration of rhHNS on Day 2 
(±2 days).  However, if feasible and there are no safety concerns in the opinion of the 
investigator, the Day 1 and Day 2 assessments may be combined and performed on 
Day 2; if this is done the results will be recorded as Day 2.  Patients will remain in the 
study centre for at least 8 hours following dosing with rhHNS and will be discharged 
from the unit when deemed clinically stable by the Investigator. 
All patients will have received a series of standardized neurodevelopment assessments; in 
the HGT-SAN-055 study, these will have occurred at Baseline and either prior to or at the 
6-month time point.  Patients will continue in HGT-SAN-067 with whichever age 
specific assessment they began with in HGT-SAN-055.  If, however, a patient’s 
capability improves and they become capable of completing assessments at a higher 
level, such additional assessments may be added.  Any additional assessments would be 
performed after the original assessments (those previously used in study HGT-SAN-055) 
have been carried out.  A MRI of the head and ABR testing will be performed at Months 
12, 24, 36, and 54 (note that assessment time point nomenclature includes the 6 months in 
the HGT-SAN-055 study).  Note:  X-rays may be performed to investigate device 
malfunction, and to verify correct catheter and port placement following surgical 
implantation or revision.  In addition, fluoroscopy may be employed intraoperatively to 
guide catheter placement.  Thus, patients may undergo 3 X-ray examinations in 
association with each episode of IDDD malfunction and subsequent IDDD revision or 
replacement.  Since the number of IDDD revisions/replacements is limited to 2 in any 
6-month period (including the time in the HGT-SAN-055 study), the number of 
protocol-associated X-ray evaluations is limited to 6 exposures in any 6-month period 
(including time in the HGT-SAN-055). 
Patients will be evaluated for safety throughout the study.  Adverse events that occur in 
HGT-SAN-055 and that are ongoing at enrollment in HGT-SAN-067 will be captured in 
the case report forms (CRFs) for study HGT-SAN-067.  Specific safety stopping criteria 
will be applied and will be based on the types and severity of adverse events (AEs) 
reported while on-study.  These data will be reviewed to inform the decision to 
discontinue a patient, a dose group, or the study as a whole.  
All patients will have an EOS visit 30 (±7) days following their last administration of 
rhHNS (ie, Month 55).  The EOS procedures will include standard clinical laboratory 
tests (serum chemistry, hematology, and urinalysis) in CSF and blood, protocol specific 
laboratory testing (eg, anti-rhHNS antibody testing), neurodevelopmental testing, ABR, 
child health questionnaires, and MRI.   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
5 
Use of concomitant medications, therapies, and procedures will be recorded and AEs will 
be monitored.  
All patients will be contacted by telephone or will have a visit for a Final Safety 
Follow-up, to be conducted at 30 (±7) days after the EOS visit (ie, Month 56) to collect 
updated information on AEs and concomitant medications, therapies, and procedures.  
It is anticipated that the IDDD will be used to obtain CSF samples and to deliver 
administrations of rhHNS.  However, if a patient’s IDDD appears nonfunctional or if its 
use is precluded on a scheduled day of dosing, site personnel will refer to the protocol 
appendix which describes the investigation and management of IDDD-related issues.  
This will include possible partial revision or complete replacement of the IDDD.  As 
noted above, a maximum of 2 partial revisions and/or complete replacements can occur in 
any 6 month period.  If revision or replacement of the IDDD cannot be scheduled in time 
to avoid a delay of the next scheduled dose of rhHNS, or if the patient experiences more 
than 2 IDDD malfunctions in a 6 month period (including participation in study 
HGT-SAN-055), rhHNS will be administered via lumbar puncture (LP).  Study drug may 
be administered via LP for a maximum of 5 successive monthly doses, after which, IDDD 
re-implantation or revision must occur.  
If there is no significant safety risk in the opinion of the Investigator, a non-functional 
IDDD may be left in situ for up to 3 months. 
Patients who discontinue or are withdrawn before receiving 3 monthly IT injections will 
not have to undergo the EOS evaluations but will have their IDDD removed.   
If a patient discontinues, or withdraws from the study, or the study is stopped by the 
Sponsor, the IDDD will be removed as part of the EOS Procedures.  
An overview of the study appears in the Schedule of Events. 
Study Population:  
A maximum of 12 patients are planned for this study.  To be eligible for participation 
patients will have completed all study requirements in Study HGT-SAN-055, including 
the EOS visit, and will have elected to continue treatment with rhHNS.  
Test Product; Dose; and Mode of Administration:  
Recombinant human heparan N-sulfatase (rhHNS) will be administered via an IDDD 
according to the same dose to which the patient was assigned in HGT-SAN-055 (ie, 
10 mg, 45 mg, or 90 mg monthly).   
Reference Therapy; Dose; and Mode of Administration:  
N/A 
Diagnosis and Main Criteria for Inclusion 
Inclusion Criteria: 
Each patient must meet the following criteria to be enrolled in this study. 
1. The patient must have completed Study HGT-SAN-055 and, in the opinion of the 
investigator, have no safety or medical issues that contraindicate participation.  

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
6 
2. The patient, patient’s parent(s) or legally authorized representative(s) has voluntarily 
signed an Institutional Review Board/Independent Ethics Committee-approved 
informed consent (and assent, if applicable) form after all relevant aspects of the 
study have been explained and discussed with them.  Informed consent/assent must be 
obtained prior to any study specific procedures. 
3. The patient received at least 5 of the 6 planned infusions of rhHNS in the 
HGT-SAN-055 study.  
4. The Patient must be medically stable, in the opinion of the Investigator, to 
accommodate the protocol requirements, including travel, assessments, and IDDD 
surgery (if necessary for replacement purposes), without placing an undue burden on 
the patient/patient's family. 
 
Exclusion Criteria: 
Subjects will be excluded from the study if there is evidence of any of the following: 
1. The patient has experienced an adverse reaction to study drug in Study 
HGT-SAN-055 that contraindicates further treatment with rhHNS. 
2. The patient has a known hypersensitivity to the active ingredient or any excipients in 
rhHNS drug product. 
3. The patient has non-MPS IIIA related central nervous system (CNS) impairment or 
behavioral disturbances that would confound the scientific integrity or interpretation 
of study assessments, as determined by the Investigator. 
4. The patient has MPS IIIA behavioral-related issues, as determined by the 
Investigator, which would preclude performance of study neurocognitive and 
developmental testing procedures. 
5. The patient is pregnant, breast feeding, or is a patient of childbearing potential who 
will not or cannot comply with the use of an acceptable method of birth control, such 
as condoms, barrier method, oral contraception, etc. 
6. The patient has any known or suspected hypersensitivity to anesthesia or is thought to 
have an unacceptably high risk for anesthesia due to airway compromise or other 
conditions. 
7. The patient has a history of a poorly controlled seizure disorder.  
8. The patient is currently receiving psychotropic or other medications, which in the 
Investigator’s opinion, would be likely to substantially confound test results and the 
dose and regimen of which cannot be kept constant throughout the study. 
9. The patient cannot sustain absence from aspirin, non-steroidal medications, or 
medications that affect blood clotting within 1 week prior to a relevant study-related 
procedure (eg, device re-implantation if applicable), or has ingested such medications 
within 1 week before any procedures in which any change in clotting activity would 
be deleterious. 
10. The patient has received treatment with any investigational drug (other than rhHNS) 
intended as a treatment for MPS IIIA within the 30 days prior to, during the study, or 
is currently enrolled in another study that involves an investigational drug or device 
(screening through safety follow-up contact). 
11. The patient has received a hematopoietic stem cell or bone marrow transplant. 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
7 
Duration of Treatment:  
The study duration will be 4 years. 
Pharmacokinetic Variables: 
N/A. 
Safety Assessments: 
Safety evaluations will include vital signs, physical examinations, AE assessments, 
electrocardiograms (ECG); serum chemistry, hematology, urine laboratory tests, and 
screening for antibodies to rhHNS (in CSF and serum).   
Statistical Methods:  
The statistical methodology supporting the trial will focus on descriptive rather than 
inferential approaches, given the early phase and objectives of the trial.  Data will be 
plotted and the mean, standard deviation, median, minimum, and maximum for each 
variable will be tabulated by dose group to look for gross trends over time, which may be 
attributed to treatment.  For continuous data, 95% confidence interval around the mean 
will be presented. 
The analysis population consists of all eligible patients from HGT-SAN-055 who have 
completed study HGT-SAN-055 and agreed to participate in this extension study.  Safety 
analyses will be performed using the above mentioned population.  The data will be 
presented by dose group. 
Date of Original Protocol:  21 June 2010 
Date of Amendment 2:  13 January 2012 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
8 
TABLE OF CONTENTS 
SYNOPSIS.................................................................................................................................2 
TABLE OF CONTENTS...........................................................................................................8 
LIST OF IN-TEXT TABLES..................................................................................................12 
LIST OF APPENDICES..........................................................................................................13 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..........................................14 
1 
INTRODUCTION ...........................................................................................................17 
1.1 
Disease Background...............................................................................................17 
1.2 
Nonclinical Overview............................................................................................19 
1.2.1 
Toxicology in Monkeys...............................................................................19 
1.2.2 
Efficacy in Murine and Canine Models of MPS IIIA..................................19 
1.3 
HGT-SAN-067 Study Rationale............................................................................20 
2 
STUDY OBJECTIVES....................................................................................................21 
2.1 
Primary Objective..................................................................................................21 
2.2 
Secondary Objectives.............................................................................................21 
3 
STUDY ENDPOINTS.....................................................................................................22 
3.1 
Primary Endpoint...................................................................................................22 
3.2 
Secondary Endpoints .............................................................................................22 
4 
INVESTIGATIONAL PLAN..........................................................................................23 
4.1 
Overall Study Design and Plan..............................................................................23 
4.2 
Rationale for Study Design and Control Group.....................................................25 
4.3 
Study Duration and Dates......................................................................................25 
5 
STUDY POPULATION SELECTION ...........................................................................26 
5.1 
Study Population....................................................................................................26 
5.2 
Inclusion Criteria ...................................................................................................26 
5.3 
Exclusion Criteria ..................................................................................................26 
6 
STUDY TREATMENT(S)..............................................................................................28 
6.1 
Description of Treatment(s)...................................................................................28 
6.1.1 
Study Drug...................................................................................................28 
6.1.2 
Placebo or Control .......................................................................................28 
6.2 
Treatment Administered ........................................................................................28 
6.2.1 
Selection and Timing of Dose for Each Patient...........................................28 
6.2.2 
Cerebral Spinal Fluid Sample Procedure.....................................................28 
6.2.3 
Intrathecal Administration of rhHNS...........................................................29 
6.2.4 
Administration of rhHNS via Lumbar Puncture..........................................29 
6.3 
Method of Assigning Subjects to Treatment Groups.............................................29 
6.4 
Blinding..................................................................................................................29 
6.5 
Concomitant Therapy.............................................................................................30 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
9 
6.6 
Restrictions ............................................................................................................30 
6.6.1 
Prior Therapy ...............................................................................................30 
6.6.2 
Fluid and Food Intake..................................................................................30 
6.6.3 
Patient Activity Restrictions ........................................................................30 
6.7 
Treatment Compliance...........................................................................................30 
6.8 
Packaging and Labeling.........................................................................................31 
6.9 
Storage and Accountability....................................................................................31 
6.10 
Investigational Product Retention at Study Site ....................................................31 
7 
STUDY PROCEDURES .................................................................................................32 
7.1 
Informed Consent...................................................................................................32 
7.2 
Physical Examination.............................................................................................32 
7.3 
Height and Weight.................................................................................................32 
7.4 
Head Circumference ..............................................................................................32 
7.5 
Vital Signs..............................................................................................................33 
7.6 
Electrocardiography...............................................................................................33 
7.6.1 
Electrocardiograms ......................................................................................33 
7.7 
Clinical Laboratory Tests.......................................................................................33 
7.7.1 
Hematology..................................................................................................33 
7.7.2 
Serum Chemistry .........................................................................................34 
7.7.3 
Pregnancy Test.............................................................................................34 
7.8 
Urinalysis...............................................................................................................34 
7.8.1.1 
Standard Urinalysis............................................................................34 
7.8.1.2 
Urine Heparan Sulfate and Heparan Sulfate Derivatives ..................34 
7.8.2 
Cerebrospinal Fluid Assessments ................................................................35 
7.8.2.1 
Cerebrospinal Fluid Cell Counts........................................................35 
7.8.2.2 
Cerebrospinal Fluid Heparan Sulfate Levels and Heparan Sulfate 
Derivatives.........................................................................................35 
7.8.2.3 
Anti-rhHNS Antibodies .....................................................................35 
7.8.2.4 
Cerebrospinal Fluid Biomarkers........................................................35 
7.8.3 
Sample Collection, Storage, and Shipping ..................................................35 
7.9 
Anesthesia..............................................................................................................35 
7.10 
Audiometry and Auditory Brainstem Response ....................................................36 
7.11 
Magnetic Resonance Imaging of the Head............................................................36 
7.12 
Surgical Re-implantation of the IDDD..................................................................36 
7.12.1 
Restrictions on the Number of Revision and/or re-implantation of the IDDD37 
7.13 
Cerebrospinal Fluid Opening Pressure Measurement............................................37 
7.14 
Dispensing Study Drug..........................................................................................37 
7.15 
Pharmacokinetic Assessments ...............................................................................37 
7.16 
Neurological Examination .....................................................................................37 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
10 
7.17 
Anti-rhHNS Antibody, Heparan Sulfate, and Heparan Sulfate Derivative 
Determination ........................................................................................................37 
7.18 
Neurocognitive and Developmental Assessments.................................................38 
7.19 
Sleep Questionnaire:  Children’s Sleep Habits Rating Scale.................................39 
7.20 
Age-Dependent, Health-Related Quality of Life in Children................................39 
7.20.1 
Quality of Life Indicator:  CHQ-50 .............................................................39 
7.20.2 
Quality of Life Indicator:  CHQ-87 .............................................................39 
7.20.3 
Quality of Life Indicator:  ITQOL...............................................................39 
7.21 
Concomitant Medications, Therapies and Medical/Surgical Procedures ..............40 
7.22 
Adverse Events ......................................................................................................40 
7.22.1 
Definitions of Adverse Events and Serious Adverse Events.......................40 
7.22.1.1 
Adverse Event....................................................................................40 
7.22.1.2 
Serious Adverse Event.......................................................................42 
7.22.2 
Procedures for Recording and Reporting Adverse Events ..........................44 
7.22.2.1 
Reporting Serious Adverse Events Related to Study Procedures......44 
7.22.2.2 
Eliciting Adverse Events....................................................................45 
7.22.2.3 
Protocol Deviations for Medical Emergency or Adverse Event........45 
7.23 
Safety-related Study Stopping Rules .....................................................................46 
7.24 
Pregnancy...............................................................................................................46 
7.25 
Removal of Subjects from the Trial or Study Drug...............................................46 
7.26 
Other Study Procedures .........................................................................................48 
7.27 
Appropriateness of Measurements.........................................................................48 
8 
STUDY ACTIVITIES .....................................................................................................49 
8.1 
Screening Visit/Study Start Visit...........................................................................49 
8.2 
Treatment:  Drug Administration and Weekly Assessments.................................50 
8.2.1 
Week 1 .........................................................................................................50 
8.2.1.1 
Day 1 (Pre-treatment) Assessments Performed Prior to Each Dose..50 
8.2.1.2 
Day 2 (±2 days) Assessments and Administration of rhHNS............51 
8.3 
End of Study/Early Termination Procedures:  Month 55 ......................................51 
8.4 
Safety Follow-up (by Telephone or Visit) Month 56 ............................................52 
9 
QUALITY CONTROL AND ASSURANCE .................................................................53 
10 PLANNED STATISTICAL METHODS ........................................................................54 
10.1 
General Statistical Methodology............................................................................54 
10.2 
Determination of Sample Size ...............................................................................54 
10.3 
Analysis Populations..............................................................................................54 
10.4 
Demographics and Baseline Characteristics..........................................................55 
10.5 
Statistical Analysis of Pharmacokinetic Variables ................................................55 
10.6 
Efficacy, Safety, and Pharmacodynamic Evaluations ...........................................55 
10.6.1 
Primary Analyses.........................................................................................55 
10.6.1.1 
Safety Analysis ..................................................................................55 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
11 
10.6.1.2 
Clinical Laboratory Evaluations ........................................................56 
10.6.1.3 
Anti-rhHNS Antibody Formation......................................................56 
10.6.2 
Secondary Analysis......................................................................................57 
10.6.2.1 
Clinical Assessments .........................................................................57 
10.6.2.2 
Pharmacodynamic Analyses..............................................................57 
11 ADMINISTRATIVE CONSIDERATIONS....................................................................58 
11.1 
Investigators and Study Administrative Structure.................................................58 
11.2 
Institutional Review Board or Independent Ethics Committee Approval .............58 
11.3 
Ethical Conduct of the Study.................................................................................58 
11.4 
Patient Information and Consent ...........................................................................58 
11.5 
Patient Confidentiality ...........................................................................................59 
11.6 
Study Monitoring...................................................................................................59 
11.7 
Case Report Forms and Study Records .................................................................60 
11.7.1 
Critical Documents ......................................................................................60 
11.8 
Data Monitoring Committee..................................................................................61 
11.9 
Protocol Violations/Deviations..............................................................................61 
11.10 Access to Source Documentation ..........................................................................61 
11.11 Data Generation and Analysis ...............................................................................61 
11.12 Premature Closure of the Study.............................................................................62 
11.12.1 Study Termination .......................................................................................62 
11.12.2 Site Termination...........................................................................................62 
11.13 Retention of Data...................................................................................................62 
11.14 Financial Disclosure...............................................................................................62 
11.15 Publication and Disclosure Policy .........................................................................62 
12 LIST OF REFERENCES.................................................................................................64 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
 
Shire 
Confidential 
12 
LIST OF IN-TEXT TABLES 
Table 7-1 
Neurodevelopmental Assessments Tests.....................................................38 
Table 7-2 
Sanfilippo-Specific Disability Assessment And Behavior Rating Scales ...39 
Table 7-3 
Adverse Event Severity................................................................................43 
Table 7-4 
Adverse Event Relatedness..........................................................................43 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
 
Shire 
Confidential 
13 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events.............................................................................66 
Appendix 2 
Neurodevelopmental and Behavioral Assessments ...........................68 
Appendix 3 
Failure of IDDD Function:  Investigation and Management.............72 
Appendix 4 
Summary of Changes for Amendment 2 ...........................................75 
Appendix 5 
Protocol Signature Page.....................................................................82 
Appendix 6 
The National Cancer Institute Common Toxicity Criteria ................83 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
14 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ABR 
auditory brainstem response 
AE 
adverse event 
ALB 
albumin 
ALK-P 
alkaline phosphatase 
ALT 
alanine aminotransferase (SGPT) 
AST 
aspartate aminotransferase (SGOT) 
βhCG 
human chorionic gonadotropin 
BSID-III 
Bayley Scales of Infant Development, Third Edition 
BBB 
blood brain barrier 
BUN 
blood urea nitrogen 
Ca 
calcium 
CFR 
Code of Federal Regulations 
CNS 
central nervous system 
CHQ-50 
Child Health Questionnaire™ Parent Form 50 
CHQ-87 
Child Health Questionnaire™ Child Form 87 
CK 
creatine kinase 
Cl 
chloride 
CO2 
carbon dioxide 
CRO 
contract research organization 
CRIM 
cross-reacting immunologic material  
CSF 
cerebrospinal fluid 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ERT 
enzyme replacement therapy 
EOS 
end of study 
EOW 
every other week 
FDA 
Food and Drug Administration 
FPSS/TDS 
Four-Point Scoring System/Total Disability Score 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
15 
GAG 
glycosaminoglycan 
GCP 
Good Clinical Practice 
GGT 
gamma glutamyl transferase 
Hct 
hematocrit 
Hgb 
hemoglobin 
HS 
heparan sulfate 
ICH 
International Conference on Harmonisation  
IDDD 
intrathecal drug delivery device 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug  
IRB 
Institutional Review Board 
IT 
intrathecal 
ITQOL 
Infant Toddler Quality of Life Questionnaire™ 
IV 
intravenous 
K 
potassium 
KABC-II 
Kaufman Assessment Battery for Children, Second Edition 
LDH 
lactic dehydrogenase 
LP 
lumbar puncture  
LSD 
lysosomal storage disease 
M6P 
mannose-6-phosphate 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MABC-2 
Movement Assessment Battery for Children, Second Edition 
MPS IIIA 
Mucopolysaccharidosis IIIA or Sanfilippo syndrome Type A 
MRI 
magnetic resonance imaging 
Na 
sodium  
QoL 
quality of life 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
16 
PE 
pressure-equalization 
Q4W 
Every 4 weeks 
RBC 
red blood cell (count) 
rhHNS 
recombinant human heparan N-sulfatase 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SBRS 
The Sanfilippo Behavior Rating Scale 
SGOT 
serum glutamic oxaloacetic transaminase (AST) 
SGPT 
serum glutamic pyruvic transaminase (ALT) 
Shire HGT 
Shire Human Genetic Therapies, Inc. 
TMF 
Trial Master File 
TX 
treatment 
UK 
United Kingdom 
US 
United States 
VABS-II 
Vineland Adaptive Behavior Scales  
WBC 
white blood cell (count) 
WHO-DD 
WHO Drug Dictionary  
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
17 
1 
INTRODUCTION 
The progressive and irreversible nature of lysosomal storage diseases (LSDs) present a challenge 
in the interpretation of clinical benefit derived from treatment in studies using enzyme 
replacement therapy (ERT).  Any short-term improvement and/or stabilization of clinically 
important manifestations of the disease may be viewed as clinically meaningful.  However, the 
demonstration of the different aspects of a long-term, clinically-meaningful improvement may be 
limited by the short duration of treatment in clinical studies.  Extended access to treatment 
through extension studies provides an opportunity for further evaluation of long-term safety and 
clinical outcomes for treated patients.  In this extension study, patients who completed study 
HGT-SAN-055, a phase I/II safety and dose-escalation trial, and elected to continue to receive 
recombinant human heparan N-sulfatase (rhHNS), will receive treatment through this extension 
protocol.  The patient’s treatment group and dosing regimen will be the same as that employed in 
study HGT-SAN-055. 
1.1 
Disease Background 
Sanfilippo syndrome, or Mucopolysaccharidosis (MPS) III, is a lysosomal storage disease (LSD) 
caused by loss in activity of 1 of 4 enzymes necessary for degradation of the glycosaminoglycan 
(GAG) heparan sulfate (HS) in lysosomes.  Four different subtypes (A, B, C, and D) have been 
identified and are each due to a specific enzyme deficiency involved in the lysosomal catabolism 
of HS.  MPS IIIA results from deficiency of the enzyme heparan N-sulfatase (sulfamidase).  In 
the absence of this enzyme, intermediates of the HS degradation process accumulate in the 
lysosomes of neurons and glial cells, with lesser accumulation outside the brain.   
MPS III is the most prevalent of all mucopolysaccharidoses, with subtypes A and B similar in 
prevalence, accounting for approximately 90% of all cases of MPS III.1  The birth prevalence of 
MPS IIIA has been estimated as 1.28 in 100,000 in Australia, 1.16 in 100,000 in the Netherlands, 
and 0.88 in 100,000 in Germany.1,2,3  In summary, MPSIIIA is a rare genetic disorder with 
apparently widespread geographic distribution and an average global birth incidence of 
approximately 1 in 100,000.  
In a recent detailed review of all MPS IIIA patients diagnosed in the Netherlands, it was reported 
that among 81 patients in whom information was available, first symptoms arose at a median of 
2.5 years (range 0.5 to 7 years).4  Owing to the rarity of the disease and the non-specific and 
often subtle nature of its initial manifestations, diagnosis is usually delayed until an average age 
of 4 to 4.5 years.4,5  Patients present a wide spectrum and severity of clinical symptoms.  The 
central nervous system (CNS) is the most severely affected organ system in patients with MPS 
IIIA, evidenced by deficits in language development, motor skills, and intellectual development.5  
In addition, there are abnormal behaviors including, but not limited to, aggression and excess 
motor activity/hyperactivity that contribute to disturbances in sleep.5,6,7  In contrast with other 
MPS types, the viscera are mildly affected, with transient enlargement of liver and spleen during 
childhood with no evidence of dysfunction.  There are also reports of unexplained, recurrent and 
severe diarrhea.8  Overall, individuals with MPS IIIA have a marked developmental delay and 
significantly reduced lifespan of 15 years of age on average.8  A milder variant has recently been 
identified with slower progression and survival to later age in approximately 10% of German 
patients with MPS IIIA.9   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
18 
No effective, disease-modifying therapies are currently approved as treatments for this rare, 
devastating and disabling disease.   
A long-range goal of Shire Human Genetic Therapies, Inc. (Shire HGT) is to develop a 
recombinant human sulfamidase ERT for patients with MPS IIIA.  A particular problem for 
LSDs that damage the brain such as MPS III is how to target ERT to the brain.10  In animal 
studies, ERT was administered into the CSF via an intrathecal (IT) route, because when 
administered intravenously (IV), it was shown to not cross the blood brain barrier (BBB) after 
the immediate postnatal period of life.11,12    
As the CNS in patients with MPS IIIA is the most severely affected body system, the main focus 
of the rhHNS clinical development program has been the development of ERT specifically for 
delivery directly to the CNS.  Recombinant human heparan N-sulfatase has been developed 
specifically for delivery into the CSF via an IDDD due to the acknowledged impermeability of 
the BBB to macromolecules.  
Heparan N-sulfatase is a highly purified recombinant form of the naturally occurring human 
lysosomal enzyme sulfamidase.  It is expressed from the well characterized continuous human 
HT-1080 cell line as a 482 amino acid peptide, following cleavage of the 20 amino acid 
N-terminal signal peptide.  The mature protein in solution is a homodimeric glycoprotein of 
approximately 122 kDa, which undergoes post-translational modifications by conversion of 
Cys50 to formylglycine, required for enzyme activity, and glycosylation at 4 of the 5 potential 
N-linked glycosylation sites.  The rhHNS glycans contain mannose-6-phosphate (M6P) residues 
which target the protein for cellular uptake and internalization in its lysosomal site of action via 
the membrane-bound M6P receptors.13,14,15,16  
The first precedent for intraspinal ERT was recently published and has been shown to be both 
safe and effective for spinal cord compression in MPS I.17   In this study, a patient with MPS I 
received 4 IT doses of enzyme (Laronidase [recombinant α-L-Idurunonidase]) at 1-month 
intervals.  Safety evaluations included CSF opening pressure, serum chemistry and CSF protein, 
glucose and cell count, in addition to clinical efficacy studies.  No changes in safety evaluations 
were observed. 
In another recent study, a patient with MPS VI and spinal cord compression received IT 
injections of enzyme (Galsulfase) monthly, for 4 months.  CSF analysis revealed no 
inflammatory reaction; no other side effects were noted.18   
Several MPS I patients have been treated since 2005 with IT Laronidase in 2 ongoing clinical 
trials (clinicaltrials.gov identifiers NCT00215527 and NCT00786968) studying efficacy on 
spinal cord compression.  No results of these trials have yet been published.  However, in 
June 2009 a study further investigating the effectiveness of IT ERT as a treatment for another 
neurological symptom in MPS I, cognitive decline, was initiated (clinicaltrials.gov identifier 
NCT00852358).  This study is a 24-month, open label, prospective, randomized trial in 
16 patients with MPS I, 6 years of age or older, who have documented evidence of cognitive 
decline.  In this study, the clinical safety of the regimen will be assessed by adverse events 
monitoring, CSF laboratory assessments, and clinical evaluations.  This study is ongoing; no 
efficacy or safety data have yet been published as of October 2011.19   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
19 
In addition, there are 4 ongoing Shire HGT-sponsored studies that are evaluating IT 
administration of ERT:  A Phase I/II safety and dose escalation study of monthly idursulfase-IT 
injection for cognitively impaired patients with Hunter syndrome (Study HGT HIT-045; 
NCT00920647), the open-label extension to this study (HGT-HIT-046); a Phase I/II ascending 
dose and dose frequency study of monthly IT injection of rhHNS in patients with Sanfilippo 
Syndrome Type A (Study HGT-SAN-055; NCT01155778), and the open-label extension to this 
study (HGT-SAN-067; NCT 01299727). 
1.2 
Nonclinical Overview 
To circumvent the restriction of the BBB, rhHNS was administered into the CSF of rats and 
monkeys via an IT route.  The non-clinical data demonstrate that IT administration of rhHNS 
leads to uptake by target CNS tissues with appropriate efficacy and distribution.  In addition, 
there were no findings noted in the toxicity studies, allowing for a 6.2-fold safety margin from 
the results in the juvenile cynomolgus monkey.  Intermittent bolus injection of rhHNS to the 
brain via the IT route of administration is hypothesized to be of benefit in stabilizing, improving, 
or preventing the CNS manifestations of disease.  
The doses tested in the non-clinical studies adequately support the efficacy of the planned doses 
(10, 45 or 90 mg/month, normalized to the brain weight of the human) in the ongoing Phase I/II 
study, HGT-SAN-055.  Specifically, in the San A mouse, the 100 µg dose corresponds to a 
2.2-fold increase (per kg brain weight) from the highest anticipated human dose (90 mg) (human 
brain = 1 kg).  The 20 µg dose given IT every-other-week (EOW) or monthly, for which efficacy 
was also observed, corresponds to a 40 mg (per kg brain weight) human dose.  In the Huntaway 
(Sanfilippo A) dogs, the 3 mg rhHNS given IT weekly (corresponding to a 33 mg/kg of brain 
weight in man), was not only well tolerated but resulted in significant effects on biomarkers of 
disease activity and improved histopathology.  
1.2.1 
Toxicology in Monkeys 
In the pivotal, 6-month IT toxicity study in juvenile cynomolgus monkeys, the highest dose of 
rhHNS was 8.3 mg given EOW.  This translates into a 138 mg/kg brain-weight dose (ie, based 
on a 60 g juvenile monkey brain).  Since no rhHNS-related adverse effects were noted, the 
nonclinical study provides for the proposed Phase I/II clinical trial a ~13.8 × safety margin 
relative to the starting clinical dose (10 mg), and a 1.5× safety margin relative to the highest 
clinical dose (90 mg).     
1.2.2 
Efficacy in Murine and Canine Models of MPS IIIA 
Non-clinical proof of concept efficacy studies were conducted using mouse and dog models of 
MPS IIIA, both of which contain naturally-occurring mutations in the HNS gene.  In the MPS 
IIIA mouse, direct injection into the CNS had a beneficial effect on clinical signs, impaired 
neurobehavioral, and the biochemical and histopathologic markers of disease activity.  In 
Huntaway (Sanfilippo A) dogs, rhHNS (3 mg) given IT weekly had a significant effect on 
biomarkers of disease activity and improved histopathology. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
20 
Efficacy has been demonstrated at a range of doses in nonclinical mouse and canine models.  In 
MPS IIIA mice, a dose-dependent reduction in the level of a heparan sulfate-derived monosulfate 
disaccharide was observed within the brain (up to 62% reduction compared with vehicle-treated 
mice) and spinal cord (up to 71% reduction).  An ultrastructural examination revealed a 
reduction in lysosomal vesicle formation in various cell types and fewer (ubiquitin-positive) 
axonal spheroids in several brain regions after repeated injections (5 to 20 µg) of rhHNS into the 
CSF of MPS III mutant mice via the cisterna magna (ie, IT).  The biochemical changes were 
accompanied by improved behavior, particularly in mice treated more frequently.20  
In the MPS IIIA mutant mouse model, intracisternal (ie, IT) injection of a single dose of 100 µg 
rhHNS resulted in a substantial (and sustained) reduction of biomarkers of disease activity 
(heparan sulfate-derived disaccharides, microgliosis, astrogliosis).21   Equally impressive was the 
improvement in neurobehavioral parameters (learning in the Morris water maze, normalization 
of aggression) in these mice post-dose.21  One-hundred µg rhHNS per mouse translates into 
200 mg/kg brain weight (ie, based on a 0.5 g mutant mouse brain).  Efficacy at lower doses of 
rhHNS (eg, 20 µg, given IT, EOW or monthly) has been demonstrated.11  A 20 µg injection 
translates into a 40 mg human dose (ie, 40 mg per kilogram of brain weight).  Thus, this data 
further suggests that efficacy will be seen at the highest clinical dose (90 mg, per month) in the 
proposed Phase I/II study.  
In the tolerized Huntaway (San A) dogs, 3 mg rhHNS was initially given IT on a weekly basis, 
then EOW, and had a significant effect on biomarkers of disease activity.22  The 3 mg dose in the 
dog translates into a 33 mg (per kg brain weight) human dose (based on a 90 g Huntaway dog 
brain).   
1.3 
HGT-SAN-067 Study Rationale 
This extension study (Study HGT-SAN-067) will evaluate the effects of long-term rhHNS 
administration on safety, clinical activity, and biomarker outcomes in patients who completed 
Study HGT-SAN-055 and elected to continue therapy with rhHNS.  
Patients who were enrolled in Study HGT-SAN-055 through Week 26 and completed the EOS 
evaluations are eligible for enrollment in this open-label extension study.  All patients enrolled in 
this study will continue to receive rhHNS at the same dose and schedule as they received in 
Study HGT-SAN-055.  The dose for each group will remain unchanged during this study unless 
safety and/or efficacy analyses of HGT-SAN-055 data indicate otherwise.  Meaningful 
composite analysis of the optimum dose and regimen will come only after all 3 dose groups 
complete the entire HGT-SAN-055 study. 
Please refer to the current edition of the rhHNS Investigator’s Brochure for further information. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
21 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective  
The primary objective of this study is: 
• To collect long-term safety and tolerability data in patients with Sanfilippo Syndrome 
Type A (MPS IIIA) who received rhHNS via a surgically implanted intrathecal drug delivery 
device (IDDD) in study HGT-SAN-055 and elect to continue therapy in study 
HGT-SAN-067. 
 
2.2 
Secondary Objectives  
The secondary objectives of this study are: 
• To collect, as measures of drug efficacy, over an extended treatment period (as change from 
baseline), the following:  clinical, neurological, cognitive, behavioral, functional, and quality 
of life (QoL) assessments, together with potential imaging and biochemical biomarkers. 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
22 
3 
STUDY ENDPOINTS 
3.1 
Primary Endpoint 
The primary endpoint of this study is: 
To determine the long-term safety of IT rhHNS administration, as measured by adverse events 
(by type and severity), changes in clinical laboratory testing (serum chemistry including liver 
function tests, hematology, and urinalysis), electrocardiograms (ECG), cerebrospinal fluid 
(CSF), chemistries (including cell counts and inflammatory markers), and anti-rhHNS antibodies 
(in CSF and serum). 
3.2 
Secondary Endpoints  
The secondary endpoints of this study are to collect over an extended treatment period (as the 
change from baseline [defined as the start of the HGT-SAN-055 study]) clinical and potential 
surrogate biomarker efficacy data:  
• Measures of standardized neurocognitive and behavioral assessments, Sanfilippo-specific 
behavioral rating scales, gross and fine motor assessments, functional adaptive rating scales, 
quality of life (QoL) questionnaires, and Children’s Sleep Habits Rating Scale. 
• Concentration of rhHNS in CSF and serum. 
• Concentration of inflammatory cytokines in serum and CSF. 
• Concentration of safety and potential surrogate efficacy biomarkers in CSF, urine, and 
serum. 
• Concentration of heparan sulfate and heparan sulfate derivatives in urine, plasma, and serum.  
• Brain magnetic resonance imaging (MRI) and auditory brainstem response (ABR), (also 
know as Brainstem Auditory Evoked Potentials). 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
23 
4 
INVESTIGATIONAL PLAN 
4.1 
Overall Study Design and Plan 
Study HGT-SAN-067, is an open-label, long term, multicenter, extension of Study 
HGT-SAN-055.  This study is designed to evaluate the long-term safety, clinical activity, and 
biomarker outcomes of intrathecal (IT) administration of 3 dose levels (10 mg, 45 mg, and 90 mg 
once per month [Q4W]) of rhHNS via an IDDD in patients with MPS IIIA who successfully 
completed HGT-SAN-055 (including the EOS assessments) and elect to continue to receive 
uninterrupted rhHNS treatment.  Patients will continue in the same treatment group they were 
assigned to in the HGT-SAN-055 study:  
• Group 1:  rhHNS administered by IT injection 10 mg once per month (Q4W)  
• Group 2:  rhHNS administered by IT injection 45 mg once per month (Q4W) 
• Group 3:  rhHNS administered by IT injection 90 mg once per month (Q4W)  
 
In order to maintain a nomenclature system based on study chronology across the original 
HGT-SAN-055 study and this extension study, the Baseline Visit for this extension study will be 
considered to be the day the patient received their first IT dose of rhHNS in 
Study HGT-SAN-055.  The HGT-SAN-055 EOS assessment information will provide the 
screening/start of study information for patients who continue into the HGT-SAN-067 extension 
study.  Note: HGT-SAN-055 EOS data must be recorded in the context of the HGT-SAN-055 
trial, and a copy of those data can be used for HGT-SAN-067 screening.  Once eligibility is 
confirmed, informed consent (and assent, if applicable), provided by the patient’s 
parent(s)/legally authorized representative(s), must be obtained prior to performing any 
HGT-SAN-067 study-related procedures.  Informed consent may be obtained anytime from 
Week 20 in HGT-SAN-055.  This would allow a patient to have a nonfunctional IDDD replaced 
or revised prior to the first rhHNS dose in HGT-SAN-067. 
Enrolled patients will check in to the study center 1 day before each of the scheduled rhHNS 
dosing days for safety assessments (designated Day 1).  If no safety concerns exist, the patient 
will subsequently receive IT administration of rhHNS on Day 2 (±2 days).  However, if feasible 
and there are no safety concerns in the opinion of the investigator, the Day 1 and Day 2 
assessments may be combined and performed on Day 2; if this is done the results will be 
recorded as Day 2.  Patients will remain in the study centre for at least 8 hours following dosing 
with rhHNS and will be discharged from the unit when deemed clinically stable by the 
Investigator.   
All patients will have received a series of standardized neurodevelopment assessments; in the 
HGT-SAN-055 study, these will have occurred at Baseline and either prior to or at the 6-month 
time point.  Patients will continue in HGT-SAN-067 with whichever age specific assessment 
they began with in HGT-SAN-055.  If, however, a patient’s capability improves and they 
become capable of completing assessments at a higher level, such additional assessments may be 
added.  Any additional assessments are to be performed after the original assessments (those 
used in study HGT-SAN-055) have been carried out.   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
24 
A MRI of the head and ABR testing will be performed at Months 12, 24, 36, and 54 (note that 
assessment time point nomenclature includes the 6 months in the HGT-SAN-055 study).  
In the event of a device malfunction, X-rays may be performed to investigate, as well as to verify 
correct catheter and port placement following surgical IDDD implantation or revision.  In 
addition, fluoroscopy may be employed intra-operatively to guide catheter placement.  Patients 
may undergo 3 X-ray examinations in association with each episode of IDDD malfunction and 
subsequent IDDD revision or replacement.  The number of IDDD revisions/replacements is 
limited to 2 in any 6-month period (including the time in the HGT-SAN-055 study), and the 
number of protocol-associated X-ray evaluations is limited to 6 exposures in any 6-month period 
(including time in study HGT-SAN-055). 
Patients will be evaluated for safety throughout the study.  Adverse events that occur in 
HGT-SAN-055 and are ongoing at enrollment in HGT-SAN-067 will be captured as ongoing in 
the HGT-SAN-055 study and also be reported as a concurrent condition in the HGT-SAN-067 
electronic case report forms (eCRFs).  Specific safety stopping criteria will be applied and will 
be based on the types and severity of AEs reported while on-study.  These data will be reviewed 
to inform the decision to discontinue a patient, a dose group, or the study as a whole.  
All patients will have an EOS visit 30 (±7) days following their last administration of rhHNS (ie, 
Month 55).  The EOS procedures will include standard clinical laboratory tests (serum 
chemistry, hematology, and urinalysis) in CSF and blood, protocol specific laboratory testing 
(eg, anti-rhHNS antibody testing), neurodevelopmental testing, ABR, child health 
questionnaires, and MRI.  Use of concomitant medications, therapies, and procedures will be 
recorded and AEs will be monitored.  
All patients will be contacted by telephone or will have a visit for a Final Safety Follow-up, 
conducted at 30 (±7) days after the EOS visit (ie, Month 56) to collect updated information on 
AEs and concomitant medications, therapies, and procedures.  
It is anticipated that the IDDD will be used to obtain CSF samples and to deliver administrations 
of rhHNS.  However, if a patient’s IDDD appears nonfunctional or if its use is precluded on a 
scheduled day of dosing, site personnel will refer to protocol Appendix 3 which describes the 
investigation and management of IDDD-related issues.  This will include possible partial 
revision or complete replacement of the IDDD.  A maximum of 2 partial revisions and/or 
complete replacements are permitted in any 6 month period (including participation in study 
HGT-SAN-055).  If a revision or replacement of the IDDD cannot be scheduled in time to avoid 
a delay of the next scheduled dose of rhHNS, or if the patient experiences more than 2 IDDD 
malfunctions in a 6 month period, rhHNS will be administered via lumbar puncture (LP).  Drug 
may be administered via LP for a maximum of 5 successive monthly doses, after which, IDDD 
re-implantation or revision must occur.  
If there is no significant safety risk in the opinion of the Investigator, a non-functional IDDD 
may be left in situ for up to 3 months. 
Patients who discontinue or are withdrawn before receiving 3 monthly IT injections will not have 
to undergo the EOS evaluations but will have their IDDD removed.   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
25 
If a patient discontinues, or withdraws from the study, or the study is stopped by the Sponsor, the 
IDDD will be removed as part of the EOS Procedures.  
An overview of the study appears in the Schedule of Events (Appendix 1).  
4.2 
Rationale for Study Design and Control Group 
The original study, Study HGT-SAN-055, is an ongoing Phase I/II safety and ascending dose 
ranging study of IT administration of rhHNS via an IDDD, in patients 3 years of age and older 
with MPS IIIA and early cognitive impairment.  This extension study is proposed to continue 
evaluation of the effects of IT rhHNS administration on long-term safety and clinical outcomes 
for patients who completed Study HGT-SAN-055 and elected to continue treatment with rhHNS 
in the HGT-SAN-067 study.  
4.3 
Study Duration and Dates 
The study duration will be 4 years. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
26 
5 
STUDY POPULATION SELECTION 
5.1 
Study Population 
Patients who have completed all study requirements in Study-HGT-SAN-055 and who elected to 
continue rhHNS treatment will be eligible to participate; a maximum of 12 patients are planned 
for this study.  
5.2 
Inclusion Criteria 
Each patient must meet the following criteria to be considered eligible for enrollment in this 
study. 
1. The patient must have completed Study HGT-SAN-055 and, in the opinion of the 
investigator, have no safety or medical issues that contraindicate participation.  
2. The patient, patient’s parent(s) or legally authorized representative(s) has voluntarily signed 
an Institutional Review Board/Independent Ethics Committee-approved informed consent 
(and assent, if applicable) form after all relevant aspects of the study have been explained and 
discussed with them.  Informed consent/assent must be obtained prior to any study specific 
procedures. 
3. The patient has received at least 5 of the 6 planned infusions of rhHNS in the HGT-SAN-055 
study.  
4. The patient must be medically stable, in the opinion of the Investigator, to accommodate the 
protocol requirements, including travel, assessments, and IDDD surgery (if necessary for 
replacement purposes), without placing an undue burden on the patient/patient's family. 
 
5.3 
Exclusion Criteria 
Patients will be excluded from the study if there is evidence of any of the following:  
1. The patient has experienced an adverse reaction to study drug in Study HGT-SAN-055 that 
contraindicates further treatment with rhHNS. 
2. The patient has a known hypersensitivity to the active ingredient or any excipients in rhHNS 
drug product. 
3. The patient has significant non-MPS IIIA related central nervous system impairment or 
behavioral disturbances that would confound the scientific integrity or interpretation of study 
assessments, as determined by the Investigator. 
4. The patient has MPS IIIA behavioral-related issues, as determined by the Investigator, which 
would preclude performance of study neurocognitive and developmental testing procedures. 
5. The patient is pregnant, breast feeding, or is of childbearing potential who will not or cannot 
comply with the use of an acceptable method of birth control, such as condoms, barrier 
method, oral contraception, etc. 
6. The patient has any known or suspected hypersensitivity to anesthesia or is thought to have 
an unacceptably high risk for anesthesia due to airway compromise or other conditions. 
7. The patient has a history of a poorly controlled seizure disorder.  

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
27 
8. The patient is currently receiving psychotropic or other medications, which in the 
Investigator’s opinion, would be likely to substantially confound test results and the dose and 
regimen of which cannot be kept constant throughout the study. 
9. The patient cannot sustain absence of aspirin, non-steroidal medications, or medications that 
affect blood clotting within 1 week prior to a relevant study-related procedure (eg, device 
re-implantation if applicable), or has ingested such medications within 1 week before any 
procedures in which any change in clotting activity would be deleterious. 
10. The patient has received treatment with any investigational drug (other than rhHNS) intended 
as a treatment for MPS IIIA within the 30 days prior to, or during the study, or is currently 
enrolled in another study that involves an investigational drug or device (screening through 
safety follow-up contact).  
11. The patient has received a hematopoietic stem cell or bone marrow transplant. 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
28 
6 
STUDY TREATMENT(S) 
6.1 
Description of Treatment(s) 
6.1.1 
Study Drug 
Recombinant human heparin N-sulfatase (rhHNS) drug product formulation is a sterile solution 
for injection in single-use vials for intrathecal (IT) administration.  It is formulated in an aqueous 
isotonic solution containing 15.0 mg/mL rhHNS in 145 mM sodium chloride, 0.005% (v/v) 
polysorbate 20, 5 mM sodium phosphate at pH 7.0. 
6.1.2 
Placebo or Control 
This study will not employ a placebo or control.   
6.2 
Treatment Administered 
rhHNS for IT administration will be provided by Shire HGT.  rhHNS will be administered by an 
IDDD.  Following the review and signing of informed consent (and assent, if applicable), 
eligible patients will receive the same dose of rhHNS they received in Study HGT-SAN-055: 
• Group 1:  rhHNS administered by IT injection 10 mg once per month (Q4W)  
• Group 2:  rhHNS administered by IT injection 45 mg once per month (Q4W) 
• Group 3:  rhHNS administered by IT injection 90 mg once per month (Q4W)  
 
6.2.1 
Selection and Timing of Dose for Each Patient 
Patients will check into the study center 1 day prior to IT rhHNS dosing for safety assessments, 
designated Day 1, on each rhHNS treatment week, and if no safety concerns exist, will receive 
IT administration of rhHNS on Day 2 (±2 days).  However, if feasible and there are no safety 
concerns in the opinion of the Investigator, the Day 1 and Day 2 assessments and dosing may be 
combined and performed on Day 2; if this is done the results will be recorded as Day 2.  Patients 
will remain in the study centre for at least 8 hours following dosing with rhHNS and will be 
discharged from the unit when deemed clinically stable by the Investigator.   
The IT injections are to be administered every 28 days (±7 days).  If a patient’s IDDD becomes 
nonfunctional, it may be revised (partial or complete) (a maximum of twice in a 6 month period) 
so that the patient can remain on study (see Section 7.12 for details).  In the event of a 
non-functional IDDD, rhHNS may be administered by LP, for up to 5 successive months (see 
Section 6.2.4).  
6.2.2 
Cerebral Spinal Fluid Sample Procedure 
CSF samples will be obtained prior to each injection for safety evaluation and biomarker studies.  
The IDDD will be used for CSF sampling and a topical anesthetic agent may be applied over the 
skin covering the IDDD reservoir prior to sampling.   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
29 
If use of the IDDD is precluded on a scheduled day of dosing, CSF samples may be obtained by 
LP, as described in the Study Operations Manual.  CSF opening pressure will be measured 
whenever a LP is performed, and at the time of IDDD revision (partial or replacement).  
Additional CSF samples may be taken during this time. 
6.2.3 
Intrathecal Administration of rhHNS 
rhHNS will be administered using an IDDD.  After appropriate pre-procedure assessments are 
completed, anesthesia cream will be applied to the skin over the port.  Patients may receive 
sedation as necessary to alleviate anxiety and/or to facilitate drug delivery. 
Patients will receive rhHNS via slow push/injection through an appropriately sized syringe (see 
the Pharmacy Manual).  Replacement of fluid, including drug, to the CSF will be an approximate 
equal volume to that removed.  The patient’s vital signs will be continuously monitored.  The 
patient will also be monitored closely during study drug administration and through the next 
8 hours for any adverse clinical reactions.  The patient will be encouraged to lie down 
comfortably for 1 to 3 hours post injection, although this may be difficult for the most 
hyperactive patients. 
In the event of IDDD malfunction, CSF collection and study drug administration may be 
performed via LP (see Section 6.2.4).  The investigation and management of a malfunctioning 
IDDD is detailed in Appendix 3.  If the failure is mechanical, partial or complete replacement of 
the IDDD may be necessary (only permitted twice in a 6-month period, including the time a 
patient was in study HGT-SAN-055), and will require scheduling of the appropriate procedure.  
The definitive diagnosis of the cause of IDDD failure may not be possible until the time of 
exploratory surgery.  Surgery will take place at the earliest convenience, so the patient may 
remain on, or as close as possible to their treatment schedule.  
6.2.4 
Administration of rhHNS via Lumbar Puncture 
In the event of a non functional IDDD, rhHNS may be administered by LP, for up to 
5 successive months.  The performance of a LP is at the discretion of the Investigator. 
If a LP is to be performed, the patient may require general anesthesia with appropriate airway 
management.  Once the patient is anesthetized, a LP will be performed and a CSF sample will be 
obtained.  Some cases may be managed with conscious sedation, if this is considered by the 
investigator to be adequate for the safe and expeditious performance of a LP. 
6.3 
Method of Assigning Subjects to Treatment Groups 
This is an open-label, non-randomized study; all patients enrolled in this study will be treated 
with rhHNS.  Patients will remain in the groups (1, 2, or 3) they were assigned to in 
Study HGT-SAN-055.  
6.4 
Blinding 
Not applicable; as this trial is not blinded. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
30 
6.5 
Concomitant Therapy 
All non-protocol treatments and procedures that occur from the time of informed consent (and 
assent, if applicable) through the safety follow-up contact are regarded as concomitant and will 
be documented on the appropriate pages of the electronic case report form (eCRF).  Concomitant 
therapy includes medications (including Genistein), therapies/interventions administered to 
patients, and medical/surgical procedures performed on the patients.  
Every effort should be made to keep the patient’s symptomatic Sanfilippo syndrome Type A 
treatment constant throughout the study.  However, changes in medications are acceptable if 
necessary according to clinical judgment.  All changes will be recorded on the appropriate eCRF.  
Concomitant medication will be coded using WHO Drug Dictionary (WHO-DD). 
6.6 
Restrictions 
6.6.1 
Prior Therapy 
Prior therapy excluded for this study consists of the following: 
• Psychotropic or other medications, which in the Investigator’s opinion would be likely to 
substantially confound test results, and the dose and regimen of which cannot be kept 
constant throughout the study. 
• The patient cannot sustain absence from aspirin, non-steroidal medications, or medications 
that affect blood clotting within 1 week prior to a relevant study related procedure (eg, device 
implantation if applicable) or medications within 1 week before any procedures in which any 
change in clotting activity would be deleterious. 
• The patient has received any investigational drug or device intended as a treatment for 
MPS IIIA within the 30 days prior to the study other than rhHNS or is enrolled in another 
study that involves an investigational drug or device. 
• Hematopoietic stem cell or bone marrow transplant. 
 
6.6.2 
Fluid and Food Intake  
Food and fluid intake are not restricted over the course of the study, with the exception of 
hospital standard pre-anesthesia dietary restrictions. 
6.6.3 
Patient Activity Restrictions 
There are no restrictions on patient activity in this study. 
6.7 
Treatment Compliance 
rhHNS is administered under controlled conditions by the Investigator; therefore, full patient 
compliance with study treatment is anticipated in this study.  

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
31 
6.8 
Packaging and Labeling 
Drug product will be supplied in a 3 mL clear, colorless glass (Type 1) vial.  Each vial holds an 
extractable volume of 1 mL of rhHNS.  The closure is a gray, 13 mm stopper composed of butyl 
rubber with a fluoro resin lamination.  The overseal is an aluminum seal with a flip-off, plastic, 
tamper evident cap.  
See the Pharmacy Manual for additional details. 
6.9 
Storage and Accountability 
Drug product should be stored refrigerated (2 to 8°C); drug product may not be stored beyond 
the expiration date on the vial. 
6.10 Investigational Product Retention at Study Site 
All rhHNS study drug delivered to an Investigator will be recorded and accounted for throughout 
the study.  All rhHNS study drug must be recorded on a patient-by-patient basis.  The lot number 
of the IDDD and the date and time of administration of the study medication will be documented 
on the appropriate eCRF. 
All unused study medication and other study materials are to be returned to the Sponsor or its 
designee or disposed of after Sponsor approval per site policy after study completion. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
32 
7 
STUDY PROCEDURES 
7.1 
Informed Consent 
Study procedures will be conducted only after written informed consent for the patient to 
participate in this study is provided by the parent(s) or the patient’s legally authorized 
representative(s) and assent from the patient (if applicable).  Detailed descriptions of patient 
evaluations required for this protocol are described in this section.  These evaluations will be 
performed during the indicated days and weeks of each study month (see Appendix 1 Schedule 
of Events). 
All data collected are to be recorded on the appropriate eCRF.  Blood, urine and CSF volumes to 
be collected for each clinical laboratory measurement are described in detail in the Laboratory 
and/or Study Operations Manual. 
7.2 
Physical Examination 
A physical examination of each patient will be performed as detailed in Appendix 1 Schedule of 
Events. 
Note:  if the patient’s hearing cannot be assessed during the physical examination, the patient 
will have an Ears, Nose, and Throat Evaluation performed under anesthesia at the screening/start 
of study visit.  If it is determined that the patient requires pressure-equalization (PE) tubes, they 
may be implanted during that evaluation (see Section 7.10).  Note:  PE tubes may be 
re-implanted if they fall out during this study. 
The physical examination findings will be recorded on the eCRF and will include a review of the 
patient’s general appearance as well as the following evaluations: 
- 
Head and neck 
- 
Eyes, ears, nose, and throat 
- 
Chest and lungs 
- 
Cardiovascular 
- 
Abdomen 
- 
Skin 
- 
Lymphatic 
- 
Musculoskeletal 
- 
Neurological 
- 
Endocrine 
- 
Genitourinary 
 
7.3 
Height and Weight 
Height or length (cm), and weight (kg) will be measured once and recorded on the eCRF. 
7.4 
Head Circumference 
Head circumference (cm) will be measured and recorded on the eCRF. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
33 
7.5 
Vital Signs 
Vital signs (blood pressure, heart rate, respiratory rate, and temperature measurements) will be 
measured and recorded on the eCRF. 
7.6 
Electrocardiography 
7.6.1 
Electrocardiograms 
An ECG will be performed.  Each ECG will include an assessment of heart rate, sinus rhythm, 
atrial or ventricular hypertrophy, PR, QRS, QT, and QTc intervals.  The ECGs will be conducted 
in accordance with the clinical site’s standard practice(s), and will be read locally at the clinical 
site.  Identification of any clinically significant findings and/or conduction abnormalities will be 
recorded on the eCRF.  
7.7 
Clinical Laboratory Tests 
Blood, urine, and CSF samples will be collected as described below for clinical laboratory 
testing.  Procedures for collection and handling of samples are included in the Laboratory and/or 
Study Operations Manual.  
Patients will be in a seated or supine position during blood collection.  Clinical laboratory tests 
will include hematology, serum chemistry, and urinalysis. 
Laboratory Parameters  
Clinical laboratory tests will be performed at a central laboratory.  Clinical laboratory tests will 
include the following: 
7.7.1 
Hematology 
• Hematocrit (Hct) 
• Hemoglobin (Hgb) 
• Mean corpuscular hemoglobin (MCH) 
• Mean corpuscular hemoglobin 
concentration (MCHC) 
 
• Mean corpuscular volume (MCV) 
• Platelet count 
• Red blood cell (RBC) count  
• White blood cell (WBC) count with 
differential  
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
34 
7.7.2 
Serum Chemistry 
• Albumin (ALB) 
• Alkaline phosphatase (ALK-P) 
• Alanine aminotransferase (ALT; SGPT) 
• Aspartate aminotransferase (AST; 
SGOT) 
• Blood urea nitrogen (BUN) 
• Calcium (Ca) 
• Carbon dioxide (CO2) 
• Chloride (Cl) 
• Creatinine 
• Creatine kinase (CK) and subtypes 
• Gamma-glutamyl transferase (GGT) 
• Globulin 
 
• Glucose 
• Lactate dehydrogenase (LDH) 
• Phosphorus 
• Potassium (K) 
• Sodium (Na) 
• Total bilirubin 
• Direct bilirubin 
• Total cholesterol 
• Total protein 
• Triglycerides 
• Uric acid 
• 
Human Chorionic Gonadotropin (βhCG) 
Pregnancy Test 
 
 
In addition a leukocyte pellet will be prepared, stored frozen, and will be used for additional 
disease-related laboratory studies, including possible assessment of cross-reactive immunologic 
material (CRIM). 
7.7.3 
Pregnancy Test 
A pregnancy test will be performed on Day 1 of each dosing week.  Pregnancy testing will be 
performed using either a serum or urine sample (at the discretion of the site), and only on 
females who have reached menarche.  All pregnancy testing and the reporting of results will be 
performed locally by the clinical site staff.  Study drug must not be administered in the event of a 
positive or inconclusive pregnancy result.  
7.8 
Urinalysis  
Patient catheterization may be required for obtaining urine samples (if deemed necessary by the 
Investigator).   
7.8.1.1 
Standard Urinalysis 
The following urinalysis parameters will be performed at a central laboratory:  pH, macroscopic 
and microscopic evaluations. 
7.8.1.2 
Urine Heparan Sulfate and Heparan Sulfate Derivatives 
A urine sample will be collected for the determination of heparan sulfate and heparan sulfate 
derivatives and the analysis will be performed at Shire HGT or designated laboratories.  A urine 
sample from each visit will be reserved for possible exploratory biomarker studies that may 
provide new indicators or markers of MPS IIIA disease severity or progression. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
35 
7.8.2 
Cerebrospinal Fluid Assessments 
Cerebrospinal fluid sample collection, processing, and shipping instructions will be provided in 
the Laboratory and/or Study Operations Manual.  A CSF sample will be reserved for possible 
exploratory biomarker studies for MPS IIIA disease. 
Each CSF sample collected will be assessed for appearance and will be analyzed using the assays 
listed in Sections 7.8.2.1, 7.8.2.2, and 7.8.2.4.  In addition, as more is learned about Sanfilippo 
CNS pathology and etiology, future exploratory assays of CSF metabolites, protein or RNA may 
become used as they become available in the future. 
7.8.2.1 
Cerebrospinal Fluid Cell Counts 
An aliquot of each CSF sample collected will be evaluated for CSF standard chemistries, 
glucose, protein, and cell counts.  These assessments will be performed at the local laboratory. 
7.8.2.2 
Cerebrospinal Fluid Heparan Sulfate Levels and Heparan Sulfate Derivatives 
An aliquot of each CSF sample collected will be quick frozen as per the Laboratory and/or Study 
Operations Manual for subsequent determination of CSF heparan sulfate and heparan sulfate 
derivatives at Shire HGT laboratories. 
7.8.2.3 
Anti-rhHNS Antibodies 
An aliquot of each CSF sample collected will be quick frozen as per the Laboratory and/or Study 
Operations Manual for subsequent determination of anti-rhHNS antibodies at Shire HGT or 
Shire HGT designated laboratories. 
7.8.2.4 
Cerebrospinal Fluid Biomarkers  
An aliquot of each CSF sample collected will be quick frozen as per the Laboratory and/or Study 
Operations Manual for subsequent determination of MPS exploratory biomarkers at Shire HGT 
laboratories. 
7.8.3 
Sample Collection, Storage, and Shipping 
Sample collection, processing, and shipping instructions will be provided in the Laboratory 
and/or Study Operations Manual to be provided by Shire HGT. 
CSF, urine, and serum samples may be reserved for potential, future, biomarker studies.  
Samples will be stored securely to ensure patient confidentiality.   
7.9 
Anesthesia 
Administration of anesthesia/sedation will be given prior to obtaining CSF (when the use of the 
IDDD is precluded), prior to performing a MRI of the head, the ABR, the CSF opening pressure, 
and the partial revision or replacement of the IDDD (if applicable).   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
36 
See Appendix 1 for the Schedule of Events.  When logistically feasible, the MRI, ABR, and 
surgical implantation of the IDDD may be performed together to reduce exposure to 
general anesthesia. 
Note:  The neurologic exam and the neurocognitive and developmental assessments must be 
performed prior to the administration of anesthesia. 
7.10 Audiometry and Auditory Brainstem Response 
The rare attenuated patients with MPS IIIA with high levels of cognitive functioning will have 
hearing tests via clinical audiometry measurement performed using age-appropriate testing 
methods based on the child’s developmental age at the time of the testing.  It is anticipated that 
most of the cognitively-impaired and/or behaviorally-deteriorated patients with Sanfilippo A will 
be unable to cooperate with a (conscious) hearing evaluation.  In these instances, the Investigator 
will utilize his best clinical judgment to estimate the extent of hearing loss (if any) during the 
physical examination.  In this situation, a specific evaluation of hearing loss will occur during an 
examination of waveforms in the auditory brainstem response (ABR) (see below).  If the patient 
has a history of multiple instances of otitis media or evidence of clinically-significant otitis 
media on physical examination, which the Investigator believes causes significant conductive 
hearing loss and impairment of daily living, the Investigator will discuss and offer the parent or 
legally authorized representative(s) placement of PE tubes as part of the scheduled anesthesia.  A 
patient’s PE tubes may be replaced if they fall out during the course of this study. 
The ABR will be conducted under anesthesia.  The ABR findings will be considered within 
normal limits if, after applying appropriate correction factors, the waveforms reveal normal 
morphology.  
7.11 Magnetic Resonance Imaging of the Head 
The regional brain volume will be assessed through a MRI, of the head.  The patient will be 
under general anesthesia for this assessment.  All MRIs will be centrally read by the University 
of Minnesota Medical Center.  Refer to the Study Operations Manual for specific procedures and 
precautions. 
7.12 Surgical Re-implantation of the IDDD 
If a patient’s IDDD becomes nonfunctional or infected, it will be replaced or revised so that the 
patient can remain on study.  Management details are provided in Appendix 3.  Procedures for 
implantation are detailed in the device’s Instructions for Use Manual and in the training materials 
provided by Shire HGT.  The patient will be under general anesthesia for this procedure.  The 
CSF opening pressure will be recorded when the intrathecal space is first entered at the time of 
the IDDD re-implantation.  Standard hospital procedure for surgery will be followed and will 
include an X-ray to confirm that the device has been (1) surgically implanted correctly (correct 
orientation of the locking device on the access port), and (2) positioned so that the intrathecal 
catheter tip is at the mid-thoracic level (a check list is provided in the Study Operations Manual).  
A post-operative check of the IDDD and incision will be performed on Day 4 following surgery.  

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
37 
X-rays may be performed to check placement of the device, as needed, throughout the study (see 
Section 7.12.1 for limits on the number of x-rays and IDDD revisions and or replacement).  
7.12.1 
Restrictions on the Number of Revision and/or re-implantation of the IDDD 
A non-functional IDDD can be replaced or revised twice in a 6-month period, including the time 
a patient was in study HGT-SAN-055.  Similarly, 6 X-rays may be taken in a 6-month period 
(including the time in HGT-SAN-055). 
7.13 Cerebrospinal Fluid Opening Pressure Measurement 
A CSF opening pressure measurement (cm of H2O) will be conducted as per standard hospital 
practice.  The measurement will be obtained whenever a LP is performed and an IDDD revision 
or replacement is done. 
7.14 Dispensing Study Drug 
rhHNS will be administered IT by means of an IDDD (or via LP if necessary) to patients on 
Day 2 (±2 days) of Week 1 of each treatment month.  
The patient may be sedated for this procedure.  rhHNS will be administered through an 
appropriately sized syringe (see the Pharmacy Manual).  If the IT space is not accessible via the 
IDDD, rhHNS may be administered via LP.  See Section 6.2.4 for details. 
7.15 Pharmacokinetic Assessments 
Pharmacokinetic assessments are not included in this study. 
7.16 Neurological Examination 
A neurological examination to monitor CNS changes in a patient’s neurological status will be 
conducted during this study.  See Appendix 2 for a complete list of the neurological 
examinations. 
7.17 Anti-rhHNS Antibody, Heparan Sulfate, and Heparan Sulfate Derivative 
Determination 
Blood samples will be collected and evaluated at Shire HGT laboratories for the determination of 
anti-rhHNS antibodies, and plasma and serum heparan sulfate and heparan sulfate derivatives.  
Samples will be reserved in accordance with local regulations for potential future MPS IIIA 
research that may determine biomarkers of disease severity and progression.  
Two blood samples will be collected from each patient at each designated time point.  One 
sample will be collected in tubes intended for serum specimens, while the second sample will be 
collected in tubes intended for plasma specimens.  Blood sample collection, processing, and 
shipping instructions will be provided in the Laboratory and/or Study Operations Manual. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
38 
7.18 Neurocognitive and Developmental Assessments 
Patients will undergo neurocognitive and neurobehavioral development testing.  The assessments 
are estimated to last between 2 and 4 hours and must be conducted prior to sedation or 
anesthesia.  
A full neurodevelopmental assessment, including global development, cognition, adaptive 
behavior, receptive and expressive language, and gross motor function, will be evaluated using 
standardized developmental and behavioral tests to provide a surrogate and quantifiable measure 
of global CNS neurodevelopmental/neurobehavioral function.  
All patients will have received a series of standardized neurodevelopment assessments; in the 
HGT-SAN-055 study, patients in HGT-SAN-067 will continue with the age specific assessment 
they began with in HGT-SAN-055.  If, however, a patient’s capability improves and they 
become capable of completing assessments at a higher level, any such additional assessments 
may be added.  Any additional assessments would be performed after the original assessments 
have been carried out.   
For this study, outcome measures will be computed for each patient enrolled.  The psychometric 
instruments and Sanfilippo-specific assessments are summarized below in Table 7-1 and 
Table 7-2, respectively.  See Appendix 2 for details on these assessments. 
Table 7-1 Neurodevelopmental Assessments Tests  
Developmental or Cognitive 
Domain(s) 
Patient Age:  Representative Cognitive Test or 
Scale 
COGNITIVE DEVELOPMENT ASSESSMENT 
Summary score and sub-domains: 
- Cognitive 
- Motor 
- Social/emotional 
 
0 to 42 months:  Bayley Scales of Infant Development-III 
(BSID-III)23  
 
- Cognitive  
- Processing skills 
 
3 to 18 years:  Kaufman Assessment Battery for Children, 
Second Edition (KABC-II)24   
GROSS AND FINE MOTOR SKILLS ASSESSMENT AND VOLUNTARY MOVEMENT 
Motor 
3.0 to 16:11 years:  Movement Assessment Battery for 
Children II (MABC-2)25   
- Cognitive 
- Motor 
0 to 5 ½ years:  Bayley Scales of Infant Development III 
(BSID-III)23   
ADAPTIVE BEHAVIOR 
Communication 
Daily Living 
Socialization 
Motor Skills 
0 to 90 years:  Vineland Adaptive Behavior Scales (VABS-II)  
Second Edition26 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
39 
Table 7-2 Sanfilippo-Specific Disability Assessment And Behavior Rating Scales 
DEVELOPMENTAL OR COGNITIVE 
DOMAIN(S) 
SANFILIPPO SPECIFIC ASSESSMENTS 
Parent-scored behavioral inventory 
- communication:  understanding 
- communication:  expression 
- tantrums 
- specific behaviors inventory 
- mood & emotions inventory 
 
Sanfilippo Behavior Rating Scale (SBRS) 
MPS-specific disability score  
- cognitive functioning 
- expressive language 
- motor score 
Four-Point Scoring System/Total Disability Score 
(FPSS/TDS)5   
 
7.19 Sleep Questionnaire:  Children’s Sleep Habits Rating Scale  
A sleep questionnaire, Children’s Sleep Habits Rating Scale, will be administered to the patient's 
parent(s)/legally authorized representative(s). 
7.20 Age-Dependent, Health-Related Quality of Life in Children 
The Quality of Life questionnaires will be administered as outlined in Sections 7.20.1, 7.20.2, 
and 7.20.3. 
7.20.1 
Quality of Life Indicator:  CHQ-50 
The Child Health Questionnaire™ Parent Form 50 Questions (CHQ-50) will be administered 
during the study.  The questionnaire is a generic quality of life instrument, measuring 14 unique 
physical and psychosocial concepts, which was developed for children from 5 to 18 years of age 
7.20.2 
Quality of Life Indicator:  CHQ-87 
The Child Health Questionnaire™ Child Form 87 (CHQ-87) will be administered during the 
study.  The CHQ-87 is a child and adolescent self-report, developed for ages 10 and older, which 
assesses the child’s self-perceived physical and psychosocial well-being 
7.20.3 
Quality of Life Indicator:  ITQOL 
The Infant Toddler Quality of Life Questionnaire™ (ITQOL) will be administered during the 
study.  The ITQOL was developed for children at least 2 months of age up to 5 years and 
assesses the physical, mental, and social well being of the child and assesses the quality of the 
parent/legally authorized representative(s) life.   
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
40 
7.21 Concomitant Medications, Therapies and Medical/Surgical Procedures 
All non-protocol treatments that occur from the time of informed consent (and assent, if 
applicable) through the safety follow-up contact are regarded as concomitant and will be 
documented on the appropriate pages of the eCRF.  Concomitant therapy includes medication 
(including Genistein), therapies/interventions administered to patients, and medical/surgical 
procedures performed on the patients. 
Every effort should be made to keep symptomatic Sanfilippo syndrome Type A treatment 
constant throughout the study.  However, changes in medications are acceptable if necessary 
according to clinical judgment.  All changes will be recorded on the appropriate eCRF.  
Concomitant medication will be coded using WHO-DD. 
7.22 Adverse Events 
7.22.1 
Definitions of Adverse Events and Serious Adverse Events 
7.22.1.1 
Adverse Event 
An adverse event (AE) is any noxious, pathologic, or unintended change in anatomical, 
physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory 
changes occurring in any phase of a clinical study, whether or not considered study drug-related.  
This includes an exacerbation of a pre-existing condition.  Once the informed consent is signed 
and dated, any adverse event prior to the start of study drug must be reported.  
AEs include: 
• Worsening (change in nature, severity, or frequency) of conditions present at the onset of the 
study 
• Intercurrent illnesses 
• Drug interactions 
• Events related to or possibly related to concomitant medications 
• Abnormal laboratory values (this includes significant shifts from baseline  within the range 
of normal that the Investigator considers to be clinically important) 
• Clinically significant abnormalities in physical examination, vital signs, and weight 
 
Throughout the study, the Investigator must record all AEs on the AE case report form (eCRF), 
regardless of the severity or relationship to study drug.  The Investigator should treat patients 
with AEs appropriately and observe them at suitable intervals until the events stabilize or 
resolve.  AEs may be discovered through observation or examination of the patient, questioning 
of the patient, complaint by the patient, or by abnormal clinical laboratory values. 
In addition, AEs may also include laboratory values that become significantly out of range.  In 
the event of an out-of-range value, the laboratory test should be repeated until it returns to 
normal or can be explained and the patient’s safety is not at risk.   
All adverse events should be recorded with causality assessment. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
41 
The information presented below is intended to provide issues to consider for AEs associated 
with intrathecal injections of rhHNS.  In general, these AEs can be classified as follows:  
• Adverse events due to systemic exposure to rhHNS caused by the drug diffusion from the 
CSF to the peripheral circulation;  
• Adverse events related to the direct delivery of rhHNS to the intrathecal CSF space and 
meninges, and subsequent diffusion into brain parenchyma, via an intrathecal route  
• IDDD–related AEs.   
 
Note:  the classification of potential AEs and the examples presented below are based on purely 
theoretical considerations and/or published literature as there is limited human experience with 
intrathecal rhHNS therapy to date. 
POTENTIAL ADVERSE EVENTS:  INTRATHECAL rhHNS 
Adverse Events Due To Systemic Exposure To rhHNS 
Although rhHNS is given intrathecally only, some proportion of the drug will diffuse from the 
CSF into the peripheral circulation.  The resulting systemic exposure may cause events that are 
typically seen in patients receiving ERT via an intravenous administration, known as 
infusion-related reactions.  An infusion-related reaction is defined as an adverse event that 
(1) begins either during or within 24 hours after the start of the infusion, and (2) is judged as 
possibly or probably related to study drug.  Other AEs that occur prior to the infusion, along with 
AEs associated with protocol-defined testing and assessments (laboratory testing and physical 
examinations) that were performed prior to the infusion will not be defined as infusion-related 
reactions.   
POTENTIAL ADVERSE EVENTS:  INTRATHECAL RECOMBINANT HUMAN HEPARAN N-SULFATASE  
Adverse Events Due to Systemic Exposure to rhHNS 
Although rhHNS is given intrathecally only, some proportion of the drug will diffuse from the 
CSF into the peripheral circulation.  The resulting systemic exposure may cause events that are 
typically seen in patients receiving ERT via an intravenous administration, known as 
infusion-related reactions.  An infusion-related reaction is defined as an adverse event that 
(1) begins either during or within 24 hours after the start of the infusion, and (2) is judged as 
possibly or probably related to study drug.  Other AEs that occur prior to the infusion, along with 
AEs associated with protocol-defined testing and assessments (laboratory testing and physical 
examinations) that were performed prior to the infusion will not be defined as infusion-related 
reactions. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
42 
Adverse Events Related to the Direct Delivery of rhHNS to the CNS through Intrathecal 
Administration 
Examples of adverse events observed in other published clinical trials with 
intrathecally-administered peptides or proteins, include, but are not limited to the following:  
headache, fever, feeling of warmth, sensory parathesias (including feelings of warmth, tingling, 
or pain) or autonomic symptoms such as dry mouth or gustatory abnormalities (including loss of 
smell and metallic taste).  Changes in mental cognitive status or level of consciousness that are 
not caused by pre-medication may either occur acutely or develop post-injection, over time. 
POTENTIAL ADVERSE EVENTS:  IDDD-RELATED ADVERSE EVENTS 
Examples of adverse events related to the insertion or use of an IDDD include, but are not 
limited to, the following:  catheter disconnection or fracture, erosion of portal/catheter through 
the skin, fibrin sheath formation around the catheter tip, hematoma, implant rejection, 
malposition of catheter, migration of portal/catheter, occlusion of portal/catheter, portal site or 
subcutaneous tract infection, and sepsis.   
In addition, there are risks associated with intraspinal access, which include the following:  
cerebrospinal fluid leaks, dura mater or epidural vein perforation, epidural or intrathecal space 
infection (which could result in meningitis), inadvertent epidural placement, pain on injection, 
and spinal cord or nerve injury. 
7.22.1.2 
Serious Adverse Event 
A serious AE (SAE) is any AE occurring at any dose that results in any of the following 
outcomes: 
• Death 
• Is life-threatening 
• Requires inpatient hospitalization 
• Requires prolongation of existing hospitalization 
• A persistent or significant disability or incapacity  
• A congenital anomaly or birth defect 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization. 
The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) 
grading scale should be referenced when assessing the severity of an AE (see Appendix 6).  If an 
AE is not described in the NCI CTC, the severity should be recorded based on the scale provided 
in Table 7-3. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
43 
The severity of all AEs/SAEs should be recorded on the appropriate eCRF page as Grade 1, 2, 3, 
4, or 5 corresponding, respectively, to a severity of mild, moderate, severe, life-threatening, or 
death. 
Table 7-3 Adverse Event Severity 
Severity 
Definition 
Grade 1 (Mild) 
No limitation of usual activities. 
Grade 2 (Moderate) 
Some limitation of usual activities. 
Grade 3 (Severe) 
Inability to carry out usual activities. 
Grade 4 (Life-threatening) 
Immediate risk of death. 
Grade 5 (Death related to an AE) 
Death 
 
Relationship of an adverse event or serious adverse event to study medication is to be determined 
by the Investigator based on the definitions in Table 7-4: 
Table 7-4 Adverse Event Relatedness 
Relationship to Product(s) 
Definition 
Not Related 
Unrelated to study drug. 
Possibly Related 
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of study drug, but which could also be 
explained by concurrent disease or other drugs or chemicals. 
Probably Related 
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of study drug, unlikely to be attributable to 
concurrent disease or other drugs and chemicals and which follows a 
clinically reasonable response on de-challenge.  The association of the 
clinical event or laboratory abnormality must also have some biologic 
plausibility, at least on theoretical grounds. 
Definitely Related 
The event follows a reasonable temporal sequence from administration 
of the medication, follows a known or suspected response pattern to 
the medication, is confirmed by improvement upon stopping the 
medication (dechallenge) and reappears upon repeated exposure 
(rechallenge).   
Note that this is not to be construed as requiring re-exposure of the 
patient to study drug; however, the determination of definitely related 
can only be used when recurrence of event is observed. 
 
 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
44 
7.22.2 
Procedures for Recording and Reporting Adverse Events 
7.22.2.1 
Reporting Serious Adverse Events Related to Study Procedures 
Any SAE that occurs in a patient after informed consent (and assent if applicable) should be 
recorded by the clinical site on an SAE form that is to be transmitted to the Shire HGT Medical 
Monitor and to the Shire Pharmacovigilance and Risk Management Department at the contact 
number provided below.  The SAE must be completely described on the patient’s eCRF, 
including the judgment of the Investigator as to the relationship of the SAE to the study 
procedure.  The Investigator will promptly supply all information identified and requested by the 
Sponsor (and/or contract research organization [CRO]) regarding the SAE as to the relationship 
of the SAE to study drug, device or procedure.  
The SAE form must be completed and FAXED or scanned and EMAILED (PDF sent by e-mail) 
within 24 hours of the Investigator’s learning of the event to:  
 
Any follow-up information must also be completed on an SAE form and faxed or scanned to the 
same numbers or e-mail address listed above. 
In the event of a severe and unexpected, fatal, or life-threatening SAE, the clinical site must 
contact the Shire HGT Medical Monitor by telephone; this is in addition to completing and 
transmitting the SAE form as stated above.  The following provides contact information for the 
Shire HGT Medical Monitor. 
Shire Pharmacovigilance and Risk Management Department: 
International FAX:  
 (UK) OR  
United States FAX: 
Email: 
AND 
Shire HGT Medical Monitor: 
FAX: 
(USA) 
 
The Investigator may also call the Medical Monitor directly (optional): 
Shire HGT Medical Monitor: 
 MD 
Shire HGT 
Work: 
Cell: 
(24 hour access) 
Email: 
AND 
Clinical Project Manager CC’d: 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
45 
If an SAE is assessed as severe and unexpected, or life-threatening, contact: 
MD  
Shire Human Genetic Therapies, Inc. 
300 Shire Way 
Lexington, MA  02421  USA 
Telephone: 
Fax: 
(USA) 
Mobile: 
(24-hour access) 
 
The Investigator must promptly report all required information to the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC).  It is the responsibility of the Sponsor to ensure that 
each Investigator receives a copy of any CIOMS I/MedWatch report that has been submitted to 
the appropriate regulatory agencies notifying them of an unexpected related SAE.  The 
Investigator or Sponsor must ensure that the IRB/IEC receives a copy of the report and that a 
copy is also filed within their study files.  In addition, the Sponsor will also notify the 
Investigators and IRBs/IECs of all deaths that occur during the study, irrespective of relationship 
to study medication 
7.22.2.2 
Eliciting Adverse Events 
Patients should be asked non-leading questions (eg, “How do you feel?”) and further questions 
should be posed if there is indication of an AE.  The questioning should be conducted with due 
regard for objectivity and, in particular, the questioner should gather information regarding AEs 
from questioning the patient, the patient’s parent/guardian, spontaneous report by the patient or 
parent/guardian, laboratory reports, and any health care provider’s observations. 
The onset date, resolution date, treatment administered, and outcome of each AE must be 
recorded on the appropriate eCRF.  In addition, the relationship of each AE to study medication 
must be recorded. 
7.22.2.3 
Protocol Deviations for Medical Emergency or Adverse Event 
During and following a patient’s participation in the study, the Investigator should ensure that 
adequate medical care is provided to a patient for any AEs, including clinically significant 
laboratory test results.   
The Investigator should inform the patient, the patient’s parent(s), or the patient’s legally 
authorized representative when medical care is needed for intercurrent illness(es) of which the 
Investigator becomes aware.  In an emergency situation, the Investigator should contact the Shire 
HGT Medical Monitor (see Section 7.22.2.1). 
Only when an emergency occurs that requires an immediate deviation from the protocol for the 
safety of a patient, will there be such a deviation and this will be only for that patient.   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
46 
The Investigator or other physician in attendance in such an emergency must contact the Shire 
HGT Medical Monitor as soon as possible.   
The Investigator, along with the Shire HGT Medical Monitor, will make a decision as to whether 
or not the patient should continue in the study prior to the next scheduled dose.  The departure 
from the protocol and the grounds for it should be stated in the eCRF. 
7.23 Safety-related Study Stopping Rules 
If any patient experiences a life-threatening (Grade 4) adverse event or death which is considered 
possibly, probably, or definitely related to study drug, or if 2 or more patients experience a 
Grade 3 adverse event during the trial that is considered possibly, probably, or definitely related 
to the study drug by the sponsor, then the site will be instructed to halt further rhHNS 
administration to all patients and the safety data reviewed.  Following a review of safety data, the 
study will be either: 
• Resumed unchanged 
• Resumed with modifications to the protocol or 
• Terminated 
 
Patient safety will be monitored on a continuous basis during this study until the last patient 
completes his or her last scheduled study visit/assessment.   
7.24 Pregnancy 
Pregnancy and breast feeding are exclusion criteria.  Only female patients who have 
reached menarche will be tested for pregnancy in HGT-SAN-067.  If applicable, this will occur 
at study start and before each dose of rhHNS throughout the study.  Pregnancy testing will be 
performed on a blood or urine sample.  Patients with a positive or inconclusive result will not be 
eligible for this study. 
At study start, a pregnancy test will be performed if more than 30 days have passed since the 
initial screening sample.  Throughout the study pregnancy testing will occur prior to each dose of 
rhHNS.  The clinical site’s local laboratory will analyze and report all pregnancy testing results.  
If a pregnancy test is positive the patient will be discontinued from the study, and the 
Investigator must contact the Shire HGT Medical Monitor.  
Pregnancy is not to be reported as an AE; the Pregnancy Reporting Form, found in the Study 
Operations Manual along with instructions for completion, should be used to report the 
pregnancy.  The pregnancy will be followed up through delivery or final outcome. 
7.25 Removal of Subjects from the Trial or Study Drug 
The patient's parent or legally authorized representative acting on behalf of the patient is free to 
withdraw consent and discontinue participation in the study at any time without prejudice to 
further treatment.  Since this is an extension trial, there will be no replacement of patients who 
discontinue the study for any reason. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
47 
A patient’s participation in the study may be discontinued at any time at the discretion of the 
Investigator, Sponsor, or Medical Monitor.  The following may be justifiable reasons for the 
Investigator, Sponsor, or Medical Monitor to remove a patient from the study: 
• Adverse Event:  If a patient experiences an AE which, in the judgment of the investigator, the 
sponsor, or the medical monitor, presents an unacceptable consequence or risk to the patient. 
• Adverse Laboratory Experience:  If a patient has an adverse laboratory experience which, in 
the judgment of the investigator, the Sponsor, or the medical monitor, presents an 
unacceptable consequence or risk to the patient, the patient may be withdrawn from the 
study. 
• Comorbidity:  If a patient develops comorbidity during the course of the study that is 
independent of the study indication, and treatment is required that is not consistent with 
protocol requirements.  
• Intercurrent Illness:  If a patient develops an illness during the course of the study that is not 
associated with the condition under study, and which requires treatment that is not consistent 
with protocol requirements. 
• Refusal of Treatment:  If the patient, the patient’s parent(s) or legally authorized 
representative(s) discontinues participation in the study, or the patient is discontinued by the 
Investigator, reasonable efforts will be made to follow the patient through the end of study 
assessments.  The reason for refusal will be documented on the eCRF.   
• Withdrawal of Informed Consent:  A patient’s parent or legally authorized representative 
may withdraw his informed consent to participate in the study at any time. 
• Cerebrospinal fluid leukocyte count >100 cells per cubic millimeter for 2 consecutive 
months. 
• New onset seizure. 
• Anaphylactic reaction beyond reasonable management as described in the Investigator’s 
Brochure. 
• Clinically problematic intubations or extubations, which may preclude safe airway 
management and anesthesia. 
• Development of refractory spinal fluid leakage.  
• Clinically significant prolonged (eg, greater than 24 to 48 hours) worsening in mental status, 
including development of new focal or non-focal neurological symptoms, or recurrence of a 
previously stable prior medical problem judged due to study drug or participation that is 
exclusive of effects from anesthesia. 
• Non-compliance, including failure to appear at 1 or more study visits. 
• The patient was erroneously included in the study. 
• The patient develops an exclusion criterion. 
• The study is terminated by the Sponsor. 
• The patient becomes pregnant during the trial. 
 
If a patient discontinues the study the Patient Completion/Discontinuation eCRF describing the 
reason for discontinuation must be completed.  Any AE’s experienced up to the point of 
discontinuation must be documented on the AE eCRF.   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
48 
If AEs are present when the patient withdraws from the study, the patient will be re-evaluated 
within 30 days of withdrawal.  All ongoing SAEs at the time of withdrawal will be followed until 
resolution. 
At the time of discontinuation or withdrawal, patients will be asked to participate in all safety 
and efficacy evaluations required for the end of study visit and for the safety follow-up visit.  
Participation in these EOS procedures will be strongly encouraged, but is voluntary for those 
patients electing to discontinue from the study.  The patient will be scheduled for the removal of 
the IDDD.  
7.26 Other Study Procedures 
This section is not applicable. 
7.27 Appropriateness of Measurements 
The neurocognitive and developmental assessments are intended to gauge which domains can be 
accurately measured, with which specific tools, despite the considerable behavioral and cognitive 
challenges in Sanfilippo syndrome.  The evaluation of these domains and the analysis of CSF, 
serum, and urine biomarkers may provide the pivotal data necessary to inform the clinical 
assessments and biomarkers used in possible future Sanfilippo syndrome ERT trials.  

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
49 
8 
STUDY ACTIVITIES 
Patients who participated in Study HGT-SAN-055 through Week 26 and completed the EOS 
evaluations may be eligible for enrollment in this open-label extension study.  Informed consent 
(and assent, if applicable) must be obtained prior to performing any study related procedures that 
are specific to HGT-SAN-067.  Informed consent may be obtained anytime from Week 20 in 
HGT-SAN-055.  This would allow a patient to have a nonfunctional IDDD replaced or revised 
prior to the first rhHNS dose in HGT-SAN-067. 
8.1 
Screening Visit/Study Start Visit  
All Screening assessments for this study are to have been performed during the Week 26 EOS 
procedures in HGT-SAN-055 (ie, 30 [±7] days after the last rhHNS administration).  If less than 
60 days have elapsed since completion of the EOS assessments for HGT-SAN-055, and the start 
of HGT-SAN-067, the assessments detailed in this Screening visit do not need to be repeated.  
The Baseline visit for this study will be the first day the patient received their first dose of 
rhHNS in the HGT-SAN-055 Study.   
If more than 60 days have elapsed following the HGT-SAN-055 EOS procedures, patients will 
be evaluated for enrollment in HGT-SAN-067 on a case-by-case basis by the Investigator.  A 
decision about enrollment will be made following discussion with the Medical Monitor.  If the 
patient is enrolled, the following assessments are to be repeated within 30 days prior to the first 
scheduled intrathecal rhHNS dose: 
• Physical examination 
• Height and weight 
• Head circumference 
• ECG 
• Vital signs 
• Hematology  
• Leukocyte pellet preparation to be used for additional disease-related laboratory studies, 
including possible assessment of cross-reactive immunologic material (if this is not 
collected at baseline, it can be collected at any subsequent pre-dosing time point) 
• Serum chemistry  
• Pregnancy testing (for post menarche premenopausal females only) 
• Urinalysis  
• Urine heparan sulfate and heparan sulfate derivatives 
• Plasma and serum heparan sulfate and heparan sulfate derivatives 
• Anti-rhHNS antibody testing 
• General anesthesia:  administration of anesthesia will be given prior to the following 
assessments: 
• Auditory Brainstem Response (ABR) 
• MRI of the head 
• Neurological examination (performed prior to the administration of anesthesia) 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
50 
• Full Neurodevelopmental assessments (performed prior to the administration of anesthesia 
• CSF sample collection (chemistry, cell count, heparan sulfate and heparan sulfate derivatives, 
and other MPS exploratory biomarkers) via the IDDD 
• Children’s Sleep Habits Rating Scale  
• CHQ-50 
• CHQ-87 
• ITQOL 
• Concomitant medications, therapies, and procedures 
• AE assessments 
 
8.2 
Treatment:  Drug Administration and Weekly Assessments 
Patients will receive rhHNS IDDD monthly (Q4W), on Day 2 (±2 days), Week 1.   
Patient assessments for safety, biochemical, and neurological baseline measures (Day 1, Week 1) 
will occur on the day before the first IT injection.  Note:  Day 1 assessments may be performed 
on the same day as the administration of study drug (Day 2).  This can occur if it is feasible for 
the patient to arrive at the study site early in the day, and if it is deemed clinically appropriate by 
the Investigator.  If the procedures on Day 1 and Day 2 are combined in this way, the 
assessments will be recorded as occurring on Day 2. 
CSF samples will be obtained from these patients on Day 2, immediately prior to the first IT 
study drug injection.  Note:  Patients will not receive study drug if the pre-dose CSF contains 
>100 WBC per cubic millimeter. 
8.2.1 
Week 1  
8.2.1.1 
Day 1 (Pre-treatment) Assessments Performed Prior to Each Dose 
• Physical examination 
• Height and weight 
• Vital signs 
• Hematology 
• Serum chemistry 
• Urinalysis 
• Pregnancy testing (applicable females only) 
• Neurological examination (performed prior to the administration of anesthesia and the 
rhHNS IT injection) 
• Concomitant medications, therapies, and procedures 
• AE assessments 
 
Note: If the HGT-SAN-055 EOS (or HGT-SAN-067 Screening) assessments were performed 
within 7 days of first intrathecal rhHNS treatment in this study, the pre-treatment assessments 
described in this section do not need to be completed prior to the first treatment in study 
HGT-SAN-067. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
51 
DAY 1 (PRE-TREATMENT) ADDITIONAL ASSESSMENTS PERFORMED AT MONTHS 12, 24, 36, AND 54 
• Head circumference 
• Visual and hearing assessments  
• Urine heparan sulfate and heparan sulfate derivatives  
• Plasma and /or serum heparan sulfate and heparan sulfate derivatives  
• Anti-rhHNS antibody testing 
• ABR 
• MRI of the head  
• Full neurodevelopmental testing (performed prior to the administration of anesthesia and the 
rhHNS IT injection) 
• Children’s Sleep Habits Rating Scale  
• Child health questionnaire-50  
• Child health questionnaire-87  
• Infant toddler QOL Questionnaire  
 
8.2.1.2 
Day 2 (±2 days) Assessments and Administration of rhHNS 
Patients may be discharged from the clinical site 8 hours after dosing, if deemed stable by the 
Investigator. 
• Physical examination 
• ECG (performed following IT study drug injection) 
• Vital signs 
• CSF sample collection (obtained prior to IT study drug injection) 
• rhHNS IT injection (Day 2 ±2 days) 
• Neurological examination 
• Concomitant medications, therapies, and procedures 
• AE assessments 
 
8.3 
End of Study/Early Termination Procedures:  Month 55 
Patients who complete the study or who discontinue prior to the end of the study, will have EOS 
assessments performed 30 (±7 days) after their last dose of rhHNS.  Patients who discontinue or 
are withdrawn prior to study completion will be asked to participate in the EOS procedures at the 
time of discontinuation.  Participation in these EOS procedures will be strongly encouraged, but 
is voluntary for those patients electing to discontinue from the study.  Note:  Scheduled removal 
of the IDDD will be required at study completion with sedation or anesthesia, as required. 
• Physical examination 
• Height and weight 
• Head circumference 
• Visual and hearing assessment 
• ECG 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
52 
• Vital signs 
• Hematology 
• Serum chemistries 
• Urinalysis 
• Urine heparan sulfate and heparan sulfate derivatives  
• Plasma and serum heparan sulfate and heparan sulfate derivatives  
• Anti-rhHNS antibody testing 
• Auditory Brainstem Response (ABR) 
• MRI of the head  
• CSF sample collection  
• Neurological examination 
• Full neurodevelopmental testing  
• Children’s Sleep Habits Rating Scale  
• Child health questionnaire-50  
• Child health questionnaire-87  
• Infant toddler QOL Questionnaire  
• Concomitant medications, therapies, and procedures 
• AE assessments 
 
All patients who discontinue the study early will have their IDDD removed.   
Patients who withdraw or discontinue after having received fewer than 3 IT injections will not 
need to complete the EOS visit.   
Patients who withdraw or discontinue from the study after having received 3 or more IT 
injections, will be asked to complete the EOS visit and undergo all the scheduled assessments. 
8.4 
Safety Follow-up (by Telephone or Visit) Month 56 
Patients who complete the study or withdraw early will have a safety follow-up telephone call or 
visit 30 Days (±7 days) after the last study visit.  This will assess: 
• Concomitant medications, therapies, and procedures 
• AE assessments 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
53 
9 
QUALITY CONTROL AND ASSURANCE 
Training will occur at an investigator meeting or at the site initiation visit or both, and instruction 
manuals (eg, laboratory manuals and pharmacy manuals) will be provided to aid consistency in 
data collection and reporting across sites. 
Clinical sites will be monitored by Shire HGT or its designee to ensure the accuracy of data 
against source documents.  The required data will be captured in a validated clinical data 
management system that is compliant with the Food and Drug Administration (FDA) 21 Code of 
Federal Regulations (CFR) Part 11 Guidance.  The clinical trial database will include an audit 
trail to document any evidence of data processing or activity on each data field by each user.  
Users will be trained and given restricted access, based on their role in the study, through a 
password protected environment.   
Data entered in the system will be reviewed manually for validity and completeness against the 
source documents by a clinical monitor from Shire HGT or its designee.  If necessary, the study 
site will be contacted for corrections or clarifications; all missing data will be accounted for. 
SAE information captured in the clinical trial database will be reconciled with the information 
captured in the Pharmacovigilance database. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
54 
10 PLANNED STATISTICAL METHODS 
10.1 General Statistical Methodology 
This is an open-label extension of study HGT-SAN-055 to evaluate the long-term safety and 
clinical outcomes of intrathecal administration of rhHNS in patients with Sanfilippo syndrome 
type A (MPS IIIA).  The statistical methodology supporting the trial will focus on descriptive 
rather than inferential approaches, given the early phase and objectives of this trial.  
Data will be summarized by dose group (10 mg, 45 mg, and 90 mg) with respect to demographic 
and baseline characteristics, efficacy variables and safety variables.  Summary statistics for 
continuous variables will include the n, mean, standard deviation, median, minimum and 
maximum.  Categorical variables will be summarized in a contingency table by the frequency 
and percentage of patients in each category.  Data will be plotted to assess trends across time.  
All hypothesis tests will be 2-sided and will be performed at the 0.05 level.  Hypothesis testing 
will be viewed as exploratory.  Any resulting p-values will not be regarded as a firm support for 
conclusions, but rather suggestive of areas of examination in future studies.  In general, variables 
will be quantified as a change from the baseline value.  The null hypothesis will be that there is 
no difference in the change from baseline between dose groups.  Note that the baseline visit for 
this study will be the first day the patient received his/her IT dose of rhHNS in study 
HGT-SAN-055.  
The primary objective of this trial is to assess the long term safety of rhHNS administration via a 
surgically implanted intrathecal drug delivery device (IDDD).  Hence an extensive safety 
assessment will be performed.  The safety analyses will consist of all enrolled patients.  To 
evaluate safety, adverse experiences will be tabulated by dose group.  Vital signs, 
electrocardiograms, serum and CSF components and chemistries, hematology, and urinalysis 
safety monitoring will be listed for each patient and abnormal values will be flagged.  In 
addition, anti-rhHNS antibodies (in CSF and serum) will also be listed.  No formal statistical 
tests will be performed on the safety parameters. 
10.2 Determination of Sample Size 
Since this is an extension study, sample size is determined by the number of patients who 
completed HGT-SAN-055 (maximum of 12 patients) and elected to continue treatment with 
rhHNS in this study 
10.3 Analysis Populations 
The analysis population consists of all eligible patients from HGT-SAN-055 who have agreed to 
participate in the extension study.  Both safety and efficacy analyses would be performed using 
the above mentioned population.  

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
55 
10.4 Demographics and Baseline Characteristics 
Patient disposition for those enrolled will be presented in a summary table using number and 
percentage of patients enrolled, completed or discontinued/withdrew, by dose group.  The 
reasons for discontinuation/withdrawal will also be presented. 
Demographic and baseline characteristics (eg, age, race, ethnicity, medical history, and surgical 
history) will be reported in summary tables. 
10.5 Statistical Analysis of Pharmacokinetic Variables 
Not applicable. 
10.6 Efficacy, Safety, and Pharmacodynamic Evaluations     
10.6.1 
Primary Analyses 
10.6.1.1 
Safety Analysis 
In general, safety assessments will be based on all assessments post-baseline.  The assessment of 
safety will be based primarily on the frequency of adverse events, and on the frequency of 
clinically notable abnormal vital sign and laboratory values.  Changes from baseline will be 
calculated by subtracting the baseline value from the post-baseline value. 
All enrolled patients will be included in the safety analysis.  Patients will be grouped according 
to the actual dose received.   
No formal statistical test will be performed in the safety evaluations.  Vital sign measurements, 
clinical chemistry, and hematology safety monitoring will be listed for each patient, and 
abnormal values will be flagged.  These will also be summarized at each time point, including 
change from baseline. 
Adverse events will be recorded throughout the study and at early termination.  Adverse events 
and medical conditions will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).   
Adverse events will be summarized by presenting, for each treatment group, the number and 
percentage of patients having any adverse event, having an adverse event in system organ class, 
and having each individual adverse event.  Note that in any given category (eg, system organ 
class) a patient will only be counted once.  In addition, those events which resulted in death or 
were otherwise classified as serious will be presented in a separate listing.  The incidence of 
treatment-emergent adverse events (new or worsened from baseline) will be summarized by 
system organ class, severity, type of adverse event and relationship to trial medication.  
Adverse events that occur up to 30 days after the last dose of study drug will be considered 
“on-treatment”.  Adverse events which are deemed probably, possibly, or definitely related to the 
device will be summarized by dose group and overall. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
56 
Laboratory data will be listed by patient and dose group.  Patients with newly occurring 
abnormalities outside the normal range will be flagged and listed separately and summarized.  
Mean change from baseline values or shift tables will also be provided by dose group at each 
visit. 
Vital signs data will be listed by patient and dose group.  Furthermore, mean changes from 
baseline for vital sign data will be summarized for each dose group.  Shift tables may be 
presented, utilizing reference ranges.  Patients with notably abnormal values will be identified 
and listed separately along with their values. 
Electrocardiograph assessments will be listed by patient and dose group.  Mean changes from 
baseline for ECG data will be summarized for each dose group.  Patients with any clinically 
significant findings and/or conduction abnormalities will be listed separately along with their 
values.  
For those patients who fail to complete the study, the reason for discontinuation will be listed by 
patient and dose group.   
Listings of all study safety data will be presented. 
10.6.1.2 
Clinical Laboratory Evaluations 
Descriptive summaries of clinical laboratory evaluations (hematology, serum chemistry, 
urinalysis) results will be presented in summary tables by evaluation visit using number of 
patients (n), mean, median, standard deviation, minimum, and maximum.  Changes from 
baseline will be summarized for each post-baseline visit.  The number of patients with clinically 
significant laboratory results or abnormal results during the study period will be presented in 
shift tables. 
For the laboratory measurements, shift tables will be presented in terms of Low (L), Normal (N), 
High (H), Missing (M).  High and Low measurements will be based on reference ranges 
provided by the laboratory at the study site. 
Clinical laboratory results will also be presented in data listings. 
10.6.1.3 
Anti-rhHNS Antibody Formation 
Anti-rhHNS antibody formation will be monitored throughout the study.  Results will be 
presented in summary tables by assay methodology used to identify antibodies, number and 
percentage of positive and negative specimens by evaluation visit and/or study week, and 
number and percentage of positive and negative specimens overall.  The effect of antibodies on 
other safety parameters will be assessed by presenting summary tables by antibody status.  These 
results will also be presented in data listings.  

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
57 
10.6.2 
Secondary Analysis 
10.6.2.1 
Clinical Assessments 
The change from baseline in neurocognitive assessment based scores will be examined by dose 
group.  Furthermore, the effect of rhHNS administration on QoL measures will be examined by 
presenting mean change from baseline across dose groups.  Other relevant assessments which 
might help in the understanding of clinical activity will also be analyzed.  
10.6.2.2 
Pharmacodynamic Analyses 
To determine the effects of rhHNS administration on biomarkers, mean change from baseline 
will be assessed at selected time points.  The heparin sulfate reduction (in CSF and urine) will be 
examined using mean change and the corresponding 95% confidence interval.  The concentration 
of inflammatory cytokines in serum and CSF will also be examined.  Other exploratory 
biomarkers in CSF, serum, and urine may also be examined. 
The effect of anti- rhHNS antibodies on the changes in CSF biomarkers may also be examined 
by presenting summary tables by antibody status. 
The planned analyses and presentations will be defined in the Statistical Analysis Plan (SAP). 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
58 
11 ADMINISTRATIVE CONSIDERATIONS 
11.1 Investigators and Study Administrative Structure 
Before initiation of the study, the Investigators must provide the Sponsor with a completed Form 
FDA 1572.  Study medications may be administered only under the supervision of the 
Investigators listed on this form.  Curriculum vitae must be provided for the Investigators and 
sub-investigators listed on Form FDA 1572. 
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, any amendments to the protocol, the study treatments, and their study related 
duties and functions.  The Investigator must maintain a list of sub-investigators and other 
appropriately qualified persons to whom he or she has delegated significant study related duties. 
11.2 Institutional Review Board or Independent Ethics Committee Approval 
Before initiation of the study, the Investigator must provide the Sponsor with a copy of the 
written Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approval of 
the protocol and the informed consent form.  This approval must refer to the informed consent 
form and to the study title, study number, and version and date of issue of the study protocol, as 
given by the Sponsor on the cover page of the protocol. 
Status reports must be submitted to the IRB/IEC at least once per year.  The IRB/IEC must be 
notified of completion of the study.  Within 3 months of study completion or termination, a final 
report must be provided to the IRB/IEC.  A copy of these reports will be sent to the study clinical 
monitor.  The Investigators must maintain an accurate and complete record of all submissions 
made to the IRB/IEC, including a list of all reports and documents submitted.  AEs which are 
reported to the U.S. Food and Drug Administration (FDA) or other Regulatory agencies 
(Investigational New Drug [IND] Safety Reports) must be submitted promptly to the IRB/IEC. 
11.3 Ethical Conduct of the Study 
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor and Investigators abide by 
good clinical practice (GCP) as described in the 21 CFR Parts 50, 56, and 312 and the 
International Conference on Harmonisation (ICH) GCP Guidelines.  
11.4 Patient Information and Consent 
Before enrolling in the clinical study, the patient’s parent(s), or the patient’s legally authorized 
representative(s) must consent to participate after the nature, scope, and possible consequences 
of the clinical study have been explained in a form understandable to him or her.  An informed 
consent form that includes information about the study will be prepared and given to the 
patient’s parent(s), or the patient’s legally authorized representative(s).  This document will 
contain all FDA and ICH-required elements.   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
59 
The informed consent form must be in a language understandable to the patient’s parent(s), or 
the patient’s legally authorized representative(s) and must specify who informed the patient’s 
parent(s), or the patient’s legally authorized representative. 
After reading the informed consent document, the patient, patient’s parent(s), or the patient’s 
legally authorized representative(s) must give consent in writing.  The patient’s consent must be 
confirmed at the time of consent by the personally dated signature of the patient, patient’s 
parent(s) or the patient’s legally authorized representative(s) and by the personally dated 
signature of the person conducting the informed consent discussions.  If the patient, patient’s 
parent(s), or the patient’s legally authorized representative(s) is unable to read, oral presentation 
and explanation of the written informed consent form and information to be supplied must take 
place in the presence of an impartial witness.  Consent (or assent) must be confirmed at the time 
of consent orally and by the personally dated signature of the patient, patient’s parent(s) or by the 
patient’s legally authorized representative(s).  The witness and the person conducting the 
informed consent discussions must also sign and personally date the informed consent document.  
It should also be recorded and dated in the source document that consent was given. 
A copy of the signed and dated consent document(s) must be given to the patient’s parent(s), or 
the patient’s legally authorized representative(s).  The original signed and dated consent 
document will be retained by the Investigator. 
The Investigator will not undertake any measures specifically required solely for the clinical 
study until valid consent has been obtained. 
A model of the informed consent form to be used in this study will be provided to the sites 
separately from this protocol.   
Where applicable, signed assent(s) to participate in the study must be obtained. 
11.5 Patient Confidentiality 
Patient names will not be supplied to the Sponsor.  Only the patient number and patient initials 
will be recorded in the eCRF, and if the patient name appears on any other document, it must be 
obliterated before a copy of the document is supplied to the Sponsor.  Study findings stored on a 
computer will be stored in accordance with local data protection laws.  The patients will be told 
that representatives of the Sponsor, a designated Clinical Research Organization (CRO), the 
IRB/IEC, or regulatory authorities may inspect their medical records to verify the information 
collected, and that all personal information made available for inspection will be handled in 
strictest confidence and in accordance with local data protection laws.  The Investigator will 
maintain a personal patient identification list (patient numbers with the corresponding patient 
names) to enable records to be identified. 
11.6 Study Monitoring 
Monitoring procedures that comply with current Good Clinical Practice (GCP) guidelines will be 
followed.  On-site review of the eCRF's for completeness and clarity, cross-checking with source 
documents, and clarification of administrative matters will be performed. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
60 
The study will be monitored by the Sponsor or its designee.  On site monitoring will be 
performed by a representative of the Sponsor (Clinical Study Monitor) who will review the CRFs 
and source documents.  The site monitor will ensure that the investigation is conducted 
according to protocol design and regulatory requirements by frequent site visits and 
communications (letter, telephone, and facsimile). 
11.7 Case Report Forms and Study Records 
Case report forms are provided for each patient in electronic format.  Electronic Data Capture 
(EDC) will be used for this study.  The study data will be recorded from the source documents 
into the eCRF.  The electronic files will be considered as the CRFs.  
All forms must be filled out by authorized study personnel.  All corrections to the original eCRF 
entry must indicate the reason for change.  The Investigator is required to sign the eCRF after all 
data have been captured for each patient.  If corrections are made after review and signature by 
the Investigator, he or she must be made aware of the changes, and his or her awareness 
documented by re-signing the eCRF.    
11.7.1 
Critical Documents 
Before Shire HGT initiates the trial (ie, obtains informed consent [assent if applicable] from the 
first patient), it is the responsibility of the Investigator to ensure that the following documents are 
available to Shire HGT or their designee: 
• Curricula vitae of Investigator and sub-investigator(s) (current, dated and signed or supported 
by an official regulatory document) 
• Current medical license of Investigator and sub investigator(s) 
• Signed and dated agreement of the final protocol 
• Signed and dated agreement of any amendment(s), if applicable 
• Approval/favorable opinion from the IRB/IEC clearly identifying the documents reviewed:  
protocol, any amendments, Patient Information/Informed Consent Form (Assent form if 
applicable), and any other written information to be provided regarding patients recruitment 
procedures 
• Copy of IRB/IEC approved Patient Information/Informed Consent Form (Assent Form if 
applicable)/any other written information/advertisement 
• Any additional regulatory approvals, ie national regulatory approvals 
• List of IRB/IEC Committee members/constitution 
• Financial agreement(s) 
• Documentation from central or local laboratory as applicable 
• 
Reference ranges 
• 
Certification/QA scheme/other documentation 
 
Regulatory approval and notification as required must also be available; these are the 
responsibility of Shire HGT.  All trial documents will be available in a Trial Master File (TMF) 
at the Investigator/trial site and at Shire HGT.      

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
61 
11.8 Data Monitoring Committee 
There will be no data monitoring committee for this study. 
11.9 Protocol Violations/Deviations 
The Investigator will conduct the study in compliance with the protocol.  The protocol will not 
be initiated until the IRB/IEC and the appropriate regulatory authorities have given 
approval/favorable opinion.  Modifications to the protocol will not be made without agreement 
of the Sponsor.  Changes to the protocol will require written IRB/IEC approval/favorable opinion 
prior to implementation, except when the modification is needed to eliminate an immediate 
hazard(s) to patients.  The IRB/IEC may provide, if applicable regulatory authorities permit, 
expedited review and approval/favorable opinion for minor change(s) in ongoing studies that 
have the approval/favorable opinion of the IRB/IEC.  The Sponsor will submit all protocol 
modifications to the regulatory authorities in accordance with the governing regulations.  A 
record of patients screened, but not entered into the study, is also to be maintained.  There will be 
no protocol exemptions granted for this study. 
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
patients, the Investigator will contact the Sponsor or its designee, if circumstances permit, to 
discuss the planned course of action.  Any departures from the protocol must be fully 
documented as a protocol deviation.  Protocol deviations will need to be reviewed by the medical 
monitor and may also be required to be submitted to the IRB/IEC 
Protocol modifications will only be initiated by the Sponsor and must be approved by the 
IRB/IEC and submitted to the FDA or other applicable international regulatory authority before 
initiation. 
11.10 Access to Source Documentation 
Regulatory authorities, the IEC/IRB, or the Sponsor may request access to all source documents, 
CRFs, and other study documentation for on-site audit or inspection.  Direct access to these 
documents must be guaranteed by the Investigator, who must provide support at all times for 
these activities.  Monitoring and auditing procedures that comply with current GCP guidelines 
will be followed.  On-site review of the CRFs for completeness and clarity, crosschecking with 
source documents, and clarification of administrative matters will be performed. 
11.11 Data Generation and Analysis 
The clinical database will be developed and maintained by a contract research organization or an 
electronic data capture technology provider as designated by Shire HGT.  Shire HGT or its 
designee will be responsible for performing study data management activities.  
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA).  
Concomitant medication will be coded using WHO-DD.  Centralized laboratories will be 
employed as described in the study manual to aid in consistent measurement of efficacy and 
safety parameters. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
62 
11.12 Premature Closure of the Study 
11.12.1 Study Termination 
If the Sponsor or an Investigator discovers conditions arising during the study which indicate that 
the clinical investigation should be halted due to an unacceptable patient risk, the study may be 
terminated after appropriate consultation between Shire HGT and the Investigators.  In addition, 
a decision on the part of Shire HGT to suspend or discontinue development of the study material 
may be made at any time. 
11.12.2 Site Termination 
A specific site may be terminated separate from the general study for, but not limited to, the 
following conditions: 
• The discovery of an unexpected, significant, or unacceptable risk to the patients enrolled at 
the site. 
• Failure of the Investigator to enter patients at an acceptable rate. 
• Insufficient adherence by the Investigator to protocol requirements. 
 
11.13 Retention of Data 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application and until there are no pending or contemplated marketing applications or 
at least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product.  The Sponsor will notify the Investigator if these documents must be 
retained for a longer period of time.  It is the responsibility of the Sponsor to inform the 
Investigator or institution as to when these documents no longer need to be retained.  
Biological samples may be reserved for potential, future, biomarker studies (see Section 7.8.3).   
11.14 Financial Disclosure 
The Investigator should disclose any financial interests in the Sponsor as described in 21 CFR 
Part 54 prior to beginning this study.  The appropriate form will be provided to the Investigator 
by the Sponsor, which will be signed and dated by the Investigator, prior to the start of the study.  
11.15 Publication and Disclosure Policy 
All information concerning the study material, such as patent applications, manufacturing 
processes, basic scientific data, and formulation information supplied by the Sponsor and not 
previously published are considered confidential and will remain the sole property of the 
Sponsor.  The Investigator agrees to use this information only in accomplishing this study and 
will not use it for other purposes. 
It is understood by the Investigator that the information developed in the clinical study may be 
disclosed as required to the authorized regulatory authorities and governmental agencies.   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
63 
In order to allow for the use of the information derived from the clinical studies, it is understood 
that there is an obligation to provide the Sponsor with complete test results and all data 
developed in the study in a timely manner. 
The Investigator and any other clinical personnel associated with this study will not publish the 
results of the study, in whole or in part, at any time, unless they have consulted with Shire HGT, 
provided Shire HGT a copy of the draft document intended for publication, and obtained Shire 
HGT’s written consent for such publication.  All information obtained during the conduct of this 
study will be regarded as confidential.  Shire HGT will use the information for registration 
purposes and for the general development of the drug. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
64 
12 LIST OF REFERENCES 
1. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. 
JAMA : the journal of the American Medical Association 1999;281:249-54. 
2. Poorthuis BJ, Wevers RA, Kleijer WJ, et al. The frequency of lysosomal storage diseases in 
The Netherlands. Human genetics 1999;105:151-6. 
3. Baehner F, Schmiedeskamp C, Krummenauer F, et al. Cumulative incidence rates of the 
mucopolysaccharidoses in Germany. J Inherit Metab Dis 2005;28:1011-7. 
4. Valstar MJ, Bruggenwirth HT, Olmer R, et al. Mucopolysaccharidosis type IIIB may 
predominantly present with an attenuated clinical phenotype. Journal of inherited metabolic 
disease 2010;33:759-67. 
5. Meyer A, Kossow K, Gal A, et al. Scoring evaluation of the natural course of 
mucopolysaccharidosis type IIIA (Sanfilippo syndrome type A). Pediatrics 
2007;120:e1255-61. 
6. Cleary MA, Wraith JE. Management of mucopolysaccharidosis type III. Arch Dis Child 
1993;69:403-6. 
7. Fraser J, Wraith JE, Delatycki MB. Sleep disturbance in mucopolysaccharidosis type III 
(Sanfilippo syndrome): a survey of managing clinicians. Clin Genet 2002;62:418-21. 
8. Neufeld E, Muenzer J. The Mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, 
Valle D, eds. The metabolic and molecular bases of inherited disease. 8th ed. New York: 
McGraw-Hill; 2001:4 v. (xivii, 6338, I-104 p.). 
9. Meyer A, Kossow K, Gal A, et al. The mutation p.Ser298Pro in the sulphamidase gene 
(SGSH) is associated with a slowly progressive clinical phenotype in mucopolysaccharidosis 
type IIIA (Sanfilippo A syndrome). Hum Mutat 2008;29:770. 
10. Vellodi A. Lysosomal storage disorders. Br J Haematol 2005;128:413-31. 
11. Hemsley KM, Beard H, King BM, Hopwood JJ. Effect of high dose, repeated intra-CSF 
injection of sulphamidase on neuropathology in MPS IIIA mice. Genes Brain Behav 2008. 
12. Urayama A, Grubb JH, Sly WS, Banks WA. Mannose 6-phosphate receptor-mediated 
transport of sulfamidase across the blood-brain barrier in the newborn mouse. Mol Ther 
2008;16:1261-6. 
13. Bielicki J, Hopwood JJ, Melville EL, Anson DS. Recombinant human sulphamidase: 
expression, amplification, purification and characterization. Biochem J 1998;329 ( Pt 
1):145-50. 
14. Di Natale P, Vanacore B, Daniele A, Esposito S. Heparan N-sulfatase: in vitro mutagenesis 
of potential N-glycosylation sites. Biochem Biophys Res Commun 2001;280:1251-7. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
65 
15. Daniele A, Di Natale P. Heparan N-sulfatase: cysteine 70 plays a role in the enzyme catalysis 
and processing. FEBS Lett 2001;505:445-8. 
16. Perkins KJ, Byers S, Yogalingam G, Weber B, Hopwood JJ. Expression and characterization 
of wild type and mutant recombinant human sulfamidase. Implications for Sanfilippo 
(Mucopolysaccharidosis IIIA) syndrome. J Biol Chem 1999;274:37193-9. 
17. Munoz-Rojas MV, Vieira T, Costa R, et al. Intrathecal enzyme replacement therapy in a 
patient with mucopolysaccharidosis type I and symptomatic spinal cord compression. Am J 
Med Genet A 2008;146A:2538-44. 
18. Muñoz-Rojas M, Dain D, Horovitz G, et al. Intrathecal administration of recombinant human 
N-acetylgalactosamine 4-sulfatase to a MPS VI patient with pachymeningitis cervicalis. 
Molecular Genetics and Metabolism 2010;99:346-50. 
19. Chen A, Dickson P, Shapiro E, Lyons B, Kan S, Guillaume D. A study of intrathecal enzyme 
replacement for cognitivedecline in mucopolysaccharidosis. Mol Genet Metab 
2010;99:S13-S4. 
20. Hemsley K, King B, Hopwood J. Injection of recombinant human sulfamidase into the CSF 
via the cerebellomedullary cistern in MPS IIIA mice. Mol Genet Metab 2007;90:313-28. 
21. Hemsley KM, Luck AJ, Crawley AC, et al. Examination of intravenous and intra-CSF 
protein delivery for treatment of neurological disease. Eur J Neurosci 2009;29:1197-214. 
22. Hemsley KM, Norman EJ, Crawley AC, et al. Effect of cisternal sulfamidase delivery in 
MPS IIIA Huntaway dogs-A proof of principle study. Mol Genet Metab 2009. 
23. Bayley N. Bayley Scales of Infant and Toddler Development: Third Edition. San Antonio, 
TX The Psychological Corporation; 2005. 
24. Kaufman S, Kaufman N. Kaufman Assessment Battery for Children (KABC-II). 2nd ed. 
25. Henderson S, Sugden D, Barnett A. Movement Assessment Battery for Children (second 
ed.). London: Harcourt Assessment; 2007. 
26. Sparrow S, Balla D, Cicchetti D. Vineland Adaptive Behavior Scales (Second Edition). 4201 
Woodland Road Circle Pines, MN 55014-1796: American Guidance Service, Inc; 2005. 
 

Recombinant human heparan N-sulfatase (rhHNS) 
 
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
 
13 January 2012 
Shire 
Confidential 
66 
Appendix 1 
Schedule of Events  
HGT-SAN-067 Study Assessments for Patients Who Have Received 6 Months of rhHNS Treatment in Study HGT-SAN-055 
 
 
 
Dosed every 28 (±7) days 
(ie, Q4W) 
 
Assessment 
Screening/or HGT-SAN-055 
EOS Visiti 
 
(Month 6 from the start of 
HGT-SAN-055)  
Pre-Tx 
Day 1a 
IT dosing 
Day 2 (±2) 
Months 12, 24, 36, 
and 54  
(from the start of 
HGT-SAN-055) 
EOSf Month 55 
 
(from the start of 
HGT-SAN-055) 
Month 56
Safety 
Follow-
uph 
Informed Consent/Enrollment 
 
● 
 
 
 
 
Physical Examination 
● 
● 
● 
 
● 
 
Height and Weight 
● 
● 
 
 
● 
 
Head Circumference 
● 
 
 
● 
● 
 
Visual and Hearing Assessment 
 
 
 
● 
● 
 
ECG 
● 
 
●b 
 
● 
 
Vital Signs 
● 
● 
● 
 
● 
 
Hematology 
● 
● 
 
 
● 
 
Serum Chemistry 
● 
● 
 
 
● 
 
Pregnancy Testing l 
● 
● 
 
 
 
 
Urinalysis 
● 
● 
 
 
● 
 
Leukocyte pellet preparationm 
● 
 
 
 
 
 
Urine Heparan Sulfate and Heparan 
Sulfate Derivatives  
● 
 
 
●e 
● 
 
Plasma and serum Heparan Sulfate and 
Heparan Sulfate Derivatives 
● 
 
 
●e 
● 
 
Anti-rhHNS antibody testing (serum and 
CSF)j 
● 
 
 
● 
● 
 
Auditory Brainstem Response (ABR) 
● 
 
 
● 
● 
 
MRI of the Head 
● 
 
 
● 
● 
 
CSF Sample Collectionk 
● 
 
●c 
 
●c 
 
rhHNS dosing: every 28 (±7) days g   
 
 
● 
 
 
 
Neurological Examination 
● 
● 
● 
 
● 
 
Full Neurodevelopmental Testing 
● 
 
 
● 
● 
 
Children’s Sleep Habits Rating Scale 
● 
 
 
● 
● 
 
Child Health Questionnaire-50 
● 
 
 
● 
● 
 
Child Health Questionnaire-87 
● 
 
 
● 
● 
 

Recombinant human heparan N-sulfatase (rhHNS) 
 
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
 
13 January 2012 
Shire 
Confidential 
67 
HGT-SAN-067 Study Assessments for Patients Who Have Received 6 Months of rhHNS Treatment in Study HGT-SAN-055 
 
 
 
Dosed every 28 (±7) days 
(ie, Q4W) 
 
Assessment 
Screening/or HGT-SAN-055 
EOS Visiti 
 
(Month 6 from the start of 
HGT-SAN-055)  
Pre-Tx 
Day 1a 
IT dosing 
Day 2 (±2) 
Months 12, 24, 36, 
and 54  
(from the start of 
HGT-SAN-055) 
EOSf Month 55 
 
(from the start of 
HGT-SAN-055) 
Month 56
Safety 
Follow-
uph 
Infant Toddler QOL Questionnaire 
● 
 
 
● 
● 
 
Concomitant Medications, Therapies, and 
Procedures 
● 
● 
● 
 
● 
● 
Adverse Event Monitoring 
● 
● 
● 
 
● 
● 
Abbreviations: 
ABR = Auditory brainstem response; CSF = cerebrospinal fluid; ECG = electrocardiogram; MRI = Magnetic resonance imaging; 
TX = treatment 
Note: The timing of assessments is calculated from the start of HGT-SAN-055.  Therefore, for example, the end-of-study visit, as presented here at Month 54, 
corresponds to Month 48 in HGT-SAN-067, but represents a total of 54 months of study treatment (48 months in HGT-SAN-067 + 6 months in 
HGT-SAN-055). 
a 
Week 1 only, and only performed if >7 days have elapsed since  HGT-SAN-055 EOS visit assessments. 
b 
ECG to be performed following administration of study drug. 
c 
CSF samples will be obtained according to the process with in the study operations manual).  An attempt will be made to obtain a CSF sample via the 
IDDD prior to each administration of rhHNS and at the End of Study visit.  If it is not possible to obtain a CSF using the IDDD, the IDDD may be replaced 
(up to twice in a 6 month period [including the time in the HGT-SAN-055 study]) or a LP may be performed (can occur up to 5 times in a 6 month period). 
d 
Patients may be discharged as early as 8 hours post rhHNS infusion (ie, on Day 2)when deemed clinically stable by the Investigator.  
e 
Specimens collected once a month, at Day 1 of the first treatment week. 
f 
All patients who complete the study will have end of study assessments performed 30 (±7 days) after their last dose of study drug. 
g 
If a patient’s IDDD becomes nonfunctional or infected; it will be replaced (up to 2 times in a 6 month period; including the time in Study HGT-SAN-055).  
h 
A safety follow up telephone call will be made 30 (±7 days) after End of Study Procedures. 
i 
Assessments will be required only if more than 60 days have elapsed following the HGT-SAN-055 procedures.  These assessments would be repeated 
within 30 days prior to the first scheduled rhHNS IT dose. 
j 
Blood sample drawn before IT injection of rhHNS. 
k 
CSF will be tested for standard chemistries, heparan sulfate and heparan sulfate derivatives, anti-rhHNS antibodies, and MPS exploratory biomarkers. 
l 
A pregnancy test will be carried out on pre-treatment Day 1 in females who are postmenarche to premenopause (childbearing).  The results must be 
negative before study drug can be administered.  
m 
A blood sample for leukocyte pellet preparation is to be taken at baseline, before dosing.  This pellet should be stored frozen, and will be used for 
additional disease-related laboratory studies, including possible assessment of cross-reactive immunologic material.  If this is not drawn at baseline, it can 
be drawn at any subsequent visit, but it must be taken before dosing.  This only needs to be taken once during the study. 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
68 
Appendix 2 
Neurodevelopmental and Behavioral Assessments  
Table 4-1 and Table 4-2 detail the specific psychometric instruments that will be used to provide 
measures of each of relevant neurobehavioral or developmental domain assessed.  The tables 
also summarize the rules used to select a test for a patient, the subtests included in each test, and 
the subscales generated by the test battery. 
Table 4-1 Summary of Neurodevelopmental Outcome Measures 
 
Domain 
Age 
Test 
Summary score and 
subdomains: 
- Cognitive 
- Motor 
- Social/Emotional 
0 to 42 months Bayley Scales of Infant Development, Third 
Edition (BSID-III)23   
- Cognitive  
- Processing skills 
3 to 18 years 
Kaufman Assessment Battery for Children, 
Second Edition (KABC-II)24   
Motor 
3.0 to 16:11 
years 
Movement Assessment Battery for Children, 
Second Edition (MABC-2)25   
Communication 
Daily Living 
Socialization 
Motor Skills 
0 to 90 years 
Vineland Adaptive Behavior Scales, Second 
Edition (VABS-II)26   
 
Table 4-2 Summary of Sanfilippo-specific Assessments 
 
Domain 
Assessment 
Parent-scored behavioral inventory 
- communication:  understanding 
- communication:  expression 
- tantrums 
- specific behaviors inventory 
- mood & emotions inventory 
Sanfilippo Behavior Rating Scale 
MPS-specific four-point scoring 
system/total disability score 
- cognition 
- expressive language 
- motor score 
Four-Point Scoring System/Total Disability 
Score (FPSS/TDS)5   
 
The term “neurodevelopmental” refers to the process by which the neurological system matures 
and changes over time.  Assessing these changes in a population of children whose neurological 
system is progressively more affected can be very challenging.   

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
69 
Typically, neurodevelopmental progress is reflected by the child’s abilities to perform certain 
skills (sitting, walking, and talking).   
However, a child with a neurological disorder may be able to perform age appropriate skills, but 
with atypical patterns.  For example, the child may be able to walk, but his gait is not normal.  
Most assessments will therefore measure the skills, but are not designed to capture the 
abnormalities in pattern or quality of the skill.   
These qualitative differences will be evident to the skilled test administrator/clinician who is 
familiar with the disorder.  However, only longitudinal tracking and repeated measures will 
reveal the significance of these abnormalities in overall function to the less experienced clinician.    
The rate at which different skills develop or regress over time will give insight into the disease 
process.  The next step is to determine how the learned skills are used for daily functional 
activities so that as the children grow up they become independent from caregivers.  These 
functional skills can be tracked to reflect quality of life issues for both parents and children.  
Neurodevelopmental assessments described below will be scheduled for administration in the 
morning and estimated to last between 2 and 4 hours. 
The list of assessments and algorithm is discussed in detail in the Study Operations Manual and 
includes: 
Bayley Scales of Infant Development, Third Edition (BSID-III)23   
The Bayley Scales of Infant Development is a standard series of measurements used primarily to 
assess the motor (fine and gross), language (receptive and expressive), and cognitive 
development of infants and toddlers, ages 0 to 42 months.  This measure consists of a series of 
developmental play tasks and takes between 45 and 60 minutes to administer.  Raw scores of 
successfully completed items are converted to scale scores and to composite scores.  These 
scores are used to determine the child's performance compared with norms taken from typically 
developing children of their age (in months).  The assessment is often used in conjunction with 
the Social-Emotional Adaptive Behavior Questionnaire.  Completed by the parent or caregiver, 
this questionnaire establishes the range of adaptive behaviors that the child can currently achieve 
and enables comparison with age norms. 
Kaufman Assessment Battery for Children, Second Edition (KABC-II)24 
Purpose: 
The KABC-II measures a child’s cognitive ability and processing skills and was designed to 
minimize verbal instructions and responses.  In addition, the assessment contains little cultural 
content to provide a more accurate assessment of children from diverse backgrounds.  Thus 
language difficulties or cultural differences are minimized in the test battery’s results. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
70 
Description: 
Investigators may choose either the Cattell-Horn-Carroll or the Luria model for a patient’s 
assessment.   
The Cattell-Horn-Carroll model is used with children from a mainstream cultural and language 
background and the Luria model is used for children with significantly limited verbal ability.  
Subtests are administered on four or five ability scales and interpreted using the chosen model.  
Movement Assessment Battery for Children, Second Edition (MABC-2)25 
Purpose: 
The Movement Assessment Battery for Children, Second Edition identifies, describes and guides 
treatment of motor impairment in children from 3.0 to 16:11 years of age. 
Description: 
The MABC-2 checklist is administered individually over approximately 30 minutes.  It yields 
both normative and qualitative measures of movement competence, manual dexterity, ball skills, 
static and dynamic balance. 
Vineland Adaptive Behavior Scales, Second Edition (VABS-II)26   
Purpose: 
The test measures adaptive behaviors, including the ability to cope with environmental changes, 
to learn new everyday skills and to demonstrate independence.  It is an instrument that supports 
the diagnosis of intellectual and developmental disabilities.  It encompasses ages from birth to 
90 years.  
Description: 
Adaptive behavior is a composite of various dimensions.  This test measures 5 domains:  
communication, daily living skills, socialization, motor skills, and maladaptive behavior 
(optional) and is administered in a semi-structured interview in through a questionnaire.  The 
scales of the VABS-II were organized within a 3-domain structure:  Communication, Daily 
Living, and Socialization.  This structure corresponds to the 3 broad domains of adaptive 
functioning by the American Association of Intellectual and Developmental Disabilities:  
Conceptual, Practical, and Social.  In addition, VABS-II offers a Motor Skills Domain and an 
optional Maladaptive Behavior Index.  The scores are interpreted by means of score equivalents 
for the raw scores in each domain, percentile ranks, age equivalents, adaptive levels, and 
maladaptive levels. 
 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
71 
Sanfilippo Behavior Rating Scale (SBRS) 
The Sanfilippo Behavior Rating Scale (SBRS) is a newly-developed scale designed by Drs. Elsa 
Shapiro and Michael Potegal to measure a cluster of behaviors known to occur in Sanfilippo 
syndrome.  The SBRS is a parent-scored behavioral inventory measuring (1) comprehensive 
language skills, (2) expressive language skills, (3) tantrums, (4) mood and emotions, and 
(5) other behaviors not otherwise classified. 
Four-Point Scoring System/Total Disability Score (FPSS/TDS) 5 
The FPSS assesses motor function, expressive language, and cognitive function on a 0 to 3 point 
scale and can be used for individuals of all ages.  The total disability score is the average of the 
motor function, speech, and cognitive function scores. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
72 
Appendix 3 
Failure of IDDD Function:  Investigation and Management 
This appendix is intended to assist in the investigation of mechanical device failure and its 
subsequent management.  
Note:  The total number of IDDD revisions a patient may undergo will be limited to 2 (partial or 
complete replacements) in a 6 month period (including the time in HGT-SAN-055).  
Additionally, the total number of X-rays to investigate and verify IDDD integrity will be limited 
to 6, in a 6-month period plus up to 3 intra-operative fluoroscopies to guide catheter placement.   
Introduction 
The device consists of a catheter, inserted into the intrathecal space in the lower lumbar area, 
tunneled subcutaneously to a site overlying an ipsilateral (so the tunneled catheter does not cross 
the midline) lower rib in the mid to anterior axillary line, and there connected to the 
subcutaneous port.  The catheter is connected to the metal outlet tube from the port via a plastic 
collar, secured by a metal locking ring.  The port is accessed percutaneously for CSF aspiration 
and drug administration, via a special non-coring needle.  The metal chamber within the port, the 
locking ring, and the catheter are radio-opaque (Figure 1).  An X-ray taken post-implantation is 
used to verify and document 1) the correct location of the catheter tip in the mid-thoracic spinal 
canal, and 2) the correct orientation and position of the metal locking ring that secures the 
catheter to the port outlet tube. 
Figure 1:  Radiographic appearance of IDDD port implanted over lower ribs, with percutaneous needle inserted.  Note that the 
tapered appearance of the locking collar permits assessment of its correct orientation. 
 
Functional failure of the IDDD is most likely to be mechanical:  blockage may occur as a result 
of luminal occlusion, fibrin sheath formation around the tip, external compression or kinking.  
Leakage may be a consequence of catheter disconnection or fracture, or breakage of the port 
outlet tube itself.  In addition, the catheter may become dislodged from the spinal canal (see 
Smith’s Medical instructions [provided in the Investigator Brochure] for additional details).   
Details of the surgical implantation procedure, designed to minimize the chance of these 
problems arising, are contained in the Smith’s Medical Instructions for Use and Shire Study 
Training materials. 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
73 
In addition, medical complications may also preclude use of the IDDD, and may lead to its 
removal, revision, or replacement.  These include infection, hematoma, inadvertent epidural 
placement, pain on injection, etc, as listed in the Smith’s Medical Instructions for Use.  These 
complications should be managed as clinically indicated. 
Investigation 
Diagnostic clues of mechanical failure, established or impending include: 
• Increasing difficulty in aspirating CSF from the IDDD 
• Blood stained appearance of CSF 
• Increasing difficulty in pushing drug or sterile normal saline through the IDDD 
• Soft tissue swelling indicating possible fluid accumulation at the site of the port, or along the 
course of the catheter, immediately following administration of drug and/or saline via IDDD 
• Increased cellularity of the pre-treatment CSF sample 
 
Note:  increased cellularity of the CSF may also indicate meningeal reactions to the drug or the 
presence of infection, and so must be interpreted in the context of the whole clinical picture. 
Approach to investigation: 
1. Clinical evaluation for swelling following drug infusion 
2. X-ray imaging, to include both the port and the full length of the catheter in the spinal canal.  
X-rays are probably the single most useful investigational approach.  Especially when 
compared with post-implantation confirmatory images, this may elucidate: 
A. Slippage of the catheter from the spinal canal 
B. Breakage or disconnection of the catheter and/or its locking device from the port 
assembly 
C. Kinking of the catheter 
 
Note:  There is no information on compatibility of the IDDD and drug product with contrast 
media, so these should be avoided. 
Management: 
1. In general, once mechanical failure of the IDDD has occurred, intervention should be 
planned to replace the IDDD in part or in its entirety. 
2. CSF may be aspirated, and drug administered via lumbar puncture while awaiting IDDD 
revision, in accordance with the protocol. 
3. If IDDD mechanical failure is confined to the port, its attachment to the catheter, or to the 
segment of catheter immediately adjacent to the port, proximal revision of the IDDD may be 
undertaken.  In such an event, the old port and locking assembly is removed.  New 
components are then implanted, leaving the original catheter in situ.  However, the end of the 
catheter must be trimmed by at least one centimeter to restore a tight connection with the new 
port outlet tube.  The patency of the apparatus must be ascertained  intra-operatively, by 
aspirating CSF through the port, and flushing the device with sterile normal saline. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
74 
4. If IDDD mechanical failure is due to dislodgment of the catheter from the spinal canal, 
kinking at a location distal to the immediate vicinity of the port, or unresolved by proximal 
revision, the whole device must be replaced, following the instructions provided by Smith’s 
Medical and the Shire training materials. 
 
Note:  All removed IDDDs must be returned to Smith’s Medical for further analysis.  Please 
refer to the Study Manual for instructions on the IDDD Return process.  You should also contact 
Shire HGT. 
Note:  All IDDD related AEs (serious and nonserious) will be reported to Shire; all IDDD related 
SAEs will also be reported to Global Shire PVRM.  
Drug Administration Following Device Revision: 
1. If a full revision of the IDDD has been performed, an interval of 7 days is required before 
resuming administration of drug via IDDD. 
2. If a proximal (ie, replacement of port only) revision of IDDD has been performed, drug 
administration through the IDDD can proceed immediately post-operatively. 
3. In the event that the IDDD fails after 2 revisions in a 6-month time period, rhHNS may be 
administered and CSF collected by lumbar puncture for up to 5 successive months after 
which, IDDD re-implantation or revision must occur.   
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
75 
Appendix 4 
Summary of Changes for Amendment 2  
Clinical protocol HGT-SAN-067 has been revised from the previous version (amendment 1, 
27-Jan-2011) to change the dose and regimen administered to patients in Group 3, the dose was 
changed from 45 mg Q2W to 90 mg every month (Q4W).  This change was made to ensure 
consistency with the revised HGT-SAN-055 study protocol and will allow patients to continue to 
receive the same dose in this extension study as they did in the original study.  Other changes 
made to this amendment include:  The addition of an appendix detailing the identification and 
management of non-functioning IDDDs.  The number of permissible IDDD revisions and X-rays 
was specified and is aligned with similar changes made to HGT-SAN-055.  Study stopping rules 
have been added.  A number of study procedures have been aligned with changes made to 
HGT-SAN-055.  In addition, the Sponsor’s address and Medical Monitor’s contact details were 
changed. 
The changes relative to amendment 1 of the protocol (27-Jan-2011) are summarized below by 
section number; new or additional text is indicated in bold and deleted text is indicated as 
strikethrough.  Other sections affected by the same change are listed below each change. 
Please note that only changes of substance are displayed here.  
Change:  The text was modified state the revise dose and regimen for patients in Group 3. 
Section impacted by this change:  Section 6.2 Treatment Administered 
Modified Text: 
rhHNS for IT administration will be provided by Shire HGT.  rhHNS will be administered 
by an IDDD.  Following the review and signing of informed consent, eligible patients will 
receive the same dose of rhHNS they received in Study HGT-SAN-055: 
• 
Group 1:  rhHNS administered by IT injection 10 mg once per month (Q4W)  
• 
Group 2:  rhHNS administered by IT injection 45 mg once per month (Q4W) 
• 
Group 3:  rhHNS administered by IT injection 45 mg Q2W 90 mg once per month 
(Q4W) 
Other sections affected by the same change:  Synopsis, Introduction, Section 4.1, Section 
5.2, Section 6.2.1, and Appendix 1 Schedule of Events.  
 
Change:  Text was added to clarify the administration of study drug via lumbar puncture 
in the event of a non-functional IDDD 
Section impacted by this change:  Section 6.2.4 Administration of rhHNS via Lumbar 
Puncture  
In the event of a non functional IDDD, rhHNS may be administered by lumbar 
puncture (LP), for re implantation of a new IDDD (see Section 7.11) up to 5 
successive months.  The performance of LP is at the discretion of the Investigator. 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
76 
If a lumbar puncture is to be performed, the patient is likely to require general 
anesthesia with appropriate airway management.  Once the patient is anesthetized, a 
lumbar puncture will be performed and a CSF sample will be obtained.  Some cases 
may be managed with conscious sedation, if this is considered by the investigator to 
be adequate for the safe and expeditious performance of a LP. 
Other sections affected by the same change:  Synopsis, Section 6.2.3 
 
Change:  The number of permissible IDDD revisions and X-rays was specified and is 
aligned with similar changes made to HGT-SAN-055. 
Section impacted by this change:  Section 7.12.1 Restrictions on the Number of Revision 
and/or re-implantation of the IDDD  
Modified Text:  This section was added to the protocol 
A non-functional IDDD can be replaced or revised twice in a 6-month period, 
including the time a patient was in study HGT-SAN-055. Similarly, 6 X-rays may be 
taken in 6-month period, also including the time in HGT-SAN-055. 
Other sections affected by the same change:  Synopsis, Section 6.2.3 
 
Change:  Genistein was specified in the Concomitant Therapy and the Drug dictionary 
used was corrected 
Section impacted by this change:  Section 6.5 Concomitant Therapy  
Modified Text: 
All non-protocol treatments and procedures that occur from the time of informed consent 
(and assent, if applicable) through the safety follow-up contact are regarded as 
concomitant and will be documented on the appropriate pages of the electronic case report 
form (eCRF).  Concomitant therapy includes medications (including Genistein), 
therapies/interventions administered to patients, and medical/surgical procedures 
performed on the patients.  
Every effort should be made to keep the patient’s symptomatic Sanfilippo syndrome Type 
A treatment constant throughout the study.  However, changes in medications are 
acceptable if necessary according to clinical judgment.  All changes will be recorded on 
the appropriate eCRF.  Concomitant medication will be coded using WHO Drug 
Dictionary (WHO-DD) Drug Reference List (WHODRL). 
 
No other sections were affected by these changes 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
77 
Change:  Text was added to clarify that MRIs will be centrally read.  
Section impacted by this change:  Section 7.11 MRI of the Head 
Modified Text:  The regional brain volume will be assessed through an MRI of the head.  
The patient will be under general anesthesia for this assessment.  The central reading for 
MRI data, across all sites All MRIs will be completed at centrally read by the University 
of Minnesota Medical Center.  Refer to the Study Operations Manual for specific 
procedures and precautions. 
 
No other sections were affected by this change 
 
Change:  Clarifications were made to the Inclusion and Exclusion Criteria, and 1 
exclusion criterion was deleted as it was covered by the inclusion criterion requiring 
signed informed consent for the study. 
Section impacted by this change:  Section 5.2 Inclusion Criteria and 5.3 Exclusion Criteria 
Modified Text:  
1. Patients The patient must have completed all study requirements Study HGT-SAN-
055 and assessments for Study HGT-SAN-055 prior to enrolling, in this extension 
study and must have the opinion of the investigator, has no safety or medical issues 
that contraindicate participation.  
2. The patient, patient’s parent(s) or legally authorized guardian representative(s) must 
have has voluntarily signed an Institutional Review Board/Independent Ethics 
Committee-approved informed consent (and assent, if applicable) form after all 
relevant aspects of the study have been explained and discussed with the patient, the 
guardians’patient’s, patient's parents or legally authorized representative’s 
consent and patient’s assent as relevant appropriate, must be obtained prior to any 
study specific procedures. 
3. The patient has received and tolerated treatment with at least 5 of the 6 planned 
infusions of rhHNS, completed the End of Study visit, and has received at least 80% 
of the total planned infusions within the last 6 months in study in the HGT-SAN-055 
(ie, at least 5/6 ([Group 1 or 2] or 10/12 infusions [Group 3]) study.  
 
Exclusion: 
10. The patient has received treatment with any investigational drug (other than rhHNS) 
intended as a treatment for MPS IIIA or used any other intrathecal delivery device 
other than what was used in Study HGT-SAN-055, within the 30 days prior to, or 
during the study, or is currently enrolled in another study that involves an 
investigational drug or device (screening through safety follow-up contact).  
12 The patient’s parent(s), or patient’s legal guardian(s) is/are unable to provide consent 
or the patient cannot provide assent, as appropriate, due to, but not limited to, the inability 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
78 
to understand the nature, scope, and possible consequences of the study, or do/does not 
agree to comply with the protocol defined schedule of assessments. 
 
Other sections affected by the same change:  Synopsis 
 
Change:  Text was added to state the study’s stopping rules 
Section impacted by this change:  Section 7.23 Safety-related Study Stopping Rules 
Modified Text:  This section was added to the protocol 
If any patient experiences a life-threatening (Grade 4) adverse event or death which 
is considered possibly, probably, or definitely related to study drug, or if 2 or more 
patients experience a Grade 3 adverse event during the trial that is considered 
possibly, probably, or definitely related to the study drug by the sponsor, then the 
site will be instructed to halt further rhHNS administration to all patients and the 
safety data reviewed (see Section 7.23).  Following that review of safety data, the 
study will be either: 
• 
Resumed unchanged 
• 
Resumed with modifications to the protocol or 
• 
Terminated 
 
Patient safety will be monitored on a continuous basis during this study until the last 
patient completes his or her last scheduled study visit/assessment 
Other sections affected by the same change:  none 
 
Change:  Text was added to state that there will be no protocol exemptions to this study 
Section impacted by this change:  Section 11.9 Protocol Violations/Deviations 
Modified Text:  the following sentence was added to the protocol 
There will be no protocol exemptions granted for this study. 
 
Other sections affected by the same change:  none 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
79 
Change:  Text was added to document the potential adverse events in response to IT 
rhHNS 
Section impacted by this change:  Section 7.22.2.1 Adverse Events 
Modified Text:  This section was added to the protocol 
POTENTIAL ADVERSE EVENTS:  INTRATHECAL RECOMBINANT HUMAN 
HEPARAN N-SULFATASE  
Adverse Events Due to Systemic Exposure to rhHNS 
Although rhHNS is given intrathecally only, some proportion of the drug will diffuse 
from the CSF into the peripheral circulation.  The resulting systemic exposure may 
cause events that are typically seen in patients receiving ERT via an intravenous 
administration, known as infusion related reactions.  An infusion related reaction is 
defined as an adverse event that (1) begins either during or within 24 hours after the 
start of the infusion, and (2) is judged as possibly or probably related to study drug.  
Other AEs that occur prior to the infusion, along with AEs associated with protocol-
defined testing and assessments (laboratory testing and physical examinations) that 
were performed prior to the infusion will not be defined as infusion-related 
reactions. 
Other sections affected by the same change:  none 
 
Change:  Text was added to clarify the end of study procedures for patients that withdraw 
early 
Section impacted by this change:  Section 8.3 End of Study/Early Termination 
Procedures:  Month 55 
Modified Text:  the following text was added to the protocol 
Patients who discontinue early:  All patients who discontinue early will have their 
IDDD removed.   
Patients who withdraw or discontinue after having received fewer than 3 IT 
injections will not need to complete the EOS visit.   
Patients who withdraw or discontinue from the study after having received 3 or 
more IT injections, will be asked to complete the EOS visit and undergo all the 
scheduled assessments 
Other sections affected by the same change:  none 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
80 
Change:  It was clarified that the nomenclature of the study months began with the time in 
the HGT-SAN-055 study 
Sections impacted by this change:  Appendix 1 Schedule of Events 
Added Text:   
(from the start of HGT SAN 055) 
Other sections affected by the same change:  Synopsis, Section 4, Section 7, and 
Section 8. 
 
Change:  The length of time a patient has to remain in the study unit after receiving study 
drug was reduced from 24 hours to 8 hours. 
Sections impacted by this change:  Synopsis 
Modified Text:   
Patients will remain in the study centre for at least 24 8 hours following dosing with 
rhHNS and will be discharged from the unit when deemed clinically stable by the 
Investigator. 
Other sections affected by the same change:  Section 4.1, Section 6.2.1, and Section 6.2.3. 
 
Change:  Text stating compliance with the Declaration of Helsinki has been removed. 
Sections impacted by this change:  Section 11.3 Ethical Conduct of the Study 
Deleted Text:   
Compliance with these regulations and guidelines also constitutes compliance with the 
ethical principles described in the Declaration of Helsinki. 
 
No other sections are affected by this change. 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
81 
Change:  A number of study procedures were changed to align with the procedures 
performed in HGT-SAN-055 
Sections impacted by this change:  Section 7. 
The following parameters were either added to the protocol or their frequency of 
assessment was changed 
• Plasma and serum heparan sulfate and heparan sulfate derivatives 
• The frequency of pregnancy testing was increased 
• Leukocyte pellet preparation to be used for additional disease-related laboratory 
studies, including possible assessment of cross-reactive immunologic material 
Other sections affected by these changes:  Appendix 1 Schedule of Events 
 
Change:  Additional of New Appendix 
Sections impacted by this change:  Appendix 4 
The following titled appendix was added to the protocol:  
•Appendix 3 Failure of IDDD Function:  Investigation and Management 
Other sections affected by the same change:  none 
 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
82 
Appendix 5 
Protocol Signature Page 
Study Title: 
An Open-Label Extension of Study HGT-SAN-055 Evaluating 
Long-Term Safety and Clinical Outcomes of Intrathecal 
Administration of rhHNS in Patients with Sanfilippo Syndrome 
Type A (MPS IIIA) 
Study Number: 
HGT-SAN-067 Amendment 2 
Final Date: 
21 June 2010 
Amendment 1 Date: 
22 January 2011 
Amendment 2 Date: 
13 January 2012 
 
I have read the protocol described above.  I agree to comply with all applicable regulations and 
to conduct the study as described in the protocol.  
Signatory: 
 
 
 
 
 
 
 
 
 
 
 
Investigator 
 
 
 
Signature 
Date 
 
 
 
 
 
 
 
<enter text> 
 
 
Printed Name 
 
 
I have read and approve the protocol described above. 
Signatory: 
 
 
 
 
 
 
 
 
 
 
 
Shire HGT 
Medical 
Monitor 
 
 
 
Signature 
Date 
 
 
 
 
 
 
 
 MD 
 
 
Printed Name 
 
 
 
 

Recombinant human heparan N-sulfatase (rhHNS)  
 
Clinical Trial Protocol: HGT-SAN-067 Amendment 2 
13 January 2012 
Shire 
Confidential 
83 
Appendix 6 
The National Cancer Institute Common Toxicity Criteria  
 

Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, Version 3.0, DCTD, NCI, NIH, DHHS 
 
March 31, 2003 (http://ctep.cancer.gov), Publish Date: August 9, 2006 
Common Terminology Criteria for Adverse Events v3.0 (CTCAE) 
Publish Date: August 9, 2006 
Quick Reference 
The NCI Common Terminology Criteria for Adverse Events 
v3.0 is a descriptive terminology which can be utilized for 
Adverse Event (AE) reporting. A grading (severity) scale is 
provided for each AE term. 
Components and Organization  
CATEGORY 
A CATEGORY is a broad classification of AEs based on 
anatomy and/or pathophysiology. Within each CATEGORY, 
AEs are listed accompanied by their descriptions of severity 
(Grade). 
Adverse Event Terms 
An AE is any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medical treatment or procedure 
that may or may not be considered related to the medical 
treatment or procedure. An AE is a term that is a unique 
representation of a specific event used for medical 
documentation and scientific analyses. Each AE term is 
mapped to a MedDRA term and code. AEs are listed 
alphabetically within CATEGORIES. 
Short AE Name 
The ‘SHORT NAME’ column is new and it is used to simplify 
documentation of AE names on Case Report Forms.   
Supra-ordinate Terms  
A supra-ordinate term is located within a CATEGORY and is a 
grouping term based on disease process, signs, symptoms, 
or diagnosis. A supra-ordinate term is followed by the word 
‘Select’ and is accompanied by specific AEs that are all 
related to the supra-ordinate term. Supra-ordinate terms 
provide clustering and consistent representation of Grade for 
related AEs. Supra-ordinate terms are not AEs, are not 
mapped to a MedDRA term and code, cannot be graded and 
cannot be used for reporting. 
REMARK 
A ‘REMARK’ is a clarification of an AE. 
ALSO CONSIDER 
An ‘ALSO CONSIDER’ indicates additional AEs that are to be 
graded if they are clinically significant. 
NAVIGATION NOTE 
A ‘NAVIGATION NOTE’ indicates the location of an AE term 
within the CTCAE document. It lists signs/symptoms 
alphabetically and the CTCAE term will appear in the same 
CATEGORY unless the ‘NAVIGATION NOTE’ states differently. 
Grades 
Grade refers to the severity of the AE. The CTCAE v3.0 
displays Grades 1 through 5 with unique clinical descriptions 
of severity for each AE based on this general guideline: 
Grade 1 
Mild AE  
Grade 2 
Moderate AE 
Grade 3 
Severe AE 
Grade 4 
Life-threatening or disabling AE 
Grade 5 
Death related to AE 
A Semi-colon indicates ‘or’ within the description of the grade. 
An ‘Em dash’ (—) indicates a grade not available. 
Not all Grades are appropriate for all AEs. Therefore, some 
AEs are listed with fewer than five options for Grade 
selection. 
Grade 5 
Grade 5 (Death) is not appropriate for some AEs and 
therefore is not an option. 
The DEATH CATEGORY is new. Only one Supra-ordinate 
term is listed in this CATEGORY: ‘Death not associated with 
CTCAE term – Select’ with 4 AE options: Death NOS; 
Disease progression NOS; Multi-organ failure; Sudden death. 
Important: 
• 
Grade 5 is the only appropriate Grade 
• 
This AE is to be used in the situation where 
a death  
1. cannot be reported using a CTCAE v3.0 
term associated with Grade 5, or 
2. cannot be reported within a CTCAE 
CATEGORY as ‘Other (Specify)’ 
 
 
 
 
 
Contents 
ALLERGY/IMMUNOLOGY ............................................1 
AUDITORY/EAR............................................................2 
BLOOD/BONE MARROW .............................................4 
CARDIAC ARRHYTHMIA..............................................5 
CARDIAC GENERAL ....................................................7 
COAGULATION ..........................................................10 
CONSTITUTIONAL SYMPTOMS................................11 
DEATH ........................................................................13 
DERMATOLOGY/SKIN ...............................................14 
ENDOCRINE...............................................................17 
GASTROINTESTINAL.................................................19 
GROWTH AND DEVELOPMENT................................29 
HEMORRHAGE/BLEEDING ....................................... 30 
HEPATOBILIARY/PANCREAS ................................... 34 
INFECTION................................................................. 35 
LYMPHATICS ............................................................. 38 
METABOLIC/LABORATORY ...................................... 40 
MUSCULOSKELETAL/SOFT TISSUE........................ 43 
NEUROLOGY ............................................................. 47 
OCULAR/VISUAL........................................................ 52 
PAIN............................................................................ 55 
PULMONARY/UPPER RESPIRATORY...................... 56 
RENAL/GENITOURINARY.......................................... 60 
SECONDARY MALIGNANCY..................................... 63 
SEXUAL/REPRODUCTIVE FUNCTION ..................... 64 
SURGERY/INTRA-OPERATIVE INJURY ................... 66 
SYNDROMES............................................................. 68 
VASCULAR................................................................. 70 
 

 
ALLERGY/IMMUNOLOGY 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 1 - 
March 31, 2003, Publish Date: August 9, 2006 
Allergic reaction/ 
hypersensitivity  
(including drug fever) 
Allergic reaction 
Transient flushing or 
rash; drug fever <38°C 
(<100.4°F) 
Rash; flushing; urticaria; 
dyspnea; drug fever 
≥38°C (≥100.4°F) 
Symptomatic 
bronchospasm, with or 
without urticaria; 
parenteral medication(s) 
indicated; allergy-related 
edema/angioedema; 
hypotension 
Anaphylaxis 
Death 
REMARK: Urticaria with manifestations of allergic or hypersensitivity reaction is graded as Allergic reaction/hypersensitivity (including drug fever). 
ALSO CONSIDER: Cytokine release syndrome/acute infusion reaction. 
Allergic rhinitis  
(including sneezing, 
nasal stuffiness, 
postnasal drip) 
Rhinitis 
Mild, intervention not 
indicated  
Moderate, intervention 
indicated 
— 
— 
— 
REMARK: Rhinitis associated with obstruction or stenosis is graded as Obstruction/stenosis of airway – Select in the PULMONARY/UPPER RESPIRATORY CATEGORY. 
Autoimmune reaction 
Autoimmune reaction 
Asymptomatic and 
serologic or other 
evidence of autoimmune 
reaction, with normal 
organ function and 
intervention not indicated 
Evidence of autoimmune 
reaction involving a non-
essential organ or 
function (e.g., 
hypothyroidism) 
Reversible autoimmune 
reaction involving function 
of a major organ or other 
adverse event (e.g., 
transient colitis or 
anemia)  
Autoimmune reaction with 
life-threatening 
consequences 
Death 
ALSO CONSIDER: Colitis; Hemoglobin; Hemolysis (e.g., immune hemolytic anemia, drug-related hemolysis); Thyroid function, low (hypothyroidism). 
Serum sickness 
Serum sickness 
— 
— 
Present 
— 
Death 
NAVIGATION NOTE: Splenic function is graded in the BLOOD/BONE MARROW CATEGORY. 
NAVIGATION NOTE: Urticaria as an isolated symptom is graded as Urticaria (hives, welts, wheals) in the DERMATOLOGY/SKIN CATEGORY. 
Vasculitis 
Vasculitis 
Mild, intervention not 
indicated 
Symptomatic, non-
steroidal medical 
intervention indicated 
Steroids indicated 
Ischemic changes; 
amputation indicated 
Death 
Allergy/Immunology – 
Other (Specify, __) 
Allergy – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
AUDITORY/EAR 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 2 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Earache (otalgia) is graded as Pain – Select in the PAIN CATEGORY. 
Hearing:  
patients with/without 
baseline audiogram and 
enrolled in a monitoring 
program1 
Hearing (monitoring 
program) 
Threshold shift or loss of 
15 – 25 dB relative to 
baseline, averaged at 2 
or more contiguous test 
frequencies in at least 
one ear; or subjective 
change in the absence of 
a Grade 1 threshold shift 
Threshold shift or loss of 
>25 – 90 dB, averaged at 
2 contiguous test 
frequencies in at least 
one ear 
Adult only: Threshold shift 
of >25 – 90 dB, averaged 
at 3 contiguous test 
frequencies in at least 
one ear  
Pediatric:  
Hearing loss sufficient to 
indicate therapeutic 
intervention, including 
hearing aids (e.g., ≥20 dB 
bilateral HL in the speech 
frequencies; ≥30 dB 
unilateral HL; and 
requiring additional 
speech-language related 
services) 
Adult only: Profound 
bilateral hearing loss 
(>90 dB) 
Pediatric:  
Audiologic indication for 
cochlear implant and 
requiring additional 
speech-language related 
services  
— 
REMARK: Pediatric recommendations are identical to those for adults, unless specified. For children and adolescents (≤18 years of age) without a baseline test, pre-exposure/pre-
treatment hearing should be considered to be <5 dB loss. 
Hearing: 
patients without baseline 
audiogram and not 
enrolled in a monitoring 
program1  
Hearing (without 
monitoring program) 
— 
Hearing loss not requiring 
hearing aid or 
intervention (i.e., not 
interfering with ADL) 
Hearing loss requiring 
hearing aid or 
intervention (i.e., 
interfering with ADL) 
Profound bilateral hearing 
loss (>90 dB) 
— 
REMARK: Pediatric recommendations are identical to those for adults, unless specified. For children and adolescents (≤18 years of age) without a baseline test, pre-exposure/pre-
treatment hearing should be considered to be <5 dB loss. 
Otitis, external ear 
(non-infectious) 
Otitis, external  
External otitis with 
erythema or dry 
desquamation  
External otitis with moist 
desquamation, edema, 
enhanced cerumen or 
discharge; tympanic 
membrane perforation; 
tympanostomy 
External otitis with 
mastoiditis; stenosis or 
osteomyelitis 
Necrosis of soft tissue or 
bone 
Death 
ALSO CONSIDER: Hearing: patients with/without baseline audiogram and enrolled in a monitoring program1; Hearing: patients without baseline audiogram and not enrolled in a 
monitoring program1.  
Otitis, middle ear  
(non-infectious) 
Otitis, middle 
Serous otitis  
Serous otitis, medical 
intervention indicated 
Otitis with discharge; 
mastoiditis  
Necrosis of the canal soft 
tissue or bone 
Death 

 
AUDITORY/EAR 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 3 - 
March 31, 2003, Publish Date: August 9, 2006 
Tinnitus 
Tinnitus 
— 
Tinnitus not interfering 
with ADL 
Tinnitus interfering with 
ADL 
Disabling 
— 
ALSO CONSIDER: Hearing: patients with/without baseline audiogram and enrolled in a monitoring program1; Hearing: patients without baseline audiogram and not enrolled in a 
monitoring program1. 
Auditory/Ear – Other 
(Specify, __) 
Auditory/Ear – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
 
 
 
 
 
 
                                            
1 Drug-induced ototoxicity should be distinguished from age-related threshold decrements or unrelated cochlear insult. When considering whether an adverse event has occurred, it is 
first necessary to classify the patient into one of two groups. (1) The patient is under standard treatment/enrolled in a clinical trial <2.5 years, and has a 15 dB or greater threshold 
shift averaged across two contiguous frequencies; or (2) The patient is under standard treatment/enrolled in a clinical trial >2.5 years, and the difference between the expected age-
related and the observed threshold shifts is 15 dB or greater averaged across two contiguous frequencies. Consult standard references for appropriate age- and gender-specific 
hearing norms, e.g., Morrell, et al. Age- and gender-specific reference ranges for hearing level and longitudinal changes in hearing level. Journal of the Acoustical Society of America 
100:1949-1967, 1996; or Shotland, et al. Recommendations for cancer prevention trials using potentially ototoxic test agents. Journal of Clinical Oncology 19:1658-1663, 2001.  
In the absence of a baseline prior to initial treatment, subsequent audiograms should be referenced to an appropriate database of normals. ANSI. (1996) 
American National Standard: Determination of occupational noise exposure and estimation of noise-induced hearing impairment, ANSI S 3.44-1996. (Standard S 3.44). New York: 
American National Standards Institute. The recommended ANSI S3.44 database is Annex B. 

 
BLOOD/BONE MARROW 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 4 - 
March 31, 2003, Publish Date: August 9, 2006 
Bone marrow cellularity 
Bone marrow cellularity 
Mildly hypocellular or  
≤25% reduction from 
normal cellularity for age 
Moderately hypocellular 
or >25 – ≤50% reduction 
from normal cellularity for 
age  
Severely hypocellular or 
>50 – ≤75% reduction 
cellularity from normal for 
age  
— 
Death 
CD4 count  
CD4 count 
<LLN – 500/mm3 
<LLN – 0.5 x 109 /L 
<500 – 200/mm3  
<0.5 – 0.2 x 109 /L 
<200 – 50/mm3  
<0.2 x 0.05 – 109 /L 
<50/mm3  
<0.05 x 109 /L 
Death 
Haptoglobin  
Haptoglobin 
<LLN  
— 
Absent 
— 
Death 
Hemoglobin  
Hemoglobin 
<LLN – 10.0 g/dL  
<LLN – 6.2 mmol/L  
<LLN – 100 g/L 
<10.0 – 8.0 g/dL 
<6.2 – 4.9 mmol/L  
<100 – 80g/L 
<8.0 – 6.5 g/dL 
<4.9 – 4.0 mmol/L 
<80 – 65 g/L 
<6.5 g/dL 
<4.0 mmol/L  
<65 g/L 
Death 
Hemolysis (e.g., immune 
hemolytic anemia, drug-
related hemolysis) 
Hemolysis 
Laboratory evidence of 
hemolysis only (e.g., 
direct antiglobulin test 
[DAT, Coombs’] 
schistocytes) 
Evidence of red cell 
destruction and ≥2 gm 
decrease in hemoglobin, 
no transfusion 
Transfusion or medical 
intervention (e.g., 
steroids) indicated 
Catastrophic 
consequences of 
hemolysis (e.g., renal 
failure, hypotension, 
bronchospasm, 
emergency splenectomy) 
Death 
ALSO CONSIDER: Haptoglobin; Hemoglobin. 
Iron overload 
Iron overload 
— 
Asymptomatic iron 
overload, intervention not 
indicated  
Iron overload, 
intervention indicated  
Organ impairment (e.g., 
endocrinopathy, 
cardiopathy) 
Death 
Leukocytes (total WBC) 
Leukocytes 
<LLN – 3000/mm3 
<LLN – 3.0 x 109 /L  
<3000 – 2000/mm3 
<3.0 – 2.0 x 109 /L 
<2000 – 1000/mm3 
<2.0 – 1.0 x 109 /L 
<1000/mm3  
<1.0 x 109 /L 
Death 
Lymphopenia  
Lymphopenia 
<LLN – 800/mm3 
<LLN x 0.8 – 109 /L 
<800 – 500/mm3 
<0.8 – 0.5 x 109 /L 
<500 – 200 mm3 
<0.5 – 0.2 x 109 /L 
<200/mm3 
<0.2 x 109 /L 
Death 
Myelodysplasia 
Myelodysplasia 
— 
— 
Abnormal marrow 
cytogenetics (marrow 
blasts ≤5%)  
RAEB or RAEB-T 
(marrow blasts >5%) 
Death 
Neutrophils/granulocytes 
(ANC/AGC) 
Neutrophils 
<LLN – 1500/mm3  
<LLN – 1.5 x 109 /L 
<1500 – 1000/mm3 
<1.5 – 1.0 x 109 /L  
<1000 – 500/mm3 
<1.0 – 0.5 x 109 /L 
<500/mm3 
<0.5 x 109 /L 
Death 
Platelets 
Platelets 
<LLN – 75,000/mm3 
<LLN – 75.0 x 109 /L 
<75,000 – 50,000/mm3 
<75.0 – 50.0 x 109 /L 
<50,000 – 25,000/mm3  
<50.0 – 25.0 x 109 /L 
<25,000/mm3  
<25.0 x 109 /L 
Death 
Splenic function 
Splenic function 
Incidental findings (e.g., 
Howell-Jolly bodies) 
Prophylactic antibiotics 
indicated 
—  
Life-threatening 
consequences 
Death 
Blood/Bone Marrow – 
Other (Specify, __) 
Blood – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
CARDIAC ARRHYTHMIA 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 5 - 
March 31, 2003, Publish Date: August 9, 2006 
Conduction abnormality/ 
atrioventricular heart 
block  
– Select:  
Conduction abnormality 
– Select 
Asymptomatic, 
intervention not indicated 
– Asystole 
– AV Block-First degree 
– AV Block-Second degree Mobitz Type I (Wenckebach)  
– AV Block-Second degree Mobitz Type II 
– AV Block-Third degree (Complete AV block) 
– Conduction abnormality NOS 
– Sick Sinus Syndrome  
– Stokes-Adams Syndrome 
– Wolff-Parkinson-White Syndrome 
Non-urgent medical 
intervention indicated 
Incompletely controlled 
medically or controlled  
with device (e.g., 
pacemaker) 
Life-threatening (e.g., 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
Death 
Palpitations 
Palpitations 
Present 
Present with associated 
symptoms (e.g., 
lightheadedness, 
shortness of breath) 
— 
— 
— 
REMARK: Grade palpitations only in the absence of a documented arrhythmia. 
Prolonged QTc interval 
Prolonged QTc 
QTc >0.45 – 0.47 second 
 QTc >0.47 – 0.50 
second; ≥0.06 second 
above baseline 
QTc >0.50 second 
QTc >0.50 second; life-
threatening signs or 
symptoms (e.g., 
arrhythmia, CHF, 
hypotension, shock 
syncope); Torsade de 
pointes 
Death 
Supraventricular and 
nodal arrhythmia  
– Select: 
Supraventricular 
arrhythmia – Select 
Asymptomatic, 
intervention not indicated 
Non-urgent medical 
intervention indicated 
– Atrial fibrillation 
– Atrial flutter  
– Atrial tachycardia/Paroxysmal Atrial Tachycardia 
– Nodal/Junctional 
– Sinus arrhythmia  
– Sinus bradycardia 
– Sinus tachycardia  
– Supraventricular arrhythmia NOS 
– Supraventricular extrasystoles (Premature Atrial Contractions; Premature Nodal/Junctional Contractions) 
– Supraventricular tachycardia 
Symptomatic and 
incompletely controlled 
medically, or controlled 
with device (e.g., 
pacemaker) 
Life-threatening (e.g., 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
Death 
NAVIGATION NOTE: Syncope is graded as Syncope (fainting) in the NEUROLOGY CATEGORY. 

 
CARDIAC ARRHYTHMIA 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 6 - 
March 31, 2003, Publish Date: August 9, 2006 
Vasovagal episode 
Vasovagal episode 
— 
Present without loss of 
consciousness 
Present with loss of 
consciousness 
Life-threatening 
consequences  
Death 
Ventricular arrhythmia 
– Select: 
Ventricular arrhythmia 
– Select 
– Bigeminy 
– Idioventricular rhythm 
– PVCs 
– Torsade de pointes 
– Trigeminy 
– Ventricular arrhythmia NOS 
– Ventricular fibrillation  
– Ventricular flutter 
– Ventricular tachycardia 
Asymptomatic, no 
intervention indicated 
Non-urgent medical 
intervention indicated 
Symptomatic and 
incompletely controlled 
medically or controlled 
with device (e.g., 
defibrillator) 
Life-threatening (e.g., 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
Death 
Cardiac Arrhythmia  
– Other (Specify, __) 
Cardiac Arrhythmia – 
Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling  
Death 

 
CARDIAC GENERAL 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 7 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Angina is graded as Cardiac ischemia/infarction in the CARDIAC GENERAL CATEGORY. 
Cardiac 
ischemia/infarction 
Cardiac 
ischemia/infarction 
Asymptomatic arterial 
narrowing without 
ischemia 
Asymptomatic and testing 
suggesting ischemia; 
stable angina  
Symptomatic and testing 
consistent with ischemia; 
unstable angina; 
intervention indicated 
Acute myocardial 
infarction 
Death 
Cardiac troponin I (cTnI) 
cTnI 
— 
— 
Levels consistent with 
unstable angina as 
defined by the 
manufacturer 
Levels consistent with 
myocardial infarction as 
defined by the 
manufacturer 
Death 
Cardiac troponin T (cTnT) 
cTnT 
0.03 – <0.05 ng/mL 
0.05 – <0.1 ng/mL 
0.1 – <0.2 ng/mL 
0.2 ng/mL 
Death 
Cardiopulmonary arrest, 
cause unknown 
(non-fatal) 
Cardiopulmonary arrest 
— 
— 
— 
Life-threatening  
— 
REMARK: Grade 4 (non-fatal) is the only appropriate grade. CTCAE provides three alternatives for reporting Death: 
1. A CTCAE term associated with Grade 5.  
2. A CTCAE 'Other (Specify, __)’ within any CATEGORY. 
3. Death not associated with CTCAE term – Select in the DEATH CATEGORY. 
NAVIGATION NOTE: Chest pain (non-cardiac and non-pleuritic) is graded as Pain – Select in the PAIN CATEGORY. 
NAVIGATION NOTE: CNS ischemia is graded as CNS cerebrovascular ischemia in the NEUROLOGY CATEGORY. 
Hypertension 
Hypertension 
Asymptomatic, transient 
(<24 hrs) increase by >20 
mmHg (diastolic) or to 
>150/100 if previously 
WNL; intervention not 
indicated  
Pediatric: 
Asymptomatic, transient 
(<24 hrs) BP increase 
>ULN; intervention not 
indicated 
Recurrent or persistent 
(≥24 hrs) or symptomatic 
increase by >20 mmHg 
(diastolic) or to >150/100 
if previously WNL; 
monotherapy may be 
indicated  
Pediatric: 
Recurrent or persistent 
(≥24 hrs) BP >ULN; 
monotherapy may be 
indicated 
Requiring more than one 
drug or more intensive 
therapy than previously 
Pediatric: 
Same as adult 
Life-threatening 
consequences (e.g., 
hypertensive crisis) 
Pediatric: 
Same as adult 
Death 
REMARK: Use age and gender-appropriate normal values >95th percentile ULN for pediatric patients. 

 
CARDIAC GENERAL 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 8 - 
March 31, 2003, Publish Date: August 9, 2006 
Hypotension 
Hypotension 
Changes, intervention not 
indicated 
Brief (<24 hrs) fluid 
replacement or other 
therapy; no physiologic 
consequences 
Sustained (≥24 hrs) 
therapy, resolves without 
persisting physiologic 
consequences 
Shock (e.g., acidemia; 
impairment of vital organ 
function)  
Death 
ALSO CONSIDER: Syncope (fainting). 
Left ventricular diastolic 
dysfunction 
Left ventricular diastolic 
dysfunction 
Asymptomatic diagnostic 
finding; intervention not 
indicated 
Asymptomatic, 
intervention indicated 
Symptomatic CHF 
responsive to intervention 
Refractory CHF, poorly 
controlled; intervention 
such as ventricular assist 
device or heart transplant 
indicated  
Death 
Left ventricular systolic 
dysfunction 
Left ventricular systolic 
dysfunction 
Asymptomatic, resting 
ejection fraction (EF)  
<60 – 50%; shortening 
fraction (SF) <30 – 24% 
Asymptomatic, resting  
EF <50 – 40%; 
SF <24 – 15% 
Symptomatic CHF 
responsive to 
intervention; 
EF <40 – 20% 
SF <15% 
Refractory CHF or poorly 
controlled; EF <20%; 
intervention such as 
ventricular assist device, 
ventricular reduction 
surgery, or heart 
transplant indicated 
Death 
NAVIGATION NOTE: Myocardial infarction is graded as Cardiac ischemia/infarction in the CARDIAC GENERAL CATEGORY. 
Myocarditis 
Myocarditis 
— 
— 
CHF responsive to 
intervention 
Severe or refractory CHF 
Death 
Pericardial effusion 
(non-malignant) 
Pericardial effusion 
Asymptomatic effusion  
—  
Effusion with physiologic 
consequences 
Life-threatening 
consequences (e.g., 
tamponade); emergency 
intervention indicated 
Death 
Pericarditis 
Pericarditis 
Asymptomatic, ECG or 
physical exam (rub) 
changes consistent with 
pericarditis 
Symptomatic pericarditis 
(e.g., chest pain) 
Pericarditis with 
physiologic 
consequences (e.g., 
pericardial constriction) 
Life-threatening 
consequences; 
emergency intervention 
indicated 
Death 
NAVIGATION NOTE: Pleuritic pain is graded as Pain – Select in the PAIN CATEGORY. 
Pulmonary hypertension 
Pulmonary hypertension 
Asymptomatic without 
therapy 
Asymptomatic, therapy 
indicated 
Symptomatic 
hypertension, responsive 
to therapy 
Symptomatic 
hypertension, poorly 
controlled 
Death 
Restrictive 
cardiomyopathy  
Restrictive 
cardiomyopathy  
Asymptomatic, therapy 
not indicated 
Asymptomatic, therapy 
indicated 
Symptomatic CHF 
responsive to intervention 
Refractory CHF, poorly 
controlled; intervention 
such as ventricular assist 
device, or heart 
transplant indicated  
Death 

 
CARDIAC GENERAL 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 9 - 
March 31, 2003, Publish Date: August 9, 2006 
Right ventricular 
dysfunction 
(cor pulmonale) 
Right ventricular 
dysfunction 
Asymptomatic without 
therapy 
Asymptomatic, therapy 
indicated 
Symptomatic cor 
pulmonale, responsive to 
intervention 
Symptomatic cor 
pulmonale poorly 
controlled; intervention 
such as ventricular assist 
device, or heart 
transplant indicated  
Death 
Valvular heart disease 
Valvular heart disease 
Asymptomatic valvular 
thickening with or without 
mild valvular regurgitation 
or stenosis; treatment 
other than endocarditis 
prophylaxis not indicated 
Asymptomatic; moderate 
regurgitation or stenosis 
by imaging 
Symptomatic; severe 
regurgitation or stenosis; 
symptoms controlled with 
medical therapy 
Life-threatening; 
disabling; intervention 
(e.g., valve replacement, 
valvuloplasty) indicated 
Death 
Cardiac General – Other 
(Specify, __) 
Cardiac General – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
COAGULATION 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 10 - 
March 31, 2003, Publish Date: August 9, 2006 
DIC (disseminated 
intravascular coagulation) 
DIC 
— 
Laboratory findings with 
no bleeding 
Laboratory findings and 
bleeding 
Laboratory findings, life-
threatening or disabling 
consequences (e.g., CNS 
hemorrhage, organ 
damage, or 
hemodynamically 
significant blood loss) 
Death 
REMARK: DIC (disseminated intravascular coagulation) must have increased fibrin split products or D-dimer.  
ALSO CONSIDER: Platelets. 
 
Fibrinogen  
Fibrinogen 
<1.0 – 0.75 x LLN 
or <25% decrease from 
baseline 
<0.75 – 0.5 x LLN 
or 25 – <50% decrease 
from baseline 
<0.5 – 0.25 x LLN 
or 50 – <75% decrease 
from baseline 
<0.25 x LLN  
or 75% decrease from 
baseline or absolute 
value <50 mg/dL  
Death 
REMARK: Use % decrease only when baseline is <LLN (local laboratory value). 
INR (International 
Normalized Ratio of 
prothrombin time) 
INR 
 
>1 – 1.5 x ULN 
>1.5 – 2 x ULN 
>2 x ULN 
— 
— 
ALSO CONSIDER: Hemorrhage, CNS; Hemorrhage, GI – Select; Hemorrhage, GU – Select; Hemorrhage, pulmonary/upper respiratory – Select. 
PTT (Partial 
Thromboplastin Time)  
PTT 
>1 – 1.5 x ULN 
>1.5 – 2 x ULN 
>2 x ULN 
— 
— 
ALSO CONSIDER: Hemorrhage, CNS; Hemorrhage, GI – Select; Hemorrhage, GU – Select; Hemorrhage, pulmonary/upper respiratory – Select. 
Thrombotic 
microangiopathy (e.g., 
thrombotic 
thrombocytopenic 
purpura [TTP] or 
hemolytic uremic 
syndrome [HUS]) 
Thrombotic 
microangiopathy 
Evidence of RBC 
destruction 
(schistocytosis) without 
clinical consequences 
— 
Laboratory findings 
present with clinical 
consequences (e.g., renal 
insufficiency, petechiae) 
Laboratory findings and 
life-threatening or 
disabling consequences, 
(e.g., CNS hemorrhage/ 
bleeding or thrombosis/ 
embolism or renal failure) 
Death 
REMARK: Must have microangiopathic changes on blood smear (e.g., schistocytes, helmet cells, red cell fragments). 
ALSO CONSIDER: Creatinine; Hemoglobin; Platelets. 
Coagulation – Other 
(Specify, __) 
Coagulation – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
CONSTITUTIONAL SYMPTOMS 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 11 - 
March 31, 2003, Publish Date: August 9, 2006 
Fatigue  
(asthenia, lethargy, 
malaise) 
Fatigue 
Mild fatigue over baseline 
Moderate or causing 
difficulty performing some 
ADL 
Severe fatigue interfering 
with ADL 
Disabling 
— 
Fever  
(in the absence of 
neutropenia, where 
neutropenia is defined as 
ANC <1.0 x 109/L) 
Fever 
38.0 – 39.0°C  
(100.4 – 102.2°F) 
>39.0 – 40.0°C 
(102.3 – 104.0°F)  
>40.0°C 
(>104.0°F) for ≤24 hrs  
>40.0°C 
(>104.0°F) for >24 hrs 
Death 
REMARK: The temperature measurements listed are oral or tympanic. 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever).  
NAVIGATION NOTE: Hot flashes are graded as Hot flashes/flushes in the ENDOCRINE CATEGORY. 
Hypothermia 
Hypothermia 
— 
35 – >32°C 
95 – >89.6°F 
32 – >28°C  
89.6 – >82.4° F 
≤28 °C  
82.4°F or life-threatening 
consequences (e.g., 
coma, hypotension, 
pulmonary edema, 
acidemia, ventricular 
fibrillation) 
Death 
Insomnia 
Insomnia 
Occasional difficulty 
sleeping, not interfering 
with function 
Difficulty sleeping, 
interfering with function 
but not interfering with 
ADL 
Frequent difficulty 
sleeping, interfering with 
ADL 
Disabling 
— 
REMARK: If pain or other symptoms interfere with sleep, do NOT grade as insomnia. Grade primary event(s) causing insomnia. 
Obesity2 
Obesity 
— 
BMI 25 – 29.9 kg/m2 
BMI 30 – 39.99 kg/m2 
BMI ≥40 kg/m2 
— 
REMARK: BMI = (weight [kg]) / (height [m])2 
Odor  
(patient odor) 
Patient odor 
Mild odor 
Pronounced odor 
— 
— 
— 
Rigors/chills 
Rigors/chills 
Mild 
Moderate, narcotics 
indicated 
Severe or prolonged, not 
responsive to narcotics 
— 
— 
                                            
2 NHLBI Obesity Task Force. "Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults," The Evidence Report, Obes Res 6:51S-
209S, 1998.  

 
CONSTITUTIONAL SYMPTOMS 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 12 - 
March 31, 2003, Publish Date: August 9, 2006 
Sweating  
(diaphoresis) 
Sweating  
Mild and occasional 
Frequent or drenching 
— 
— 
— 
ALSO CONSIDER: Hot flashes/flushes.  
Weight gain  
Weight gain 
5 – <10% of baseline 
10 – <20% of baseline 
≥20% of baseline 
— 
— 
REMARK: Edema, depending on etiology, is graded in the CARDIAC GENERAL or LYMPHATICS CATEGORIES. 
ALSO CONSIDER: Ascites (non-malignant); Pleural effusion (non-malignant). 
Weight loss 
Weight loss 
5 to <10% from baseline; 
intervention not indicated 
10 – <20% from baseline; 
nutritional support 
indicated 
≥20% from baseline; tube 
feeding or TPN indicated 
— 
— 
Constitutional Symptoms 
– Other (Specify, __) 
Constitutional Symptoms 
– Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
DEATH 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 13 - 
March 31, 2003, Publish Date: August 9, 2006 
Death not associated with 
CTCAE term  
– Select: 
Death not associated with 
CTCAE term – Select 
– Death NOS 
– Disease progression NOS 
– Multi-organ failure 
– Sudden death 
— 
— 
— 
— 
Death 
REMARK: Grade 5 is the only appropriate grade. 'Death not associated with CTCAE term – Select' is to be used where a death: 
1. Cannot be attributed to a CTCAE term associated with Grade 5. 
2. Cannot be reported within any CATEGORY using a CTCAE 'Other (Specify, __)’.  

 
DERMATOLOGY/SKIN 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 14 - 
March 31, 2003, Publish Date: August 9, 2006 
Atrophy, skin 
Atrophy, skin 
Detectable 
Marked 
— 
— 
— 
Atrophy, subcutaneous 
fat 
Atrophy, subcutaneous 
fat 
Detectable 
Marked 
— 
— 
— 
ALSO CONSIDER: Induration/fibrosis (skin and subcutaneous tissue). 
Bruising  
(in absence of Grade 3 or 
4 thrombocytopenia) 
Bruising  
Localized or in a 
dependent area 
Generalized 
— 
— 
— 
Burn 
Burn 
Minimal symptoms; 
intervention not indicated  
Medical intervention; 
minimal debridement 
indicated  
Moderate to major 
debridement or 
reconstruction indicated  
Life-threatening 
consequences 
Death 
REMARK: Burn refers to all burns including radiation, chemical, etc. 
Cheilitis 
Cheilitis 
Asymptomatic 
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
— 
— 
Dry skin 
Dry skin 
Asymptomatic 
Symptomatic, not 
interfering with ADL 
Interfering with ADL 
— 
— 
Flushing 
Flushing 
Asymptomatic 
Symptomatic 
— 
— 
— 
Hair loss/alopecia 
(scalp or body) 
Alopecia 
Thinning or patchy 
Complete 
— 
— 
— 
Hyperpigmentation 
Hyperpigmentation 
Slight or localized 
Marked or generalized 
— 
— 
— 
Hypopigmentation 
Hypopigmentation 
Slight or localized 
Marked or generalized 
— 
— 
— 
Induration/fibrosis 
(skin and subcutaneous 
tissue) 
Induration  
Increased density on 
palpation 
Moderate impairment of 
function not interfering 
with ADL; marked 
increase in density and 
firmness on palpation 
with or without minimal 
retraction 
Dysfunction interfering 
with ADL; very marked 
density, retraction or 
fixation 
— 
— 
ALSO CONSIDER: Fibrosis-cosmesis; Fibrosis-deep connective tissue.  
Injection site reaction/ 
extravasation changes 
Injection site reaction 
Pain; itching; erythema 
Pain or swelling, with 
inflammation or phlebitis 
Ulceration or necrosis 
that is severe; operative 
intervention indicated  
— 
— 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever); Ulceration. 

 
DERMATOLOGY/SKIN 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 15 - 
March 31, 2003, Publish Date: August 9, 2006 
Nail changes 
Nail changes 
Discoloration; ridging 
(koilonychias); pitting 
Partial or complete loss of 
nail(s); pain in nailbed(s) 
Interfering with ADL  
— 
— 
NAVIGATION NOTE: Petechiae is graded as Petechiae/purpura (hemorrhage/bleeding into skin or mucosa) in the HEMORRHAGE/BLEEDING CATEGORY. 
Photosensitivity 
Photosensitivity 
Painless erythema 
Painful erythema 
Erythema with 
desquamation 
Life-threatening; disabling 
Death 
Pruritus/itching 
Pruritus 
Mild or localized 
Intense or widespread 
Intense or widespread 
and interfering with ADL  
— 
— 
ALSO CONSIDER: Rash/desquamation. 
Rash/desquamation  
Rash 
Macular or papular 
eruption or erythema 
without associated 
symptoms 
Macular or papular 
eruption or erythema with 
pruritus or other 
associated symptoms; 
localized desquamation 
or other lesions covering 
<50% of body surface 
area (BSA) 
Severe, generalized 
erythroderma or macular, 
papular or vesicular 
eruption; desquamation 
covering ≥50% BSA 
Generalized exfoliative, 
ulcerative, or bullous 
dermatitis 
Death 
REMARK: Rash/desquamation may be used for GVHD. 
Rash:  
acne/acneiform 
Acne 
Intervention not indicated  
Intervention indicated 
Associated with pain, 
disfigurement, ulceration, 
or desquamation 
— 
Death 
Rash:  
dermatitis associated with 
radiation  
– Select: 
– Chemoradiation 
– Radiation 
Dermatitis – Select  
Faint erythema or dry 
desquamation 
Moderate to brisk 
erythema; patchy moist 
desquamation, mostly 
confined to skin folds and 
creases; moderate 
edema 
Moist desquamation other 
than skin folds and 
creases; bleeding 
induced by minor trauma 
or abrasion 
Skin necrosis or 
ulceration of full thickness 
dermis; spontaneous 
bleeding from involved 
site  
Death 
Rash:  
erythema multiforme 
(e.g., Stevens-Johnson 
syndrome, toxic 
epidermal necrolysis) 
Erythema multiforme 
— 
Scattered, but not 
generalized eruption 
Severe (e.g., generalized 
rash or painful stomatitis); 
IV fluids, tube feedings, 
or TPN indicated 
Life-threatening; disabling 
Death 
Rash:  
hand-foot skin reaction 
Hand-foot 
Minimal skin changes or 
dermatitis (e.g., 
erythema) without pain  
Skin changes (e.g., 
peeling, blisters, 
bleeding, edema) or pain, 
not interfering with 
function  
Ulcerative dermatitis or 
skin changes with pain 
interfering with function  
— 
— 

 
DERMATOLOGY/SKIN 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 16 - 
March 31, 2003, Publish Date: August 9, 2006 
Skin breakdown/ 
decubitus ulcer 
Decubitus  
— 
Local wound care; 
medical intervention 
indicated 
Operative debridement or 
other invasive 
intervention indicated 
(e.g., hyperbaric oxygen)  
Life-threatening 
consequences; major 
invasive intervention 
indicated (e.g., tissue 
reconstruction, flap, or 
grafting) 
Death 
REMARK: Skin breakdown/decubitus ulcer is to be used for loss of skin integrity or decubitus ulcer from pressure or as the result of operative or medical intervention. 
Striae 
Striae 
Mild 
Cosmetically significant 
— 
— 
— 
Telangiectasia 
Telangiectasia 
Few 
Moderate number 
Many and confluent 
— 
— 
Ulceration 
Ulceration 
— 
Superficial ulceration  
<2 cm size; local wound 
care; medical intervention 
indicated 
Ulceration ≥2 cm size; 
operative debridement, 
primary closure or other 
invasive intervention 
indicated (e.g., hyperbaric 
oxygen)  
Life-threatening 
consequences; major 
invasive intervention 
indicated (e.g., complete 
resection, tissue 
reconstruction, flap, or 
grafting) 
Death 
Urticaria  
(hives, welts, wheals) 
Urticaria 
Intervention not indicated 
Intervention indicated for 
<24 hrs 
Intervention indicated for 
≥24 hrs 
— 
— 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever). 
Wound complication, 
non-infectious  
Wound complication, 
non-infectious 
Incisional separation of  
≤25% of wound, no 
deeper than superficial 
fascia 
Incisional separation 
>25% of wound with local 
care; asymptomatic 
hernia 
Symptomatic hernia 
without evidence of 
strangulation; fascial 
disruption/dehiscence 
without evisceration; 
primary wound closure or 
revision by operative 
intervention indicated; 
hospitalization or 
hyperbaric oxygen 
indicated 
Symptomatic hernia with 
evidence of strangulation; 
fascial disruption with 
evisceration; major 
reconstruction flap, 
grafting, resection, or 
amputation indicated 
Death 
REMARK: Wound complication, non-infectious is to be used for separation of incision, hernia, dehiscence, evisceration, or second surgery for wound revision. 
Dermatology/Skin – Other 
(Specify, __) 
Dermatology – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
ENDOCRINE 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 17 - 
March 31, 2003, Publish Date: August 9, 2006 
Adrenal insufficiency 
Adrenal insufficiency 
Asymptomatic, 
intervention not indicated 
Symptomatic, intervention 
indicated 
Hospitalization  
Life-threatening; disabling 
Death 
REMARK: Adrenal insufficiency includes any of the following signs and symptoms: abdominal pain, anorexia, constipation, diarrhea, hypotension, pigmentation of mucous membranes, 
pigmentation of skin, salt craving, syncope (fainting), vitiligo, vomiting, weakness, weight loss. Adrenal insufficiency must be confirmed by laboratory studies (low cortisol frequently 
accompanied by low aldosterone). 
ALSO CONSIDER: Potassium, serum-high (hyperkalemia); Thyroid function, low (hypothyroidism). 
Cushingoid appearance 
(e.g., moon face, buffalo 
hump, centripetal obesity, 
cutaneous striae) 
Cushingoid  
— 
Present 
— 
— 
— 
ALSO CONSIDER: Glucose, serum-high (hyperglycemia); Potassium, serum-low (hypokalemia). 
Feminization of male 
Feminization of male 
— 
— 
Present 
— 
— 
NAVIGATION NOTE: Gynecomastia is graded in the SEXUAL/REPRODUCTIVE FUNCTION CATEGORY. 
Hot flashes/flushes3 
Hot flashes 
Mild  
Moderate  
Interfering with ADL 
— 
— 
Masculinization of female 
Masculinization of female 
— 
— 
Present 
— 
— 
Neuroendocrine: 
ACTH deficiency 
ACTH  
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL; hospitalization 
indicated 
Life-threatening 
consequences (e.g., 
severe hypotension) 
Death 
Neuroendocrine: 
ADH secretion 
abnormality (e.g., SIADH 
or low ADH) 
ADH 
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL 
Life-threatening 
consequences 
Death 
Neuroendocrine: 
gonadotropin secretion 
abnormality 
Gonadotropin 
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL; osteopenia; 
fracture; infertility 
— 
— 
Neuroendocrine:  
growth hormone 
secretion abnormality 
Growth hormone  
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
— 
— 
— 
Neuroendocrine:  
prolactin hormone 
secretion abnormality 
Prolactin  
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL; amenorrhea; 
galactorrhea 
— 
Death 
                                            
3 Sloan JA, Loprinzi CL, Novotny PJ, Barton DL, Lavasseur BI, Windschitl HJ, "Methodologic Lessons Learned from Hot Flash Studies," J Clin Oncol 2001 Dec 1;19(23):4280-90 

 
ENDOCRINE 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 18 - 
March 31, 2003, Publish Date: August 9, 2006 
Pancreatic endocrine:  
glucose intolerance 
Diabetes 
Asymptomatic, 
intervention not indicated 
Symptomatic; dietary 
modification or oral agent 
indicated 
Symptoms interfering with 
ADL; insulin indicated 
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar non-ketotic 
coma)  
Death 
Parathyroid function, low 
(hypoparathyroidism) 
Hypoparathyroidism 
Asymptomatic, 
intervention not indicated 
Symptomatic; intervention 
indicated 
— 
— 
— 
Thyroid function, high 
(hyperthyroidism, 
thyrotoxicosis) 
Hyperthyroidism  
Asymptomatic, 
intervention not indicated 
Symptomatic, not 
interfering with ADL; 
thyroid suppression 
therapy indicated 
Symptoms interfering with 
ADL; hospitalization 
indicated  
Life-threatening 
consequences (e.g., 
thyroid storm) 
Death 
Thyroid function, low 
(hypothyroidism) 
Hypothyroidism 
Asymptomatic, 
intervention not indicated 
Symptomatic, not 
interfering with ADL; 
thyroid replacement 
indicated 
Symptoms interfering with 
ADL; hospitalization 
indicated  
Life-threatening 
myxedema coma 
Death 
Endocrine – Other  
(Specify, __) 
Endocrine – Other  
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
GASTROINTESTINAL 
Page 1 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 19 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Abdominal pain or cramping is graded as Pain – Select in the PAIN CATEGORY. 
Anorexia 
Anorexia 
Loss of appetite without 
alteration in eating habits 
Oral intake altered 
without significant weight 
loss or malnutrition; oral 
nutritional supplements 
indicated 
Associated with 
significant weight loss or 
malnutrition (e.g., 
inadequate oral caloric 
and/or fluid intake); IV 
fluids, tube feedings or 
TPN indicated 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Weight loss. 
Ascites (non-malignant) 
Ascites 
Asymptomatic 
Symptomatic, medical 
intervention indicated 
Symptomatic, invasive 
procedure indicated 
Life-threatening 
consequences 
Death 
REMARK: Ascites (non-malignant) refers to documented non-malignant ascites or unknown etiology, but unlikely malignant, and includes chylous ascites. 
Colitis 
Colitis 
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain; mucus 
or blood in stool 
Abdominal pain, fever, 
change in bowel habits 
with ileus; peritoneal 
signs 
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis, toxic 
megacolon) 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select.  
Constipation 
Constipation 
Occasional or intermittent 
symptoms; occasional 
use of stool softeners, 
laxatives, dietary 
modification, or enema 
Persistent symptoms with 
regular use of laxatives 
or enemas indicated 
Symptoms interfering 
with ADL; obstipation 
with manual evacuation 
indicated  
Life-threatening 
consequences (e.g., 
obstruction, toxic 
megacolon) 
Death 
ALSO CONSIDER: Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation); Obstruction, GI – Select. 
Dehydration 
Dehydration 
Increased oral fluids 
indicated; dry mucous 
membranes; diminished 
skin turgor 
IV fluids indicated <24 
hrs 
IV fluids indicated ≥24 hrs 
Life-threatening 
consequences (e.g., 
hemodynamic collapse) 
Death 
ALSO CONSIDER: Diarrhea; Hypotension; Vomiting. 
Dental:  
dentures or prosthesis 
Dentures  
Minimal discomfort, no 
restriction in activities  
Discomfort preventing 
use in some activities 
(e.g., eating), but not 
others (e.g., speaking) 
Unable to use dentures 
or prosthesis at any time 
— 
— 

 
GASTROINTESTINAL 
Page 2 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 20 - 
March 31, 2003, Publish Date: August 9, 2006 
Dental:  
periodontal disease  
Periodontal  
Gingival recession or 
gingivitis; limited bleeding 
on probing; mild local 
bone loss 
Moderate gingival 
recession or gingivitis; 
multiple sites of bleeding 
on probing; moderate 
bone loss 
Spontaneous bleeding; 
severe bone loss with or 
without tooth loss; 
osteonecrosis of maxilla 
or mandible  
— 
— 
REMARK: Severe periodontal disease leading to osteonecrosis is graded as Osteonecrosis (avascular necrosis) in the MUSCULOSKELETAL CATEGORY. 
Dental: 
teeth  
Teeth 
Surface stains; dental 
caries; restorable, without 
extractions 
Less than full mouth 
extractions; tooth fracture 
or crown amputation or 
repair indicated 
Full mouth extractions 
indicated 
— 
— 
Dental:  
teeth development 
Teeth development 
Hypoplasia of tooth or 
enamel not interfering 
with function 
Functional impairment 
correctable with oral 
surgery 
Maldevelopment with 
functional impairment not 
surgically correctable 
— 
— 
Diarrhea 
Diarrhea 
Increase of <4 stools per 
day over baseline; mild 
increase in ostomy output 
compared to baseline 
Increase of 4 – 6 stools 
per day over baseline; IV 
fluids indicated <24hrs; 
moderate increase in 
ostomy output compared 
to baseline; not 
interfering with ADL 
Increase of ≥7 stools per 
day over baseline; 
incontinence; IV fluids 
≥24 hrs; hospitalization; 
severe increase in 
ostomy output compared 
to baseline; interfering 
with ADL 
Life-threatening 
consequences (e.g., 
hemodynamic collapse) 
Death 
REMARK: Diarrhea includes diarrhea of small bowel or colonic origin, and/or ostomy diarrhea. 
ALSO CONSIDER: Dehydration; Hypotension. 
Distension/bloating, 
abdominal 
Distension 
Asymptomatic  
Symptomatic, but not 
interfering with GI 
function 
Symptomatic, interfering 
with GI function 
— 
— 
ALSO CONSIDER: Ascites (non-malignant); Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation); Obstruction, GI – Select.  

 
GASTROINTESTINAL 
Page 3 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 21 - 
March 31, 2003, Publish Date: August 9, 2006 
Dry mouth/salivary gland 
(xerostomia) 
Dry mouth 
Symptomatic (dry or thick 
saliva) without significant 
dietary alteration; 
unstimulated saliva flow 
>0.2 ml/min 
Symptomatic and 
significant oral intake 
alteration (e.g., copious 
water, other lubricants, 
diet limited to purees 
and/or soft, moist foods); 
unstimulated saliva 
0.1 to 0.2 ml/min 
Symptoms leading to 
inability to adequately 
aliment orally; IV fluids, 
tube feedings, or TPN 
indicated; unstimulated 
saliva <0.1 ml/min 
— 
— 
REMARK: Dry mouth/salivary gland (xerostomia) includes descriptions of grade using both subjective and objective assessment parameters. Record this event consistently throughout 
a patient’s participation on study. If salivary flow measurements are used for initial assessment, subsequent assessments must use salivary flow. 
ALSO CONSIDER: Salivary gland changes/saliva.  
Dysphagia 
(difficulty swallowing) 
Dysphagia 
Symptomatic, able to eat 
regular diet  
Symptomatic and altered 
eating/swallowing (e.g., 
altered dietary habits, 
oral supplements); IV 
fluids indicated <24 hrs 
Symptomatic and 
severely altered 
eating/swallowing (e.g., 
inadequate oral caloric or 
fluid intake); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences (e.g., 
obstruction, perforation) 
 
Death 
REMARK: Dysphagia (difficulty swallowing) is to be used for swallowing difficulty from oral, pharyngeal, esophageal, or neurologic origin. Dysphagia requiring dilation is graded as 
Stricture/stenosis (including anastomotic), GI – Select. 
ALSO CONSIDER: Dehydration; Esophagitis. 
Enteritis  
(inflammation of the small 
bowel) 
Enteritis 
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain; mucus 
or blood in stool 
Abdominal pain, fever, 
change in bowel habits 
with ileus; peritoneal 
signs 
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis) 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select; Typhlitis (cecal inflammation).  
Esophagitis 
Esophagitis 
Asymptomatic pathologic, 
radiographic, or 
endoscopic findings only 
Symptomatic; altered 
eating/swallowing (e.g., 
altered dietary habits, 
oral supplements); IV 
fluids indicated <24 hrs 
Symptomatic and 
severely altered 
eating/swallowing (e.g., 
inadequate oral caloric or 
fluid intake); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences 
Death 
REMARK: Esophagitis includes reflux esophagitis.  
ALSO CONSIDER: Dysphagia (difficulty swallowing). 

 
GASTROINTESTINAL 
Page 4 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 22 - 
March 31, 2003, Publish Date: August 9, 2006 
Fistula, GI 
– Select: 
Fistula, GI – Select  
– Abdomen NOS 
– Anus 
– Biliary tree  
– Colon/cecum/appendix 
– Duodenum 
– Esophagus 
– Gallbladder  
– Ileum 
– Jejunum 
– Oral cavity 
– Pancreas 
– Pharynx 
– Rectum 
– Salivary gland  
– Small bowel NOS 
– Stomach 
Asymptomatic, 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, diarrhea, 
or GI fluid loss); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered GI 
function (e.g., altered 
dietary habits, diarrhea, 
or GI fluid loss); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences  
Death 
REMARK: A fistula is defined as an abnormal communication between two body cavities, potential spaces, and/or the skin. The site indicated for a fistula should be the site from which 
the abnormal process is believed to have originated. For example, a tracheo-esophageal fistula arising in the context of a resected or irradiated esophageal cancer is graded as 
Fistula, GI – esophagus. 
Flatulence 
Flatulence 
Mild 
Moderate 
— 
— 
— 
Gastritis (including bile 
reflux gastritis) 
Gastritis 
Asymptomatic 
radiographic or 
endoscopic findings only 
Symptomatic; altered 
gastric function (e.g., 
inadequate oral caloric or 
fluid intake); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered gastric 
function (e.g., inadequate 
oral caloric or fluid 
intake); IV fluids, tube 
feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., gastrectomy)  
Death 
ALSO CONSIDER: Hemorrhage, GI – Select; Ulcer, GI – Select. 
NAVIGATION NOTE: Head and neck soft tissue necrosis is graded as Soft tissue necrosis – Select in the MUSCULOSKELETAL/SOFT TISSUE CATEGORY. 
Heartburn/dyspepsia 
Heartburn 
Mild 
Moderate 
Severe 
— 
— 
Hemorrhoids 
Hemorrhoids 
Asymptomatic 
Symptomatic; banding or 
medical intervention 
indicated 
Interfering with ADL; 
interventional radiology, 
endoscopic, or operative 
intervention indicated 
Life-threatening 
consequences 
Death 

 
GASTROINTESTINAL 
Page 5 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 23 - 
March 31, 2003, Publish Date: August 9, 2006 
Ileus, GI (functional 
obstruction of bowel, i.e., 
neuroconstipation) 
Ileus 
Asymptomatic, 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered GI 
function; IV fluids, tube 
feeding, or TPN indicated 
≥24 hrs 
Life-threatening 
consequences 
Death 
REMARK: Ileus, GI is to be used for altered upper or lower GI function (e.g., delayed gastric or colonic emptying). 
ALSO CONSIDER: Constipation; Nausea; Obstruction, GI – Select; Vomiting. 
Incontinence, anal 
Incontinence, anal 
Occasional use of pads 
required 
Daily use of pads 
required 
Interfering with ADL; 
operative intervention 
indicated 
Permanent bowel 
diversion indicated 
Death 
REMARK: Incontinence, anal is to be used for loss of sphincter control as sequelae of operative or therapeutic intervention. 
Leak (including 
anastomotic), GI 
– Select: 
– Biliary tree 
– Esophagus 
– Large bowel 
– Leak NOS 
– Pancreas 
– Pharynx 
– Rectum 
– Small bowel  
– Stoma 
– Stomach 
Leak, GI – Select  
Asymptomatic 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and 
interfering with GI 
function; invasive or 
endoscopic intervention 
indicated  
Life-threatening 
consequences 
Death 
REMARK: Leak (including anasomotic), GI – Select is to be used for clinical signs/symptoms or radiographic confirmation of anastomotic or conduit leak (e.g., biliary, esophageal, 
intestinal, pancreatic, pharyngeal, rectal), but without development of fistula. 
Malabsorption  
Malabsorption 
— 
Altered diet; oral 
therapies indicated (e.g., 
enzymes, medications, 
dietary supplements)  
Inability to aliment 
adequately via GI tract 
(i.e., TPN indicated) 
Life-threatening 
consequences 
Death 

 
GASTROINTESTINAL 
Page 6 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 24 - 
March 31, 2003, Publish Date: August 9, 2006 
Mucositis/stomatitis 
(clinical exam)  
– Select: 
– Anus 
– Esophagus 
– Large bowel 
– Larynx 
– Oral cavity 
– Pharynx 
– Rectum 
– Small bowel 
– Stomach 
– Trachea 
Mucositis (clinical exam) 
– Select  
Erythema of the mucosa 
Patchy ulcerations or 
pseudomembranes  
Confluent ulcerations or 
pseudomembranes; 
bleeding with minor 
trauma 
Tissue necrosis; 
significant spontaneous 
bleeding; life-threatening 
consequences 
Death 
REMARK: Mucositis/stomatitis (functional/symptomatic) may be used for mucositis of the upper aero-digestive tract caused by radiation, agents, or GVHD.  
Mucositis/stomatitis 
(functional/symptomatic)  
– Select: 
– Anus 
– Esophagus 
– Large bowel 
– Larynx 
– Oral cavity 
– Pharynx 
– Rectum 
– Small bowel 
– Stomach 
– Trachea 
Mucositis (functional/ 
symptomatic) – Select  
Upper aerodigestive tract 
sites: Minimal symptoms, 
normal diet; minimal 
respiratory symptoms but 
not interfering with 
function 
Lower GI sites: 
Minimal discomfort, 
intervention not indicated 
Upper aerodigestive tract 
sites: Symptomatic but 
can eat and swallow 
modified diet; respiratory 
symptoms interfering with 
function but not 
interfering with ADL 
Lower GI sites:  
Symptomatic, medical 
intervention indicated but 
not interfering with ADL 
Upper aerodigestive tract 
sites: Symptomatic and 
unable to adequately 
aliment or hydrate orally; 
respiratory symptoms 
interfering with ADL 
Lower GI sites: 
Stool incontinence or 
other symptoms 
interfering with ADL 
Symptoms associated 
with life-threatening 
consequences  
Death 
Nausea 
Nausea 
Loss of appetite without 
alteration in eating habits 
Oral intake decreased 
without significant weight 
loss, dehydration or 
malnutrition; IV fluids 
indicated <24 hrs 
Inadequate oral caloric or 
fluid intake; IV fluids, tube 
feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Anorexia; Vomiting. 

 
GASTROINTESTINAL 
Page 7 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 25 - 
March 31, 2003, Publish Date: August 9, 2006 
Necrosis, GI 
– Select:  
Necrosis, GI – Select  
– Anus 
– Colon/cecum/appendix 
– Duodenum 
– Esophagus 
– Gallbladder 
– Hepatic 
– Ileum 
– Jejunum 
– Oral 
– Pancreas 
– Peritoneal cavity 
– Pharynx  
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
— 
— 
Inability to aliment 
adequately by GI tract 
(e.g., requiring enteral or 
parenteral nutrition); 
interventional radiology, 
endoscopic, or operative 
intervention indicated  
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., total colectomy)  
Death 
ALSO CONSIDER: Visceral arterial ischemia (non-myocardial). 
Obstruction, GI 
– Select: 
– Cecum 
– Colon 
– Duodenum 
– Esophagus 
– Gallbladder 
– Ileum 
– Jejunum 
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
Obstruction, GI – Select 
Asymptomatic 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, vomiting, 
diarrhea, or GI fluid loss); 
IV fluids indicated <24 
hrs 
Symptomatic and 
severely altered GI 
function (e.g., altered 
dietary habits, vomiting, 
diarrhea, or GI fluid loss); 
IV fluids, tube feedings, 
or TPN indicated ≥24 hrs; 
operative intervention 
indicated 
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., total colectomy)  
Death 
NAVIGATION NOTE: Operative injury is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY CATEGORY. 
NAVIGATION NOTE: Pelvic pain is graded as Pain – Select in the PAIN CATEGORY. 

 
GASTROINTESTINAL 
Page 8 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 26 - 
March 31, 2003, Publish Date: August 9, 2006 
Perforation, GI 
– Select: 
– Appendix 
– Biliary tree 
– Cecum 
– Colon 
– Duodenum 
– Esophagus 
– Gallbladder 
– Ileum 
– Jejunum 
– Rectum 
– Small bowel NOS 
– Stomach 
Perforation, GI – Select 
Asymptomatic 
radiographic findings only 
Medical intervention 
indicated; IV fluids 
indicated <24 hrs 
IV fluids, tube feedings, 
or TPN indicated ≥24 hrs; 
operative intervention 
indicated 
Life-threatening 
consequences 
Death 
Proctitis  
Proctitis 
Rectal discomfort, 
intervention not indicated 
Symptoms not interfering 
with ADL; medical 
intervention indicated  
Stool incontinence or 
other symptoms 
interfering with ADL; 
operative intervention 
indicated 
Life-threatening 
consequences (e.g., 
perforation) 
Death 
Prolapse of stoma, GI 
Prolapse of stoma, GI 
Asymptomatic  
Extraordinary local care 
or maintenance; minor 
revision indicated 
Dysfunctional stoma; 
major revision indicated  
Life-threatening 
consequences 
Death 
REMARK: Other stoma complications may be graded as Fistula, GI – Select; Leak (including anastomotic), GI – Select; Obstruction, GI – Select; Perforation, GI – Select; 
Stricture/stenosis (including anastomotic), GI – Select. 
NAVIGATION NOTE: Rectal or perirectal pain (proctalgia) is graded as Pain – Select in the PAIN CATEGORY.  
Salivary gland 
changes/saliva 
Salivary gland changes 
Slightly thickened saliva; 
slightly altered taste (e.g., 
metallic) 
Thick, ropy, sticky saliva; 
markedly altered taste; 
alteration in diet 
indicated; secretion-
induced symptoms not 
interfering with ADL 
Acute salivary gland 
necrosis; severe 
secretion-induced 
symptoms interfering with 
ADL  
Disabling 
— 
ALSO CONSIDER: Dry mouth/salivary gland (xerostomia); Mucositis/stomatitis (clinical exam) – Select; Mucositis/stomatitis (functional/symptomatic) – Select; Taste alteration 
(dysgeusia). 
NAVIGATION NOTE: Splenic function is graded in the BLOOD/BONE MARROW CATEGORY. 

 
GASTROINTESTINAL 
Page 9 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 27 - 
March 31, 2003, Publish Date: August 9, 2006 
Stricture/stenosis 
(including anastomotic), 
GI 
– Select:  
Stricture, GI – Select  
– Anus 
– Biliary tree 
– Cecum 
– Colon  
– Duodenum  
– Esophagus 
– Ileum 
– Jejunum 
– Pancreas/pancreatic duct 
– Pharynx 
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
Asymptomatic 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, vomiting, 
bleeding, diarrhea); IV 
fluids indicated <24 hrs 
Symptomatic and 
severely altered GI 
function (e.g., altered 
dietary habits, diarrhea, 
or GI fluid loss); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs; 
operative intervention 
indicated 
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., total colectomy)  
Death 
Taste alteration 
(dysgeusia) 
Taste alteration 
Altered taste but no 
change in diet 
Altered taste with change 
in diet (e.g., oral 
supplements); noxious or 
unpleasant taste; loss of 
taste 
— 
— 
— 
Typhlitis 
(cecal inflammation) 
Typhlitis 
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain; mucus 
or blood in stool 
Abdominal pain, fever, 
change in bowel habits 
with ileus; peritoneal 
signs 
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis); 
operative intervention 
indicated 
Death 
ALSO CONSIDER: Colitis; Hemorrhage, GI – Select ; Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation).  

 
GASTROINTESTINAL 
Page 10 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 28 - 
March 31, 2003, Publish Date: August 9, 2006 
Ulcer, GI 
– Select: 
– Anus 
– Cecum 
– Colon 
– Duodenum 
– Esophagus 
– Ileum 
– Jejunum 
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
Ulcer, GI – Select 
Asymptomatic, 
radiographic or 
endoscopic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, oral 
supplements); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered GI 
function (e.g., inadequate 
oral caloric or fluid 
intake); IV fluids, tube 
feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select. 
Vomiting 
Vomiting 
1 episode in 24 hrs 
2 – 5 episodes in 24 hrs; 
IV fluids indicated  
<24 hrs 
≥6 episodes in 24 hrs; IV 
fluids, or TPN indicated 
≥24 hrs 
Life-threatening 
consequences  
Death 
ALSO CONSIDER: Dehydration. 
Gastrointestinal – Other 
(Specify, __) 
GI – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling 
Death 

 
GROWTH AND DEVELOPMENT 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 29 - 
March 31, 2003, Publish Date: August 9, 2006 
Bone age 
(alteration in bone age) 
Bone age 
— 
+2 SD (standard 
deviation) from normal 
— 
— 
— 
Bone growth: 
femoral head; slipped 
capital femoral epiphysis 
Femoral head growth 
Mild valgus/varus 
deformity 
Moderate valgus/varus 
deformity, symptomatic, 
interfering with function 
but not interfering with 
ADL 
Mild slipped capital 
femoral epiphysis; 
operative intervention 
(e.g., fixation) indicated; 
interfering with ADL 
Disabling; severe slipped 
capital femoral epiphysis 
>60%; avascular necrosis 
— 
Bone growth: 
limb length discrepancy 
Limb length  
Mild length discrepancy 
<2 cm 
Moderate length 
discrepancy 2 – 5 cm; 
shoe lift indicated 
Severe length 
discrepancy >5 cm; 
operative intervention 
indicated; interfering with 
ADL 
Disabling; epiphysiodesis 
— 
Bone growth: 
spine kyphosis/lordosis 
Kyphosis/lordosis 
Mild radiographic 
changes  
Moderate accentuation; 
interfering with function 
but not interfering with 
ADL 
Severe accentuation; 
operative intervention 
indicated; interfering with 
ADL 
Disabling (e.g., cannot lift 
head) 
— 
Growth velocity 
(reduction in growth 
velocity) 
Reduction in growth 
velocity 
10 – 29% reduction in 
growth from the baseline 
growth curve 
30 – 49% reduction in 
growth from the baseline 
growth curve 
≥50% reduction in growth 
from the baseline growth 
curve  
— 
— 
Puberty (delayed) 
Delayed puberty 
— 
No breast development 
by age 13 yrs for females; 
no Tanner Stage 2 
development by age 14.5 
yrs for males 
No sexual development 
by age 14 yrs for girls, 
age 16 yrs for boys; 
hormone replacement 
indicated 
— 
— 
REMARK: Do not use testicular size for Tanner Stage in male cancer survivors. 
Puberty (precocious)  
Precocious puberty 
— 
Physical signs of puberty 
<7 years for females,  
<9 years for males 
— 
— 
— 
Short stature 
Short stature 
Beyond two standard 
deviations of age and 
gender mean height 
Altered ADL 
— 
— 
— 
REMARK: Short stature is secondary to growth hormone deficiency. 
ALSO CONSIDER: Neuroendocrine: growth hormone secretion abnormality. 
Growth and Development 
– Other (Specify, __) 
Growth and Development 
– Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
HEMORRHAGE/BLEEDING 
Page 1 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 30 - 
March 31, 2003, Publish Date: August 9, 2006 
Hematoma  
Hematoma 
Minimal symptoms, 
invasive intervention not 
indicated  
Minimally invasive 
evacuation or aspiration 
indicated 
Transfusion, 
interventional radiology, 
or operative intervention 
indicated 
Life-threatening 
consequences; major 
urgent intervention 
indicated 
Death 
REMARK: Hematoma refers to extravasation at wound or operative site or secondary to other intervention. Transfusion implies pRBC.  
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Hemorrhage/bleeding 
associated with surgery, 
intra-operative or 
postoperative 
Hemorrhage with surgery 
— 
— 
Requiring transfusion of  
2 units non-autologous 
(10 cc/kg for pediatrics) 
pRBCs beyond protocol 
specification; 
postoperative 
interventional radiology, 
endoscopic, or operative 
intervention indicated 
Life-threatening 
consequences  
Death 
REMARK: Postoperative period is defined as ≤72 hours after surgery. Verify protocol-specific acceptable guidelines regarding pRBC transfusion. 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Hemorrhage, CNS 
CNS hemorrhage 
Asymptomatic, 
radiographic findings only 
Medical intervention 
indicated  
Ventriculostomy, ICP 
monitoring, 
intraventricular 
thrombolysis, or operative 
intervention indicated 
Life-threatening 
consequences; 
neurologic deficit or 
disability 
Death 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 

 
HEMORRHAGE/BLEEDING 
Page 2 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 31 - 
March 31, 2003, Publish Date: August 9, 2006 
Hemorrhage, GI  
– Select: 
– Abdomen NOS 
– Anus 
– Biliary tree  
– Cecum/appendix  
– Colon 
– Duodenum 
– Esophagus 
– Ileum 
– Jejunum 
– Liver 
– Lower GI NOS 
– Oral cavity 
– Pancreas 
– Peritoneal cavity 
– Rectum 
– Stoma 
– Stomach 
– Upper GI NOS 
– Varices (esophageal) 
– Varices (rectal) 
Hemorrhage, GI – Select 
Mild, intervention (other 
than iron supplements) 
not indicated 
Symptomatic and medical 
intervention or minor 
cauterization indicated 
Transfusion, 
interventional radiology, 
endoscopic, or operative 
intervention indicated; 
radiation therapy (i.e., 
hemostasis of bleeding 
site) 
Life-threatening 
consequences; major 
urgent intervention 
indicated  
Death 
REMARK: Transfusion implies pRBC. 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 

 
HEMORRHAGE/BLEEDING 
Page 3 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 32 - 
March 31, 2003, Publish Date: August 9, 2006 
Hemorrhage, GU  
– Select:  
– Bladder 
– Fallopian tube 
– Kidney 
– Ovary 
– Prostate  
– Retroperitoneum  
– Spermatic cord 
– Stoma 
– Testes 
– Ureter 
– Urethra 
– Urinary NOS 
– Uterus 
– Vagina 
– Vas deferens 
Hemorrhage, GU – Select 
Minimal or microscopic 
bleeding; intervention not 
indicated 
Gross bleeding, medical 
intervention, or urinary 
tract irrigation indicated 
Transfusion, 
interventional radiology, 
endoscopic, or operative 
intervention indicated; 
radiation therapy (i.e., 
hemostasis of bleeding 
site) 
Life-threatening 
consequences; major 
urgent intervention 
indicated 
Death 
REMARK: Transfusion implies pRBC. 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Hemorrhage, pulmonary/ 
upper respiratory  
– Select: 
Hemorrhage pulmonary  
– Select 
– Bronchopulmonary NOS 
– Bronchus  
– Larynx  
– Lung  
– Mediastinum 
– Nose 
– Pharynx 
– Pleura 
– Respiratory tract NOS 
– Stoma 
– Trachea 
Mild, intervention not 
indicated 
Symptomatic and 
medical intervention 
indicated 
Transfusion, 
interventional radiology, 
endoscopic, or operative 
intervention indicated; 
radiation therapy (i.e., 
hemostasis of bleeding 
site) 
Life-threatening 
consequences; major 
urgent intervention 
indicated 
Death 
REMARK: Transfusion implies pRBC.  
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Petechiae/purpura 
(hemorrhage/bleeding 
into skin or mucosa) 
Petechiae 
Few petechiae 
Moderate petechiae; 
purpura 
Generalized petechiae or 
purpura 
— 
— 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 

 
HEMORRHAGE/BLEEDING 
Page 4 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 33 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Vitreous hemorrhage is graded in the OCULAR/VISUAL CATEGORY. 
Hemorrhage/Bleeding – 
Other (Specify, __) 
Hemorrhage – Other 
(Specify) 
Mild without transfusion 
— 
Transfusion indicated 
Catastrophic bleeding, 
requiring major non-
elective intervention 
Death 

 
HEPATOBILIARY/PANCREAS 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 34 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Biliary tree damage is graded as Fistula, GI – Select; Leak (including anastomotic), GI – Select; Necrosis, GI – Select; Obstruction, GI – Select; Perforation, GI – 
Select; Stricture/stenosis (including anastomotic), GI – Select in the GASTROINTESTINAL CATEGORY. 
Cholecystitis 
Cholecystitis 
Asymptomatic, 
radiographic findings only 
Symptomatic, medical 
intervention indicated 
Interventional radiology, 
endoscopic, or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
sepsis or perforation)  
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection 
with unknown ANC – Select.  
Liver dysfunction/failure 
(clinical)  
Liver dysfunction  
— 
Jaundice  
Asterixis 
Encephalopathy or coma 
Death 
REMARK: Jaundice is not an AE, but occurs when the liver is not working properly or when a bile duct is blocked. It is graded as a result of liver dysfunction/failure or elevated bilirubin. 
ALSO CONSIDER: Bilirubin (hyperbilirubinemia). 
Pancreas, exocrine 
enzyme deficiency 
Pancreas, exocrine 
enzyme deficiency 
— 
Increase in stool 
frequency, bulk, or odor; 
steatorrhea 
Sequelae of absorption 
deficiency (e.g., weight 
loss)  
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Diarrhea. 
Pancreatitis  
Pancreatitis 
Asymptomatic, enzyme 
elevation and/or 
radiographic findings  
Symptomatic, medical 
intervention indicated 
Interventional radiology or 
operative intervention 
indicated 
Life-threatening 
consequences 
(e.g., circulatory failure, 
hemorrhage, sepsis) 
Death 
ALSO CONSIDER: Amylase. 
NAVIGATION NOTE: Stricture (biliary tree, hepatic or pancreatic) is graded as Stricture/stenosis (including anastomotic), GI – Select in the GASTROINTESTINAL CATEGORY. 
Hepatobiliary/Pancreas – 
Other (Specify, __) 
Hepatobiliary – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
INFECTION 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 35 - 
March 31, 2003, Publish Date: August 9, 2006 
Colitis, infectious 
(e.g., Clostridium difficile) 
Colitis, infectious  
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain with 
mucus and/or blood in 
stool 
IV antibiotics or TPN 
indicated  
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis or 
toxic megacolon); 
operative resection or 
diversion indicated 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select; Typhlitis (cecal inflammation).  
Febrile neutropenia 
(fever of unknown origin 
without clinically or 
microbiologically 
documented infection) 
(ANC <1.0 x 109/L, fever 
≥38.5°C) 
Febrile neutropenia 
— 
— 
Present 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
ALSO CONSIDER: Neutrophils/granulocytes (ANC/AGC). 
Infection  
(documented clinically or 
microbiologically) with 
Grade 3 or 4 neutrophils  
(ANC <1.0 x 109/L) 
– Select  
‘Select’ AEs appear at the 
end of the CATEGORY. 
Infection (documented 
clinically) with Grade 3 or 
4 ANC – Select 
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
REMARK: Fever with Grade 3 or 4 neutrophils in the absence of documented infection is graded as Febrile neutropenia (fever of unknown origin without clinically or microbiologically 
documented infection). 
ALSO CONSIDER: Neutrophils/granulocytes (ANC/AGC). 
Infection with normal 
ANC or Grade 1 or 2 
neutrophils  
– Select  
‘Select’ AEs appear at the 
end of the CATEGORY. 
Infection with normal 
ANC – Select 
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 

 
INFECTION 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 36 - 
March 31, 2003, Publish Date: August 9, 2006 
Infection with unknown 
ANC 
– Select  
‘Select’ AEs appear at the 
end of the CATEGORY. 
Infection with unknown 
ANC – Select 
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
REMARK: Infection with unknown ANC – Select is to be used in the rare case when ANC is unknown. 
Opportunistic infection 
associated with ≥Grade 2 
Lymphopenia 
Opportunistic infection  
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
ALSO CONSIDER: Lymphopenia. 
Viral hepatitis 
Viral hepatitis 
Present; transaminases 
and liver function normal 
Transaminases 
abnormal, liver function 
normal  
Symptomatic liver 
dysfunction; fibrosis by 
biopsy; compensated 
cirrhosis 
Decompensated liver 
function (e.g., ascites, 
coagulopathy, 
encephalopathy, coma) 
Death 
REMARK: Non-viral hepatitis is graded as Infection – Select. 
ALSO CONSIDER: Albumin, serum-low (hypoalbuminemia); ALT, SGPT (serum glutamic pyruvic transaminase); AST, SGOT (serum glutamic oxaloacetic transaminase); Bilirubin 
(hyperbilirubinemia); Encephalopathy. 
Infection – Other 
(Specify, __) 
Infection – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
INFECTION – SELECT 
Page 3 of 3 
CTCAE v3.0  
- 37 - 
March 31, 2003, Publish Date: August 9, 2006 
AUDITORY/EAR 
– External ear (otitis externa) 
– Middle ear (otitis media) 
CARDIOVASCULAR 
– Artery 
– Heart (endocarditis) 
– Spleen 
– Vein 
DERMATOLOGY/SKIN  
– Lip/perioral 
– Peristomal 
– Skin (cellulitis) 
– Ungual (nails) 
GASTROINTESTINAL  
– Abdomen NOS 
– Anal/perianal 
– Appendix 
– Cecum 
– Colon 
– Dental-tooth 
– Duodenum 
– Esophagus 
– Ileum 
– Jejunum 
– Oral cavity-gums (gingivitis) 
– Peritoneal cavity 
– Rectum 
– Salivary gland 
– Small bowel NOS 
– Stomach 
GENERAL 
– Blood 
– Catheter-related 
– Foreign body (e.g., graft, implant,  
prosthesis, stent) 
– Wound  
HEPATOBILIARY/PANCREAS 
– Biliary tree 
– Gallbladder (cholecystitis) 
– Liver 
– Pancreas 
LYMPHATIC 
– Lymphatic 
MUSCULOSKELETAL 
– Bone (osteomyelitis) 
– Joint 
– Muscle (infection myositis) 
– Soft tissue NOS 
NEUROLOGY 
– Brain (encephalitis, infectious) 
– Brain + Spinal cord (encephalomyelitis) 
– Meninges (meningitis) 
– Nerve-cranial 
– Nerve-peripheral 
– Spinal cord (myelitis) 
OCULAR 
– Conjunctiva 
– Cornea 
– Eye NOS 
– Lens 
PULMONARY/UPPER RESPIRATORY 
– Bronchus 
– Larynx 
– Lung (pneumonia) 
– Mediastinum NOS 
– Mucosa 
– Neck NOS 
– Nose 
– Paranasal 
– Pharynx 
– Pleura (empyema) 
– Sinus 
– Trachea 
– Upper aerodigestive NOS 
– Upper airway NOS  
RENAL/GENITOURINARY  
– Bladder (urinary) 
– Kidney 
– Prostate 
– Ureter 
– Urethra 
– Urinary tract NOS 
SEXUAL/REPRODUCTIVE FUNCTION 
– Cervix 
– Fallopian tube 
– Pelvis NOS 
– Penis 
– Scrotum 
– Uterus 
– Vagina 
– Vulva 
 

 
LYMPHATICS 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 38 - 
March 31, 2003, Publish Date: August 9, 2006 
Chyle or lymph leakage  
Chyle or lymph leakage 
Asymptomatic, clinical or 
radiographic findings 
Symptomatic, medical 
intervention indicated  
Interventional radiology 
or operative intervention 
indicated 
Life-threatening 
complications 
Death 
ALSO CONSIDER: Chylothorax. 
Dermal change 
lymphedema, 
phlebolymphedema  
Dermal change 
Trace thickening or faint 
discoloration 
Marked discoloration; 
leathery skin texture; 
papillary formation 
— 
— 
— 
REMARK: Dermal change lymphedema, phlebolymphedema refers to changes due to venous stasis. 
ALSO CONSIDER: Ulceration.  
Edema: 
head and neck 
Edema: head and neck 
Localized to dependent 
areas, no disability or 
functional impairment 
Localized facial or neck 
edema with functional 
impairment 
Generalized facial or 
neck edema with 
functional impairment 
(e.g., difficulty in turning 
neck or opening mouth 
compared to baseline) 
Severe with ulceration or 
cerebral edema; 
tracheotomy or feeding 
tube indicated 
Death 
Edema: 
limb 
Edema: limb 
5 – 10% inter-limb 
discrepancy in volume or 
circumference at point of 
greatest visible 
difference; swelling or 
obscuration of anatomic 
architecture on close 
inspection; pitting edema 
>10 – 30% inter-limb 
discrepancy in volume or 
circumference at point of 
greatest visible 
difference; readily 
apparent obscuration of 
anatomic architecture; 
obliteration of skin folds; 
readily apparent 
deviation from normal 
anatomic contour  
>30% inter-limb 
discrepancy in volume; 
lymphorrhea; gross 
deviation from normal 
anatomic contour; 
interfering with ADL 
Progression to 
malignancy (i.e., 
lymphangiosarcoma); 
amputation indicated; 
disabling 
Death 
Edema: 
trunk/genital 
Edema: trunk/genital 
Swelling or obscuration 
of anatomic architecture 
on close inspection; 
pitting edema 
Readily apparent 
obscuration of anatomic 
architecture; obliteration 
of skin folds; readily 
apparent deviation from 
normal anatomic contour 
Lymphorrhea; interfering 
with ADL; gross deviation 
from normal anatomic 
contour 
Progression to 
malignancy (i.e., 
lymphangiosarcoma); 
disabling  
Death 
Edema: 
viscera 
Edema: viscera 
Asymptomatic; clinical or 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and unable 
to aliment adequately 
orally; interventional 
radiology or operative 
intervention indicated  
Life-threatening 
consequences 
Death 

 
LYMPHATICS 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 39 - 
March 31, 2003, Publish Date: August 9, 2006 
Lymphedema-related 
fibrosis 
Lymphedema-related 
fibrosis 
Minimal to moderate 
redundant soft tissue, 
unresponsive to elevation 
or compression, with 
moderately firm texture or 
spongy feel 
Marked increase in 
density and firmness, 
with or without tethering 
Very marked density and 
firmness with tethering 
affecting ≥40% of the 
edematous area 
— 
— 
Lymphocele 
Lymphocele 
Asymptomatic, clinical or 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and 
interventional radiology 
or operative intervention 
indicated 
— 
— 
Phlebolymphatic cording  
Phlebolymphatic cording 
Asymptomatic, clinical 
findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and leading 
to contracture or reduced 
range of motion 
— 
— 
Lymphatics – Other  
(Specify, __) 
Lymphatics – Other  
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling 
Death 

 
METABOLIC/LABORATORY 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 40 - 
March 31, 2003, Publish Date: August 9, 2006 
Acidosis  
(metabolic or respiratory) 
Acidosis  
pH <normal, but ≥7.3 
— 
pH <7.3 
pH <7.3 with life-
threatening 
consequences 
Death 
Albumin, serum-low 
(hypoalbuminemia)  
Hypoalbuminemia 
<LLN – 3 g/dL  
<LLN – 30 g/L 
<3 – 2 g/dL 
<30 – 20 g/L  
<2 g/dL  
<20 g/L 
— 
Death 
Alkaline phosphatase 
Alkaline phosphatase 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Alkalosis  
(metabolic or respiratory) 
Alkalosis 
pH >normal, but ≤7.5 
— 
pH >7.5 
pH >7.5 with life-
threatening 
consequences 
Death 
ALT, SGPT  
(serum glutamic pyruvic 
transaminase) 
ALT 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Amylase 
Amylase 
>ULN – 1.5 x ULN 
>1.5 – 2.0 x ULN 
>2.0 – 5.0 x ULN 
>5.0 x ULN 
— 
AST, SGOT 
(serum glutamic 
oxaloacetic 
transaminase) 
AST 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Bicarbonate, serum-low  
Bicarbonate, serum-low 
<LLN – 16 mmol/L 
<16 – 11 mmol/L 
<11 – 8 mmol/L 
<8 mmol/L 
Death 
Bilirubin 
(hyperbilirubinemia) 
Bilirubin 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x ULN 
>3.0 – 10.0 x ULN 
>10.0 x ULN 
— 
REMARK: Jaundice is not an AE, but may be a manifestation of liver dysfunction/failure or elevated bilirubin. If jaundice is associated with elevated bilirubin, grade bilirubin. 
Calcium, serum-low 
(hypocalcemia) 
Hypocalcemia 
<LLN – 8.0 mg/dL 
<LLN – 2.0 mmol/L 
Ionized calcium: 
<LLN – 1.0 mmol/L 
<8.0 – 7.0 mg/dL 
<2.0 – 1.75 mmol/L 
Ionized calcium: 
<1.0 – 0.9 mmol/L 
<7.0 – 6.0 mg/dL 
<1.75 – 1.5 mmol/L 
Ionized calcium: 
<0.9 – 0.8 mmol/L 
<6.0 mg/dL 
<1.5 mmol/L 
Ionized calcium: 
<0.8 mmol/L 
Death 
REMARK: Calcium can be falsely low if hypoalbuminemia is present. Serum albumin is <4.0 g/dL, hypocalcemia is reported after the following corrective calculation has been 
performed: Corrected Calcium (mg/dL) = Total Calcium (mg/dL) – 0.8 [Albumin (g/dL) – 4] 4. Alternatively, direct measurement of ionized calcium is the definitive method to diagnose 
metabolically relevant alterations in serum calcium. 
                                            
4Crit Rev Clin Lab Sci 1984;21(1):51-97 

 
METABOLIC/LABORATORY 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 41 - 
March 31, 2003, Publish Date: August 9, 2006 
Calcium, serum-high 
(hypercalcemia) 
Hypercalcemia 
>ULN – 11.5 mg/dL 
>ULN – 2.9 mmol/L 
Ionized calcium: 
>ULN – 1.5 mmol/L 
>11.5 – 12.5 mg/dL 
>2.9 – 3.1 mmol/L 
Ionized calcium: 
>1.5 – 1.6 mmol/L 
>12.5 – 13.5 mg/dL 
>3.1 – 3.4 mmol/L 
Ionized calcium: 
>1.6 – 1.8 mmol/L 
>13.5 mg/dL 
>3.4 mmol/L 
Ionized calcium: 
>1.8 mmol/L 
Death 
Cholesterol, serum-high 
(hypercholesteremia) 
Cholesterol 
>ULN – 300 mg/dL 
>ULN – 7.75 mmol/L 
>300 – 400 mg/dL 
>7.75 – 10.34 mmol/L 
>400 – 500 mg/dL 
>10.34 – 12.92 mmol/L 
>500 mg/dL 
>12.92 mmol/L 
Death 
CPK (creatine 
phosphokinase) 
CPK 
>ULN – 2.5 x ULN 
>2.5 x ULN – 5 x ULN 
>5 x ULN – 10 x ULN 
>10 x ULN 
Death 
Creatinine 
Creatinine 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x ULN 
>3.0 – 6.0 x ULN 
>6.0 x ULN 
Death 
REMARK: Adjust to age-appropriate levels for pediatric patients.  
ALSO CONSIDER: Glomerular filtration rate. 
GGT (γ-Glutamyl 
transpeptidase) 
GGT 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Glomerular filtration rate  
GFR 
<75 – 50% LLN 
<50 – 25% LLN 
<25% LLN, chronic 
dialysis not indicated 
Chronic dialysis or renal 
transplant indicated 
Death 
ALSO CONSIDER: Creatinine. 
Glucose, serum-high 
(hyperglycemia)  
Hyperglycemia 
>ULN – 160 mg/dL 
>ULN – 8.9 mmol/L 
>160 – 250 mg/dL 
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL 
>13.9 – 27.8 mmol/L 
>500 mg/dL 
>27.8 mmol/L or acidosis 
Death 
REMARK: Hyperglycemia, in general, is defined as fasting unless otherwise specified in protocol. 
Glucose, serum-low 
(hypoglycemia) 
Hypoglycemia 
<LLN – 55 mg/dL 
<LLN – 3.0 mmol/L 
<55 – 40 mg/dL 
<3.0 – 2.2 mmol/L 
<40 – 30 mg/dL 
<2.2 – 1.7 mmol/L 
<30 mg/dL 
<1.7 mmol/L 
Death 
Hemoglobinuria 
Hemoglobinuria 
Present 
— 
— 
— 
Death 
Lipase 
Lipase 
>ULN – 1.5 x ULN 
>1.5 – 2.0 x ULN 
>2.0 – 5.0 x ULN 
>5.0 x ULN 
— 
Magnesium, serum-high 
(hypermagnesemia) 
Hypermagnesemia 
>ULN – 3.0 mg/dL 
>ULN – 1.23 mmol/L 
— 
>3.0 – 8.0 mg/dL 
>1.23 – 3.30 mmol/L 
>8.0 mg/dL 
>3.30 mmol/L 
Death 
Magnesium, serum-low 
(hypomagnesemia)  
Hypomagnesemia 
<LLN – 1.2 mg/dL 
<LLN – 0.5 mmol/L 
<1.2 – 0.9 mg/dL 
<0.5 – 0.4 mmol/L 
<0.9 – 0.7 mg/dL 
<0.4 – 0.3 mmol/L 
<0.7 mg/dL 
<0.3 mmol/L 
Death 
Phosphate, serum-low 
(hypophosphatemia)  
Hypophosphatemia 
<LLN – 2.5 mg/dL 
<LLN – 0.8 mmol/L 
<2.5 – 2.0 mg/dL  
<0.8 – 0.6 mmol/L 
<2.0 – 1.0 mg/dL 
<0.6 – 0.3 mmol/L 
<1.0 mg/dL 
<0.3 mmol/L 
Death 
Potassium, serum-high 
(hyperkalemia) 
Hyperkalemia 
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L 
>6.0 – 7.0 mmol/L 
>7.0 mmol/L 
Death 

 
METABOLIC/LABORATORY 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 42 - 
March 31, 2003, Publish Date: August 9, 2006 
Potassium, serum-low 
(hypokalemia)  
Hypokalemia 
<LLN – 3.0 mmol/L 
— 
<3.0 – 2.5 mmol/L 
<2.5 mmol/L 
Death 
Proteinuria 
Proteinuria 
1+ or 
0.15 – 1.0 g/24 hrs 
2+ to 3+ or 
>1.0 – 3.5 g/24 hrs  
4+ or 
>3.5 g/24 hrs 
Nephrotic syndrome 
Death 
Sodium, serum-high 
(hypernatremia) 
Hypernatremia 
>ULN – 150 mmol/L 
>150 – 155 mmol/L 
>155 – 160 mmol/L 
>160 mmol/L 
Death 
Sodium, serum-low 
(hyponatremia) 
Hyponatremia 
<LLN – 130 mmol/L 
— 
<130 – 120 mmol/L 
<120 mmol/L 
Death 
Triglyceride, serum-high 
(hypertriglyceridemia) 
Hypertriglyceridemia 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 10 x ULN 
>10 x ULN 
Death 
Uric acid, serum-high 
(hyperuricemia) 
Hyperuricemia 
>ULN – 10 mg/dL 
≤0.59 mmol/L without 
physiologic 
consequences 
— 
>ULN – 10 mg/dL 
≤0.59 mmol/L with 
physiologic 
consequences 
>10 mg/dL 
>0.59 mmol/L 
Death 
ALSO CONSIDER: Creatinine; Potassium, serum-high (hyperkalemia); Renal failure; Tumor lysis syndrome. 
Metabolic/Laboratory – 
Other (Specify, __) 
Metabolic/Lab – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
MUSCULOSKELETAL/SOFT TISSUE 
Page 1 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 43 - 
March 31, 2003, Publish Date: August 9, 2006 
Arthritis (non-septic) 
Arthritis 
Mild pain with 
inflammation, erythema, 
or joint swelling, but not 
interfering with function 
Moderate pain with 
inflammation, erythema, 
or joint swelling 
interfering with function, 
but not interfering with 
ADL 
Severe pain with 
inflammation, erythema, 
or joint swelling and 
interfering with ADL 
Disabling 
Death 
REMARK: Report only when the diagnosis of arthritis (e.g., inflammation of a joint or a state characterized by inflammation of joints) is made. Arthralgia (sign or symptom of pain in a 
joint, especially non-inflammatory in character) is graded as Pain – Select in the PAIN CATEGORY.  
Bone: 
spine-scoliosis 
Scoliosis  
≤20 degrees; clinically 
undetectable 
>20 – 45 degrees; visible 
by forward flexion; 
interfering with function 
but not interfering with 
ADL 
>45 degrees; scapular 
prominence in forward 
flexion; operative 
intervention indicated; 
interfering with ADL 
Disabling (e.g., interfering 
with cardiopulmonary 
function) 
Death 
Cervical spine-range of 
motion 
Cervical spine ROM 
Mild restriction of rotation 
or flexion between  
60 – 70 degrees 
Rotation <60 degrees to 
right or left; <60 degrees 
of flexion 
Ankylosed/fused over 
multiple segments with 
no C-spine rotation 
— 
— 
REMARK: 60 – 65 degrees of rotation is required for reversing a car; 60 – 65 degrees of flexion is required to tie shoes. 
Exostosis 
Exostosis 
Asymptomatic 
Involving multiple sites; 
pain or interfering with 
function  
Excision indicated 
Progression to 
malignancy (i.e., 
chondrosarcoma) 
Death 
Extremity-lower 
(gait/walking) 
Gait/walking 
Limp evident only to 
trained observer and able 
to walk ≥1 kilometer; 
cane indicated for 
walking 
Noticeable limp, or 
limitation of limb function, 
but able to walk ≥0.1 
kilometer (1 city block); 
quad cane indicated for 
walking 
Severe limp with stride 
modified to maintain 
balance (widened base of 
support, marked 
reduction in step length); 
ambulation limited to 
walker; crutches 
indicated 
Unable to walk 
— 
ALSO CONSIDER: Ataxia (incoordination); Muscle weakness, generalized or specific area (not due to neuropathy) – Select.  
Extremity-upper 
(function)  
Extremity-upper 
(function) 
Able to perform most 
household or work 
activities with affected 
limb 
Able to perform most 
household or work 
activities with 
compensation from 
unaffected limb 
Interfering with ADL  
Disabling; no function of 
affected limb 
— 
Fibrosis-cosmesis 
Fibrosis-cosmesis 
Visible only on close 
examination 
Readily apparent but not 
disfiguring 
Significant disfigurement; 
operative intervention 
indicated if patient 
chooses 
— 
— 

 
MUSCULOSKELETAL/SOFT TISSUE 
Page 2 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 44 - 
March 31, 2003, Publish Date: August 9, 2006 
Fibrosis-deep connective 
tissue 
Fibrosis-deep connective 
tissue  
Increased density, 
“spongy” feel 
Increased density with 
firmness or tethering 
Increased density with 
fixation of tissue; 
operative intervention 
indicated; interfering with 
ADL 
Life-threatening; 
disabling; loss of limb; 
interfering with vital organ 
function 
Death 
ALSO CONSIDER: Induration/fibrosis (skin and subcutaneous tissue); Muscle weakness, generalized or specific area (not due to neuropathy) – Select; Neuropathy: motor; Neuropathy: 
sensory. 
Fracture 
Fracture 
Asymptomatic, 
radiographic findings only 
(e.g., asymptomatic rib 
fracture on plain x-ray, 
pelvic insufficiency 
fracture on MRI, etc.) 
Symptomatic but non-
displaced; immobilization 
indicated 
Symptomatic and 
displaced or open wound 
with bone exposure; 
operative intervention 
indicated 
Disabling; amputation 
indicated 
Death 
Joint-effusion 
Joint-effusion 
Asymptomatic, clinical or 
radiographic findings only 
Symptomatic; interfering 
with function but not 
interfering with ADL 
Symptomatic and 
interfering with ADL 
Disabling 
Death 
ALSO CONSIDER: Arthritis (non-septic). 
Joint-function5 
Joint-function 
Stiffness interfering with 
athletic activity; ≤25% 
loss of range of motion 
(ROM) 
Stiffness interfering with 
function but not 
interfering with ADL;  
>25 – 50% decrease in 
ROM 
Stiffness interfering with 
ADL; >50 – 75% 
decrease in ROM  
Fixed or non-functional 
joint (arthrodesis); 
>75% decrease in ROM 
— 
ALSO CONSIDER: Arthritis (non-septic). 
Local complication –
device/prosthesis-related 
Device/prosthesis 
Asymptomatic  
Symptomatic, but not 
interfering with ADL; local 
wound care; medical 
intervention indicated 
Symptomatic, interfering 
with ADL; operative 
intervention indicated 
(e.g., hardware/device 
replacement or removal, 
reconstruction)  
Life-threatening; 
disabling; loss of limb or 
organ 
Death 
Lumbar spine-range of 
motion 
Lumbar spine ROM 
Stiffness and difficulty 
bending to the floor to 
pick up a very light object 
but able to do activity 
Some lumbar spine 
flexion but requires a 
reaching aid to pick up a 
very light object from the 
floor 
Ankylosed/fused over 
multiple segments with 
no L-spine flexion (i.e., 
unable to reach to floor to 
pick up a very light 
— 
— 
                                            
5 Adapted from the International SFTR Method of Measuring and Recording Joint Motion, International Standard Orthopedic Measurements (ISOM), Jon J. Gerhardt and Otto A. 
Russee, Bern, Switzerland, Han Huber 9 Publisher), 1975. 

 
MUSCULOSKELETAL/SOFT TISSUE 
Page 3 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 45 - 
March 31, 2003, Publish Date: August 9, 2006 
object) 
Muscle weakness, 
generalized or specific 
area (not due to 
neuropathy)  
– Select: 
Muscle weakness  
– Select  
– Extraocular 
– Extremity-lower  
– Extremity-upper 
– Facial 
– Left-sided 
– Ocular 
– Pelvic 
– Right-sided 
– Trunk 
– Whole body/generalized  
Asymptomatic, weakness 
on physical exam 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Life-threatening; disabling 
Death 
ALSO CONSIDER: Fatigue (asthenia, lethargy, malaise). 
Muscular/skeletal 
hypoplasia 
Muscular/skeletal 
hypoplasia 
Cosmetically and 
functionally insignificant 
hypoplasia  
Deformity, hypoplasia, or 
asymmetry able to be 
remediated by prosthesis 
(e.g., shoe insert) or 
covered by clothing  
Functionally significant 
deformity, hypoplasia, or 
asymmetry, unable to be 
remediated by prosthesis 
or covered by clothing  
Disabling 
— 
Myositis 
(inflammation/damage of 
muscle) 
Myositis 
Mild pain, not interfering 
with function 
Pain interfering with 
function, but not 
interfering with ADL 
Pain interfering with ADL 
Disabling 
Death 
REMARK: Myositis implies muscle damage (i.e., elevated CPK). 
ALSO CONSIDER: CPK (creatine phosphokinase); Pain – Select. 
Osteonecrosis  
(avascular necrosis) 
Osteonecrosis 
Asymptomatic, 
radiographic findings only 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL; minimal bone 
removal indicated (i.e., 
minor sequestrectomy)  
Symptomatic and 
interfering with ADL; 
operative intervention or 
hyperbaric oxygen 
indicated 
Disabling  
Death 

 
MUSCULOSKELETAL/SOFT TISSUE 
Page 4 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 46 - 
March 31, 2003, Publish Date: August 9, 2006 
Osteoporosis6 
Osteoporosis 
Radiographic evidence of 
osteoporosis or Bone 
Mineral Density (BMD) 
t-score –1 to –2.5 
(osteopenia) and no loss 
of height or therapy 
indicated 
BMD t-score < –2.5; loss 
of height <2 cm; anti-
osteoporotic therapy 
indicated 
Fractures; loss of height 
≥2 cm 
Disabling 
Death 
Seroma 
Seroma 
Asymptomatic 
Symptomatic; medical 
intervention or simple 
aspiration indicated 
Symptomatic, 
interventional radiology 
or operative intervention 
indicated 
— 
— 
Soft tissue necrosis 
– Select: 
– Abdomen 
– Extremity-lower 
– Extremity-upper  
– Head 
– Neck 
– Pelvic 
– Thorax 
Soft tissue necrosis 
– Select 
— 
Local wound care; 
medical intervention 
indicated 
Operative debridement or 
other invasive 
intervention indicated 
(e.g., hyperbaric oxygen)  
Life-threatening 
consequences; major 
invasive intervention 
indicated (e.g., tissue 
reconstruction, flap, or 
grafting) 
Death 
Trismus (difficulty, 
restriction or pain when 
opening mouth) 
Trismus 
Decreased range of 
motion without impaired 
eating  
Decreased range of 
motion requiring small 
bites, soft foods or 
purees 
Decreased range of 
motion with inability to 
adequately aliment or 
hydrate orally 
— 
— 
NAVIGATION NOTE: Wound-infectious is graded as Infection – Select in the INFECTION CATEGORY. 
NAVIGATION NOTE: Wound non-infectious is graded as Wound complication, non-infectious in the DERMATOLOGY/SKIN CATEGORY.  
Musculoskeletal/Soft 
Tissue – Other 
(Specify, __) 
Musculoskeletal – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
                                            
6 "Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis," Report of a WHO Study Group Technical Report Series, No. 843, 1994, v + 129 
pages [C*, E, F, R, S], ISBN 92 4 120843 0, Sw.fr. 22.-/US $19.80; in developing countries: Sw.fr. 15.40, Order no. 1100843 

 
NEUROLOGY 
Page 1 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 47 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: ADD (Attention Deficit Disorder) is graded as Cognitive disturbance. 
NAVIGATION NOTE: Aphasia, receptive and/or expressive, is graded as Speech impairment (e.g., dysphasia or aphasia). 
Apnea 
Apnea 
— 
— 
Present 
Intubation indicated  
Death 
Arachnoiditis/ 
meningismus/radiculitis 
Arachnoiditis 
Symptomatic, not 
interfering with function; 
medical intervention 
indicated 
Symptomatic (e.g., 
photophobia, nausea) 
interfering with function 
but not interfering with 
ADL  
Symptomatic, interfering 
with ADL 
Life-threatening; disabling 
(e.g., paraplegia) 
Death 
ALSO CONSIDER: Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 109/L); Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select; Pain – Select; Vomiting. 
Ataxia (incoordination) 
Ataxia 
Asymptomatic  
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL; mechanical 
assistance indicated  
Disabling 
Death 
REMARK: Ataxia (incoordination) refers to the consequence of medical or operative intervention. 
Brachial plexopathy 
Brachial plexopathy 
Asymptomatic 
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
Disabling 
Death 
CNS cerebrovascular 
ischemia 
CNS ischemia 
— 
Asymptomatic, 
radiographic findings only 
Transient ischemic event 
or attack (TIA) ≤24 hrs 
duration 
Cerebral vascular 
accident (CVA, stroke), 
neurologic deficit 
>24 hrs  
Death 
NAVIGATION NOTE: CNS hemorrhage/bleeding is graded as Hemorrhage, CNS in the HEMORRHAGE/BLEEDING CATEGORY.  
CNS necrosis/cystic 
progression 
CNS necrosis 
Asymptomatic, 
radiographic findings only 
Symptomatic, not 
interfering with ADL; 
medical intervention 
indicated 
Symptomatic and 
interfering with ADL; 
hyperbaric oxygen 
indicated 
Life-threatening; 
disabling; operative 
intervention indicated to 
prevent or treat CNS 
necrosis/cystic 
progression 
Death 
Cognitive disturbance 
Cognitive disturbance 
Mild cognitive disability; 
not interfering with 
work/school/life 
performance; specialized 
educational 
services/devices not 
indicated 
Moderate cognitive 
disability; interfering with 
work/school/life 
performance but capable 
of independent living; 
specialized resources on 
part-time basis indicated 
Severe cognitive 
disability; significant 
impairment of 
work/school/life 
performance 
Unable to perform ADL; 
full-time specialized 
resources or 
institutionalization 
indicated 
Death 
REMARK: Cognitive disturbance may be used for Attention Deficit Disorder (ADD). 

 
NEUROLOGY 
Page 2 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 48 - 
March 31, 2003, Publish Date: August 9, 2006 
Confusion 
Confusion 
Transient confusion, 
disorientation, or attention 
deficit 
Confusion, disorientation, 
or attention deficit 
interfering with function, 
but not interfering with 
ADL 
Confusion or delirium 
interfering with ADL 
Harmful to others or self; 
hospitalization indicated 
Death 
REMARK: Attention Deficit Disorder (ADD) is graded as Cognitive disturbance. 
NAVIGATION NOTE: Cranial neuropathy is graded as Neuropathy-cranial – Select. 
Dizziness  
Dizziness 
With head movements or 
nystagmus only; not 
interfering with function 
Interfering with function, 
but not interfering with 
ADL 
Interfering with ADL 
Disabling 
— 
REMARK: Dizziness includes disequilibrium, lightheadedness, and vertigo. 
ALSO CONSIDER: Neuropathy: cranial – Select; Syncope (fainting). 
NAVIGATION NOTE: Dysphasia, receptive and/or expressive, is graded as Speech impairment (e.g., dysphasia or aphasia). 
Encephalopathy 
Encephalopathy 
— 
Mild signs or symptoms; 
not interfering with ADL 
Signs or symptoms 
interfering with ADL; 
hospitalization indicated 
Life-threatening; disabling 
Death 
ALSO CONSIDER: Cognitive disturbance; Confusion; Dizziness; Memory impairment; Mental status; Mood alteration – Select; Psychosis (hallucinations/delusions); 
Somnolence/depressed level of consciousness. 
Extrapyramidal/ 
involuntary movement/ 
restlessness 
Involuntary movement 
Mild involuntary 
movements not 
interfering with function 
Moderate involuntary 
movements interfering 
with function, but not 
interfering with ADL 
Severe involuntary 
movements or torticollis 
interfering with ADL 
Disabling 
 
Death 
NAVIGATION NOTE: Headache/neuropathic pain (e.g., jaw pain, neurologic pain, phantom limb pain, post-infectious neuralgia, or painful neuropathies) is graded as Pain – Select in the 
PAIN CATEGORY. 
Hydrocephalus 
Hydrocephalus 
Asymptomatic, 
radiographic findings only 
Mild to moderate 
symptoms not interfering 
with ADL 
Severe symptoms or 
neurological deficit 
interfering with ADL 
Disabling  
Death 
Irritability (children <3 
years of age) 
Irritability 
Mild; easily consolable 
Moderate; requiring 
increased attention 
Severe; inconsolable 
— 
— 
Laryngeal nerve 
dysfunction  
Laryngeal nerve 
Asymptomatic, weakness 
on clinical 
examination/testing only 
Symptomatic, but not 
interfering with ADL; 
intervention not indicated 
Symptomatic, interfering 
with ADL; intervention 
indicated (e.g., 
thyroplasty, vocal cord 
injection) 
Life-threatening; 
tracheostomy indicated 
 
Death 

 
NEUROLOGY 
Page 3 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 49 - 
March 31, 2003, Publish Date: August 9, 2006 
Leak, cerebrospinal fluid 
(CSF) 
CSF leak 
Transient headache; 
postural care indicated 
Symptomatic, not 
interfering with ADL; 
blood patch indicated 
Symptomatic, interfering 
with ADL; operative 
intervention indicated 
Life-threatening; disabling 
Death 
REMARK: Leak, cerebrospinal fluid (CSF) may be used for CSF leak associated with operation and persisting >72 hours. 
Leukoencephalopathy 
(radiographic findings) 
Leukoencephalopathy  
Mild increase in 
subarachnoid space 
(SAS); mild 
ventriculomegaly; small 
(+/- multiple) focal T2 
hyperintensities, involving 
periventricular white 
matter or <1/3 of 
susceptible areas of 
cerebrum 
Moderate increase in 
SAS; moderate 
ventriculomegaly; focal 
T2 hyperintensities 
extending into centrum 
ovale or involving 1/3 to 
2/3 of susceptible areas 
of cerebrum 
Severe increase in SAS; 
severe ventriculomegaly; 
near total white matter T2 
hyperintensities or diffuse 
low attenuation (CT) 
— 
— 
REMARK: Leukoencephalopathy is a diffuse white matter process, specifically NOT associated with necrosis. Leukoencephalopathy (radiographic findings) does not include lacunas, 
which are areas that become void of neural tissue.  
Memory impairment 
Memory impairment 
Memory impairment not 
interfering with function 
Memory impairment 
interfering with function, 
but not interfering with 
ADL 
Memory impairment 
interfering with ADL 
Amnesia 
— 
Mental status7 
Mental status 
— 
1 – 3 point below age  
and educational norm in 
Folstein Mini-Mental 
Status Exam (MMSE) 
>3 point below age and 
educational norm in 
Folstein MMSE  
— 
— 
Mood alteration  
– Select: 
– Agitation 
– Anxiety 
– Depression 
– Euphoria 
Mood alteration – Select 
Mild mood alteration not 
interfering with function 
Moderate mood alteration 
interfering with function, 
but not interfering with 
ADL; medication 
indicated 
Severe mood alteration 
interfering with ADL 
Suicidal ideation; danger 
to self or others 
Death 
Myelitis 
Myelitis 
Asymptomatic, mild signs 
(e.g., Babinski’s or 
Lhermitte’s sign) 
Weakness or sensory 
loss not interfering with 
ADL 
Weakness or sensory 
loss interfering with ADL 
Disabling 
Death 
                                            
7 Folstein MF, Folstein, SE and McHugh PR (1975) "Mini-Mental State: A Practical Method for Grading the State of Patients for the Clinician," Journal of Psychiatric Research, 12: 
189-198 

 
NEUROLOGY 
Page 4 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 50 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Neuropathic pain is graded as Pain – Select in the PAIN CATEGORY.  
Neuropathy: 
cranial  
– Select: 
Neuropathy: cranial  
– Select 
Asymptomatic, detected 
on exam/testing only 
– CN I  
Smell 
– CN II  Vision 
– CN III  Pupil, upper eyelid, extra ocular movements 
– CN IV  Downward, inward movement of eye 
– CN V  Motor-jaw muscles; Sensory-facial 
– CN VI  Lateral deviation of eye 
– CN VII Motor-face; Sensory-taste 
– CN VIII Hearing and balance 
– CN IX Motor-pharynx; Sensory-ear, pharynx, tongue 
– CN X 
Motor-palate; pharynx, larynx 
– CN XI Motor-sternomastoid and trapezius 
– CN XII Motor-tongue 
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
Life-threatening; disabling 
Death 
Neuropathy: 
motor  
Neuropathy-motor 
Asymptomatic, weakness 
on exam/testing only 
Symptomatic weakness 
interfering with function, 
but not interfering with 
ADL 
Weakness interfering with 
ADL; bracing or 
assistance to walk (e.g., 
cane or walker) indicated 
Life-threatening; disabling 
(e.g., paralysis)  
Death 
REMARK: Cranial nerve motor neuropathy is graded as Neuropathy: cranial – Select. 
ALSO CONSIDER: Laryngeal nerve dysfunction; Phrenic nerve dysfunction.  
Neuropathy: 
sensory 
Neuropathy-sensory 
Asymptomatic; loss of 
deep tendon reflexes or 
paresthesia (including 
tingling) but not 
interfering with function 
Sensory alteration or 
paresthesia (including 
tingling), interfering with 
function, but not 
interfering with ADL 
Sensory alteration or 
paresthesia interfering 
with ADL  
Disabling  
Death 
REMARK: Cranial nerve sensory neuropathy is graded as Neuropathy: cranial – Select. 
Personality/behavioral 
Personality 
Change, but not 
adversely affecting 
patient or family 
Change, adversely 
affecting patient or family  
Mental health intervention 
indicated 
Change harmful to others 
or self; hospitalization 
indicated 
Death 
Phrenic nerve dysfunction  Phrenic nerve 
Asymptomatic weakness 
on exam/testing only 
Symptomatic but not 
interfering with ADL; 
intervention not indicated 
Significant dysfunction; 
intervention indicated 
(e.g., diaphragmatic 
plication) 
Life-threatening 
respiratory compromise; 
mechanical ventilation 
indicated 
Death 
Psychosis (hallucinations/ 
delusions) 
Psychosis 
— 
Transient episode 
Interfering with ADL; 
medication, supervision 
Harmful to others or self; 
life-threatening 
Death 

 
NEUROLOGY 
Page 5 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 51 - 
March 31, 2003, Publish Date: August 9, 2006 
or restraints indicated  
consequences 
Pyramidal tract 
dysfunction (e.g., ↑ tone, 
hyperreflexia, positive 
Babinski, ↓ fine motor 
coordination) 
Pyramidal tract 
dysfunction 
Asymptomatic, 
abnormality on exam or 
testing only  
Symptomatic; interfering 
with function but not 
interfering with ADL 
Interfering with ADL 
Disabling; paralysis 
Death 
Seizure 
Seizure 
— 
One brief generalized 
seizure; seizure(s) well 
controlled by 
anticonvulsants or 
infrequent focal motor 
seizures not interfering 
with ADL 
Seizures in which 
consciousness is altered; 
poorly controlled seizure 
disorder, with 
breakthrough generalized 
seizures despite medical 
intervention 
Seizures of any kind 
which are prolonged, 
repetitive, or difficult to 
control (e.g., status 
epilepticus, intractable 
epilepsy) 
Death 
Somnolence/depressed 
level of consciousness 
Somnolence 
— 
Somnolence or sedation 
interfering with function, 
but not interfering with 
ADL 
Obtundation or stupor; 
difficult to arouse; 
interfering with ADL 
Coma 
Death 
Speech impairment  
(e.g., dysphasia or 
aphasia)  
Speech impairment 
— 
Awareness of receptive 
or expressive dysphasia, 
not impairing ability to 
communicate 
Receptive or expressive 
dysphasia, impairing 
ability to communicate 
Inability to communicate 
— 
REMARK: Speech impairment refers to a primary CNS process, not neuropathy or end organ dysfunction. 
ALSO CONSIDER: Laryngeal nerve dysfunction; Voice changes/dysarthria (e.g., hoarseness, loss, or alteration in voice, laryngitis). 
Syncope (fainting) 
Syncope (fainting) 
— 
— 
Present 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: CNS cerebrovascular ischemia; Conduction abnormality/atrioventricular heart block – Select; Dizziness; Supraventricular and nodal arrhythmia – Select; Vasovagal 
episode; Ventricular arrhythmia – Select. 
NAVIGATION NOTE: Taste alteration (CN VII, IX) is graded as Taste alteration (dysgeusia) in the GASTROINTESTINAL CATEGORY. 
Tremor 
Tremor 
Mild and brief or 
intermittent but not 
interfering with function 
Moderate tremor 
interfering with function, 
but not interfering with 
ADL 
Severe tremor interfering 
with ADL 
Disabling 
— 
Neurology – Other 
(Specify, __) 
Neurology – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
OCULAR/VISUAL 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 52 - 
March 31, 2003, Publish Date: August 9, 2006 
Cataract 
Cataract 
Asymptomatic, detected 
on exam only  
Symptomatic, with 
moderate decrease in 
visual acuity  
(20/40 or better); 
decreased visual function 
correctable with glasses  
Symptomatic with marked 
decrease in visual acuity 
(worse than 20/40); 
operative intervention 
indicated (e.g., cataract 
surgery) 
— 
— 
Dry eye syndrome  
Dry eye 
Mild, intervention not 
indicated 
Symptomatic, interfering 
with function but not 
interfering with ADL; 
medical intervention 
indicated  
Symptomatic or decrease 
in visual acuity interfering 
with ADL; operative 
intervention indicated 
— 
— 
Eyelid dysfunction  
Eyelid dysfunction 
Asymptomatic  
Symptomatic, interfering 
with function but not ADL; 
requiring topical agents or 
epilation 
Symptomatic; interfering 
with ADL; surgical 
intervention indicated 
— 
— 
REMARK: Eyelid dysfunction includes canalicular stenosis, ectropion, entropion, erythema, madarosis, symblepharon, telangiectasis, thickening, and trichiasis. 
ALSO CONSIDER: Neuropathy: cranial – Select. 
Glaucoma  
Glaucoma 
Elevated intraocular 
pressure (EIOP) with 
single topical agent for 
intervention; no visual 
field deficit 
EIOP causing early visual 
field deficit (i.e., nasal 
step or arcuate deficit); 
multiple topical or oral 
agents indicated 
EIOP causing marked 
visual field deficits (i.e., 
involving both superior 
and inferior visual fields); 
operative intervention 
indicated 
EIOP resulting in 
blindness (20/200 or 
worse); enucleation 
indicated 
— 
Keratitis (corneal 
inflammation/corneal 
ulceration) 
Keratitis 
Abnormal ophthalmologic 
changes only; 
intervention not indicated 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL; 
operative intervention 
indicated 
Perforation or blindness 
(20/200 or worse)  
— 
NAVIGATION NOTE: Ocular muscle weakness is graded as Muscle weakness, generalized or specific area (not due to neuropathy) – Select in the MUSCULOSKELETAL/SOFT TISSUE 
CATEGORY.  
Night blindness 
(nyctalopia) 
Nyctalopia 
Symptomatic, not 
interfering with function 
Symptomatic and 
interfering with function 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL  
Disabling 
— 

 
OCULAR/VISUAL 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 53 - 
March 31, 2003, Publish Date: August 9, 2006 
Nystagmus 
Nystagmus 
Asymptomatic 
Symptomatic and 
interfering with function 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
ALSO CONSIDER: Neuropathy: cranial – Select; Ophthalmoplegia/diplopia (double vision). 
Ocular surface disease  
Ocular surface disease  
Asymptomatic or 
minimally symptomatic 
but not interfering with 
function 
Symptomatic, interfering 
with function but not 
interfering with ADL; 
topical antibiotics or other 
topical intervention 
indicated 
Symptomatic, interfering 
with ADL; operative 
intervention indicated 
— 
— 
REMARK: Ocular surface disease includes conjunctivitis, keratoconjunctivitis sicca, chemosis, keratinization, and palpebral conjunctival epithelial metaplasia. 
Ophthalmoplegia/ 
diplopia (double vision) 
Diplopia 
Intermittently 
symptomatic, intervention 
not indicated 
Symptomatic and 
interfering with function 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL; 
surgical intervention 
indicated 
Disabling 
— 
ALSO CONSIDER: Neuropathy: cranial – Select. 
Optic disc edema 
Optic disc edema 
Asymptomatic 
Decreased visual acuity 
(20/40 or better); visual 
field defect present 
Decreased visual acuity 
(worse than 20/40); 
marked visual field defect 
but sparing the central 20 
degrees 
Blindness  
(20/200 or worse) 
— 
ALSO CONSIDER: Neuropathy: cranial – Select.  
Proptosis/enophthalmos 
Proptosis/enophthalmos 
Asymptomatic, 
intervention not indicated 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
— 
— 
Retinal detachment 
Retinal detachment 
Exudative; no central 
vision loss; intervention 
not indicated 
Exudative and visual 
acuity 20/40 or better but 
intervention not indicated 
Rhegmatogenous or 
exudative detachment; 
operative intervention 
indicated 
Blindness 
(20/200 or worse) 
— 
Retinopathy  
Retinopathy 
Asymptomatic  
Symptomatic with 
moderate decrease in 
visual acuity 
(20/40 or better) 
Symptomatic with marked 
decrease in visual acuity 
(worse than 20/40) 
Blindness 
(20/200 or worse) 
— 

 
OCULAR/VISUAL 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 54 - 
March 31, 2003, Publish Date: August 9, 2006 
Scleral necrosis/melt 
Scleral necrosis 
Asymptomatic or 
symptomatic but not 
interfering with function 
Symptomatic, interfering 
with function but not 
interfering with ADL; 
moderate decrease in 
visual acuity (20/40 or 
better); medical 
intervention indicated 
Symptomatic, interfering 
with ADL; marked 
decrease in visual acuity 
(worse than 20/40); 
operative intervention 
indicated 
Blindness (20/200 or 
worse); painful eye with 
enucleation indicated 
— 
Uveitis  
Uveitis 
Asymptomatic 
Anterior uveitis; medical 
intervention indicated 
Posterior or pan-uveitis; 
operative intervention 
indicated 
Blindness 
(20/200 or worse) 
— 
Vision-blurred vision 
Blurred vision 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
Vision-flashing 
lights/floaters 
Flashing lights 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
Vision-photophobia 
Photophobia 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
Vitreous hemorrhage 
Vitreous hemorrhage 
Asymptomatic, clinical 
findings only 
Symptomatic, interfering 
with function, but not 
interfering with ADL; 
intervention not indicated 
Symptomatic, interfering 
with ADL; vitrectomy 
indicated  
— 
— 
Watery eye (epiphora, 
tearing) 
Watery eye 
Symptomatic, intervention 
not indicated 
Symptomatic, interfering 
with function but not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
— 
— 
Ocular/Visual – Other  
(Specify, __) 
Ocular – Other  
(Specify) 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Blindness 
(20/200 or worse) 
Death 

 
PAIN 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 55 - 
March 31, 2003, Publish Date: August 9, 2006 
Pain  
– Select: 
‘Select’ AEs appear at the 
end of the CATEGORY. 
Pain – Select  
Mild pain not interfering 
with function 
Moderate pain; pain or 
analgesics interfering with 
function, but not 
interfering with ADL 
Severe pain; pain or 
analgesics severely 
interfering with ADL 
Disabling 
— 
Pain – Other 
(Specify, __) 
Pain – Other (Specify) 
Mild pain not interfering 
with function 
Moderate pain; pain or 
analgesics interfering with 
function, but not 
interfering with ADL 
Severe pain; pain or 
analgesics severely 
interfering with ADL 
Disabling 
— 
PAIN – SELECT 
AUDITORY/EAR 
– External ear 
– Middle ear 
CARDIOVASCULAR 
– Cardiac/heart  
– Pericardium 
DERMATOLOGY/SKIN 
– Face 
– Lip 
– Oral-gums 
– Scalp 
– Skin 
GASTROINTESTINAL 
– Abdomen NOS 
– Anus 
– Dental/teeth/peridontal 
– Esophagus 
– Oral cavity 
– Peritoneum 
– Rectum 
– Stomach 
GENERAL 
– Pain NOS 
– Tumor pain  
HEPATOBILIARY/PANCREAS 
– Gallbladder 
– Liver  
LYMPHATIC 
– Lymph node 
MUSCULOSKELETAL 
– Back 
– Bone 
– Buttock 
– Extremity-limb 
– Intestine 
– Joint 
– Muscle 
– Neck 
– Phantom (pain associated with missing limb) 
NEUROLOGY 
– Head/headache 
– Neuralgia/peripheral nerve 
OCULAR 
– Eye 
PULMONARY/UPPER RESPIRATORY 
– Chest wall 
– Chest/thorax NOS 
PULMONARY/UPPER RESPIRATORY (continued) 
– Larynx 
– Pleura 
– Sinus 
– Throat/pharynx/larynx 
RENAL/GENITOURINARY 
– Bladder 
– Kidney 
SEXUAL/REPRODUCTIVE FUNCTION 
– Breast 
– Ovulatory 
– Pelvis 
– Penis 
– Perineum 
– Prostate 
– Scrotum 
– Testicle 
– Urethra 
– Uterus 
– Vagina 
 
 

 
PULMONARY/UPPER RESPIRATORY 
Page 1 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 56 - 
March 31, 2003, Publish Date: August 9, 2006 
Adult Respiratory 
Distress Syndrome 
(ARDS) 
ARDS 
— 
— 
Present, intubation not 
indicated  
Present, intubation 
indicated 
Death 
ALSO CONSIDER: Dyspnea (shortness of breath); Hypoxia; Pneumonitis/pulmonary infiltrates. 
Aspiration 
Aspiration 
Asymptomatic (“silent 
aspiration”); endoscopy 
or radiographic (e.g., 
barium swallow) findings  
Symptomatic (e.g., 
altered eating habits, 
coughing or choking 
episodes consistent with 
aspiration); medical 
intervention indicated 
(e.g., antibiotics, suction 
or oxygen) 
Clinical or radiographic 
signs of pneumonia or 
pneumonitis; unable to 
aliment orally 
Life-threatening (e.g., 
aspiration pneumonia or 
pneumonitis)  
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils 
– Select; Infection with unknown ANC – Select; Laryngeal nerve dysfunction; Neuropathy: cranial – Select; Pneumonitis/pulmonary infiltrates. 
Atelectasis  
Atelectasis  
Asymptomatic  
Symptomatic (e.g., 
dyspnea, cough), medical 
intervention indicated 
(e.g., bronchoscopic 
suctioning, chest 
physiotherapy, 
suctioning)  
Operative (e.g., stent, 
laser) intervention 
indicated  
Life-threatening 
respiratory compromise 
Death 
ALSO CONSIDER: Adult Respiratory Distress Syndrome (ARDS); Cough; Dyspnea (shortness of breath); Hypoxia; Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select; Obstruction/stenosis of airway – 
Select; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes). 
Bronchospasm, 
wheezing  
Bronchospasm 
Asymptomatic  
Symptomatic not 
interfering with function 
Symptomatic interfering 
with function 
Life-threatening 
Death 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever); Dyspnea (shortness of breath).  
Carbon monoxide 
diffusion capacity (DLCO) 
DLCO 
90 – 75% of predicted 
value 
<75 – 50% of predicted 
value 
<50 – 25% of predicted 
value 
<25% of predicted value 
Death 
ALSO CONSIDER: Hypoxia; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes). 
Chylothorax  
Chylothorax 
Asymptomatic 
Symptomatic; 
thoracentesis or tube 
drainage indicated  
Operative intervention 
indicated 
Life-threatening (e.g., 
hemodynamic instability 
or ventilatory support 
indicated) 
Death 
Cough 
Cough 
Symptomatic, non-
narcotic medication only 
indicated  
Symptomatic and 
narcotic medication 
indicated  
Symptomatic and 
significantly interfering 
with sleep or ADL 
— 
— 

 
PULMONARY/UPPER RESPIRATORY 
Page 2 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 57 - 
March 31, 2003, Publish Date: August 9, 2006 
Dyspnea (shortness of 
breath)  
Dyspnea  
Dyspnea on exertion, but 
can walk 1 flight of stairs 
without stopping 
Dyspnea on exertion but 
unable to walk 1 flight of 
stairs or 1 city block 
(0.1km) without stopping 
Dyspnea with ADL 
Dyspnea at rest; 
intubation/ventilator 
indicated  
Death 
ALSO CONSIDER: Hypoxia; Neuropathy: motor; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes). 
Edema, larynx  
Edema, larynx 
Asymptomatic edema by 
exam only 
Symptomatic edema, no 
respiratory distress  
Stridor; respiratory 
distress; interfering with 
ADL 
Life-threatening airway 
compromise; 
tracheotomy, intubation, 
or laryngectomy indicated 
Death 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever). 
FEV1  
FEV1 
90 – 75% of predicted 
value 
<75 – 50% of predicted 
value 
<50 – 25% of predicted 
value 
<25% of predicted 
Death 
Fistula, pulmonary/upper 
respiratory  
– Select: 
– Bronchus 
– Larynx 
– Lung 
– Oral cavity 
– Pharynx  
– Pleura 
– Trachea 
Fistula, pulmonary  
– Select  
Asymptomatic, 
radiographic findings only 
Symptomatic, tube 
thoracostomy or medical 
management indicated; 
associated with altered 
respiratory function but 
not interfering with ADL 
Symptomatic and 
associated with altered 
respiratory function 
interfering with ADL; or 
endoscopic (e.g., stent) 
or primary closure by 
operative intervention 
indicated 
Life-threatening 
consequences; operative 
intervention with 
thoracoplasty, chronic 
open drainage or multiple 
thoracotomies indicated 
Death 
REMARK: A fistula is defined as an abnormal communication between two body cavities, potential spaces, and/or the skin. The site indicated for a fistula should be the site from which 
the abnormal process is believed to have arisen. For example, a tracheo-esophageal fistula arising in the context of a resected or irradiated esophageal cancer should be graded as 
Fistula, GI – esophagus in the GASTROINTESTINAL CATEGORY. 
NAVIGATION NOTE: Hemoptysis is graded as Hemorrhage, pulmonary/upper respiratory – Select in the HEMORRHAGE/BLEEDING CATEGORY.  
Hiccoughs (hiccups, 
singultus) 
Hiccoughs 
Symptomatic, 
intervention not indicated 
Symptomatic, 
intervention indicated  
Symptomatic, 
significantly interfering 
with sleep or ADL 
— 
— 
Hypoxia 
Hypoxia 
— 
Decreased O2 saturation 
with exercise (e.g., pulse 
oximeter <88%); 
intermittent supplemental 
oxygen  
Decreased O2 saturation 
at rest; continuous 
oxygen indicated 
Life-threatening; 
intubation or ventilation 
indicated  
Death 

 
PULMONARY/UPPER RESPIRATORY 
Page 3 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 58 - 
March 31, 2003, Publish Date: August 9, 2006 
Nasal cavity/paranasal 
sinus reactions 
Nasal/paranasal 
reactions 
Asymptomatic mucosal 
crusting, blood-tinged 
secretions 
Symptomatic stenosis or 
edema/narrowing 
interfering with airflow 
Stenosis with significant 
nasal obstruction; 
interfering with ADL 
Necrosis of soft tissue or 
bone 
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils 
– Select; Infection with unknown ANC – Select. 
Obstruction/stenosis of 
airway 
– Select: 
– Bronchus 
– Larynx 
– Pharynx 
– Trachea 
Airway obstruction  
– Select  
Asymptomatic obstruction 
or stenosis on exam, 
endoscopy, or radiograph 
Symptomatic (e.g., noisy 
airway breathing), but 
causing no respiratory 
distress; medical 
management indicated 
(e.g., steroids)  
Interfering with ADL; 
stridor or endoscopic 
intervention indicated 
(e.g., stent, laser)  
Life-threatening airway 
compromise; tracheotomy 
or intubation indicated 
Death 
Pleural effusion 
(non-malignant)  
Pleural effusion 
Asymptomatic 
Symptomatic, 
intervention such as 
diuretics or up to 2 
therapeutic 
thoracenteses indicated 
Symptomatic and 
supplemental oxygen,  
>2 therapeutic 
thoracenteses, tube 
drainage, or pleurodesis 
indicated 
Life-threatening (e.g., 
causing hemodynamic 
instability or ventilatory 
support indicated)  
Death 
ALSO CONSIDER: Atelectasis; Cough; Dyspnea (shortness of breath); Hypoxia; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes).  
NAVIGATION NOTE: Pleuritic pain is graded as Pain – Select in the PAIN CATEGORY. 
Pneumonitis/pulmonary 
infiltrates  
Pneumonitis 
Asymptomatic, 
radiographic findings only 
Symptomatic, not 
interfering with ADL  
Symptomatic, interfering 
with ADL; O2 indicated  
Life-threatening; 
ventilatory support 
indicated 
Death 
ALSO CONSIDER: Adult Respiratory Distress Syndrome (ARDS); Cough; Dyspnea (shortness of breath); Hypoxia; Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select; Pneumonitis/pulmonary infiltrates; 
Pulmonary fibrosis (radiographic changes). 
Pneumothorax  
Pneumothorax  
Asymptomatic, 
radiographic findings only 
Symptomatic; 
intervention indicated 
(e.g., hospitalization for 
observation, tube 
placement without 
sclerosis) 
Sclerosis and/or 
operative intervention 
indicated 
Life-threatening, causing 
hemodynamic instability 
(e.g., tension 
pneumothorax); 
ventilatory support 
indicated 
Death 
Prolonged chest tube 
drainage or air leak after 
pulmonary resection 
Chest tube drainage or 
leak 
— 
Sclerosis or additional 
tube thoracostomy 
indicated 
Operative intervention 
indicated (e.g., 
thoracotomy with stapling 
or sealant application) 
Life-threatening; 
debilitating; organ 
resection indicated 
Death 

 
PULMONARY/UPPER RESPIRATORY 
Page 4 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 59 - 
March 31, 2003, Publish Date: August 9, 2006 
Prolonged intubation 
after pulmonary resection 
(>24 hrs after surgery)  
Prolonged intubation 
— 
Extubated within  
24 – 72 hrs 
postoperatively 
Extubated >72 hrs 
postoperatively, but 
before tracheostomy 
indicated 
Tracheostomy indicated 
Death 
NAVIGATION NOTE: Pulmonary embolism is graded as Grade 4 either as Thrombosis/embolism (vascular access-related) or Thrombosis/thrombus/embolism in the VASCULAR 
CATEGORY.  
Pulmonary fibrosis 
(radiographic changes)  
Pulmonary fibrosis 
Minimal radiographic 
findings (or patchy or bi-
basilar changes) with 
estimated radiographic 
proportion of total lung 
volume that is fibrotic of 
<25% 
Patchy or bi-basilar 
changes with estimated 
radiographic proportion of 
total lung volume that is 
fibrotic of 25 – <50% 
Dense or widespread 
infiltrates/consolidation 
with estimated 
radiographic proportion of 
total lung volume that is 
fibrotic of 50 – <75% 
Estimated radiographic 
proportion of total lung 
volume that is fibrotic is 
≥75%; honeycombing 
Death 
REMARK: Fibrosis is usually a “late effect” seen >3 months after radiation or combined modality therapy (including surgery). It is thought to represent scar/fibrotic lung tissue. It may be 
difficult to distinguish from pneumonitis that is generally seen within 3 months of radiation or combined modality therapy.  
ALSO CONSIDER: Adult Respiratory Distress Syndrome (ARDS); Cough; Dyspnea (shortness of breath); Hypoxia; Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select. 
NAVIGATION NOTE: Recurrent laryngeal nerve dysfunction is graded as Laryngeal nerve dysfunction in the NEUROLOGY CATEGORY. 
Vital capacity  
Vital capacity 
90 – 75% of predicted 
value 
<75 – 50% of predicted 
value 
<50 – 25% of predicted 
value 
<25% of predicted value 
Death 
Voice changes/dysarthria 
(e.g., hoarseness, loss or 
alteration in voice, 
laryngitis)  
Voice changes  
Mild or intermittent 
hoarseness or voice 
change, but fully 
understandable 
Moderate or persistent 
voice changes, may 
require occasional 
repetition but 
understandable on 
telephone 
Severe voice changes 
including predominantly 
whispered speech; may 
require frequent repetition 
or face-to-face contact for 
understandability; 
requires voice aid (e.g., 
electrolarynx) for ≤50% of 
communication 
Disabling; 
non-understandable voice 
or aphonic; requires voice 
aid (e.g., electrolarynx) 
for >50% of 
communication or 
requires >50% written 
communication 
Death 
ALSO CONSIDER: Laryngeal nerve dysfunction; Speech impairment (e.g., dysphasia or aphasia). 
Pulmonary/Upper 
Respiratory – Other 
(Specify, __) 
Pulmonary – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling 
Death 

 
RENAL/GENITOURINARY 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 60 - 
March 31, 2003, Publish Date: August 9, 2006 
Bladder spasms 
Bladder spasms 
Symptomatic, intervention 
not indicated 
Symptomatic, 
antispasmodics indicated 
Narcotics indicated 
Major surgical 
intervention indicated 
(e.g., cystectomy) 
— 
Cystitis 
Cystitis 
Asymptomatic 
Frequency with dysuria; 
macroscopic hematuria 
Transfusion; IV pain 
medications; bladder 
irrigation indicated 
Catastrophic bleeding; 
major non-elective 
intervention indicated 
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils 
– Select; Infection with unknown ANC – Select; Pain – Select. 
Fistula, GU 
– Select:  
– Bladder 
– Genital tract-female 
– Kidney 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
Fistula, GU – Select  
Asymptomatic, 
radiographic findings only 
Symptomatic; 
noninvasive intervention 
indicated  
Symptomatic interfering 
with ADL; invasive 
intervention indicated  
Life-threatening 
consequences; operative 
intervention requiring 
partial or full organ 
resection; permanent 
urinary diversion  
Death 
REMARK: A fistula is defined as an abnormal communication between two body cavities, potential spaces, and/or the skin. The site indicated for a fistula should be the site from which 
the abnormal process is believed to have originated. 
Incontinence, urinary  
Incontinence, urinary 
Occasional (e.g., with 
coughing, sneezing, etc.), 
pads not indicated 
Spontaneous, pads 
indicated  
Interfering with ADL; 
intervention indicated 
(e.g., clamp, collagen 
injections) 
Operative intervention 
indicated (e.g., 
cystectomy or permanent 
urinary diversion) 
— 
Leak (including 
anastomotic), GU 
– Select: 
– Bladder 
– Fallopian tube  
– Kidney 
– Spermatic cord 
– Stoma 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Leak, GU – Select  
Asymptomatic, 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic, interfering 
with GU function; invasive 
or endoscopic 
intervention indicated 
Life-threatening 
Death 
REMARK: Leak (including anastomotic), GU – Select refers to clinical signs and symptoms or radiographic confirmation of anastomotic leak but without development of fistula. 

 
RENAL/GENITOURINARY 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 61 - 
March 31, 2003, Publish Date: August 9, 2006 
Obstruction, GU  
– Select: 
– Bladder 
– Fallopian tube 
– Prostate 
– Spermatic cord 
– Stoma 
– Testes 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Obstruction, GU – Select  
Asymptomatic, 
radiographic or 
endoscopic findings only 
Symptomatic but no 
hydronephrosis, sepsis or 
renal dysfunction; dilation 
or endoscopic repair or 
stent placement indicated 
Symptomatic and altered 
organ function (e.g., 
sepsis or hydronephrosis, 
or renal dysfunction); 
operative intervention 
indicated  
Life-threatening 
consequences; organ 
failure or operative 
intervention requiring 
complete organ resection 
indicated  
Death 
NAVIGATION NOTE: Operative injury is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY CATEGORY.  
Perforation, GU  
– Select: 
– Bladder 
– Fallopian tube 
– Kidney  
– Ovary 
– Prostate 
– Spermatic cord 
– Stoma 
– Testes 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Perforation, GU – Select 
Asymptomatic 
radiographic findings only 
Symptomatic, associated 
with altered renal/GU 
function 
Symptomatic, operative 
intervention indicated 
Life-threatening 
consequences or organ 
failure; operative 
intervention requiring 
organ resection indicated 
Death 
Prolapse of stoma, GU 
Prolapse stoma, GU 
Asymptomatic; special 
intervention, 
extraordinary care not 
indicated 
Extraordinary local care 
or maintenance; minor 
revision under local 
anesthesia indicated 
Dysfunctional stoma; 
operative intervention or 
major stomal revision 
indicated 
Life-threatening 
consequences 
Death 
REMARK: Other stoma complications may be graded as Fistula, GU – Select; Leak (including anastomotic), GU – Select; Obstruction, GU – Select; Perforation, GU – Select; 
Stricture/stenosis (including anastomotic), GU – Select. 
Renal failure  
Renal failure 
— 
— 
Chronic dialysis not 
indicated 
Chronic dialysis or renal 
transplant indicated 
Death 
ALSO CONSIDER: Glomerular filtration rate. 

 
RENAL/GENITOURINARY 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 62 - 
March 31, 2003, Publish Date: August 9, 2006 
Stricture/stenosis 
(including anastomotic), 
GU 
– Select: 
– Bladder 
– Fallopian tube 
– Prostate 
– Spermatic cord 
– Stoma 
– Testes 
– Ureter  
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Stricture, anastomotic, 
GU – Select  
Asymptomatic, 
radiographic or 
endoscopic findings only 
Symptomatic but no 
hydronephrosis, sepsis or 
renal dysfunction; dilation 
or endoscopic repair or 
stent placement indicated 
Symptomatic and altered 
organ function (e.g., 
sepsis or hydronephrosis, 
or renal dysfunction); 
operative intervention 
indicated  
Life-threatening 
consequences; organ 
failure or operative 
intervention requiring 
organ resection indicated  
Death 
ALSO CONSIDER: Obstruction, GU – Select. 
Urinary electrolyte 
wasting (e.g., Fanconi’s 
syndrome, renal tubular 
acidosis) 
Urinary electrolyte 
wasting 
Asymptomatic, 
intervention not indicated 
Mild, reversible and 
manageable with 
replacement 
Irreversible, requiring 
continued replacement  
— 
— 
ALSO CONSIDER: Acidosis (metabolic or respiratory); Bicarbonate, serum-low; Calcium, serum-low (hypocalcemia); Phosphate, serum-low (hypophosphatemia). 
Urinary 
frequency/urgency 
Urinary frequency 
Increase in frequency or 
nocturia up to 2 x normal; 
enuresis 
Increase >2 x normal but 
<hourly 
≥1 x/hr; urgency; catheter 
indicated 
— 
— 
Urinary retention 
(including neurogenic 
bladder)  
Urinary retention 
Hesitancy or dribbling, no 
significant residual urine; 
retention occurring during 
the immediate 
postoperative period 
Hesitancy requiring 
medication; or operative 
bladder atony requiring 
indwelling catheter 
beyond immediate 
postoperative period but 
for <6 weeks 
More than daily 
catheterization indicated; 
urological intervention 
indicated (e.g., TURP, 
suprapubic tube, 
urethrotomy) 
Life-threatening 
consequences; organ 
failure (e.g., bladder 
rupture); operative 
intervention requiring 
organ resection indicated 
Death 
REMARK: The etiology of retention (if known) is graded as Obstruction, GU – Select; Stricture/stenosis (including anastomotic), GU – Select. 
ALSO CONSIDER: Obstruction, GU – Select; Stricture/stenosis (including anastomotic), GU – Select. 
Urine color change  
Urine color change 
Present 
— 
— 
— 
— 
REMARK: Urine color refers to change that is not related to other dietary or physiologic cause (e.g., bilirubin, concentrated urine, and hematuria). 
Renal/Genitourinary – 
Other (Specify, __) 
Renal – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
SECONDARY MALIGNANCY 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 63 - 
March 31, 2003, Publish Date: August 9, 2006 
Secondary Malignancy – 
possibly related to cancer 
treatment (Specify, __)  
Secondary Malignancy 
(possibly related to 
cancer treatment) 
— 
— 
Non-life-threatening basal 
or squamous cell 
carcinoma of the skin 
Solid tumor, leukemia or 
lymphoma  
Death 
REMARK: Secondary malignancy excludes metastasis from initial primary. Any malignancy possibly related to cancer treatment (including AML/MDS) should be reported via the routine 
reporting mechanisms outlined in each protocol. Important: Secondary Malignancy is an exception to NCI Expedited Adverse Event Reporting Guidelines. Secondary Malignancy is 
“Grade 4, present” but NCI does not require AdEERS Expedited Reporting for any (related or unrelated to treatment) Secondary Malignancy. A diagnosis of AML/MDS following 
treatment with an NCI-sponsored investigational agent is to be reported using the form available from the CTEP Web site at http://ctep.cancer.gov. Cancers not suspected of being 
treatment-related are not to be reported here. 

 
SEXUAL/REPRODUCTIVE FUNCTION 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 64 - 
March 31, 2003, Publish Date: August 9, 2006 
Breast function/lactation 
Breast function 
Mammary abnormality, 
not functionally significant 
Mammary abnormality, 
functionally significant 
— 
— 
— 
Breast nipple/areolar 
deformity  
Nipple/areolar 
Limited areolar 
asymmetry with no 
change in nipple/areolar 
projection 
Asymmetry of nipple 
areolar complex with 
slight deviation in nipple 
projection 
Marked deviation of 
nipple projection  
— 
— 
Breast volume/hypoplasia 
Breast 
Minimal asymmetry; 
minimal hypoplasia 
Asymmetry exists, ≤1/3 of 
the breast volume; 
moderate hypoplasia  
Asymmetry exists, >1/3 of 
the breast volume; severe 
hypoplasia 
— 
— 
REMARK: Breast volume is referenced with both arms straight overhead. 
NAVIGATION NOTE: Dysmenorrhea is graded as Pain – Select in the PAIN CATEGORY.  
NAVIGATION NOTE: Dyspareunia is graded as Pain – Select in the PAIN CATEGORY.  
NAVIGATION NOTE: Dysuria (painful urination) is graded as Pain – Select in the PAIN CATEGORY.  
Erectile dysfunction 
Erectile dysfunction 
Decrease in erectile 
function 
(frequency/rigidity of 
erections) but erectile 
aids not indicated 
Decrease in erectile 
function 
(frequency/rigidity of 
erections), erectile aids 
indicated 
Decrease in erectile 
function 
(frequency/rigidity of 
erections) but erectile 
aids not helpful; penile 
prosthesis indicated 
— 
— 
Ejaculatory dysfunction 
Ejaculatory dysfunction 
Diminished ejaculation 
Anejaculation or 
retrograde ejaculation 
— 
— 
— 
NAVIGATION NOTE: Feminization of male is graded in the ENDOCRINE CATEGORY. 
Gynecomastia 
Gynecomastia 
— 
Asymptomatic breast 
enlargement 
Symptomatic breast 
enlargement; intervention 
indicated 
— 
— 
ALSO CONSIDER: Pain – Select.  
Infertility/sterility 
Infertility/sterility 
— 
Male: oligospermia/low 
sperm count 
Female: diminished 
fertility/ovulation 
Male: sterile/azoospermia 
Female: infertile/ 
anovulatory 
— 
— 
Irregular menses  
(change from baseline) 
Irregular menses 
1 – 3 months without 
menses 
>3 – 6 months without 
menses but continuing 
menstrual cycles 
Persistent amenorrhea 
for >6 months 
— 
— 

 
SEXUAL/REPRODUCTIVE FUNCTION 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 65 - 
March 31, 2003, Publish Date: August 9, 2006 
Libido 
Libido 
Decrease in interest but 
not affecting relationship; 
intervention not indicated 
Decrease in interest and 
adversely affecting 
relationship; intervention 
indicated 
— 
— 
— 
NAVIGATION NOTE: Masculinization of female is graded in the ENDOCRINE CATEGORY. 
Orgasmic dysfunction 
Orgasmic function 
Transient decrease 
Decrease in orgasmic 
response requiring 
intervention 
Complete inability of 
orgasmic response; not 
responding to intervention 
— 
— 
NAVIGATION NOTE: Pelvic pain is graded as Pain – Select in the PAIN CATEGORY. 
NAVIGATION NOTE: Ulcers of the labia or perineum are graded as Ulceration in DERMATOLOGY/SKIN CATEGORY. 
Vaginal discharge  
(non-infectious) 
Vaginal discharge 
Mild 
Moderate to heavy; pad 
use indicated 
— 
— 
— 
Vaginal dryness 
Vaginal dryness 
Mild 
Interfering with sexual 
function; dyspareunia; 
intervention indicated 
— 
— 
— 
ALSO CONSIDER: Pain – Select. 
Vaginal mucositis 
Vaginal mucositis 
Erythema of the mucosa; 
minimal symptoms 
Patchy ulcerations; 
moderate symptoms or 
dyspareunia 
Confluent ulcerations; 
bleeding with trauma; 
unable to tolerate vaginal 
exam, sexual intercourse 
or tampon placement  
Tissue necrosis; 
significant spontaneous 
bleeding; life-threatening 
consequences 
— 
Vaginal stenosis/length 
Vaginal stenosis 
Vaginal narrowing and/or 
shortening not interfering 
with function  
Vaginal narrowing and/or 
shortening interfering with 
function  
Complete obliteration; not 
surgically correctable 
— 
— 
Vaginitis (not due to 
infection) 
Vaginitis 
Mild, intervention not 
indicated 
Moderate, intervention 
indicated 
Severe, not relieved with 
treatment; ulceration, but 
operative intervention not 
indicated 
Ulceration and operative 
intervention indicated 
— 
Sexual/Reproductive 
Function – Other 
(Specify, __) 
Sexual – Other (Specify) 
Mild 
Moderate 
Severe 
Disabling 
Death 

 
SURGERY/INTRA-OPERATIVE INJURY 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 66 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Intra-operative hemorrhage is graded as Hemorrhage/bleeding associated with surgery, intra-operative or postoperative in the HEMORRHAGE/BLEEDING 
CATEGORY.  
Intra-operative injury  
– Select Organ or 
Structure 
‘Select’ AEs appear at the 
end of the CATEGORY. 
Intraop injury – Select  
Primary repair of injured 
organ/structure indicated  
Partial resection of 
injured organ/structure 
indicated 
Complete resection or 
reconstruction of injured 
organ/structure indicated 
Life threatening 
consequences; disabling 
— 
REMARK: The ‘Select’ AEs are defined as significant, unanticipated injuries that are recognized at the time of surgery. These AEs do not refer to additional surgical procedures that 
must be performed because of a change in the operative plan based on intra-operative findings. Any sequelae resulting from the intra-operative injury that result in an adverse 
outcome for the patient must also be recorded and graded under the relevant CTCAE Term. 
Intra-operative Injury – 
Other (Specify, __) 
Intraop Injury – Other 
(Specify) 
Primary repair of injured 
organ/structure indicated  
Partial resection of 
injured organ/structure 
indicated 
Complete resection or 
reconstruction of injured 
organ/structure indicated 
Life threatening 
consequences; disabling 
— 
REMARK: Intra-operative Injury – Other (Specify, __) is to be used only to report an organ/structure not included in the ‘Select’ AEs found at the end of the CATEGORY. Any sequelae 
resulting from the intra-operative injury that result in an adverse outcome for the patient must also be recorded and graded under the relevant CTCAE Term. 

 
SURGERY/INTRA-OPERATIVE INJURY – SELECT  
Page 2 of 2 
CTCAE v3.0  
- 67 - 
March 31, 2003, Publish Date: August 9, 2006 
AUDITORY/EAR 
– Inner ear  
– Middle ear  
– Outer ear NOS  
– Outer ear-Pinna  
CARDIOVASCULAR 
– Artery-aorta  
– Artery-carotid  
– Artery-cerebral  
– Artery-extremity (lower)  
– Artery-extremity (upper)  
– Artery-hepatic  
– Artery-major visceral artery  
– Artery-pulmonary  
– Artery NOS 
– Heart  
– Spleen 
– Vein-extremity (lower)  
– Vein-extremity (upper)  
– Vein-hepatic  
– Vein-inferior vena cava  
– Vein-jugular  
– Vein-major visceral vein  
– Vein-portal vein  
– Vein-pulmonary  
– Vein-superior vena cava  
– Vein NOS 
DERMATOLOGY/SKIN 
– Breast  
– Nails  
– Skin 
ENDOCRINE 
– Adrenal gland 
– Parathyroid 
– Pituitary  
ENDOCRINE (continued) 
– Thyroid 
HEAD AND NECK 
– Gingiva  
– Larynx  
– Lip/perioral area  
– Face NOS  
– Nasal cavity  
– Nasopharynx  
– Neck NOS 
– Nose  
– Oral cavity NOS  
– Parotid gland  
– Pharynx  
– Salivary duct  
– Salivary gland  
– Sinus  
– Teeth  
– Tongue  
– Upper aerodigestive NOS 
GASTROINTESTINAL 
– Abdomen NOS  
– Anal sphincter  
– Anus 
– Appendix  
– Cecum  
– Colon  
– Duodenum  
– Esophagus  
– Ileum  
– Jejunum  
– Oral  
– Peritoneal cavity  
– Rectum 
– Small bowel NOS 
GASTROINTESTINAL (continued) 
– Stoma (GI)  
– Stomach  
HEPATOBILIARY/ PANCREAS 
– Biliary tree-common bile  
duct  
– Biliary tree-common hepatic 
duct  
– Biliary tree-left hepatic duct  
– Biliary tree-right hepatic duct  
– Biliary tree NOS  
– Gallbladder  
– Liver 
– Pancreas 
– Pancreatic duct 
MUSCULOSKELETAL 
– Bone  
– Cartilage  
– Extremity-lower 
– Extremity-upper 
– Joint  
– Ligament  
– Muscle  
– Soft tissue NOS 
– Tendon 
NEUROLOGY  
– Brain  
– Meninges  
– Spinal cord 
NERVES: 
– Brachial plexus 
– CN I (olfactory) 
– CN II (optic) 
– CN III (oculomotor) 
– CN IV (trochlear)  
NEUROLOGY (continued) 
NERVES: 
– CN V (trigeminal) motor  
– CN V (trigeminal) sensory  
– CN VI (abducens)  
– CN VII (facial) motor-face  
– CN VII (facial) sensory-
taste  
– CN VIII (vestibulocochlear)  
– CN IX (glossopharyngeal) 
motor pharynx  
– CN IX (glossopharyngeal) 
sensory ear-pharynx-
tongue  
– CN X (vagus)  
– CN XI (spinal accessory)  
– CN XII (hypoglossal)  
– Cranial nerve or branch 
NOS  
– Lingual  
– Lung thoracic  
– Peripheral motor NOS 
– Peripheral sensory NOS 
– Recurrent laryngeal  
– Sacral plexus  
– Sciatic 
– Thoracodorsal 
OCULAR 
– Conjunctiva  
– Cornea  
– Eye NOS 
– Lens 
– Retina 
PULMONARY/UPPER 
RESPIRATORY 
– Bronchus  
– Lung  
– Mediastinum  
– Pleura  
– Thoracic duct  
– Trachea 
– Upper airway NOS 
RENAL/GENITOURINARY 
– Bladder  
– Cervix  
– Fallopian tube  
– Kidney  
– Ovary  
– Pelvis NOS  
– Penis  
– Prostate  
– Scrotum  
– Testis  
– Ureter  
– Urethra  
– Urinary conduit  
– Urinary tract NOS  
– Uterus  
– Vagina  
– Vulva 
 
 

 
SYNDROMES 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 68 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Acute vascular leak syndrome is graded in the VASCULAR CATEGORY. 
NAVIGATION NOTE: Adrenal insufficiency is graded in the ENDOCRINE CATEGORY. 
NAVIGATION NOTE: Adult Respiratory Distress Syndrome (ARDS) is graded in the PULMONARY/UPPER RESPIRATORY CATEGORY. 
Alcohol intolerance 
syndrome (antabuse-like 
syndrome) 
Alcohol intolerance 
syndrome 
— 
— 
Present 
— 
Death 
REMARK: An antabuse-like syndrome occurs with some new anti-androgens (e.g., nilutamide) when patient also consumes alcohol. 
NAVIGATION NOTE: Autoimmune reaction is graded as Autoimmune reaction/hypersensitivity (including drug fever) in the ALLERGY/IMMUNOLOGY CATEGORY. 
Cytokine release 
syndrome/acute infusion 
reaction 
Cytokine release 
syndrome 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDS, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption of 
infusion); recurrence of 
symptoms following initial 
improvement; 
hospitalization indicated 
for other clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates) 
Life-threatening; pressor 
or ventilatory support 
indicated 
Death 
REMARK: Cytokine release syndromes/acute infusion reactions are different from Allergic/hypersensitive reactions, although some of the manifestations are common to both AEs. An 
acute infusion reaction may occur with an agent that causes cytokine release (e.g., monoclonal antibodies or other biological agents). Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hrs of completion of infusion. Signs/symptoms may include: Allergic reaction/hypersensitivity (including drug 
fever); Arthralgia (joint pain); Bronchospasm; Cough; Dizziness; Dyspnea (shortness of breath); Fatigue (asthenia, lethargy, malaise); Headache; Hypertension; Hypotension; Myalgia 
(muscle pain); Nausea; Pruritis/itching; Rash/desquamation; Rigors/chills; Sweating (diaphoresis); Tachycardia; Tumor pain (onset or exacerbation of tumor pain due to treatment); 
Urticaria (hives, welts, wheals); Vomiting.  
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever); Bronchospasm, wheezing; Dyspnea (shortness of breath); Hypertension; Hypotension; Hypoxia; Prolonged 
QTc interval; Supraventricular and nodal arrhythmia – Select; Ventricular arrhythmia – Select.  
NAVIGATION NOTE: Disseminated intravascular coagulation (DIC) is graded in the COAGULATION CATEGORY. 
NAVIGATION NOTE: Fanconi’s syndrome is graded as Urinary electrolyte wasting (e.g., Fanconi’s syndrome, renal tubular acidosis) in the RENAL/GENITOURINARY CATEGORY. 
Flu-like syndrome 
Flu-like syndrome 
Symptoms present but 
not interfering with 
function 
Moderate or causing 
difficulty performing some 
ADL 
Severe symptoms 
interfering with ADL 
Disabling 
Death 
REMARK: Flu-like syndrome represents a constellation of symptoms which may include cough with catarrhal symptoms, fever, headache, malaise, myalgia, prostration, and is to be 
used when the symptoms occur in a cluster consistent with one single pathophysiological process. 
NAVIGATION NOTE: Renal tubular acidosis is graded as Urinary electrolyte wasting (e.g., Fanconi’s syndrome, renal tubular acidosis) in the RENAL/GENITOURINARY CATEGORY. 

 
SYNDROMES 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 69 - 
March 31, 2003, Publish Date: August 9, 2006 
“Retinoic acid syndrome”  
“Retinoic acid syndrome” 
Fluid retention; less than 
3 kg of weight gain; 
intervention with fluid 
restriction and/or diuretics 
indicated 
Mild to moderate signs/ 
symptoms; steroids 
indicated 
Severe signs/symptoms; 
hospitalization indicated 
Life-threatening; 
ventilatory support 
indicated 
Death 
REMARK: Patients with acute promyelocytic leukemia may experience a syndrome similar to “retinoic acid syndrome” in association with other agents such as arsenic trioxide. The 
syndrome is usually manifested by otherwise unexplained fever, weight gain, respiratory distress, pulmonary infiltrates and/or pleural effusion, with or without leukocytosis.  
ALSO CONSIDER: Acute vascular leak syndrome; Pleural effusion (non-malignant); Pneumonitis/pulmonary infiltrates. 
NAVIGATION NOTE: SIADH is graded as Neuroendocrine: ADH secretion abnormality (e.g., SIADH or low ADH) in the ENDOCRINE CATEGORY.  
NAVIGATION NOTE: Stevens-Johnson syndrome is graded as Rash: erythema multiforme (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis) in the DERMATOLOGY/SKIN 
CATEGORY. 
NAVIGATION NOTE: Thrombotic microangiopathy is graded as Thrombotic microangiopathy (e.g., thrombotic thrombocytopenic purpura [TTP] or hemolytic uremic syndrome [HUS]) in 
the COAGULATION CATEGORY. 
Tumor flare 
Tumor flare 
Mild pain not interfering 
with function 
Moderate pain; pain or 
analgesics interfering with 
function, but not 
interfering with ADL 
Severe pain; pain or 
analgesics interfering with 
function and interfering 
with ADL 
Disabling 
Death 
REMARK: Tumor flare is characterized by a constellation of signs and symptoms in direct relation to initiation of therapy (e.g., anti-estrogens/androgens or additional hormones). The 
symptoms/signs include tumor pain, inflammation of visible tumor, hypercalcemia, diffuse bone pain, and other electrolyte disturbances.  
ALSO CONSIDER: Calcium, serum-high (hypercalcemia). 
Tumor lysis syndrome 
Tumor lysis syndrome 
— 
— 
Present 
— 
Death 
ALSO CONSIDER: Creatinine; Potassium, serum-high (hyperkalemia). 
Syndromes – Other 
(Specify, __) 
Syndromes – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
VASCULAR 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 70 - 
March 31, 2003, Publish Date: August 9, 2006 
Acute vascular leak 
syndrome 
Acute vascular leak 
syndrome 
— 
Symptomatic, fluid 
support not indicated 
Respiratory compromise 
or fluids indicated 
Life-threatening; pressor 
support or ventilatory 
support indicated  
Death 
Peripheral arterial 
ischemia 
Peripheral arterial 
ischemia 
— 
Brief (<24 hrs) episode of 
ischemia managed non-
surgically and without 
permanent deficit 
Recurring or prolonged 
(≥24 hrs) and/or invasive 
intervention indicated 
Life-threatening, disabling 
and/or associated with 
end organ damage 
(e.g., limb loss) 
Death 
Phlebitis (including 
superficial thrombosis) 
Phlebitis 
— 
Present 
— 
— 
— 
ALSO CONSIDER: Injection site reaction/extravasation changes. 
Portal vein flow 
Portal flow 
— 
Decreased portal vein 
flow 
Reversal/retrograde 
portal vein flow 
— 
— 
Thrombosis/embolism 
(vascular access-related) 
Thrombosis/embolism 
(vascular access) 
— 
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
not indicated 
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
indicated 
Embolic event including 
pulmonary embolism or 
life-threatening thrombus 
Death 
Thrombosis/thrombus/ 
embolism 
Thrombosis/thrombus/ 
embolism 
— 
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
not indicated  
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
indicated  
Embolic event including 
pulmonary embolism or 
life-threatening thrombus 
Death 
Vessel injury-artery  
– Select:  
– Aorta 
– Carotid 
– Extremity-lower 
– Extremity-upper  
– Other NOS 
– Visceral 
Artery injury – Select 
Asymptomatic diagnostic 
finding; intervention not 
indicated 
Symptomatic (e.g., 
claudication); not 
interfering with ADL; 
repair or revision not 
indicated 
Symptomatic interfering 
with ADL; repair or 
revision indicated 
Life-threatening; 
disabling; evidence of 
end organ damage (e.g., 
stroke, MI, organ or limb 
loss) 
Death 
NAVIGATION NOTE: Vessel injury to an artery intra-operatively is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY 
CATEGORY. 

 
VASCULAR 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 71 - 
March 31, 2003, Publish Date: August 9, 2006 
Vessel injury-vein  
– Select: 
– Extremity-lower  
– Extremity-upper 
– IVC 
– Jugular 
– Other NOS 
– SVC 
– Viscera 
Vein injury – Select 
Asymptomatic diagnostic 
finding; intervention not 
indicated 
Symptomatic (e.g., 
claudication); not 
interfering with ADL; 
repair or revision not 
indicated  
Symptomatic interfering 
with ADL; repair or 
revision indicated 
Life-threatening; 
disabling; evidence of 
end organ damage  
Death 
NAVIGATION NOTE: Vessel injury to a vein intra-operatively is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY CATEGORY. 
Visceral arterial ischemia 
(non-myocardial) 
Visceral arterial ischemia 
— 
Brief (<24 hrs) episode of 
ischemia managed 
medically and without 
permanent deficit 
Prolonged (≥24 hrs) or 
recurring symptoms 
and/or invasive 
intervention indicated 
Life-threatening; 
disabling; evidence of 
end organ damage  
Death 
ALSO CONSIDER: CNS cerebrovascular ischemia.  
Vascular – Other  
(Specify, __) 
Vascular – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
 

Clinical Trial Protocol:  HGT-SAN-067
Study Title:
An Open-Label Extension of Study HGT-SAN-055 Evaluating 
Long-Term Safety and Clinical Outcomes of Intrathecal 
Administration of rhHNS in Patients with Sanfilippo Syndrome
Type A (MPS IIIA)
Study Number:
HGT-SAN-067
Study Phase:
I/II
Product Name:
Recombinant human heparan N-sulfatase (rhHNS)
EudraCT 
Number:
2010-021348-16
Indication:
Sanfilippo Syndrome A
Investigators:
Multicenter
Sponsor:
Shire Human Genetic Therapies, Inc. 
300 Shire Way
Lexington, MA  02421, United States
Medical Monitor:
MD,
Date
Original Protocol:
21 June 2010
Amendment 1:
27 January 2011
Amendment 2:
13 January 2012
Amendment 3:
28 August 2012
Confidentiality Statement
This document is the proprietary and confidential property of 
Shire Human Genetic Therapies, Inc.

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
2
TABLE OF CONTENTS
TABLE OF CONTENTS...........................................................................................................2
SYNOPSIS.................................................................................................................................7
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..........................................13
1
INTRODUCTION ...........................................................................................................16
1.1
Disease Background...............................................................................................16
1.2
Nonclinical Overview............................................................................................18
1.2.1
Toxicology in Monkeys ...............................................................................18
1.2.2
Efficacy in Murine and Canine Models of MPS IIIA..................................18
1.3
HGT-SAN-067 Study Rationale............................................................................19
2
STUDY OBJECTIVES....................................................................................................20
2.1
Primary Objective..................................................................................................20
2.2
Secondary Objectives.............................................................................................20
3
STUDY ENDPOINTS.....................................................................................................21
3.1
Primary Endpoint...................................................................................................21
3.2
Secondary Endpoints .............................................................................................21
4
INVESTIGATIONAL PLAN..........................................................................................22
4.1
Overall Study Design and Plan..............................................................................22
4.2
Rationale for Study Design and Control Group.....................................................24
4.3
Study Duration and Dates......................................................................................24
5
STUDY POPULATION SELECTION ...........................................................................25
5.1
Study Population....................................................................................................25
5.2
Inclusion Criteria ...................................................................................................25
5.3
Exclusion Criteria ..................................................................................................25
6
STUDY TREATMENT(S)..............................................................................................27
6.1
Description of Treatment(s)...................................................................................27
6.1.1
Study Drug...................................................................................................27
6.1.2
Placebo or Control .......................................................................................27
6.2
Treatment Administered ........................................................................................27
6.2.1
Selection and Timing of Dose for Each Patient...........................................27
6.2.2
Cerebral Spinal Fluid Sample Procedure.....................................................27
6.2.3
Intrathecal Administration of rhHNS...........................................................28
6.2.4
Administration of rhHNS via Lumbar Puncture..........................................28
6.3
Method of Assigning Subjects to Treatment Groups.............................................28
6.4
Blinding..................................................................................................................28
6.5
Concomitant Therapy.............................................................................................29
6.6
Restrictions ............................................................................................................29
6.6.1
Prior Therapy ...............................................................................................29

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
3
6.6.2
Fluid and Food Intake..................................................................................29
6.6.3
Patient Activity Restrictions ........................................................................29
6.7
Treatment Compliance...........................................................................................29
6.8
Packaging and Labeling.........................................................................................30
6.9
Storage and Accountability....................................................................................30
6.10
Investigational Product Retention at Study Site ....................................................30
7
STUDY PROCEDURES .................................................................................................31
7.1
Informed Consent...................................................................................................31
7.2
Physical Examination.............................................................................................31
7.3
Height and Weight .................................................................................................31
7.4
Head Circumference ..............................................................................................31
7.5
Vital Signs..............................................................................................................32
7.6
Electrocardiography...............................................................................................32
7.6.1
Electrocardiograms ......................................................................................32
7.7
Clinical Laboratory Tests.......................................................................................32
7.7.1
Hematology..................................................................................................32
7.7.2
Serum Chemistry .........................................................................................33
7.7.3
Pregnancy Test.............................................................................................33
7.8
Urinalysis ...............................................................................................................33
7.8.1.1
Standard Urinalysis............................................................................33
7.8.1.2
Urine Heparan Sulfate and Heparan Sulfate Derivatives ..................33
7.8.2
Cerebrospinal Fluid Assessments ................................................................34
7.8.2.1
Cerebrospinal Fluid Cell Counts........................................................34
7.8.2.2
Cerebrospinal Fluid Heparan Sulfate Levels and Heparan Sulfate 
Derivatives.........................................................................................34
7.8.2.3
Anti-rhHNS Antibodies .....................................................................34
7.8.2.4
Cerebrospinal Fluid Biomarkers........................................................34
7.8.3
Sample Collection, Storage, and Shipping ..................................................34
7.9
Anesthesia..............................................................................................................34
7.10
Audiometry and Auditory Brainstem Response ....................................................35
7.11
Magnetic Resonance Imaging of the Head ............................................................35
7.12
Surgical Re-implantation of the IDDD..................................................................35
7.12.1
Restrictions on the Number of Revision and/or re-implantation of the 
IDDD............................................................................................................36
7.13
Cerebrospinal Fluid Opening Pressure Measurement............................................36
7.14
Dispensing Study Drug..........................................................................................36
7.15
Pharmacokinetic Assessments ...............................................................................36
7.16
Neurological Examination .....................................................................................36
7.17
Anti-rhHNS Antibody, Heparan Sulfate, and Heparan Sulfate Derivative 
Determination ........................................................................................................36

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
4
7.18
Neurocognitive and Developmental Assessments.................................................37
7.19
Sleep Questionnaire:  Children’s Sleep Habits Rating Scale.................................38
7.20
Age-Dependent, Health-Related Quality of Life in Children................................39
7.20.1
Quality of Life Indicator:  CHQ-50 .............................................................39
7.20.2
Quality of Life Indicator:  CHQ-87 .............................................................39
7.20.3
Quality of Life Indicator:  ITQOL...............................................................39
7.21
Concomitant Medications, Therapies and Medical/Surgical Procedures ..............39
7.22
Adverse Events ......................................................................................................40
7.22.1
Definitions of Adverse Events and Serious Adverse Events.......................40
7.22.1.1
Adverse Event....................................................................................40
7.22.1.2
Serious Adverse Event.......................................................................42
7.22.2
Procedures for Recording and Reporting Adverse Events ..........................44
7.22.2.1
Reporting Serious Adverse Events Related to Study Procedures......44
7.22.2.2
Eliciting Adverse Events....................................................................45
7.22.2.3
Protocol Deviations for Medical Emergency or Adverse Event........45
7.23
Safety-related Study Stopping Rules .....................................................................46
7.24
Pregnancy...............................................................................................................46
7.25
Removal of Subjects from the Trial or Study Drug...............................................46
7.26
Other Study Procedures .........................................................................................48
7.27
Appropriateness of Measurements.........................................................................48
8
STUDY ACTIVITIES .....................................................................................................49
8.1
Screening Visit/Study Start Visit...........................................................................49
8.2
Treatment:  Drug Administration and Weekly Assessments.................................50
8.2.1
Week 1 .........................................................................................................50
8.2.1.1
Day 1 (Pre-treatment) Assessments Performed Prior to Each Dose..50
8.2.1.2
Day 2 (±2 days) Assessments and Administration of rhHNS............51
8.3
End of Study/Early Termination Procedures:  Month 55 ......................................51
8.4
Safety Follow-up (by Telephone or Visit) Month 56 ............................................52
9
QUALITY CONTROL AND ASSURANCE .................................................................54
10
PLANNED STATISTICAL METHODS ........................................................................55
10.1
General Statistical Methodology............................................................................55
10.2
Determination of Sample Size ...............................................................................55
10.3
Analysis Populations..............................................................................................55
10.4
Demographics and Baseline Characteristics..........................................................56
10.5
Statistical Analysis of Pharmacokinetic Variables ................................................56
10.6
Efficacy, Safety, and Pharmacodynamic Evaluations ...........................................56
10.6.1
Primary Analyses.........................................................................................56
10.6.1.1
Safety Analysis ..................................................................................56
10.6.1.2
Clinical Laboratory Evaluations ........................................................57
10.6.1.3
Anti-rhHNS Antibody Formation......................................................57

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
5
10.6.2
Secondary Analysis......................................................................................58
10.6.2.1
Clinical Assessments .........................................................................58
10.6.2.2
Pharmacodynamic Analyses..............................................................58
11
ADMINISTRATIVE CONSIDERATIONS....................................................................59
11.1
Investigators and Study Administrative Structure.................................................59
11.2
Institutional Review Board or Independent Ethics Committee Approval .............59
11.3
Ethical Conduct of the Study.................................................................................59
11.4
Patient Information and Consent ...........................................................................59
11.5
Patient Confidentiality...........................................................................................60
11.6
Study Monitoring...................................................................................................60
11.7
Case Report Forms and Study Records .................................................................61
11.7.1
Critical Documents ......................................................................................61
11.8
Data Monitoring Committee..................................................................................62
11.9
Protocol Violations/Deviations..............................................................................62
11.10 Access to Source Documentation ..........................................................................62
11.11 Data Generation and Analysis ...............................................................................62
11.12 Premature Closure of the Study.............................................................................63
11.12.1
Study Termination .......................................................................................63
11.12.2
Site Termination...........................................................................................63
11.13 Retention of Data...................................................................................................63
11.14 Financial Disclosure...............................................................................................63
11.15 Publication and Disclosure Policy .........................................................................63
12
LIST OF REFERENCES.................................................................................................65
LIST OF IN-TEXT TABLES
Table 7-1
Neurodevelopmental Assessments Tests.....................................................38
Table 7-2
Sanfilippo-Specific Disability Assessment And Behavior Rating Scales ...38
Table 7-3
Adverse Event Severity................................................................................43
Table 7-4
Adverse Event Relatedness..........................................................................43
Table 4-1
Summary of Neurodevelopmental Outcome Measures ...............................69
Table 4-2
Summary of Sanfilippo-specific Assessments.............................................69
LIST OF IN-TEXT FIGURES
Figure 1:  Radiographic appearance of IDDD port implanted over lower ribs, with 
percutaneous needle inserted.  Note that the tapered appearance of the locking collar 
permits assessment of its correct orientation. ..............................................................73

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
6
LIST OF APPENDICES
Appendix 1
Schedule of Events.............................................................................67
Appendix 2
Neurodevelopmental and Behavioral Assessments ...........................69
Appendix 3
Failure of IDDD Function:  Investigation and Management.............73
Appendix 4
Summary of Changes for Amendment 3 ...........................................76
Appendix 5
Protocol Signature Page.....................................................................79
Appendix 6
The National Cancer Institute Common Toxicity Criteria ................80

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
7
SYNOPSIS
Sponsor:
Shire Human Genetic Therapies, Inc.
300 Shire Way
Lexington, MA  02421, United States
Name of Finished Product:
Recombinant human heparan N-sulfatase (rhHNS)
Name of Active Ingredient:
rhHNS
Name of Inactive Ingredient:
N/A
Study Title:
An Open-Label Extension of Study HGT-SAN-055 Evaluating Long-Term Safety and 
Clinical Outcomes of Intrathecal Administration of rhHNS in Patients with Sanfilippo 
Syndrome Type A (MPS IIIA)
Study Number:
HGT-SAN-067
Study Phase:  I/II
Study Objectives:
Primary Objective: 
The primary objective of this study is:
•
To collect long-term safety and tolerability data in patients with Sanfilippo Syndrome 
Type A (MPS IIIA) who received rhHNS via a surgically implanted intrathecal drug 
delivery device (IDDD) in study HGT-SAN-055 and elected to continue therapy in 
study HGT-SAN-067.
Secondary Objectives:
The secondary objectives of this study are:
•
To collect as measures of drug efficacy, over an extended treatment period (as change 
from baseline), the following:  clinical, neurological, cognitive, behavioral, 
functional, and quality of life (QoL) assessments, together with potential imaging and 
biochemical biomarkers.

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
8
Study Endpoints: 
Primary Endpoints:
The primary endpoint of this study is:
•
To determine the long-term safety of intrathecal rhHNS administration, as measured 
by the adverse events (type and severity), changes in clinical laboratory testing 
(serum chemistry including liver function tests, hematology, and urinalysis), 
electrocardiograms (ECG), cerebrospinal fluid (CSF), chemistries (including cell 
counts and inflammatory markers), and anti-rhHNS antibodies (in CSF and serum).
Secondary Endpoints:
The secondary endpoints of this study are to collect over an extended treatment period (as 
change from baseline) clinical and potential surrogate biomarker efficacy data:
•
Standardized neurocognitive and behavioral assessments, Sanfilippo-specific 
behavioral rating scales, gross and fine motor assessments, functional adaptive
rating scales, quality of life questionnaires, and Children’s Sleep Habits Rating 
Scale.
•
Concentration of rhHNS in CSF and serum.
•
Concentration of inflammatory cytokines in serum and CSF.
•
Concentration of safety and potential surrogate efficacy biomarkers in CSF, urine, 
and serum.
•
Concentration of heparan sulfate and heparan sulfate derivatives in urine and/or 
CSF, and if possible, in serum and/or plasma.
•
Brain magnetic resonance imaging (MRI) and auditory brainstem response 
(ABR), Brainstem Auditory Evoked Potentials).
Study Design:
This study, HGT-SAN-067, is an open-label, long term, multicenter, extension of 
Study HGT-SAN-055.  The study is designed to evaluate the long-term safety, clinical 
activity, and biomarker outcomes of intrathecal (IT) administration of 3 dose levels 
(10 mg, 45 mg, and 90 mg once per month [Q4W]) of rhHNS via an IDDD in patients 
with MPS IIIA who successfully complete the Phase I/II study HGT-SAN-055 (including 
end of study [EOS] assessments) and elect to continue to receive rhHNS treatment.  
Patients will continue in the same treatment group they were assigned to in the 
HGT-SAN-055 study. 
For nomenclature of chronology purposes, the Baseline Visit for this extension study will 
be considered to be the first day the patient received his/her IT dose of rhHNS in 
Study HGT-SAN-055.  The HGT-SAN-055 EOS assessment information will provide the 
screening/start of study information for patients who continue into the HGT-SAN-067 
extension study.  Note:  HGT-SAN-055 EOS data must be recorded in the context of the 
HGT-SAN-055 trial, and a copy of those data can be used for HGT-SAN-067 screening.  
Once eligibility is confirmed, informed consent must be obtained prior to performing any 
study-related procedures that are specific to HGT-SAN-067.  

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
9
Informed consent will be provided by the patient’s parent(s)/legally authorized 
representative(s) prior to the start of the extension study procedures.  Informed consent 
may be obtained anytime from week 20 in HGT-SAN-055.  This would allow a patient to 
have a nonfunctional IDDD replaced or revised prior to the first rhHNS dose in 
HGT-SAN-067.
Enrolled patients will check in to the study center 1 day before each of the scheduled 
rhHNS dosing days for safety assessments (designated Day 1).  If no safety concerns 
exist, the patient will subsequently receive IT administration of rhHNS on Day 2 
(±2 days).  However, if feasible and there are no safety concerns in the opinion of the 
investigator, the Day 1 and Day 2 assessments may be combined and performed on 
Day 2; if this is done the results will be recorded as Day 2.  Patients will remain in the 
study centre for at least 8 hours following dosing with rhHNS and will be discharged 
from the unit when deemed clinically stable by the Investigator.
All patients will have received a series of standardized neurodevelopment assessments; in 
the HGT-SAN-055 study, these will have occurred at Baseline and either prior to or at the 
6-month time point.  Patients will continue in HGT-SAN-067 with whichever age 
specific assessment they began with in HGT-SAN-055.  If, however, a patient’s 
capability improves and they become capable of completing assessments at a higher 
level, such additional assessments may be added.  Any additional assessments would be 
performed after the original assessments (those previously used in study HGT-SAN-055) 
have been carried out.  A MRI of the head and ABR testing will be performed at Months 
12, 24, 36, and 54 (note that assessment time point nomenclature includes the 6 months in 
the HGT-SAN-055 study).  Note:  X-rays may be performed to investigate device 
malfunction, and to verify correct catheter and port placement following surgical 
implantation or revision.  In addition, fluoroscopy may be employed intraoperatively to 
guide catheter placement.  Thus, patients may undergo 3 X-ray examinations in 
association with each episode of IDDD malfunction and subsequent IDDD revision or 
replacement.  Since the number of IDDD revisions/replacements is limited to 2 in any 
6-month period (including the time in the HGT-SAN-055 study), the number of 
protocol-associated X-ray evaluations is limited to 6 exposures in any 6-month period 
(including time in the HGT-SAN-055).
Patients will be evaluated for safety throughout the study.  Adverse events that occur in 
HGT-SAN-055 and that are ongoing at enrollment in HGT-SAN-067 will be captured in 
the case report forms (CRFs) for study HGT-SAN-067.  Specific safety stopping criteria 
will be applied and will be based on the types and severity of adverse events (AEs) 
reported while on-study.  These data will be reviewed to inform the decision to 
discontinue a patient, a dose group, or the study as a whole. 
All patients will have an EOS visit 30 (±7) days following their last administration of 
rhHNS (ie, Month 55).  The EOS procedures will include standard clinical laboratory 
tests (serum chemistry, hematology, and urinalysis) in CSF and blood, protocol specific 
laboratory testing (eg, anti-rhHNS antibody testing), neurodevelopmental testing, ABR, 
child health questionnaires, and MRI.  

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
10
Use of concomitant medications, therapies, and procedures will be recorded and AEs will 
be monitored. 
All patients will be contacted by telephone or will have a visit for a Final Safety 
Follow-up, to be conducted at 30 (±7) days after the EOS visit (ie, Month 56) to collect 
updated information on AEs and concomitant medications, therapies, and procedures. 
It is anticipated that the IDDD will be used to obtain CSF samples and to deliver 
administrations of rhHNS.  However, if a patient’s IDDD appears nonfunctional or if its 
use is precluded on a scheduled day of dosing, site personnel will refer to the protocol 
appendix which describes the investigation and management of IDDD-related issues.  
This will include possible partial revision or complete replacement of the IDDD.  As 
noted above, a maximum of 2 partial revisions and/or complete replacements can occur in 
any 6 month period.  If revision or replacement of the IDDD cannot be scheduled in time 
to avoid a delay of the next scheduled dose of rhHNS, or if the patient experiences more 
than 2 IDDD malfunctions in a 6 month period (including participation in study 
HGT-SAN-055), rhHNS will be administered via lumbar puncture (LP).  Study drug may 
be administered via LP for a maximum of 5 successive monthly doses, after which, IDDD 
re-implantation or revision must occur. 
If there is no significant safety risk in the opinion of the Investigator, a non-functional 
IDDD may be left in situ for up to 3 months.
Patients who discontinue or are withdrawn before receiving 3 monthly IT injections will 
not have to undergo the EOS evaluations but will have their IDDD removed.  
If a patient discontinues, or withdraws from the study, or the study is stopped by the 
Sponsor, the IDDD will be removed as part of the EOS Procedures. 
An overview of the study appears in the Schedule of Events.
Study Population: 
A maximum of 12 patients are planned for this study.  To be eligible for participation 
patients will have completed all study requirements in Study HGT-SAN-055, including 
the EOS visit, and will have elected to continue treatment with rhHNS. 
Test Product; Dose; and Mode of Administration: 
Recombinant human heparan N-sulfatase (rhHNS) will be administered via an IDDD 
according to the same dose to which the patient was assigned in HGT-SAN-055 (ie, 
10 mg, 45 mg, or 90 mg monthly).  
Reference Therapy; Dose; and Mode of Administration: 
N/A
Diagnosis and Main Criteria for Inclusion
Inclusion Criteria:
Each patient must meet the following criteria to be enrolled in this study.
1. The patient must have completed Study HGT-SAN-055 and, in the opinion of the 
investigator, have no safety or medical issues that contraindicate participation. 

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
11
2. The patient, patient’s parent(s) or legally authorized representative(s) has voluntarily 
signed an Institutional Review Board/Independent Ethics Committee-approved 
informed consent (and assent, if applicable) form after all relevant aspects of the 
study have been explained and discussed with them.  Informed consent/assent must be 
obtained prior to any study specific procedures.
3. The patient received at least 5 of the 6 planned infusions of rhHNS in the 
HGT-SAN-055 study. 
4. The Patient must be medically stable, in the opinion of the Investigator, to 
accommodate the protocol requirements, including travel, assessments, and IDDD 
surgery (if necessary for replacement purposes), without placing an undue burden on 
the patient/patient's family.
Exclusion Criteria:
Subjects will be excluded from the study if there is evidence of any of the following:
1. The patient has experienced an adverse reaction to study drug in Study 
HGT-SAN-055 that contraindicates further treatment with rhHNS.
2. The patient has a known hypersensitivity to the active ingredient or any excipients in 
rhHNS drug product.
3. The patient has non-MPS IIIA related central nervous system (CNS) impairment or 
behavioral disturbances that would confound the scientific integrity or interpretation 
of study assessments, as determined by the Investigator.
4. The patient has MPS IIIA behavioral-related issues, as determined by the 
Investigator, which would preclude performance of study neurocognitive and 
developmental testing procedures.
5. The patient is pregnant, breast feeding, or is a patient of childbearing potential who 
will not or cannot comply with the use of an acceptable method of birth control, such 
as condoms, barrier method, oral contraception, etc.
6. The patient has any known or suspected hypersensitivity to anesthesia or is thought to 
have an unacceptably high risk for anesthesia due to airway compromise or other 
conditions.
7. The patient has a history of a poorly controlled seizure disorder. 
8. The patient is currently receiving psychotropic or other medications, which in the 
Investigator’s opinion, would be likely to substantially confound test results and the 
dose and regimen of which cannot be kept constant throughout the study.
9. The patient cannot sustain absence from aspirin, non-steroidal medications, or 
medications that affect blood clotting within 1 week prior to a relevant study-related 
procedure (eg, device re-implantation if applicable), or has ingested such medications 
within 1 week before any procedures in which any change in clotting activity would 
be deleterious.
10. The patient has received treatment with any investigational drug (other than rhHNS) 
intended as a treatment for MPS IIIA within the 30 days prior to, during the study, or 
is currently enrolled in another study that involves an investigational drug or device 
(screening through safety follow-up contact).
11. The patient has received a hematopoietic stem cell or bone marrow transplant.

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
12
Duration of Treatment: 
The study duration will be 4 years.
Pharmacokinetic Variables:
N/A.
Safety Assessments: 
Safety evaluations will include vital signs, physical examinations, AE assessments, 
electrocardiograms (ECG); serum chemistry, hematology, urine laboratory tests, and 
screening for antibodies to rhHNS (in CSF and serum).  
Statistical Methods: 
The statistical methodology supporting the trial will focus on descriptive rather than 
inferential approaches, given the early phase and objectives of the trial.  Data will be 
plotted and the mean, standard deviation, median, minimum, and maximum for each 
variable will be tabulated by dose group to look for gross trends over time, which may be 
attributed to treatment.  For continuous data, 95% confidence interval around the mean 
will be presented.
The analysis population consists of all eligible patients from HGT-SAN-055 who have 
completed study HGT-SAN-055 and agreed to participate in this extension study.  Safety 
analyses will be performed using the above mentioned population.  The data will be 
presented by dose group.
Date of Original Protocol: 21 June 2010
Date of Amendment 3:  28 August 2012

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
13
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
ABR
auditory brainstem response
AE
adverse event
ALB
albumin
ALK-P
alkaline phosphatase
ALT
alanine aminotransferase (SGPT)
AST
aspartate aminotransferase (SGOT)
βhCG
human chorionic gonadotropin
BSID-III
Bayley Scales of Infant Development, Third Edition
BBB
blood brain barrier
BUN
blood urea nitrogen
Ca
calcium
CFR
Code of Federal Regulations
CNS
central nervous system
CHQ-50
Child Health Questionnaire™ Parent Form 50
CHQ-87
Child Health Questionnaire™ Child Form 87
CK
creatine kinase
Cl
chloride
CO2
carbon dioxide
CTCAE
Common Terminology Criteria for Adverse Events
CRO
contract research organization
CRIM
cross-reacting immunologic material 
CSF
cerebrospinal fluid
ECG
electrocardiogram
eCRF
electronic case report form
EDC
Electronic Data Capture 
ERT
enzyme replacement therapy
EOS
end of study
EOW
every other hweek

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
14
FDA
Food and Drug Administration
FPSS/TDS
Four-Point Scoring System/Total Disability Score
GAG
glycosaminoglycan
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
H
High
Hct
hematocrit
Hgb
hemoglobin
HS
heparan sulfate
ICH
International Conference on Harmonization
IDDD
intrathecal drug delivery device
IEC
Independent Ethics Committee
IND
Investigational New Drug 
IRB
Institutional Review Board
IT
intrathecal
ITQOL
Infant Toddler Quality of Life Questionnaire™
IV
intravenous
K
potassium
KABC-II
Kaufman Assessment Battery for Children, Second Edition
L
Low 
LDH
lactic dehydrogenase
LP
lumbar puncture 
LSD
lysosomal storage disease
M
Missing 
M6P
mannose-6-phosphate
MABC-2
Movement Assessment Battery for Children
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
15
MedDRA
Medical Dictionary for Regulatory Activities
MABC-2
Movement Assessment Battery for Children, Second Edition
MPS
Mucopolysaccharidosis 
MPS IIIA
Mucopolysaccharidosis IIIA or Sanfilippo syndrome Type A
MRI
magnetic resonance imaging
N
Normal 
Na
sodium 
PE
pressure-equalization
QoL
quality of life
Q4W
once per month
RBC
red blood cell (count)
rhHNS
recombinant human heparan N-sulfatase
SAE
serious adverse event
SAP
Statistical Analysis Plan
SBRS
The Sanfilippo Behavior Rating Scale
SGOT
serum glutamic oxaloacetic transaminase (AST)
SGPT
serum glutamic pyruvic transaminase (ALT)
Shire HGT
Shire Human Genetic Therapies, Inc.
TMF
Trial Master File
TX
treatment
VABS-II
Vineland Adaptive Behavior Scales 
WBC
white blood cell (count)
WHO-DD
WHO Drug Dictionary 

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
16
1
INTRODUCTION 
The progressive and irreversible nature of lysosomal storage diseases (LSDs) present a challenge 
in the interpretation of clinical benefit derived from treatment in studies using enzyme 
replacement therapy (ERT).  Any short-term improvement and/or stabilization of clinically 
important manifestations of the disease may be viewed as clinically meaningful.  However, the 
demonstration of the different aspects of a long-term, clinically-meaningful improvement may be 
limited by the short duration of treatment in clinical studies.  Extended access to treatment 
through extension studies provides an opportunity for further evaluation of long-term safety and 
clinical outcomes for treated patients.  In this extension study, patients who completed study 
HGT-SAN-055, a phase I/II safety and dose-escalation trial, and elected to continue to receive 
recombinant human heparan N-sulfatase (rhHNS), will receive treatment through this extension 
protocol.  The patient’s treatment group and dosing regimen will be the same as that employed in 
study HGT-SAN-055. 
1.1
Disease Background 
Sanfilippo syndrome, or Mucopolysaccharidosis (MPS) III, is a lysosomal storage disease (LSD) 
caused by loss in activity of 1 of 4 enzymes necessary for degradation of the glycosaminoglycan 
(GAG) heparan sulfate (HS) in lysosomes.  Four different subtypes (A, B, C, and D) have been 
identified and are each due to a specific enzyme deficiency involved in the lysosomal catabolism 
of HS. Mucopolysaccharidosis IIIA or Sanfilippo syndrome Type A (MPS IIIA) results from 
deficiency of the enzyme heparan N-sulfatase (sulfamidase).  In the absence of this enzyme, 
intermediates of the HS degradation process accumulate in the lysosomes of neurons and glial 
cells, with lesser accumulation outside the brain.  
MPS III is the most prevalent of all mucopolysaccharidoses, with subtypes A and B similar in 
prevalence, accounting for approximately 90% of all cases of MPS III.1 The birth prevalence of 
MPS IIIA has been estimated as 1.28 in 100,000 in Australia, 1.16 in 100,000 in the Netherlands, 
and 0.88 in 100,000 in Germany.1-,3 In summary, MPSIIIA is a rare genetic disorder with 
apparently widespread geographic distribution and an average global birth incidence of 
approximately 1 in 100,000. 
In a recent detailed review of all MPS IIIA patients diagnosed in the Netherlands, it was reported 
that among 81 patients in whom information was available, first symptoms arose at a median of 
2.5 years (range 0.5 to 7 years).4  Owing to the rarity of the disease and the non-specific and 
often subtle nature of its initial manifestations, diagnosis is usually delayed until an average age 
of 4 to 4.5 years.4, 5 Patients present a wide spectrum and severity of clinical symptoms.  The 
central nervous system (CNS) is the most severely affected organ system in patients with MPS 
IIIA, evidenced by deficits in language development, motor skills, and intellectual development.5  
In addition, there are abnormal behaviors including, but not limited to, aggression and excess 
motor activity/hyperactivity that contribute to disturbances in sleep.5 - 7 In contrast with other 
MPS types, the viscera are mildly affected, with transient enlargement of liver and spleen during 
childhood with no evidence of dysfunction.  There are also reports of unexplained, recurrent and 
severe diarrhea.8  Overall, individuals with MPS IIIA have a marked developmental delay and 
significantly reduced lifespan of 15 years of age on average.8  

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
17
A milder variant has recently been identified with slower progression and survival to later age in 
approximately 10% of German patients with MPS IIIA.9
No effective, disease-modifying therapies are currently approved as treatments for this rare, 
devastating and disabling disease.  
A long-range goal of Shire Human Genetic Therapies, Inc. (Shire HGT) is to develop a 
recombinant human sulfamidase ERT for patients with MPS IIIA.  A particular problem for 
LSDs that damage the brain such as MPS III is how to target ERT to the brain.10  In animal 
studies, ERT was administered into the cerebrospinal fluid (CSF) via an intrathecal (IT) route, 
because when administered intravenously (IV), it was shown to not cross the blood brain barrier 
(BBB) after the immediate postnatal period of life.11, 12  
As the CNS in patients with MPS IIIA is the most severely affected body system, the main focus 
of the rhHNS clinical development program has been the development of ERT specifically for 
delivery directly to the CNS.  Recombinant human heparan N-sulfatase has been developed 
specifically for delivery into the CSF via an intrathecal drug delivery device (IDDD) due to the 
acknowledged impermeability of the BBB to macromolecules. 
Heparan N-sulfatase is a highly purified recombinant form of the naturally occurring human 
lysosomal enzyme sulfamidase.  It is expressed from the well characterized continuous human 
HT-1080 cell line as a 482 amino acid peptide, following cleavage of the 20 amino acid 
N-terminal signal peptide.  The mature protein in solution is a homodimeric glycoprotein of 
approximately 122 kDa, which undergoes post-translational modifications by conversion of 
Cys50 to formylglycine, required for enzyme activity, and glycosylation at 4 of the 5 potential 
N-linked glycosylation sites.  The rhHNS glycans contain mannose-6-phosphate (M6P) residues 
which target the protein for cellular uptake and internalization in its lysosomal site of action via 
the membrane-bound M6P receptors.13, 14 -,16
The first precedent for intraspinal ERT was recently published and has been shown to be both 
safe and effective for spinal cord compression in MPS I.17   In this study, a patient with MPS I 
received 4 IT doses of enzyme (Laronidase [recombinant α-L-Idurunonidase]) at 1-month 
intervals.  Safety evaluations included CSF opening pressure, serum chemistry and CSF protein, 
glucose and cell count, in addition to clinical efficacy studies.  No changes in safety evaluations 
were observed.
In another recent study, a patient with MPS VI and spinal cord compression received IT 
injections of enzyme (Galsulfase) monthly, for 4 months.  CSF analysis revealed no 
inflammatory reaction; no other side effects were noted.18
Several MPS I patients have been treated since 2005 with IT Laronidase in 2 ongoing clinical 
trials (clinicaltrials.gov identifiers NCT00215527 and NCT00786968) studying efficacy on 
spinal cord compression. No results of these trials have yet been published. However, in 
June 2009 a study further investigating the effectiveness of IT ERT as a treatment for another 
neurological symptom in MPS I, cognitive decline, was initiated (clinicaltrials.gov identifier 
NCT00852358). 

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
18
This study is a 24-month, open label, prospective, randomized trial in 16 patients with MPS I, 6 
years of age or older, who have documented evidence of cognitive decline. In this study, the 
clinical safety of the regimen will be assessed by adverse events monitoring, CSF laboratory 
assessments, and clinical evaluations.  This study is ongoing; no efficacy or safety data have yet 
been published as of October 2011.19 
In addition, there are 4 ongoing Shire HGT-sponsored studies that are evaluating IT 
administration of ERT:  A Phase I/II safety and dose escalation study of monthly idursulfase-IT 
injection for cognitively impaired patients with Hunter syndrome (Study HGT HIT-045; 
NCT00920647), the open-label extension to this study (HGT-HIT-046); a Phase I/II ascending 
dose and dose frequency study of monthly IT injection of rhHNS in patients with Sanfilippo 
Syndrome Type A (Study HGT-SAN-055; NCT01155778), and the open-label extension to this 
study (HGT-SAN-067; NCT 01299727).
1.2
Nonclinical Overview
To circumvent the restriction of the BBB, rhHNS was administered into the CSF of rats and 
monkeys via an IT route.  The non-clinical data demonstrate that IT administration of rhHNS 
leads to uptake by target CNS tissues with appropriate efficacy and distribution.  In addition, 
there were no findings noted in the toxicity studies, allowing for a 6.2-fold safety margin from 
the results in the juvenile cynomolgus monkey.  Intermittent bolus injection of rhHNS to the 
brain via the IT route of administration is hypothesized to be of benefit in stabilizing, improving, 
or preventing the CNS manifestations of disease. 
The doses tested in the non-clinical studies adequately support the efficacy of the planned doses 
(10, 45 or 90 mg/month, normalized to the brain weight of the human) in the ongoing Phase I/II 
study, HGT-SAN-055.  Specifically, in the San A mouse, the 100 μg dose corresponds to a 
2.2-fold increase (per kg brain weight) from the highest anticipated human dose (90 mg) (human 
brain = 1 kg).  The 20 μg dose given IT every-other-week (EOW) or monthly, for which efficacy 
was also observed, corresponds to a 40 mg (per kg brain weight) human dose.  In the Huntaway 
(Sanfilippo A) dogs, the 3 mg rhHNS given IT weekly (corresponding to a 33 mg/kg of brain 
weight in man), was not only well tolerated but resulted in significant effects on biomarkers of 
disease activity and improved histopathology. 
1.2.1
Toxicology in Monkeys
In the pivotal, 6-month IT toxicity study in juvenile cynomolgus monkeys, the highest dose of 
rhHNS was 8.3 mg given EOW.  This translates into a 138 mg/kg brain-weight dose (ie, based 
on a 60 g juvenile monkey brain).  Since no rhHNS-related adverse effects were noted, the 
nonclinical study provides for the proposed Phase I/II clinical trial a ~13.8 × safety margin 
relative to the starting clinical dose (10 mg), and a 1.5× safety margin relative to the highest 
clinical dose (90 mg).    
1.2.2
Efficacy in Murine and Canine Models of MPS IIIA
Non-clinical proof of concept efficacy studies were conducted using mouse and dog models of 
MPS IIIA, both of which contain naturally-occurring mutations in the HNS gene.  

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
19
In the MPS IIIA mouse, direct injection into the CNS had a beneficial effect on clinical signs, 
impaired neurobehavioral, and the biochemical and histopathologic markers of disease activity.  
In Huntaway (Sanfilippo A) dogs, rhHNS (3 mg) given IT weekly had a significant effect on 
biomarkers of disease activity and improved histopathology.
Efficacy has been demonstrated at a range of doses in nonclinical mouse and canine models.  In 
MPS IIIA mice, a dose-dependent reduction in the level of a heparan sulfate-derived monosulfate 
disaccharide was observed within the brain (up to 62% reduction compared with vehicle-treated 
mice) and spinal cord (up to 71% reduction).  An ultrastructural examination revealed a 
reduction in lysosomal vesicle formation in various cell types and fewer (ubiquitin-positive) 
axonal spheroids in several brain regions after repeated injections (5 to 20 µg) of rhHNS into the 
CSF of MPS III mutant mice via the cisterna magna (ie, IT).  The biochemical changes were 
accompanied by improved behavior, particularly in mice treated more frequently.20
In the MPS IIIA mutant mouse model, intracisternal (ie, IT) injection of a single dose of 100 µg 
rhHNS resulted in a substantial (and sustained) reduction of biomarkers of disease activity 
(heparan sulfate-derived disaccharides, microgliosis, astrogliosis).21  Equally impressive was the 
improvement in neurobehavioral parameters (learning in the Morris water maze, normalization 
of aggression) in these mice post-dose.21  One-hundred µg rhHNS per mouse translates into 
200 mg/kg brain weight (ie, based on a 0.5 g mutant mouse brain).  Efficacy at lower doses of 
rhHNS (eg, 20 µg, given IT, EOW or monthly) has been demonstrated.11  A 20 µg injection 
translates into a 40 mg human dose (ie, 40 mg per kilogram of brain weight).  Thus, this data 
further suggests that efficacy will be seen at the highest clinical dose (90 mg, per month) in the 
proposed Phase I/II study. 
In the tolerized Huntaway (San A) dogs, 3 mg rhHNS was initially given IT on a weekly basis, 
then EOW, and had a significant effect on biomarkers of disease activity.22 The 3 mg dose in the 
dog translates into a 33 mg (per kg brain weight) human dose (based on a 90 g Huntaway dog 
brain). 
1.3
HGT-SAN-067 Study Rationale
This extension study (Study HGT-SAN-067) will evaluate the effects of long-term rhHNS 
administration on safety, clinical activity, and biomarker outcomes in patients who completed 
Study HGT-SAN-055 and elected to continue therapy with rhHNS.
Patients who were enrolled in Study HGT-SAN-055 through Week 26 and completed the end of 
study (EOS) evaluations are eligible for enrollment in this open-label extension study.  All 
patients enrolled in this study will continue to receive rhHNS at the same dose and schedule as 
they received in Study HGT-SAN-055.  The dose for each group will remain unchanged during 
this study unless safety and/or efficacy analyses of HGT-SAN-055 data indicate otherwise.  
Meaningful composite analysis of the optimum dose and regimen will come only after all 3 dose 
groups complete the entire HGT-SAN-055 study.
Please refer to the current edition of the rhHNS Investigator’s Brochure for further information.

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
20
2
STUDY OBJECTIVES
2.1
Primary Objective 
The primary objective of this study is:
•
To collect long-term safety and tolerability data in patients with Sanfilippo Syndrome 
Type A (MPS IIIA) who received rhHNS via a surgically implanted IDDD in study 
HGT-SAN-055 and elect to continue therapy in study HGT-SAN-067.
2.2
Secondary Objectives 
The secondary objectives of this study are:
•
To collect, as measures of drug efficacy, over an extended treatment period (as change from 
baseline), the following:  clinical, neurological, cognitive, behavioral, functional, and quality 
of life (QoL) assessments, together with potential imaging and biochemical biomarkers.

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
21
3
STUDY ENDPOINTS
3.1
Primary Endpoint
The primary endpoint of this study is:
To determine the long-term safety of IT rhHNS administration, as measured by adverse events 
(by type and severity), changes in clinical laboratory testing (serum chemistry including liver 
function tests, hematology, and urinalysis), ECG, CSF, chemistries (including cell counts and 
inflammatory markers), and anti-rhHNS antibodies (in CSF and serum).
3.2
Secondary Endpoints 
The secondary endpoints of this study are to collect over an extended treatment period (as the 
change from baseline [defined as the start of the HGT-SAN-055 study]) clinical and potential
surrogate biomarker efficacy data: 
•
Measures of standardized neurocognitive and behavioral assessments, Sanfilippo-specific 
behavioral rating scales, gross and fine motor assessments, functional adaptive rating scales, 
QoL questionnaires, and Children’s Sleep Habits Rating Scale.
•
Concentration of rhHNS in CSF and serum.
•
Concentration of inflammatory cytokines in serum and CSF.
•
Concentration of safety and potential surrogate efficacy biomarkers in CSF, urine, and 
serum.
•
Concentration of heparan sulfate and heparan sulfate derivatives in urine, plasma, and serum. 
•
Brain MRI and ABR, (also know as Brainstem Auditory Evoked Potentials).

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
22
4
INVESTIGATIONAL PLAN
4.1
Overall Study Design and Plan
Study HGT-SAN-067, is an open-label, long term, multicenter, extension of Study 
HGT-SAN-055.  This study is designed to evaluate the long-term safety, clinical activity, and 
biomarker outcomes of IT administration of 3 dose levels (10 mg, 45 mg, and 90 mg once per 
month [Q4W]) of rhHNS via an IDDD in patients with MPS IIIA who successfully completed 
HGT-SAN-055 (including the EOS assessments) and elect to continue to receive uninterrupted 
rhHNS treatment.  Patients will continue in the same treatment group they were assigned to in 
the HGT-SAN-055 study: 
•
Group 1:  rhHNS administered by IT injection 10 mg once per month (Q4W) 
•
Group 2:  rhHNS administered by IT injection 45 mg once per month (Q4W)
•
Group 3:  rhHNS administered by IT injection 90 mg once per month (Q4W) 
In order to maintain a nomenclature system based on study chronology across the original 
HGT-SAN-055 study and this extension study, the Baseline Visit for this extension study will be 
considered to be the day the patient received their first IT dose of rhHNS in 
Study HGT-SAN-055.  The HGT-SAN-055 EOS assessment information will provide the 
screening/start of study information for patients who continue into the HGT-SAN-067 extension 
study.  Note: HGT-SAN-055 EOS data must be recorded in the context of the HGT-SAN-055 
trial, and a copy of those data can be used for HGT-SAN-067 screening.  Once eligibility is 
confirmed, informed consent (and assent, if applicable), provided by the patient’s 
parent(s)/legally authorized representative(s), must be obtained prior to performing any 
HGT-SAN-067 study-related procedures.  Informed consent may be obtained anytime from 
Week 20 in HGT-SAN-055.  This would allow a patient to have a nonfunctional IDDD replaced 
or revised prior to the first rhHNS dose in HGT-SAN-067.
Enrolled patients will check in to the study center 1 day before each of the scheduled rhHNS 
dosing days for safety assessments (designated Day 1).  If no safety concerns exist, the patient 
will subsequently receive IT administration of rhHNS on Day 2 (±2 days).  However, if feasible 
and there are no safety concerns in the opinion of the investigator, the Day 1 and Day 2 
assessments may be combined and performed on Day 2; if this is done the results will be 
recorded as Day 2.  Patients will remain in the study centre for at least 8 hours following dosing 
with rhHNS and will be discharged from the unit when deemed clinically stable by the 
Investigator.  
All patients will have received a series of standardized neurodevelopment assessments; in the 
HGT-SAN-055 study, these will have occurred at Baseline and either prior to or at the 6-month 
time point.  Patients will continue in HGT-SAN-067 with whichever age specific assessment 
they began with in HGT-SAN-055.  If, however, a patient’s capability improves and they 
become capable of completing assessments at a higher level, such additional assessments may be 
added.  Any additional assessments are to be performed after the original assessments (those 
used in study HGT-SAN-055) have been carried out.  

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
23
A MRI of the head and ABR testing will be performed at Months 12, 24, 36, and 54 (note that 
assessment time point nomenclature includes the 6 months in the HGT-SAN-055 study). 
In the event of a device malfunction, X-rays may be performed to investigate, as well as to verify 
correct catheter and port placement following surgical IDDD implantation or revision.  In 
addition, fluoroscopy may be employed intra-operatively to guide catheter placement.  Patients 
may undergo 3 X-ray examinations in association with each episode of IDDD malfunction and 
subsequent IDDD revision or replacement. The number of IDDD revisions/replacements is 
limited to 2 in any 6-month period (including the time in the HGT-SAN-055 study), and the 
number of protocol-associated X-ray evaluations is limited to 6 exposures in any 6-month period 
(including time in study HGT-SAN-055).
Patients will be evaluated for safety throughout the study.  Adverse events that occur in 
HGT-SAN-055 and are ongoing at enrollment in HGT-SAN-067 will be captured as ongoing in 
the HGT-SAN-055 study and also be reported as a concurrent condition in the HGT-SAN-067 
electronic case report forms (eCRFs).  Specific safety stopping criteria will be applied and will 
be based on the types and severity of AEs reported while on-study.  These data will be reviewed 
to inform the decision to discontinue a patient, a dose group, or the study as a whole. 
All patients will have an EOS visit 30 (±7) days following their last administration of rhHNS 
(ie, Month 55).  The EOS procedures will include standard clinical laboratory tests (serum 
chemistry, hematology, and urinalysis) in CSF and blood, protocol specific laboratory testing 
(eg, anti-rhHNS antibody testing), neurodevelopmental testing, ABR, child health 
questionnaires, and MRI.  Use of concomitant medications, therapies, and procedures will be 
recorded and AEs will be monitored. 
All patients will be contacted by telephone or will have a visit for a Final Safety Follow-up, 
conducted at 30 (±7) days after the EOS visit (ie, Month 56) to collect updated information on 
AEs and concomitant medications, therapies, and procedures. 
It is anticipated that the IDDD will be used to obtain CSF samples and to deliver administrations 
of rhHNS.  However, if a patient’s IDDD appears nonfunctional or if its use is precluded on a 
scheduled day of dosing, site personnel will refer to protocol Appendix 3 which describes the 
investigation and management of IDDD-related issues.  This will include possible partial 
revision or complete replacement of the IDDD.  A maximum of 2 partial revisions and/or 
complete replacements are permitted in any 6 month period (including participation in study 
HGT-SAN-055).  If a revision or replacement of the IDDD cannot be scheduled in time to avoid 
a delay of the next scheduled dose of rhHNS, or if the patient experiences more than 2 IDDD 
malfunctions in a 6 month period, rhHNS will be administered via LP.  Drug may be 
administered via LP for a maximum of 5 successive monthly doses, after which, IDDD re-
implantation or revision must occur. 
If there is no significant safety risk in the opinion of the Investigator, a non-functional IDDD 
may be left in situ for up to 3 months.
Patients who discontinue or are withdrawn before receiving 3 monthly IT injections will not have 
to undergo the EOS evaluations but will have their IDDD removed.  

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
24
If a patient discontinues, or withdraws from the study, or the study is stopped by the Sponsor, the 
IDDD will be removed as part of the EOS Procedures. 
An overview of the study appears in the Schedule of Events (Appendix 1).
4.2
Rationale for Study Design and Control Group
The original study, Study HGT-SAN-055, is an ongoing Phase I/II safety and ascending dose 
ranging study of IT administration of rhHNS via an IDDD, in patients 3 years of age and older 
with MPS IIIA and early cognitive impairment.  This extension study is proposed to continue 
evaluation of the effects of IT rhHNS administration on long-term safety and clinical outcomes 
for patients who completed Study HGT-SAN-055 and elected to continue treatment with rhHNS 
in the HGT-SAN-067 study. 
4.3
Study Duration and Dates
The study duration will be 4 years.

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
25
5
STUDY POPULATION SELECTION
5.1
Study Population
Patients who have completed all study requirements in Study-HGT-SAN-055 and who elected to 
continue rhHNS treatment will be eligible to participate; a maximum of 12 patients are planned 
for this study. 
5.2
Inclusion Criteria
Each patient must meet the following criteria to be considered eligible for enrollment in this 
study.
1. The patient must have completed Study HGT-SAN-055 and, in the opinion of the 
investigator, have no safety or medical issues that contraindicate participation. 
2. The patient, patient’s parent(s) or legally authorized representative(s) has voluntarily signed 
an Institutional Review Board/Independent Ethics Committee-approved informed consent 
(and assent, if applicable) form after all relevant aspects of the study have been explained and 
discussed with them.  Informed consent/assent must be obtained prior to any study specific 
procedures.
3. The patient has received at least 5 of the 6 planned infusions of rhHNS in the HGT-SAN-055 
study. 
4. The patient must be medically stable, in the opinion of the Investigator, to accommodate the 
protocol requirements, including travel, assessments, and IDDD surgery (if necessary for 
replacement purposes), without placing an undue burden on the patient/patient's family.
5.3
Exclusion Criteria
Patients will be excluded from the study if there is evidence of any of the following: 
1. The patient has experienced an adverse reaction to study drug in Study HGT-SAN-055 that 
contraindicates further treatment with rhHNS.
2. The patient has a known hypersensitivity to the active ingredient or any excipients in rhHNS 
drug product.
3. The patient has significant non-MPS IIIA related central nervous system impairment or 
behavioral disturbances that would confound the scientific integrity or interpretation of study 
assessments, as determined by the Investigator.
4. The patient has MPS IIIA behavioral-related issues, as determined by the Investigator, which 
would preclude performance of study neurocognitive and developmental testing procedures.
5. The patient is pregnant, breast feeding, or is of childbearing potential who will not or cannot 
comply with the use of an acceptable method of birth control, such as condoms, barrier 
method, oral contraception, etc.
6. The patient has any known or suspected hypersensitivity to anesthesia or is thought to have 
an unacceptably high risk for anesthesia due to airway compromise or other conditions.
7. The patient has a history of a poorly controlled seizure disorder. 

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
26
8. The patient is currently receiving psychotropic or other medications, which in the 
Investigator’s opinion, would be likely to substantially confound test results and the dose and 
regimen of which cannot be kept constant throughout the study.
9. The patient cannot sustain absence of aspirin, non-steroidal medications, or medications that 
affect blood clotting within 1 week prior to a relevant study-related procedure (eg, device 
re-implantation if applicable), or has ingested such medications within 1 week before any 
procedures in which any change in clotting activity would be deleterious.
10. The patient has received treatment with any investigational drug (other than rhHNS) intended 
as a treatment for MPS IIIA within the 30 days prior to, or during the study, or is currently 
enrolled in another study that involves an investigational drug or device (screening through 
safety follow-up contact). 
11. The patient has received a hematopoietic stem cell or bone marrow transplant.

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
27
6
STUDY TREATMENT(S)
6.1
Description of Treatment(s)
6.1.1
Study Drug
Recombinant human heparan N-sulfatase (rhHNS drug product formulation is a sterile solution 
for injection in single-use vials for IT administration.  It is formulated in an aqueous isotonic 
solution containing 15.0 mg/mL rhHNS in 145 mM sodium chloride, 0.02% (v/v) polysorbate 
20, 5 mM sodium phosphate at pH 7.0.
6.1.2
Placebo or Control
This study will not employ a placebo or control.  
6.2
Treatment Administered
rhHNS for IT administration will be provided by Shire HGT.  rhHNS will be administered by an 
IDDD.  Following the review and signing of informed consent (and assent, if applicable), 
eligible patients will receive the same dose of rhHNS they received in Study HGT-SAN-055:
•
Group 1:  rhHNS administered by IT injection 10 mg once per month (Q4W) 
•
Group 2:  rhHNS administered by IT injection 45 mg once per month (Q4W)
•
Group 3:  rhHNS administered by IT injection 90 mg once per month (Q4W) 
6.2.1
Selection and Timing of Dose for Each Patient
Patients will check into the study center 1 day prior to IT rhHNS dosing for safety assessments, 
designated Day 1, on each rhHNS treatment week, and if no safety concerns exist, will receive 
IT administration of rhHNS on Day 2 (±2 days).  However, if feasible and there are no safety 
concerns in the opinion of the Investigator, the Day 1 and Day 2 assessments and dosing may be 
combined and performed on Day 2; if this is done the results will be recorded as Day 2.  Patients 
will remain in the study centre for at least 8 hours following dosing with rhHNS and will be 
discharged from the unit when deemed clinically stable by the Investigator.  
The IT injections are to be administered every 28 days (±7 days).  If a patient’s IDDD becomes 
nonfunctional, it may be revised (partial or complete) (a maximum of twice in a 6 month period) 
so that the patient can remain on study (see Section 7.12 for details).  In the event of a 
non-functional IDDD, rhHNS may be administered by LP, for up to 5 successive months (see 
Section 6.2.4). 
6.2.2
Cerebral Spinal Fluid Sample Procedure
CSF samples will be obtained prior to each injection for safety evaluation and biomarker studies.  
The IDDD will be used for CSF sampling and a topical anesthetic agent may be applied over the 
skin covering the IDDD reservoir prior to sampling.  

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
28
If use of the IDDD is precluded on a scheduled day of dosing, CSF samples may be obtained by 
LP, as described in the Study Operations Manual.  CSF opening pressure will be measured 
whenever a LP is performed, and at the time of IDDD revision (partial or replacement).  
Additional CSF samples may be taken during this time.
6.2.3
Intrathecal Administration of rhHNS
rhHNS will be administered using an IDDD.  After appropriate pre-procedure assessments are 
completed, anesthesia cream will be applied to the skin over the port.  Patients may receive 
sedation as necessary to alleviate anxiety and/or to facilitate drug delivery.
Patients will receive rhHNS via slow push/injection through an appropriately sized syringe (see 
the Pharmacy Manual).  Replacement of fluid, including drug, to the CSF will be an approximate 
equal volume to that removed.  The patient’s vital signs will be continuously monitored.  The 
patient will also be monitored closely during study drug administration and through the next 
8 hours for any adverse clinical reactions.  The patient will be encouraged to lie down 
comfortably for 1 to 3 hours post injection, although this may be difficult for the most 
hyperactive patients.
In the event of IDDD malfunction, CSF collection and study drug administration may be 
performed via LP (see Section 6.2.4).  The investigation and management of a malfunctioning 
IDDD is detailed in Appendix 3.  If the failure is mechanical, partial or complete replacement of 
the IDDD may be necessary (only permitted twice in a 6-month period, including the time a 
patient was in study HGT-SAN-055), and will require scheduling of the appropriate procedure.  
The definitive diagnosis of the cause of IDDD failure may not be possible until the time of 
exploratory surgery.  Surgery will take place at the earliest convenience, so the patient may 
remain on, or as close as possible to their treatment schedule. 
6.2.4
Administration of rhHNS via Lumbar Puncture
In the event of a non functional IDDD, rhHNS may be administered by LP, for up to 
5 successive months.  The performance of a LP is at the discretion of the Investigator.
If a LP is to be performed, the patient may require general anesthesia with appropriate airway 
management.  Once the patient is anesthetized, a LP will be performed and a CSF sample will be 
obtained.  Some cases may be managed with conscious sedation, if this is considered by the 
investigator to be adequate for the safe and expeditious performance of a LP.
6.3
Method of Assigning Subjects to Treatment Groups
This is an open-label, non-randomized study; all patients enrolled in this study will be treated 
with rhHNS.  Patients will remain in the groups (1, 2, or 3) they were assigned to in 
Study HGT-SAN-055. 
6.4
Blinding
Not applicable; as this trial is not blinded.

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
29
6.5
Concomitant Therapy
All non-protocol treatments and procedures that occur from the time of informed consent (and 
assent, if applicable) through the safety follow-up contact are regarded as concomitant and will 
be documented on the appropriate pages of the eCRF.  Concomitant therapy includes 
medications (including Genistein), therapies/interventions administered to patients, and 
medical/surgical procedures performed on the patients. 
Every effort should be made to keep the patient’s symptomatic Sanfilippo syndrome Type A 
treatment constant throughout the study.  However, changes in medications are acceptable if 
necessary according to clinical judgment.  All changes will be recorded on the appropriate eCRF.  
Concomitant medication will be coded using WHO Drug Dictionary (WHO-DD).
6.6
Restrictions
6.6.1
Prior Therapy
Prior therapy excluded for this study consists of the following:
•
Psychotropic or other medications, which in the Investigator’s opinion would be likely to 
substantially confound test results, and the dose and regimen of which cannot be kept 
constant throughout the study.
•
The patient cannot sustain absence from aspirin, non-steroidal medications, or medications 
that affect blood clotting within 1 week prior to a relevant study related procedure (eg, device 
implantation if applicable) or medications within 1 week before any procedures in which any 
change in clotting activity would be deleterious.
•
The patient has received any investigational drug or device intended as a treatment for 
MPS IIIA within the 30 days prior to the study other than rhHNS or is enrolled in another 
study that involves an investigational drug or device.
•
Hematopoietic stem cell or bone marrow transplant.
6.6.2
Fluid and Food Intake 
Food and fluid intake are not restricted over the course of the study, with the exception of 
hospital standard pre-anesthesia dietary restrictions.
6.6.3
Patient Activity Restrictions
There are no restrictions on patient activity in this study.
6.7
Treatment Compliance
rhHNS is administered under controlled conditions by the Investigator; therefore, full patient 
compliance with study treatment is anticipated in this study. 

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
30
6.8
Packaging and Labeling
Drug product will be supplied in a 3 mL clear, colorless glass (Type 1) vial.  Each vial holds an 
extractable volume of 1 mL of rhHNS.  The closure is a gray, 13 mm stopper composed of butyl 
rubber with a fluoro resin lamination.  The overseal is an aluminum seal with a flip-off, plastic, 
tamper evident cap.
See the Pharmacy Manual for additional details.
6.9
Storage and Accountability
Drug product should be stored refrigerated (2 to 8°C); drug product may not be stored beyond 
the expiration date on the vial.
6.10
Investigational Product Retention at Study Site
All rhHNS study drug delivered to an Investigator will be recorded and accounted for throughout 
the study.  All rhHNS study drug must be recorded on a patient-by-patient basis.  The lot number 
of the IDDD and the date and time of administration of the study medication will be documented 
on the appropriate eCRF.
All unused study medication and other study materials are to be returned to the Sponsor or its 
designee or disposed of after Sponsor approval per site policy after study completion.

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
31
7
STUDY PROCEDURES
7.1
Informed Consent
Study procedures will be conducted only after written informed consent for the patient to 
participate in this study is provided by the parent(s) or the patient’s legally authorized 
representative(s) and assent from the patient (if applicable).  Detailed descriptions of patient 
evaluations required for this protocol are described in this section.  These evaluations will be 
performed during the indicated days and weeks of each study month (see Appendix 1 Schedule 
of Events).
All data collected are to be recorded on the appropriate eCRF.  Blood, urine and CSF volumes to 
be collected for each clinical laboratory measurement are described in detail in the Laboratory 
and/or Study Operations Manual.
7.2
Physical Examination
A physical examination of each patient will be performed as detailed in Appendix 1 Schedule of 
Events.
Note:  if the patient’s hearing cannot be assessed during the physical examination, the patient 
will have an Ears, Nose, and Throat Evaluation performed under anesthesia at the screening/start 
of study visit.  If it is determined that the patient requires pressure-equalization (PE) tubes, they 
may be implanted during that evaluation (see Section 7.10).  Note:  PE tubes may be 
re-implanted if they fall out during this study.
The physical examination findings will be recorded on the eCRF and will include a review of the 
patient’s general appearance as well as the following evaluations:
-
Head and neck
-
Eyes, ears, nose, and throat
-
Chest and lungs
-
Cardiovascular
-
Abdomen
-
Skin
-
Lymphatic
-
Musculoskeletal
-
Neurological
-
Endocrine
-
Genitourinary
7.3
Height and Weight
Height or length (cm), and weight (kg) will be measured once and recorded on the eCRF.
7.4
Head Circumference
Head circumference (cm) will be measured and recorded on the eCRF.

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
32
7.5
Vital Signs
Vital signs (blood pressure, heart rate, respiratory rate, and temperature measurements) will be 
measured and recorded on the eCRF.
7.6
Electrocardiography
7.6.1
Electrocardiograms
An ECG will be performed.  Each ECG will include an assessment of heart rate, sinus rhythm, 
atrial or ventricular hypertrophy, PR, QRS, QT, and QTc intervals.  The ECGs will be conducted 
in accordance with the clinical site’s standard practice(s), and will be read locally at the clinical 
site.  Identification of any clinically significant findings and/or conduction abnormalities will be 
recorded on the eCRF. 
7.7
Clinical Laboratory Tests
Blood, urine, and CSF samples will be collected as described below for clinical laboratory 
testing.  Procedures for collection and handling of samples are included in the Laboratory and/or 
Study Operations Manual. 
Patients will be in a seated or supine position during blood collection.  Clinical laboratory tests 
will include hematology, serum chemistry, and urinalysis.
Laboratory Parameters 
Clinical laboratory tests will be performed at a central laboratory.  Clinical laboratory tests will 
include the following:
7.7.1
Hematology
•
Hematocrit (Hct)
•
Hemoglobin (Hgb)
•
Mean corpuscular hemoglobin (MCH)
•
Mean corpuscular hemoglobin 
concentration (MCHC)
•
Mean corpuscular volume (MCV)
•
Platelet count
•
Red blood cell (RBC) count 
•
White blood cell (WBC) count with 
differential 

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
33
7.7.2
Serum Chemistry
•
Albumin (ALB)
•
Alkaline phosphatase (ALK-P)
•
Alanine aminotransferase (ALT; SGPT)
•
Aspartate aminotransferase (AST; 
SGOT)
•
Blood urea nitrogen (BUN)
•
Calcium (Ca)
•
Carbon dioxide (CO2)
•
Chloride (Cl)
•
Creatinine
•
Creatine kinase (CK) and subtypes
•
Gamma-glutamyl transferase (GGT)
•
Globulin
•
Glucose
•
Lactate dehydrogenase (LDH)
•
Phosphorus
•
Potassium (K)
•
Sodium (Na)
•
Total bilirubin
•
Direct bilirubin
•
Total cholesterol
•
Total protein
•
Triglycerides
•
Uric acid
•
Human Chorionic Gonadotropin (βhCG) 
Pregnancy Test
In addition a leukocyte pellet will be prepared, stored frozen, and will be used for additional 
disease-related laboratory studies, including possible assessment of cross-reactive immunologic 
material (CRIM).
7.7.3
Pregnancy Test
A pregnancy test will be performed on Day 1 of each dosing week.  Pregnancy testing will be 
performed using either a serum or urine sample (at the discretion of the site), and only on 
females who have reached menarche.  All pregnancy testing and the reporting of results will be 
performed locally by the clinical site staff.  Study drug must not be administered in the event of a 
positive or inconclusive pregnancy result. 
7.8
Urinalysis 
Patient catheterization may be required for obtaining urine samples (if deemed necessary by the 
Investigator).  
7.8.1.1
Standard Urinalysis
The following urinalysis parameters will be performed at a central laboratory:  pH, macroscopic 
and microscopic evaluations.
7.8.1.2
Urine Heparan Sulfate and Heparan Sulfate Derivatives
A urine sample will be collected for the determination of heparan sulfate and heparan sulfate 
derivatives and the analysis will be performed at Shire HGT or designated laboratories.  A urine 
sample from each visit will be reserved for possible exploratory biomarker studies that may 
provide new indicators or markers of MPS IIIA disease severity or progression.

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
34
7.8.2
Cerebrospinal Fluid Assessments
Cerebrospinal fluid sample collection, processing, and shipping instructions will be provided in 
the Laboratory and/or Study Operations Manual.  A CSF sample will be reserved for possible 
exploratory biomarker studies for MPS IIIA disease.
Each CSF sample collected will be assessed for appearance and will be analyzed using the assays 
listed in Sections 7.8.2.1, 7.8.2.2, and 7.8.2.4.  In addition, as more is learned about Sanfilippo 
CNS pathology and etiology, future exploratory assays of CSF metabolites, protein or RNA may 
become used as they become available in the future.
7.8.2.1
Cerebrospinal Fluid Cell Counts
An aliquot of each CSF sample collected will be evaluated for CSF standard chemistries, 
glucose, protein, and cell counts.  These assessments will be performed at the local laboratory.
7.8.2.2
Cerebrospinal Fluid Heparan Sulfate Levels and Heparan Sulfate Derivatives
An aliquot of each CSF sample collected will be quick frozen as per the Laboratory and/or Study 
Operations Manual for subsequent determination of CSF heparan sulfate and heparan sulfate 
derivatives at Shire HGT laboratories.
7.8.2.3
Anti-rhHNS Antibodies
An aliquot of each CSF sample collected will be quick frozen as per the Laboratory and/or Study 
Operations Manual for subsequent determination of anti-rhHNS antibodies at Shire HGT or 
Shire HGT designated laboratories.
7.8.2.4
Cerebrospinal Fluid Biomarkers 
An aliquot of each CSF sample collected will be quick frozen as per the Laboratory and/or Study 
Operations Manual for subsequent determination of MPS exploratory biomarkers at Shire HGT 
laboratories.
7.8.3
Sample Collection, Storage, and Shipping
Sample collection, processing, and shipping instructions will be provided in the Laboratory 
and/or Study Operations Manual to be provided by Shire HGT.
CSF, urine, and serum samples may be reserved for potential, future, biomarker studies.  
Samples will be stored securely to ensure patient confidentiality.  
7.9
Anesthesia
Administration of anesthesia/sedation will be given prior to obtaining CSF (when the use of the 
IDDD is precluded), prior to performing a MRI of the head, the ABR, the CSF opening pressure, 
and the partial revision or replacement of the IDDD (if applicable).  

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
35
See Appendix 1 for the Schedule of Events. When logistically feasible, the MRI, ABR, and 
surgical implantation of the IDDD may be performed together to reduce exposure to 
general anesthesia.
Note:  The neurologic exam and the neurocognitive and developmental assessments must be 
performed prior to the administration of anesthesia.
7.10
Audiometry and Auditory Brainstem Response
The rare attenuated patients with MPS IIIA with high levels of cognitive functioning will have 
hearing tests via clinical audiometry measurement performed using age-appropriate testing 
methods based on the child’s developmental age at the time of the testing.  It is anticipated that 
most of the cognitively-impaired and/or behaviorally-deteriorated patients with Sanfilippo A will 
be unable to cooperate with a (conscious) hearing evaluation.  In these instances, the Investigator 
will utilize his best clinical judgment to estimate the extent of hearing loss (if any) during the 
physical examination.  In this situation, a specific evaluation of hearing loss will occur during an 
examination of waveforms in the ABR (see below).  If the patient has a history of multiple 
instances of otitis media or evidence of clinically-significant otitis media on physical 
examination, which the Investigator believes causes significant conductive hearing loss and 
impairment of daily living, the Investigator will discuss and offer the parent or legally authorized 
representative(s) placement of PE tubes as part of the scheduled anesthesia.  A patient’s PE tubes 
may be replaced if they fall out during the course of this study.
The ABR will be conducted under anesthesia.  The ABR findings will be considered within 
normal limits if, after applying appropriate correction factors, the waveforms reveal normal 
morphology. 
7.11
Magnetic Resonance Imaging of the Head
The regional brain volume will be assessed through a MRI, of the head.  The patient will be 
under general anesthesia for this assessment.  All MRIs will be centrally read by the University 
of Minnesota Medical Center.  Refer to the Study Operations Manual for specific procedures and 
precautions.
7.12
Surgical Re-implantation of the IDDD
If a patient’s IDDD becomes nonfunctional or infected, it will be replaced or revised so that the 
patient can remain on study.  Management details are provided in Appendix 3.  Procedures for 
implantation are detailed in the device’s Instructions for Use Manual and in the training materials 
provided by Shire HGT.  The patient will be under general anesthesia for this procedure.  The 
CSF opening pressure will be recorded when the intrathecal space is first entered at the time of 
the IDDD re-implantation.  Standard hospital procedure for surgery will be followed and will 
include an X-ray to confirm that the device has been (1) surgically implanted correctly (correct 
orientation of the locking device on the access port), and (2) positioned so that the intrathecal 
catheter tip is at the mid-thoracic level (a check list is provided in the Study Operations Manual).  

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
36
A post-operative check of the IDDD and incision will be performed on Day 4 following surgery.  
X-rays may be performed to check placement of the device, as needed, throughout the study (see 
Section 7.12.1 for limits on the number of x-rays and IDDD revisions and or replacement).
7.12.1
Restrictions on the Number of Revision and/or re-implantation of the IDDD
A non-functional IDDD can be replaced or revised twice in a 6-month period, including the time 
a patient was in study HGT-SAN-055.  Similarly, 6 X-rays may be taken in a 6-month period 
(including the time in HGT-SAN-055).
7.13
Cerebrospinal Fluid Opening Pressure Measurement
A CSF opening pressure measurement (cm of H2O) will be conducted as per standard hospital 
practice.  The measurement will be obtained whenever a LP is performed and an IDDD revision 
or replacement is done.
7.14
Dispensing Study Drug
rhHNS will be administered IT by means of an IDDD (or via LP if necessary) to patients on 
Day 2 (±2 days) of Week 1 of each treatment month. 
The patient may be sedated for this procedure.  rhHNS will be administered through an 
appropriately sized syringe (see the Pharmacy Manual).  If the IT space is not accessible via the 
IDDD, rhHNS may be administered via LP.  See Section 6.2.4 for details.
7.15
Pharmacokinetic Assessments
Pharmacokinetic assessments are not included in this study.
7.16
Neurological Examination
A neurological examination to monitor CNS changes in a patient’s neurological status will be 
conducted during this study.  See Appendix 2 for a complete list of the neurological 
examinations.
The neurological exam should not occur sooner than 4 hours after study drug administration or 
before the patient has fully recovered from any anesthesia administered for the dosing, 
whichever occurs later.
7.17
Anti-rhHNS Antibody, Heparan Sulfate, and Heparan Sulfate Derivative 
Determination
Blood samples will be collected and evaluated at Shire HGT laboratories for the determination of 
anti-rhHNS antibodies, and plasma and serum heparan sulfate and heparan sulfate derivatives.  
Samples will be reserved in accordance with local regulations for potential future MPS IIIA 
research that may determine biomarkers of disease severity and progression. 

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
37
Two blood samples will be collected from each patient at each designated time point.  One 
sample will be collected in tubes intended for serum specimens, while the second sample will be 
collected in tubes intended for plasma specimens.  Blood sample collection, processing, and 
shipping instructions will be provided in the Laboratory and/or Study Operations Manual.
7.18
Neurocognitive and Developmental Assessments
Patients will undergo neurocognitive and neurobehavioral development testing.  The assessments 
are estimated to last between 2 and 4 hours and must be conducted prior to sedation or 
anesthesia. 
A full neurodevelopmental assessment, including global development, cognition, adaptive 
behavior, receptive and expressive language, and gross motor function, will be evaluated using 
standardized developmental and behavioral tests to provide a surrogate and quantifiable measure 
of global CNS neurodevelopmental/neurobehavioral function. 
All patients will have received a series of standardized neurodevelopment assessments; in the 
HGT-SAN-055 study, patients in HGT-SAN-067 will continue with the age specific assessment 
they began with in HGT-SAN-055.  If, however, a patient’s capability improves and they 
become capable of completing assessments at a higher level, any such additional assessments 
may be added.  Any additional assessments would be performed after the original assessments 
have been carried out.  
For this study, outcome measures will be computed for each patient enrolled.  The psychometric 
instruments and Sanfilippo-specific assessments are summarized below in Table 7-1 and 
Table 7-2, respectively.  See Appendix 2 for details on these assessments.

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
38
Table 7-1 Neurodevelopmental Assessments Tests 
Developmental or Cognitive 
Domain(s)
Patient Age:  Representative Cognitive Test or 
Scale
COGNITIVE DEVELOPMENT ASSESSMENT
Summary score and sub-domains:
- Cognitive
- Motor
- Social/emotional
0 to 42 months:  Bayley Scales of Infant Development-III 
Bayley Scales of Infant Development, Third Edition
(BSID-III)23
- Cognitive 
- Processing skills
3 to 18 years:  Kaufman Assessment Battery for Children, 
Second Edition (KABC-II)24  
GROSS AND FINE MOTOR SKILLS ASSESSMENT AND VOLUNTARY MOVEMENT
Motor
3.0 to 16:11 years:  Movement Assessment Battery for 
Children II (MABC-2)25
- Cognitive
- Motor
0 to 5 ½ years:  Bayley Scales of Infant Development III 
(BSID-III)23
ADAPTIVE BEHAVIOR
Communication
Daily Living
Socialization
Motor Skills
0 to 90 years:  Vineland Adaptive Behavior Scales (VABS-II)  
Second Edition26
Table 7-2 Sanfilippo-Specific Disability Assessment And Behavior Rating Scales
DEVELOPMENTAL OR COGNITIVE 
DOMAIN(S)
SANFILIPPO SPECIFIC ASSESSMENTS
Parent-scored behavioral inventory
- communication:  understanding
- communication:  expression
- tantrums
- specific behaviors inventory
- mood & emotions inventory
Sanfilippo Behavior Rating Scale (SBRS)
MPS-specific disability score 
- cognitive functioning
- expressive language
- motor score
Four-Point Scoring System/Total Disability Score 
(FPSS/TDS)5 
7.19
Sleep Questionnaire:  Children’s Sleep Habits Rating Scale 
A sleep questionnaire, Children’s Sleep Habits Rating Scale, will be administered to the patient's 
parent(s)/legally authorized representative(s).

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
39
7.20
Age-Dependent, Health-Related Quality of Life in Children
The Quality of Life questionnaires will be administered as outlined in Sections 7.20.1, 7.20.2, 
and 7.20.3.
7.20.1
Quality of Life Indicator:  CHQ-50
The Child Health Questionnaire™ Parent Form 50 Questions (CHQ-50) will be administered 
during the study.  The questionnaire is a generic quality of life instrument, measuring 14 unique 
physical and psychosocial concepts, which was developed for children from 5 to 18 years of age
7.20.2
Quality of Life Indicator:  CHQ-87
The Child Health Questionnaire™ Child Form 87 (CHQ-87) will be administered during the 
study.  The CHQ-87 is a child and adolescent self-report, developed for ages 10 and older, which 
assesses the child’s self-perceived physical and psychosocial well-being
7.20.3
Quality of Life Indicator:  ITQOL
The Infant Toddler Quality of Life Questionnaire™ (ITQOL) will be administered during the 
study.  The ITQOL was developed for children at least 2 months of age up to 5 years and 
assesses the physical, mental, and social well being of the child and assesses the quality of the 
parent/legally authorized representative(s) life.  
7.21
Concomitant Medications, Therapies and Medical/Surgical Procedures
All non-protocol treatments that occur from the time of informed consent (and assent, if 
applicable) through the safety follow-up contact are regarded as concomitant and will be 
documented on the appropriate pages of the eCRF.  Concomitant therapy includes medication 
(including Genistein), therapies/interventions administered to patients, and medical/surgical 
procedures performed on the patients.
Every effort should be made to keep symptomatic Sanfilippo syndrome Type A treatment 
constant throughout the study.  However, changes in medications are acceptable if necessary 
according to clinical judgment.  All changes will be recorded on the appropriate eCRF.  
Concomitant medication will be coded using WHO-DD.

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
40
7.22
Adverse Events
7.22.1
Definitions of Adverse Events and Serious Adverse Events
7.22.1.1
Adverse Event
An adverse event (AE) is any noxious, pathologic, or unintended change in anatomical, 
physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory 
changes occurring in any phase of a clinical study, whether or not considered study drug-related.  
This includes an exacerbation of a pre-existing condition.  Once the informed consent is signed 
and dated, any adverse event prior to the start of study drug must be reported. 
AEs include:
•
Worsening (change in nature, severity, or frequency) of conditions present at the onset of the 
study
•
Intercurrent illnesses
•
Drug interactions
•
Events related to or possibly related to concomitant medications
•
Abnormal laboratory values (this includes significant shifts from baseline  within the range 
of normal that the Investigator considers to be clinically important)
•
Clinically significant abnormalities in physical examination, vital signs, and weight
Throughout the study, the Investigator must record all AEs on the AE eCRF, regardless of the 
severity or relationship to study drug.  The Investigator should treat patients with AEs 
appropriately and observe them at suitable intervals until the events stabilize or resolve.  AEs 
may be discovered through observation or examination of the patient, questioning of the patient, 
complaint by the patient, or by abnormal clinical laboratory values.
In addition, AEs may also include laboratory values that become significantly out of range.  In 
the event of an out-of-range value, the laboratory test should be repeated until it returns to 
normal or can be explained and the patient’s safety is not at risk.  
All adverse events should be recorded with causality assessment.
The information presented below is intended to provide issues to consider for AEs associated 
with intrathecal injections of rhHNS.  In general, these AEs can be classified as follows: 
•
Adverse events due to systemic exposure to rhHNS caused by the drug diffusion from the 
CSF to the peripheral circulation; 
•
Adverse events related to the direct delivery of rhHNS to the intrathecal CSF space and 
meninges, and subsequent diffusion into brain parenchyma, via an intrathecal route 
•
IDDD–related AEs.  

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
41
Note:  the classification of potential AEs and the examples presented below are based on purely 
theoretical considerations and/or published literature as there is limited human experience with 
intrathecal rhHNS therapy to date.
POTENTIAL ADVERSE EVENTS:  INTRATHECAL RECOMBINANT HUMAN HEPARAN N-SULFATASE 
Adverse Events Due to Systemic Exposure to rhHNS
Although rhHNS is given intrathecally only, some proportion of the drug will diffuse from the 
CSF into the peripheral circulation.  The resulting systemic exposure may cause events that are 
typically seen in patients receiving ERT via an intravenous administration, known as 
infusion-related reactions.  An infusion-related reaction is defined as an adverse event that 
(1) begins either during or within 24 hours after the start of the infusion, and (2) is judged as 
possibly or probably related to study drug.  Other AEs that occur prior to the infusion, along with 
AEs associated with protocol-defined testing and assessments (laboratory testing and physical 
examinations) that were performed prior to the infusion will not be defined as infusion-related 
reactions.

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
42
Adverse Events Related to the Direct Delivery of rhHNS to the CNS through Intrathecal 
Administration
Examples of adverse events observed in other published clinical trials with 
intrathecally-administered peptides or proteins, include, but are not limited to the following:  
headache, fever, feeling of warmth, sensory parathesias (including feelings of warmth, tingling, 
or pain) or autonomic symptoms such as dry mouth or gustatory abnormalities (including loss of 
smell and metallic taste).  Changes in mental cognitive status or level of consciousness that are 
not caused by pre-medication may either occur acutely or develop post-injection, over time.
POTENTIAL ADVERSE EVENTS:  IDDD-RELATED ADVERSE EVENTS
Examples of adverse events related to the insertion or use of an IDDD include, but are not 
limited to, the following:  catheter disconnection or fracture, erosion of portal/catheter through 
the skin, fibrin sheath formation around the catheter tip, hematoma, implant rejection, 
malposition of catheter, migration of portal/catheter, occlusion of portal/catheter, portal site or 
subcutaneous tract infection, and sepsis.  
In addition, there are risks associated with intraspinal access, which include the following:  
cerebrospinal fluid leaks, dura mater or epidural vein perforation, epidural or intrathecal space 
infection (which could result in meningitis), inadvertent epidural placement, pain on injection, 
and spinal cord or nerve injury.
7.22.1.2
Serious Adverse Event
A serious AE (SAE) is any AE occurring at any dose that results in any of the following 
outcomes:
•
Death
•
Is life-threatening
•
Requires inpatient hospitalization
•
Requires prolongation of existing hospitalization
•
A persistent or significant disability or incapacity 
•
A congenital anomaly or birth defect
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition.  Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization.
The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) 
grading scale should be referenced when assessing the severity of an AE (see Appendix 6).  If an 
AE is not described in the NCI CTC, the severity should be recorded based on the scale provided 
in Table 7-3.

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
43
The severity of all AEs/SAEs should be recorded on the appropriate eCRF page as Grade 1, 2, 3, 
4, or 5 corresponding, respectively, to a severity of mild, moderate, severe, life-threatening, or 
death.
Table 7-3 Adverse Event Severity
Severity
Definition
Grade 1 (Mild)
No limitation of usual activities.
Grade 2 (Moderate)
Some limitation of usual activities.
Grade 3 (Severe)
Inability to carry out usual activities.
Grade 4 (Life-threatening)
Immediate risk of death.
Grade 5 (Death related to an AE)
Death
Relationship of an adverse event or serious adverse event to study medication is to be determined 
by the Investigator based on the definitions in Table 7-4:
Table 7-4 Adverse Event Relatedness
Relationship to Product(s)
Definition
Not Related
Unrelated to study drug.
Possibly Related
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of study drug, but which could also be 
explained by concurrent disease or other drugs or chemicals.
Probably Related
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of study drug, unlikely to be attributable to 
concurrent disease or other drugs and chemicals and which follows a 
clinically reasonable response on de-challenge.  The association of the 
clinical event or laboratory abnormality must also have some biologic 
plausibility, at least on theoretical grounds.
Definitely Related
The event follows a reasonable temporal sequence from administration 
of the medication, follows a known or suspected response pattern to 
the medication, is confirmed by improvement upon stopping the 
medication (dechallenge) and reappears upon repeated exposure 
(rechallenge).  
Note that this is not to be construed as requiring re-exposure of the 
patient to study drug; however, the determination of definitely related 
can only be used when recurrence of event is observed.

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
44
7.22.2
Procedures for Recording and Reporting Adverse Events
7.22.2.1
Reporting Serious Adverse Events Related to Study Procedures
Any SAE that occurs in a patient after informed consent (and assent if applicable) should be 
recorded by the clinical site on an SAE form that is to be transmitted to the Shire HGT Medical 
Monitor and to the Shire Pharmacovigilance and Risk Management Department at the contact 
number provided below.  The SAE must be completely described on the patient’s eCRF, 
including the judgment of the Investigator as to the relationship of the SAE to the study 
procedure.  The Investigator will promptly supply all information identified and requested by the 
Sponsor (and/or contract research organization [CRO]) regarding the SAE as to the relationship 
of the SAE to study drug, device or procedure. 
The SAE form must be completed and FAXED or scanned and EMAILED (PDF sent by e-mail) 
within 24 hours of the Investigator’s learning of the event to: 
Any follow-up information must also be completed on an SAE form and faxed or scanned to the 
same numbers or e-mail address listed above.
In the event of a severe and unexpected, fatal, or life-threatening SAE, the clinical site must 
contact the Shire HGT Medical Monitor by telephone; this is in addition to completing and 
transmitting the SAE form as stated above.  The following provides contact information for the 
Shire HGT Medical Monitor.
Shire Pharmacovigilance and Risk Management Department:
International FAX:  
United Kingdom OR 
United States FAX: 
Email: 
AND
Shire HGT Medical Monitor:
FAX: 
(United States)
The Investigator may also call the Medical Monitor directly (optional):
Shire HGT Medical Monitor: 
, MD
Shire HGT
Work: 
Cell: 
(24 hour access)
Email: 
AND
Clinical Project Manager CC’d: 

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
45
If an SAE is assessed as severe and unexpected, or life-threatening, contact:
MD 
Shire Human Genetic Therapies, Inc.
300 Shire Way
Lexington, MA  02421,  United States
Telephone: 
Fax: 
(United States)
Mobile: 
 (24-hour access)
The Investigator must promptly report all required information to the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC).  It is the responsibility of the Sponsor to ensure that 
each Investigator receives a copy of any CIOMS I/MedWatch report that has been submitted to 
the appropriate regulatory agencies notifying them of an unexpected related SAE.  The 
Investigator or Sponsor must ensure that the IRB/IEC receives a copy of the report and that a 
copy is also filed within their study files.  In addition, the Sponsor will also notify the 
Investigators and IRBs/IECs of all deaths that occur during the study, irrespective of relationship 
to study medication
7.22.2.2
Eliciting Adverse Events
Patients should be asked non-leading questions (eg, “How do you feel?”) and further questions 
should be posed if there is indication of an AE.  The questioning should be conducted with due 
regard for objectivity and, in particular, the questioner should gather information regarding AEs 
from questioning the patient, the patient’s parent/guardian, spontaneous report by the patient or 
parent/guardian, laboratory reports, and any health care provider’s observations.
The onset date, resolution date, treatment administered, and outcome of each AE must be 
recorded on the appropriate eCRF.  In addition, the relationship of each AE to study medication 
must be recorded.
7.22.2.3
Protocol Deviations for Medical Emergency or Adverse Event
During and following a patient’s participation in the study, the Investigator should ensure that 
adequate medical care is provided to a patient for any AEs, including clinically significant 
laboratory test results.  
The Investigator should inform the patient, the patient’s parent(s), or the patient’s legally 
authorized representative when medical care is needed for intercurrent illness(es) of which the 
Investigator becomes aware.  In an emergency situation, the Investigator should contact the Shire 
HGT Medical Monitor (see Section 7.22.2.1).
Only when an emergency occurs that requires an immediate deviation from the protocol for the 
safety of a patient, will there be such a deviation and this will be only for that patient.  

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
46
The Investigator or other physician in attendance in such an emergency must contact the Shire 
HGT Medical Monitor as soon as possible.  
The Investigator, along with the Shire HGT Medical Monitor, will make a decision as to whether 
or not the patient should continue in the study prior to the next scheduled dose.  The departure 
from the protocol and the grounds for it should be stated in the eCRF.
7.23
Safety-related Study Stopping Rules
If any patient experiences a life-threatening (Grade 4) adverse event or death which is considered 
possibly, probably, or definitely related to study drug, or if 2 or more patients experience a 
Grade 3 adverse event during the trial that is considered possibly, probably, or definitely related 
to the study drug by the sponsor, then the site will be instructed to halt further rhHNS 
administration to all patients and the safety data reviewed. Following a review of safety data, the 
study will be either:
•
Resumed unchanged
•
Resumed with modifications to the protocol or
•
Terminated
Patient safety will be monitored on a continuous basis during this study until the last patient 
completes his or her last scheduled study visit/assessment.  
7.24
Pregnancy
Pregnancy and breast feeding are exclusion criteria.  Only female patients who have 
reached menarche will be tested for pregnancy in HGT-SAN-067.  If applicable, this will occur 
at study start and before each dose of rhHNS throughout the study.  Pregnancy testing will be 
performed on a blood or urine sample.  Patients with a positive or inconclusive result will not be 
eligible for this study.
At study start, a pregnancy test will be performed if more than 30 days have passed since the 
initial screening sample.  Throughout the study pregnancy testing will occur prior to each dose of 
rhHNS.  The clinical site’s local laboratory will analyze and report all pregnancy testing results.  
If a pregnancy test is positive the patient will be discontinued from the study, and the 
Investigator must contact the Shire HGT Medical Monitor. 
Pregnancy is not to be reported as an AE; the Pregnancy Reporting Form, found in the Study 
Operations Manual along with instructions for completion, should be used to report the 
pregnancy.  The pregnancy will be followed up through delivery or final outcome.
7.25
Removal of Subjects from the Trial or Study Drug
The patient's parent or legally authorized representative acting on behalf of the patient is free to 
withdraw consent and discontinue participation in the study at any time without prejudice to 
further treatment.  Since this is an extension trial, there will be no replacement of patients who 
discontinue the study for any reason.

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
47
A patient’s participation in the study may be discontinued at any time at the discretion of the 
Investigator, Sponsor, or Medical Monitor.  The following may be justifiable reasons for the 
Investigator, Sponsor, or Medical Monitor to remove a patient from the study:
•
Adverse Event:  If a patient experiences an AE which, in the judgment of the investigator, the 
sponsor, or the medical monitor, presents an unacceptable consequence or risk to the patient.
•
Adverse Laboratory Experience:  If a patient has an adverse laboratory experience which, in 
the judgment of the investigator, the Sponsor, or the medical monitor, presents an 
unacceptable consequence or risk to the patient, the patient may be withdrawn from the 
study.
•
Comorbidity:  If a patient develops comorbidity during the course of the study that is 
independent of the study indication, and treatment is required that is not consistent with 
protocol requirements. 
•
Intercurrent Illness:  If a patient develops an illness during the course of the study that is not 
associated with the condition under study, and which requires treatment that is not consistent 
with protocol requirements.
•
Refusal of Treatment:  If the patient, the patient’s parent(s) or legally authorized 
representative(s) discontinues participation in the study, or the patient is discontinued by the 
Investigator, reasonable efforts will be made to follow the patient through the end of study 
assessments.  The reason for refusal will be documented on the eCRF.  
•
Withdrawal of Informed Consent:  A patient’s parent or legally authorized representative 
may withdraw his informed consent to participate in the study at any time.
•
Cerebrospinal fluid leukocyte count >100 cells per cubic millimeter for 2 consecutive 
months.
•
New onset seizure.
•
Anaphylactic reaction beyond reasonable management as described in the Investigator’s 
Brochure.
•
Clinically problematic intubations or extubations, which may preclude safe airway 
management and anesthesia.
•
Development of refractory spinal fluid leakage. 
•
Clinically significant prolonged (eg, greater than 24 to 48 hours) worsening in mental status, 
including development of new focal or non-focal neurological symptoms, or recurrence of a 
previously stable prior medical problem judged due to study drug or participation that is 
exclusive of effects from anesthesia.
•
Non-compliance, including failure to appear at 1 or more study visits.
•
The patient was erroneously included in the study.
•
The patient develops an exclusion criterion.
•
The study is terminated by the Sponsor.
•
The patient becomes pregnant during the trial.
If a patient discontinues the study the Patient Completion/Discontinuation eCRF describing the 
reason for discontinuation must be completed.  Any AE’s experienced up to the point of 
discontinuation must be documented on the AE eCRF.  

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
48
If AEs are present when the patient withdraws from the study, the patient will be re-evaluated 
within 30 days of withdrawal.  All ongoing SAEs at the time of withdrawal will be followed until 
resolution.
At the time of discontinuation or withdrawal, patients will be asked to participate in all safety 
and efficacy evaluations required for the end of study visit and for the safety follow-up visit.  
Participation in these EOS procedures will be strongly encouraged, but is voluntary for those 
patients electing to discontinue from the study.  The patient will be scheduled for the removal of 
the IDDD. 
7.26
Other Study Procedures
This section is not applicable.
7.27
Appropriateness of Measurements
The neurocognitive and developmental assessments are intended to gauge which domains can be 
accurately measured, with which specific tools, despite the considerable behavioral and cognitive 
challenges in Sanfilippo syndrome.  The evaluation of these domains and the analysis of CSF, 
serum, and urine biomarkers may provide the pivotal data necessary to inform the clinical 
assessments and biomarkers used in possible future Sanfilippo syndrome ERT trials.

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
49
8
STUDY ACTIVITIES
Patients who participated in Study HGT-SAN-055 through Week 26 and completed the EOS 
evaluations may be eligible for enrollment in this open-label extension study.  Informed consent 
(and assent, if applicable) must be obtained prior to performing any study related procedures that 
are specific to HGT-SAN-067.  Informed consent may be obtained anytime from Week 20 in 
HGT-SAN-055.  This would allow a patient to have a nonfunctional IDDD replaced or revised 
prior to the first rhHNS dose in HGT-SAN-067.
8.1
Screening Visit/Study Start Visit 
All Screening assessments for this study are to have been performed during the Week 26 EOS 
procedures in HGT-SAN-055 (ie, 30 [±7] days after the last rhHNS administration).  If less than 
60 days have elapsed since completion of the EOS assessments for HGT-SAN-055, and the start 
of HGT-SAN-067, the assessments detailed in this Screening visit do not need to be repeated.  
The Baseline visit for this study will be the first day the patient received their first dose of 
rhHNS in the HGT-SAN-055 Study.  
If more than 60 days have elapsed following the HGT-SAN-055 EOS procedures, patients will 
be evaluated for enrollment in HGT-SAN-067 on a case-by-case basis by the Investigator.  A 
decision about enrollment will be made following discussion with the Medical Monitor.  If the 
patient is enrolled, the following assessments are to be repeated within 30 days prior to the first 
scheduled intrathecal rhHNS dose:
•
Physical examination
•
Height and weight
•
Head circumference
•
ECG
•
Vital signs
•
Hematology 
•
Leukocyte pellet preparation to be used for additional disease-related laboratory studies, 
including possible assessment of cross-reactive immunologic material (if this is not 
collected at baseline, it can be collected at any subsequent pre-dosing time point)
•
Serum chemistry 
•
Pregnancy testing (for post menarche premenopausal females only)
•
Urinalysis 
•
Urine heparan sulfate and heparan sulfate derivatives
•
Plasma and serum heparan sulfate and heparan sulfate derivatives
•
Anti-rhHNS antibody testing
•
General anesthesia:  administration of anesthesia will be given prior to the following 
assessments:
•
ABR
•
MRI of the head
•
Neurological examination (performed prior to the administration of anesthesia)

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
50
•
Full Neurodevelopmental assessments, including Vineland Adaptive Behavior Scales, 
Second Edition (VABS-II; all assessments performed prior to the administration of 
anesthesia)
•
CSF sample collection (chemistry, cell count, heparan sulfate and heparan sulfate derivatives, 
and other MPS exploratory biomarkers) via the IDDD
•
Children’s Sleep Habits Rating Scale 
•
CHQ-50
•
CHQ-87
•
ITQOL
•
Concomitant medications, therapies, and procedures
•
AE assessments
8.2
Treatment:  Drug Administration and Weekly Assessments
Patients will receive rhHNS IDDD monthly (Q4W), on Day 2 (±2 days), Week 1.  
Patient assessments for safety, biochemical, and neurological baseline measures (Day 1, Week 1) 
will occur on the day before the first IT injection.  Note:  Day 1 assessments may be performed 
on the same day as the administration of study drug (Day 2).  This can occur if it is feasible for 
the patient to arrive at the study site early in the day, and if it is deemed clinically appropriate by 
the Investigator.  If the procedures on Day 1 and Day 2 are combined in this way, the 
assessments will be recorded as occurring on Day 2.
CSF samples will be obtained from these patients on Day 2, immediately prior to the first IT 
study drug injection.  Note:  Patients will not receive study drug if the pre-dose CSF contains 
>100 WBC per cubic millimeter.
8.2.1
Week 1 
8.2.1.1
Day 1 (Pre-treatment) Assessments Performed Prior to Each Dose
•
Physical examination
•
Height and weight
•
Vital signs
•
Hematology
•
Serum chemistry
•
Urinalysis
•
Pregnancy testing (applicable females only)
•
Neurological examination (performed prior to the administration of anesthesia and the 
rhHNS IT injection)
•
Concomitant medications, therapies, and procedures
•
AE assessments

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
51
Note: If the HGT-SAN-055 EOS (or HGT-SAN-067 Screening) assessments were performed 
within 7 days of first intrathecal rhHNS treatment in this study, the pre-treatment assessments 
described in this section do not need to be completed prior to the first treatment in study 
HGT-SAN-067.
DAY 1 (PRE-TREATMENT) ADDITIONAL ASSESSMENTS PERFORMED AT MONTHS 12, 24, 36, AND 54
•
Head circumference
•
Visual and hearing assessments 
•
Urine heparan sulfate and heparan sulfate derivatives 
•
Plasma and /or serum heparan sulfate and heparan sulfate derivatives 
•
Anti-rhHNS antibody testing
•
ABR
•
MRI of the head 
•
Full neurodevelopmental testing, including VABS-II (performed prior to the administration 
of anesthesia and the rhHNS IT injection)
•
Children’s Sleep Habits Rating Scale 
•
Child health questionnaire-50 
•
Child health questionnaire-87 
•
Infant toddler QOL Questionnaire 
8.2.1.2
Day 2 (±2 days) Assessments and Administration of rhHNS
Patients may be discharged from the clinical site 8 hours after dosing, if deemed stable by the 
Investigator.
•
Physical examination
•
ECG (performed following IT study drug injection)
•
Vital signs
•
CSF sample collection (obtained prior to IT study drug injection)
•
rhHNS IT injection (Day 2 ±2 days)
•
Neurological examination 
•
Concomitant medications, therapies, and procedures
•
AE assessments
The neurological exam should not occur sooner than 4 hours after study drug administration or 
before the patient has fully recovered from any anesthesia administered for the dosing, 
whichever occurs later.
8.3
End of Study/Early Termination Procedures:  Month 55
Patients who complete the study or who discontinue prior to the end of the study, will have EOS 
assessments performed 30 (±7 days) after their last dose of rhHNS.  

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
52
Patients who discontinue or are withdrawn prior to study completion will be asked to participate 
in the EOS procedures at the time of discontinuation.  Participation in these EOS procedures will 
be strongly encouraged, but is voluntary for those patients electing to discontinue from the study.  
Note:  Scheduled removal of the IDDD will be required at study completion with sedation or 
anesthesia, as required.
•
Physical examination
•
Height and weight
•
Head circumference
•
Visual and hearing assessment
•
ECG
•
Vital signs
•
Hematology
•
Serum chemistries
•
Urinalysis
•
Urine heparan sulfate and heparan sulfate derivatives 
•
Plasma and serum heparan sulfate and heparan sulfate derivatives 
•
Anti-rhHNS antibody testing
•
ABR
•
MRI of the head 
•
CSF sample collection 
•
Neurological examination
•
Full neurodevelopmental testing, including VABS-II 
•
Children’s Sleep Habits Rating Scale 
•
Child health questionnaire-50 
•
Child health questionnaire-87 
•
Infant toddler QOL Questionnaire 
•
Concomitant medications, therapies, and procedures
•
AE assessments
All patients who discontinue the study early will have their IDDD removed.  
Patients who withdraw or discontinue after having received fewer than 3 IT injections will not 
need to complete the EOS visit.  
Patients who withdraw or discontinue from the study after having received 3 or more IT 
injections, will be asked to complete the EOS visit and undergo all the scheduled assessments.
8.4
Safety Follow-up (by Telephone or Visit) Month 56
Patients who complete the study or withdraw early will have a safety follow-up telephone call or 
visit 30 Days (±7 days) after the last study visit.  This will assess:
•
Concomitant medications, therapies, and procedures

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
53
•
AE assessments

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
54
9
QUALITY CONTROL AND ASSURANCE
Training will occur at an investigator meeting or at the site initiation visit or both, and instruction 
manuals (eg, laboratory manuals and pharmacy manuals) will be provided to aid consistency in 
data collection and reporting across sites.
Clinical sites will be monitored by Shire HGT or its designee to ensure the accuracy of data 
against source documents.  The required data will be captured in a validated clinical data 
management system that is compliant with the Food and Drug Administration (FDA) 21 Code of 
Federal Regulations (CFR) Part 11 Guidance.  The clinical trial database will include an audit 
trail to document any evidence of data processing or activity on each data field by each user.  
Users will be trained and given restricted access, based on their role in the study, through a 
password protected environment.  
Data entered in the system will be reviewed manually for validity and completeness against the 
source documents by a clinical monitor from Shire HGT or its designee.  If necessary, the study 
site will be contacted for corrections or clarifications; all missing data will be accounted for.
SAE information captured in the clinical trial database will be reconciled with the information 
captured in the Pharmacovigilance database.

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
55
10 PLANNED STATISTICAL METHODS
10.1
General Statistical Methodology
This is an open-label extension of study HGT-SAN-055 to evaluate the long-term safety and 
clinical outcomes of intrathecal administration of rhHNS in patients with MPS IIIA.  The 
statistical methodology supporting the trial will focus on descriptive rather than inferential 
approaches, given the early phase and objectives of this trial. 
Data will be summarized by dose group (10 mg, 45 mg, and 90 mg) with respect to demographic 
and baseline characteristics, efficacy variables and safety variables.  Summary statistics for 
continuous variables will include the n, mean, standard deviation, median, minimum and 
maximum.  Categorical variables will be summarized in a contingency table by the frequency 
and percentage of patients in each category. Data will be plotted to assess trends across time. 
All hypothesis tests will be 2-sided and will be performed at the 0.05 level.  Hypothesis testing 
will be viewed as exploratory.  Any resulting p-values will not be regarded as a firm support for 
conclusions, but rather suggestive of areas of examination in future studies.  In general, variables 
will be quantified as a change from the baseline value.  The null hypothesis will be that there is 
no difference in the change from baseline between dose groups. Note that the baseline visit for 
this study will be the first day the patient received his/her IT dose of rhHNS in study 
HGT-SAN-055. 
The primary objective of this trial is to assess the long term safety of rhHNS administration via a 
surgically implanted IDDD.  Hence an extensive safety assessment will be performed.  The 
safety analyses will consist of all enrolled patients.  To evaluate safety, adverse experiences will 
be tabulated by dose group.  Vital signs, electrocardiograms, serum and CSF components and 
chemistries, hematology, and urinalysis safety monitoring will be listed for each patient and 
abnormal values will be flagged.  In addition, anti-rhHNS antibodies (in CSF and serum) will 
also be listed.  No formal statistical tests will be performed on the safety parameters.
10.2
Determination of Sample Size
Since this is an extension study, sample size is determined by the number of patients who 
completed HGT-SAN-055 (maximum of 12 patients) and elected to continue treatment with 
rhHNS in this study
10.3
Analysis Populations
The analysis population consists of all eligible patients from HGT-SAN-055 who have agreed to 
participate in the extension study.  Both safety and efficacy analyses would be performed using 
the above mentioned population. 

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
56
10.4
Demographics and Baseline Characteristics
Patient disposition for those enrolled will be presented in a summary table using number and 
percentage of patients enrolled, completed or discontinued/withdrew, by dose group.  The 
reasons for discontinuation/withdrawal will also be presented.
Demographic and baseline characteristics (eg, age, race, ethnicity, medical history, and surgical 
history) will be reported in summary tables.
10.5
Statistical Analysis of Pharmacokinetic Variables
Not applicable.
10.6
Efficacy, Safety, and Pharmacodynamic Evaluations    
10.6.1
Primary Analyses
10.6.1.1
Safety Analysis
In general, safety assessments will be based on all assessments post-baseline.  The assessment of 
safety will be based primarily on the frequency of adverse events, and on the frequency of 
clinically notable abnormal vital sign and laboratory values.  Changes from baseline will be 
calculated by subtracting the baseline value from the post-baseline value.
All enrolled patients will be included in the safety analysis.  Patients will be grouped according 
to the actual dose received.  
No formal statistical test will be performed in the safety evaluations.  Vital sign measurements, 
clinical chemistry, and hematology safety monitoring will be listed for each patient, and 
abnormal values will be flagged.  These will also be summarized at each time point, including 
change from baseline.
Adverse events will be recorded throughout the study and at early termination.  Adverse events 
and medical conditions will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). 
Adverse events will be summarized by presenting, for each treatment group, the number and 
percentage of patients having any adverse event, having an adverse event in system organ class, 
and having each individual adverse event.  Note that in any given category (eg, system organ 
class) a patient will only be counted once.  In addition, those events which resulted in death or 
were otherwise classified as serious will be presented in a separate listing.  The incidence of 
treatment-emergent adverse events (new or worsened from baseline) will be summarized by 
system organ class, severity, type of adverse event and relationship to trial medication. 
Adverse events that occur up to 30 days after the last dose of study drug will be considered 
“on-treatment”.  Adverse events which are deemed probably, possibly, or definitely related to the 
device will be summarized by dose group and overall.

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
57
Laboratory data will be listed by patient and dose group.  Patients with newly occurring 
abnormalities outside the normal range will be flagged and listed separately and summarized.  
Mean change from baseline values or shift tables will also be provided by dose group at each 
visit.
Vital signs data will be listed by patient and dose group.  Furthermore, mean changes from 
baseline for vital sign data will be summarized for each dose group.  Shift tables may be 
presented, utilizing reference ranges.  Patients with notably abnormal values will be identified 
and listed separately along with their values.
Electrocardiograph assessments will be listed by patient and dose group.  Mean changes from 
baseline for ECG data will be summarized for each dose group.  Patients with any clinically 
significant findings and/or conduction abnormalities will be listed separately along with their 
values. 
For those patients who fail to complete the study, the reason for discontinuation will be listed by 
patient and dose group. 
Listings of all study safety data will be presented.
10.6.1.2
Clinical Laboratory Evaluations
Descriptive summaries of clinical laboratory evaluations (hematology, serum chemistry, 
urinalysis) results will be presented in summary tables by evaluation visit using number of 
patients (n), mean, median, standard deviation, minimum, and maximum.  Changes from 
baseline will be summarized for each post-baseline visit.  The number of patients with clinically 
significant laboratory results or abnormal results during the study period will be presented in 
shift tables.
For the laboratory measurements, shift tables will be presented in terms of Low (L), Normal (N), 
High (H), Missing (M).  High and Low measurements will be based on reference ranges 
provided by the laboratory at the study site.
Clinical laboratory results will also be presented in data listings.
10.6.1.3
Anti-rhHNS Antibody Formation
Anti-rhHNS antibody formation will be monitored throughout the study.  Results will be 
presented in summary tables by assay methodology used to identify antibodies, number and 
percentage of positive and negative specimens by evaluation visit and/or study week, and 
number and percentage of positive and negative specimens overall.  The effect of antibodies on 
other safety parameters will be assessed by presenting summary tables by antibody status.  These 
results will also be presented in data listings. 

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
58
10.6.2
Secondary Analysis
10.6.2.1
Clinical Assessments
The change from baseline in neurocognitive assessment based scores will be examined by dose 
group.  Furthermore, the effect of rhHNS administration on QoL measures will be examined by 
presenting mean change from baseline across dose groups.  Other relevant assessments which 
might help in the understanding of clinical activity will also be analyzed.
10.6.2.2
Pharmacodynamic Analyses
To determine the effects of rhHNS administration on biomarkers, mean change from baseline 
will be assessed at selected time points.  The heparin sulfate reduction (in CSF and urine) will be 
examined using mean change and the corresponding 95% confidence interval.  The concentration 
of inflammatory cytokines in serum and CSF will also be examined.  Other exploratory 
biomarkers in CSF, serum, and urine may also be examined.
The effect of anti- rhHNS antibodies on the changes in CSF biomarkers may also be examined 
by presenting summary tables by antibody status.
The planned analyses and presentations will be defined in the Statistical Analysis Plan (SAP).

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
59
11 ADMINISTRATIVE CONSIDERATIONS
11.1
Investigators and Study Administrative Structure
Before initiation of the study, the Investigators must provide the Sponsor with a completed Form 
FDA 1572.  Study medications may be administered only under the supervision of the 
Investigators listed on this form.  Curriculum vitae must be provided for the Investigators and 
sub-investigators listed on Form FDA 1572.
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, any amendments to the protocol, the study treatments, and their study related 
duties and functions.  The Investigator must maintain a list of sub-investigators and other 
appropriately qualified persons to whom he or she has delegated significant study related duties.
11.2
Institutional Review Board or Independent Ethics Committee Approval
Before initiation of the study, the Investigator must provide the Sponsor with a copy of the 
written IRB or IEC approval of the protocol and the informed consent form.  This approval must 
refer to the informed consent form and to the study title, study number, and version and date of 
issue of the study protocol, as given by the Sponsor on the cover page of the protocol.
Status reports must be submitted to the IRB/IEC at least once per year.  The IRB/IEC must be 
notified of completion of the study.  Within 3 months of study completion or termination, a final 
report must be provided to the IRB/IEC.  A copy of these reports will be sent to the study clinical 
monitor.  The Investigators must maintain an accurate and complete record of all submissions 
made to the IRB/IEC, including a list of all reports and documents submitted.  AEs which are 
reported to the Unites States FDA or other Regulatory agencies (Investigational New Drug 
[IND] Safety Reports) must be submitted promptly to the IRB/IEC.
11.3
Ethical Conduct of the Study
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor and Investigators abide by 
good clinical practice (GCP) as described in the 21 CFR Parts 50, 56, and 312 and the 
International Conference on Harmonization (ICH) GCP Guidelines. 
11.4
Patient Information and Consent
Before enrolling in the clinical study, the patient’s parent(s), or the patient’s legally authorized 
representative(s) must consent to participate after the nature, scope, and possible consequences 
of the clinical study have been explained in a form understandable to him or her.  An informed 
consent form that includes information about the study will be prepared and given to the 
patient’s parent(s), or the patient’s legally authorized representative(s).  This document will 
contain all FDA and ICH-required elements.  

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
60
The informed consent form must be in a language understandable to the patient’s parent(s), or 
the patient’s legally authorized representative(s) and must specify who informed the patient’s 
parent(s), or the patient’s legally authorized representative.
After reading the informed consent document, the patient, patient’s parent(s), or the patient’s 
legally authorized representative(s) must give consent in writing.  The patient’s consent must be 
confirmed at the time of consent by the personally dated signature of the patient, patient’s 
parent(s) or the patient’s legally authorized representative(s) and by the personally dated 
signature of the person conducting the informed consent discussions.  If the patient, patient’s 
parent(s), or the patient’s legally authorized representative(s) is unable to read, oral presentation 
and explanation of the written informed consent form and information to be supplied must take 
place in the presence of an impartial witness.  Consent (or assent) must be confirmed at the time 
of consent orally and by the personally dated signature of the patient, patient’s parent(s) or by the 
patient’s legally authorized representative(s).  The witness and the person conducting the 
informed consent discussions must also sign and personally date the informed consent document.  
It should also be recorded and dated in the source document that consent was given.
A copy of the signed and dated consent document(s) must be given to the patient’s parent(s), or 
the patient’s legally authorized representative(s).  The original signed and dated consent 
document will be retained by the Investigator.
The Investigator will not undertake any measures specifically required solely for the clinical 
study until valid consent has been obtained.
A model of the informed consent form to be used in this study will be provided to the sites 
separately from this protocol.  
Where applicable, signed assent(s) to participate in the study must be obtained.
11.5
Patient Confidentiality
Patient names will not be supplied to the Sponsor.  Only the patient number and patient initials 
will be recorded in the eCRF, and if the patient name appears on any other document, it must be 
obliterated before a copy of the document is supplied to the Sponsor.  Study findings stored on a 
computer will be stored in accordance with local data protection laws.  The patients will be told 
that representatives of the Sponsor, a designated Clinical Research Organization (CRO), the 
IRB/IEC, or regulatory authorities may inspect their medical records to verify the information 
collected, and that all personal information made available for inspection will be handled in 
strictest confidence and in accordance with local data protection laws.  The Investigator will 
maintain a personal patient identification list (patient numbers with the corresponding patient 
names) to enable records to be identified.
11.6
Study Monitoring
Monitoring procedures that comply with current GCP guidelines will be followed.  On-site 
review of the eCRFs for completeness and clarity, cross-checking with source documents, and 
clarification of administrative matters will be performed.

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
61
The study will be monitored by the Sponsor or its designee.  On site monitoring will be 
performed by a representative of the Sponsor (Clinical Study Monitor) who will review the CRFs 
and source documents.  The site monitor will ensure that the investigation is conducted 
according to protocol design and regulatory requirements by frequent site visits and 
communications (letter, telephone, and facsimile).
11.7
Case Report Forms and Study Records
Case report forms are provided for each patient in electronic format.  Electronic Data Capture 
(EDC) will be used for this study.  The study data will be recorded from the source documents 
into the eCRF.  The electronic files will be considered as the CRFs. 
All forms must be filled out by authorized study personnel.  All corrections to the original eCRF 
entry must indicate the reason for change.  The Investigator is required to sign the eCRF after all 
data have been captured for each patient.  If corrections are made after review and signature by 
the Investigator, he or she must be made aware of the changes, and his or her awareness 
documented by re-signing the eCRF.   
11.7.1
Critical Documents
Before Shire HGT initiates the trial (ie, obtains informed consent [assent if applicable] from the 
first patient), it is the responsibility of the Investigator to ensure that the following documents are 
available to Shire HGT or their designee:
•
Curricula vitae of Investigator and sub-investigator(s) (current, dated and signed or supported 
by an official regulatory document)
•
Current medical license of Investigator and sub investigator(s)
•
Signed and dated agreement of the final protocol
•
Signed and dated agreement of any amendment(s), if applicable
•
Approval/favorable opinion from the IRB/IEC clearly identifying the documents reviewed:  
protocol, any amendments, Patient Information/Informed Consent Form (Assent form if 
applicable), and any other written information to be provided regarding patients recruitment 
procedures
•
Copy of IRB/IEC approved Patient Information/Informed Consent Form (Assent Form if 
applicable)/any other written information/advertisement
•
Any additional regulatory approvals, ie national regulatory approvals
•
List of IRB/IEC Committee members/constitution
•
Financial agreement(s)
•
Documentation from central or local laboratory as applicable
•
Reference ranges
•
Certification/QA scheme/other documentation
Regulatory approval and notification as required must also be available; these are the 
responsibility of Shire HGT.  All trial documents will be available in a Trial Master File (TMF) 
at the Investigator/trial site and at Shire HGT.     

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
62
11.8
Data Monitoring Committee
There will be no data monitoring committee for this study.
11.9
Protocol Violations/Deviations
The Investigator will conduct the study in compliance with the protocol.  The protocol will not 
be initiated until the IRB/IEC and the appropriate regulatory authorities have given 
approval/favorable opinion.  Modifications to the protocol will not be made without agreement 
of the Sponsor.  Changes to the protocol will require written IRB/IEC approval/favorable opinion 
prior to implementation, except when the modification is needed to eliminate an immediate 
hazard(s) to patients.  The IRB/IEC may provide, if applicable regulatory authorities permit, 
expedited review and approval/favorable opinion for minor change(s) in ongoing studies that 
have the approval/favorable opinion of the IRB/IEC.  The Sponsor will submit all protocol 
modifications to the regulatory authorities in accordance with the governing regulations.  A 
record of patients screened, but not entered into the study, is also to be maintained.  There will be 
no protocol exemptions granted for this study.
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
patients, the Investigator will contact the Sponsor or its designee, if circumstances permit, to 
discuss the planned course of action.  Any departures from the protocol must be fully 
documented as a protocol deviation.  Protocol deviations will need to be reviewed by the medical 
monitor and may also be required to be submitted to the IRB/IEC
Protocol modifications will only be initiated by the Sponsor and must be approved by the 
IRB/IEC and submitted to the FDA or other applicable international regulatory authority before 
initiation.
11.10 Access to Source Documentation
Regulatory authorities, the IEC/IRB, or the Sponsor may request access to all source documents, 
CRFs, and other study documentation for on-site audit or inspection.  Direct access to these 
documents must be guaranteed by the Investigator, who must provide support at all times for 
these activities.  Monitoring and auditing procedures that comply with current GCP guidelines 
will be followed.  On-site review of the CRFs for completeness and clarity, crosschecking with 
source documents, and clarification of administrative matters will be performed.
11.11 Data Generation and Analysis
The clinical database will be developed and maintained by a contract research organization or an 
electronic data capture technology provider as designated by Shire HGT.  Shire HGT or its 
designee will be responsible for performing study data management activities. 
Adverse events will be coded using MedDRA.  Concomitant medication will be coded using 
WHO-DD.  Centralized laboratories will be employed as described in the study manual to aid in 
consistent measurement of efficacy and safety parameters.

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
63
11.12 Premature Closure of the Study
11.12.1
Study Termination
If the Sponsor or an Investigator discovers conditions arising during the study which indicate that 
the clinical investigation should be halted due to an unacceptable patient risk, the study may be 
terminated after appropriate consultation between Shire HGT and the Investigators.  In addition, 
a decision on the part of Shire HGT to suspend or discontinue development of the study material 
may be made at any time.
11.12.2
Site Termination
A specific site may be terminated separate from the general study for, but not limited to, the 
following conditions:
•
The discovery of an unexpected, significant, or unacceptable risk to the patients enrolled at 
the site.
•
Failure of the Investigator to enter patients at an acceptable rate.
•
Insufficient adherence by the Investigator to protocol requirements.
11.13 Retention of Data
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application and until there are no pending or contemplated marketing applications or 
at least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product.  The Sponsor will notify the Investigator if these documents must be 
retained for a longer period of time.  It is the responsibility of the Sponsor to inform the 
Investigator or institution as to when these documents no longer need to be retained. 
Biological samples may be reserved for potential, future, biomarker studies (see Section 7.8.3).  
11.14 Financial Disclosure
The Investigator should disclose any financial interests in the Sponsor as described in 21 CFR 
Part 54 prior to beginning this study.  The appropriate form will be provided to the Investigator 
by the Sponsor, which will be signed and dated by the Investigator, prior to the start of the study. 
11.15 Publication and Disclosure Policy
All information concerning the study material, such as patent applications, manufacturing 
processes, basic scientific data, and formulation information supplied by the Sponsor and not 
previously published are considered confidential and will remain the sole property of the 
Sponsor.  The Investigator agrees to use this information only in accomplishing this study and 
will not use it for other purposes.
It is understood by the Investigator that the information developed in the clinical study may be 
disclosed as required to the authorized regulatory authorities and governmental agencies.  

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
64
In order to allow for the use of the information derived from the clinical studies, it is understood 
that there is an obligation to provide the Sponsor with complete test results and all data 
developed in the study in a timely manner.
The Investigator and any other clinical personnel associated with this study will not publish the 
results of the study, in whole or in part, at any time, unless they have consulted with Shire HGT, 
provided Shire HGT a copy of the draft document intended for publication, and obtained Shire 
HGT’s written consent for such publication.  All information obtained during the conduct of this 
study will be regarded as confidential.  Shire HGT will use the information for registration 
purposes and for the general development of the drug.

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
65
12 LIST OF REFERENCES
1. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. 
JAMA : the journal of the American Medical Association 1999;281:249-54.
2. Poorthuis BJ, Wevers RA, Kleijer WJ, et al. The frequency of lysosomal storage diseases in 
The Netherlands. Human genetics 1999;105:151-6.
3. Baehner F, Schmiedeskamp C, Krummenauer F, et al. Cumulative incidence rates of the 
mucopolysaccharidoses in Germany. J Inherit Metab Dis 2005;28:1011-7.
4. Valstar MJ, Bruggenwirth HT, Olmer R, et al. Mucopolysaccharidosis type IIIB may 
predominantly present with an attenuated clinical phenotype. Journal of inherited metabolic 
disease 2010;33:759-67.
5. Meyer A, Kossow K, Gal A, et al. Scoring evaluation of the natural course of 
mucopolysaccharidosis type IIIA (Sanfilippo syndrome type A). Pediatrics 
2007;120:e1255-61.
6. Cleary MA, Wraith JE. Management of mucopolysaccharidosis type III. Arch Dis Child 
1993;69:403-6.
7. Fraser J, Wraith JE, Delatycki MB. Sleep disturbance in mucopolysaccharidosis type III 
(Sanfilippo syndrome): a survey of managing clinicians. Clin Genet 2002;62:418-21.
8. Neufeld E, Muenzer J. The Mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, 
Valle D, eds. The metabolic and molecular bases of inherited disease. 8th ed. New York: 
McGraw-Hill; 2001:4 v. (xivii, 6338, I-104 p.).
9. Meyer A, Kossow K, Gal A, et al. The mutation p.Ser298Pro in the sulphamidase gene 
(SGSH) is associated with a slowly progressive clinical phenotype in mucopolysaccharidosis 
type IIIA (Sanfilippo A syndrome). Hum Mutat 2008;29:770.
10. Vellodi A. Lysosomal storage disorders. Br J Haematol 2005;128:413-31.
11. Hemsley KM, Beard H, King BM, Hopwood JJ. Effect of high dose, repeated intra-CSF 
injection of sulphamidase on neuropathology in MPS IIIA mice. Genes Brain Behav 2008.
12. Urayama A, Grubb JH, Sly WS, Banks WA. Mannose 6-phosphate receptor-mediated 
transport of sulfamidase across the blood-brain barrier in the newborn mouse. Mol Ther 
2008;16:1261-6.
13. Bielicki J, Hopwood JJ, Melville EL, Anson DS. Recombinant human sulphamidase: 
expression, amplification, purification and characterization. Biochem J 1998;329 ( Pt 
1):145-50.
14. Di Natale P, Vanacore B, Daniele A, Esposito S. Heparan N-sulfatase: in vitro mutagenesis 
of potential N-glycosylation sites. Biochem Biophys Res Commun 2001;280:1251-7.

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
66
15. Daniele A, Di Natale P. Heparan N-sulfatase: cysteine 70 plays a role in the enzyme catalysis 
and processing. FEBS Lett 2001;505:445-8.
16. Perkins KJ, Byers S, Yogalingam G, Weber B, Hopwood JJ. Expression and characterization 
of wild type and mutant recombinant human sulfamidase. Implications for Sanfilippo 
(Mucopolysaccharidosis IIIA) syndrome. J Biol Chem 1999;274:37193-9.
17. Munoz-Rojas MV, Vieira T, Costa R, et al. Intrathecal enzyme replacement therapy in a 
patient with mucopolysaccharidosis type I and symptomatic spinal cord compression. Am J 
Med Genet A 2008;146A:2538-44.
18. Muñoz-Rojas M, Dain D, Horovitz G, et al. Intrathecal administration of recombinant human 
N-acetylgalactosamine 4-sulfatase to a MPS VI patient with pachymeningitis cervicalis. 
Molecular Genetics and Metabolism 2010;99:346-50.
19. Chen A, Dickson P, Shapiro E, Lyons B, Kan S, Guillaume D. A study of intrathecal enzyme 
replacement for cognitivedecline in mucopolysaccharidosis. Mol Genet Metab 
2010;99:S13-S4.
20. Hemsley K, King B, Hopwood J. Injection of recombinant human sulfamidase into the CSF 
via the cerebellomedullary cistern in MPS IIIA mice. Mol Genet Metab 2007;90:313-28.
21. Hemsley KM, Luck AJ, Crawley AC, et al. Examination of intravenous and intra-CSF 
protein delivery for treatment of neurological disease. Eur J Neurosci 2009;29:1197-214.
22. Hemsley KM, Norman EJ, Crawley AC, et al. Effect of cisternal sulfamidase delivery in 
MPS IIIA Huntaway dogs-A proof of principle study. Mol Genet Metab 2009.
23. Bayley N. Bayley Scales of Infant and Toddler Development: Third Edition. San Antonio, 
TX The Psychological Corporation; 2005.
24. Kaufman S, Kaufman N. Kaufman Assessment Battery for Children (KABC-II). 2nd ed.
25. Henderson S, Sugden D, Barnett A. Movement Assessment Battery for Children (second 
ed.). London: Harcourt Assessment; 2007.
26. Sparrow S, Balla D, Cicchetti D. Vineland Adaptive Behavior Scales (Second Edition). 4201 
Woodland Road Circle Pines, MN 55014-1796: American Guidance Service, Inc; 2005.

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
67
Appendix 1
Schedule of Events 
HGT-SAN-067 Study Assessments for Patients Who Have Received 6 Months of rhHNS Treatment in Study HGT-SAN-055
Dosed every 28 (±7) days 
(ie, Q4W)
Assessment
Screening/or HGT-SAN-055 
EOS Visitk
(Month 6 from the start of 
HGT-SAN-055)
Pre-Tx
Day 1a
IT dosing
Day 2 (±2)
Months 12, 24, 36, 
and 54 
(from the start of 
HGT-SAN-055)
EOSf Month 55
(from the start of 
HGT-SAN-055)
Month 56
Safety 
Follow-upj
Informed Consent/Enrollment
●
Physical Examination
●
●
●
●
Height and Weight
●
●
●
Head Circumference
●
●
●
Visual and Hearing Assessment
●
●
ECG
●
●b
●
Vital Signs
●
●
●
●
Hematology
●
●
●
Serum Chemistry
●
●
●
Pregnancy Testingn
●
●
Urinalysis
●
●
●
Leukocyte pellet preparationo
●
Urine Heparan Sulfate and Heparan 
Sulfate Derivatives 
●
●e
●
Plasma and serum Heparan Sulfate and 
Heparan Sulfate Derivatives
●
●e
●
Anti-rhHNS antibody testing (serum and 
CSF)l
●
●
●
Auditory Brainstem Response (ABR)
●
●
●
MRI of the Head
●
●
●
CSF Sample Collectionm
●
●c
●c
rhHNS dosing: every 28 (7) days g , d
●
Neurological Examinationh
●
●
●
●
Full Neurodevelopmental Testingi
●
●
●
Children’s Sleep Habits Rating Scale
●
●
●
Child Health Questionnaire-50
●
●
●
Child Health Questionnaire-87
●
●
●
Infant Toddler QOL Questionnaire
●
●
●

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
68
HGT-SAN-067 Study Assessments for Patients Who Have Received 6 Months of rhHNS Treatment in Study HGT-SAN-055
Dosed every 28 (±7) days 
(ie, Q4W) 
Assessment 
Screening/or HGT-SAN-055 
EOS Visitk 
(Month 6 from the start of 
HGT-SAN-055) 
Pre-Tx 
Day 1a 
IT dosing 
Day 2 (±2) 
Months 12, 24, 36, 
and 54 
(from the start of 
HGT-SAN-055) 
EOSf Month 55 
(from the start of 
HGT-SAN-055) 
Month 56 
Safety 
Follow-upj 
Concomitant Medications, Therapies, and 
Procedures 
● 
●
●
●
● 
Adverse Event Monitoring
●
●
●
●
● 
Abbreviations:
ABR = Auditory brainstem response; CSF = cerebrospinal fluid; EOS  = end of study ; ECG = electrocardiogram; IT = intrathecal; 
MRI = Magnetic resonance imaging; TX = treatment 
Note: The timing of assessments is calculated from the start of HGT-SAN-055.  Therefore, for example, the end-of-study visit, as presented here at Month 54, 
corresponds to Month 48 in HGT-SAN-067, but represents a total of 54 months of study treatment (48 months in HGT-SAN-067 + 6 months in 
HGT-SAN-055). 
a
Week 1 only, and only performed if >7 days have elapsed since  HGT-SAN-055 EOS visit assessments. 
b
ECG to be performed following administration of study drug. 
c
CSF samples will be obtained according to the process with in the study operations manual).  An attempt will be made to obtain a CSF sample via the IDDD 
prior to each administration of rhHNS and at the End of Study visit.  If it is not possible to obtain a CSF using the IDDD, the IDDD may be replaced (up to 
twice in a 6 month period [including the time in the HGT-SAN-055 study]) or a LP may be performed (can occur up to 5 times in a 6 month period). 
d
Patients may be discharged as early as 8 hours post rhHNS infusion (ie, on Day 2) when deemed clinically stable by the Investigator. 
e
Specimens collected once a month, at Day 1 of the first treatment week. 
f
All patients who complete the study will have end of study assessments performed 30 (±7 days) after their last dose of study drug. 
g
If a patient’s IDDD becomes nonfunctional or infected; it will be replaced (up to 2 times in a 6 month period; including the time in Study HGT-SAN-055).  
h
The neurological exam should not occur sooner than 4 hours after administration of study drug or before the patient has fully recovered from any anesthesia 
administered for the dosing, whichever occurs later. 
i
Full neurodevelopmental testing includes an assessment with the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) 
j
A safety follow up telephone call will be made 30 (±7 days) after End of Study Procedures. 
k
Assessments will be required only if more than 60 days have elapsed following the HGT-SAN-055 procedures.  These assessments would be repeated 
within 30 days prior to the first scheduled rhHNS IT dose. 
l
Blood sample drawn before IT injection of rhHNS. 
m
CSF will be tested for standard chemistries, heparan sulfate and heparan sulfate derivatives, anti-rhHNS antibodies, and MPS exploratory biomarkers. 
n
A pregnancy test will be carried out on pre-treatment Day 1 in females who are postmenarche to premenopause (childbearing).  The results must be negative 
before study drug can be administered. 
o
A blood sample for leukocyte pellet preparation is to be taken at baseline, before dosing.  This pellet should be stored frozen, and will be used for additional 
disease-related laboratory studies, including possible assessment of cross-reactive immunologic material.  If this is not drawn at baseline, it can be drawn at 
any subsequent visit, but it must be taken before dosing.  This only needs to be taken once during the study. 

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
69
Appendix 2
Neurodevelopmental and Behavioral Assessments 
Table 4-1 and Table 4-2 detail the specific psychometric instruments that will be used to provide 
measures of each of relevant neurobehavioral or developmental domain assessed.  The tables 
also summarize the rules used to select a test for a patient, the subtests included in each test, and 
the subscales generated by the test battery.
Table 4-1 Summary of Neurodevelopmental Outcome Measures
Domain
Age
Test
Summary score and 
subdomains:
- Cognitive
- Motor
- Social/Emotional
0 to 42 months
Bayley Scales of Infant Development, Third 
Edition (BSID-III)23
- Cognitive 
- Processing skills
3 to 18 years
Kaufman Assessment Battery for Children, 
Second Edition (KABC-II)24  
Motor
3.0 to 16:11 
years
Movement Assessment Battery for Children, 
Second Edition (MABC-2)25  
Communication
Daily Living
Socialization
Motor Skills
0 to 90 years
Vineland Adaptive Behavior Scales, Second 
Edition (VABS-II)26
Table 4-2 Summary of Sanfilippo-specific Assessments
Domain
Assessment
Parent-scored behavioral inventory
- communication:  understanding
- communication:  expression
- tantrums
- specific behaviors inventory
- mood & emotions inventory
Sanfilippo Behavior Rating Scale
MPS-specific four-point scoring 
system/total disability score
- cognition
- expressive language
- motor score
Four-Point Scoring System/Total Disability 
Score (FPSS/TDS)5
The term “neurodevelopmental” refers to the process by which the neurological system matures 
and changes over time.  Assessing these changes in a population of children whose neurological 
system is progressively more affected can be very challenging.  

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
70
Typically, neurodevelopmental progress is reflected by the child’s abilities to perform certain 
skills (sitting, walking, and talking).  
However, a child with a neurological disorder may be able to perform age appropriate skills, but 
with atypical patterns.  For example, the child may be able to walk, but his gait is not normal.  
Most assessments will therefore measure the skills, but are not designed to capture the 
abnormalities in pattern or quality of the skill.  
These qualitative differences will be evident to the skilled test administrator/clinician who is 
familiar with the disorder.  However, only longitudinal tracking and repeated measures will 
reveal the significance of these abnormalities in overall function to the less experienced clinician.   
The rate at which different skills develop or regress over time will give insight into the disease 
process.  The next step is to determine how the learned skills are used for daily functional 
activities so that as the children grow up they become independent from caregivers.  These 
functional skills can be tracked to reflect quality of life issues for both parents and children. 
Neurodevelopmental assessments described below will be scheduled for administration in the 
morning and estimated to last between 2 and 4 hours. 
The list of assessments and algorithm is discussed in detail in the Study Operations Manual and 
includes: 
Bayley Scales of Infant Development, Third Edition (BSID-III) 23 
The Bayley Scales of Infant Development is a standard series of measurements used primarily to 
assess the motor (fine and gross), language (receptive and expressive), and cognitive 
development of infants and toddlers, ages 0 to 42 months.  This measure consists of a series of 
developmental play tasks and takes between 45 and 60 minutes to administer.  Raw scores of 
successfully completed items are converted to scale scores and to composite scores.  These 
scores are used to determine the child's performance compared with norms taken from typically 
developing children of their age (in months).  The assessment is often used in conjunction with 
the Social-Emotional Adaptive Behavior Questionnaire.  Completed by the parent or caregiver, 
this questionnaire establishes the range of adaptive behaviors that the child can currently achieve 
and enables comparison with age norms. 
Kaufman Assessment Battery for Children, Second Edition (KABC-II) 24 
Purpose: 
The KABC-II measures a child’s cognitive ability and processing skills and was designed to 
minimize verbal instructions and responses.  In addition, the assessment contains little cultural 
content to provide a more accurate assessment of children from diverse backgrounds.  Thus 
language difficulties or cultural differences are minimized in the test battery’s results. 

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
71
Description:
Investigators may choose either the Cattell-Horn-Carroll or the Luria model for a patient’s 
assessment.  
The Cattell-Horn-Carroll model is used with children from a mainstream cultural and language 
background and the Luria model is used for children with significantly limited verbal ability.  
Subtests are administered on four or five ability scales and interpreted using the chosen model. 
Movement Assessment Battery for Children, Second Edition (MABC-2)25
Purpose:
The Movement Assessment Battery for Children, Second Edition identifies, describes and guides 
treatment of motor impairment in children from 3.0 to 16:11 years of age.
Description:
The MABC-2 checklist is administered individually over approximately 30 minutes.  It yields 
both normative and qualitative measures of movement competence, manual dexterity, ball skills, 
static and dynamic balance.
Vineland Adaptive Behavior Scales, Second Edition (VABS-II) 26
Purpose:
The test measures adaptive behaviors, including the ability to cope with environmental changes, 
to learn new everyday skills and to demonstrate independence.  It is an instrument that supports 
the diagnosis of intellectual and developmental disabilities.  It encompasses ages from birth to 
90 years. 
Description:
Adaptive behavior is a composite of various dimensions.  This test measures 5 domains:  
communication, daily living skills, socialization, motor skills, and maladaptive behavior 
(optional) and is administered in a semi-structured interview in through a questionnaire.  The 
scales of the VABS-II were organized within a 3-domain structure:  Communication, Daily 
Living, and Socialization.  This structure corresponds to the 3 broad domains of adaptive 
functioning by the American Association of Intellectual and Developmental Disabilities:  
Conceptual, Practical, and Social.  In addition, VABS-II offers a Motor Skills Domain and an 
optional Maladaptive Behavior Index.  The scores are interpreted by means of score equivalents 
for the raw scores in each domain, percentile ranks, age equivalents, adaptive levels, and 
maladaptive levels.

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
72
Sanfilippo Behavior Rating Scale (SBRS)
The Sanfilippo Behavior Rating Scale (SBRS) is a newly-developed scale designed by Drs. Elsa 
Shapiro and Michael Potegal to measure a cluster of behaviors known to occur in Sanfilippo 
syndrome.  The SBRS is a parent-scored behavioral inventory measuring (1) comprehensive 
language skills, (2) expressive language skills, (3) tantrums, (4) mood and emotions, and 
(5) other behaviors not otherwise classified.
Four-Point Scoring System/Total Disability Score (FPSS/TDS) 5
The FPSS assesses motor function, expressive language, and cognitive function on a 0 to 3 point 
scale and can be used for individuals of all ages.  The total disability score is the average of the 
motor function, speech, and cognitive function scores.

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
73
Appendix 3
Failure of IDDD Function:  Investigation and Management
This appendix is intended to assist in the investigation of mechanical device failure and its 
subsequent management. 
Note:  The total number of IDDD revisions a patient may undergo will be limited to 2 (partial or 
complete replacements) in a 6 month period (including the time in HGT-SAN-055).  
Additionally, the total number of X-rays to investigate and verify IDDD integrity will be limited 
to 6, in a 6-month period plus up to 3 intra-operative fluoroscopies to guide catheter placement.  
Introduction
1. The device consists of a catheter, inserted into the intrathecal space in the lower lumbar area, 
tunneled subcutaneously to a site overlying an ipsilateral (so the tunneled catheter does not 
cross the midline) lower rib in the mid to anterior axillary line, and there connected to the 
subcutaneous port.  The catheter is connected to the metal outlet tube from the port via a 
plastic collar, secured by a metal locking ring.  The port is accessed percutaneously for CSF 
aspiration and drug administration, via a special non-coring needle.  The metal chamber 
within the port, the locking ring, and the catheter are radio-opaque (Figure 1).  An X-ray 
taken post-implantation is used to verify and document 1) the correct location of the catheter 
tip in the mid-thoracic spinal canal, and 2) the correct orientation and position of the metal 
locking ring that secures the catheter to the port outlet tube.
Figure 1:  Radiographic appearance of IDDD port implanted over lower ribs, with 
percutaneous needle inserted.  Note that the tapered appearance of the locking collar 
permits assessment of its correct orientation.
Functional failure of the IDDD is most likely to be mechanical:  blockage may occur as a result 
of luminal occlusion, fibrin sheath formation around the tip, external compression or kinking.  
Leakage may be a consequence of catheter disconnection or fracture, or breakage of the port 
outlet tube itself.  In addition, the catheter may become dislodged from the spinal canal (see 
Smith’s Medical instructions [provided in the Investigator Brochure] for additional details).  
Details of the surgical implantation procedure, designed to minimize the chance of these 
problems arising, are contained in the Smith’s Medical Instructions for Use and Shire Study 
Training materials.

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
74
In addition, medical complications may also preclude use of the IDDD, and may lead to its 
removal, revision, or replacement.  These include infection, hematoma, inadvertent epidural 
placement, pain on injection, etc, as listed in the Smith’s Medical Instructions for Use.  These 
complications should be managed as clinically indicated.
Investigation
Diagnostic clues of mechanical failure, established or impending include:
•
Increasing difficulty in aspirating CSF from the IDDD
•
Blood stained appearance of CSF
•
Increasing difficulty in pushing drug or sterile normal saline through the IDDD
•
Soft tissue swelling indicating possible fluid accumulation at the site of the port, or along the 
course of the catheter, immediately following administration of drug and/or saline via IDDD
•
Increased cellularity of the pre-treatment CSF sample
Note:  increased cellularity of the CSF may also indicate meningeal reactions to the drug or the 
presence of infection, and so must be interpreted in the context of the whole clinical picture.
Approach to investigation:
1. Clinical evaluation for swelling following drug infusion
2. X-ray imaging, to include both the port and the full length of the catheter in the spinal canal.  
X-rays are probably the single most useful investigational approach.  Especially when 
compared with post-implantation confirmatory images, this may elucidate:
A. Slippage of the catheter from the spinal canal
B. Breakage or disconnection of the catheter and/or its locking device from the port 
assembly
C. Kinking of the catheter
Note:  There is no information on compatibility of the IDDD and drug product with contrast 
media, so these should be avoided.
Management:
1. In general, once mechanical failure of the IDDD has occurred, intervention should be 
planned to replace the IDDD in part or in its entirety.
2. CSF may be aspirated, and drug administered via lumbar puncture while awaiting IDDD 
revision, in accordance with the protocol.
3. If IDDD mechanical failure is confined to the port, its attachment to the catheter, or to the 
segment of catheter immediately adjacent to the port, proximal revision of the IDDD may be 
undertaken.  In such an event, the old port and locking assembly is removed.  New 
components are then implanted, leaving the original catheter in situ.  However, the end of the 
catheter must be trimmed by at least one centimeter to restore a tight connection with the new 
port outlet tube.  The patency of the apparatus must be ascertained intra-operatively, by 
aspirating CSF through the port, and flushing the device with sterile normal saline.

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
75
4. If IDDD mechanical failure is due to dislodgment of the catheter from the spinal canal, 
kinking at a location distal to the immediate vicinity of the port, or unresolved by proximal 
revision, the whole device must be replaced, following the instructions provided by Smith’s 
Medical and the Shire training materials.
Note:  All removed IDDDs must be returned to Smith’s Medical for further analysis.  Please 
refer to the Study Manual for instructions on the IDDD Return process. You should also contact 
Shire HGT.
Note:  All IDDD related AEs (serious and nonserious) will be reported to Shire; all IDDD related 
SAEs will also be reported to Global Shire PVRM. 
Drug Administration Following Device Revision:
1. If a full revision of the IDDD has been performed, an interval of 7 days is required before 
resuming administration of drug via IDDD.
2. If a proximal (ie, replacement of port only) revision of IDDD has been performed, drug 
administration through the IDDD can proceed immediately post-operatively.
3. In the event that the IDDD fails after 2 revisions in a 6-month time period, rhHNS may be 
administered and CSF collected by lumbar puncture for up to 5 successive months after 
which, IDDD re-implantation or revision must occur.  

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
76
Appendix 4
Summary of Changes for Amendment 3 
Clinical protocol HGT-SAN-067 has been revised from the previous version (Amendment 2, 
13-Jan-2012) to update the study drug description to reflect a change in formulation.  The 
protocol was also revised for the following purposes:
•
Update the sponsor’s contact phone number
•
Clarify the timing of the neurological examination on days of study drug administration
•
Clarify that Full Developmental Testing includes VABS-II 
•
Remove duplicative text describing the adverse events due to systemic exposure to rhHNS
The changes relative to Amendment 2 of the protocol (13-Jan-2012) are summarized below by 
section number; new or additional text is indicated in Bold and deleted text is indicated as 
Strikethrough.  Other sections affected by the same change are listed below each change.
Please note that only changes of substance are displayed here. 
Change:  The sponsor’s contact phone number was updated.
Section impacted by this change:  Title Page
Modified Text:
Shire Human Genetic Therapies, Inc. 
300 Shire Way
Lexington, MA  02421 USAUnited States
No other sections were affected by this change. 
Change:  The text was updated to reflect a new study drug formulation with a higher 
concentration of the excipient polysorbate 20 and to correct a typo in the study drug name.
Section impacted by this change:  Section 6.1.1 Study Drug
Modified Text:
Recombinant human heparian N-sulfatase (rhHNS) drug product formulation is a sterile 
solution for injection in single-use vials for intrathecal (IT) administration.  It is 
formulated in an aqueous isotonic solution containing 15.0 mg/mL rhHNS in 145 mM 
sodium chloride, 0.020.005% (v/v) polysorbate 20, 5 mM sodium phosphate at pH 7.0.
No other sections were affected by this change. 

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
77
Change:  Text was added to clarify the timing of the neurological examination with 
respect to study drug administration.
Section impacted by this change:  Section 7.16 Neurological Examination
The neurological exam should not occur sooner than 4 hours after study drug 
administration or before the patient has fully recovered from any anesthesia 
administered for the dosing, whichever occurs later.
Other sections affected by the same change:  Section 8.2.1.2 Day 2 (±2 days) Assessments 
and Administration of rhHNS, Appendix 1 Schedule of Events
Change:  Text was added to clarify that Full Developmental Testing includes VABS-II.
Section impacted by this change:  Section 8.1 Screening Visit/Study Start Visit
Modified Text:  
•
Full Neurodevelopmental assessments, including Vineland Adaptive Behavior 
Scales, Second Edition (VABS-II; all assessments performed prior to the 
administration of anesthesia)
Other sections affected by the same change:  Section 8.2.1.1 Day 1 (Pre-treatment) 
Assessments Performed Prior to Each Dose, Section 8.3 End of Study/Early Termination 
Procedures:  Month 55, and Appendix 1 Schedule of Events
Change:  Duplicative text describing the adverse events due to systemic exposure to 
rhHNS was removed.
Section impacted by this change:  Section 7.22.1.1 Adverse Event
Deleted Text:  
POTENTIAL ADVERSE EVENTS:  INTRATHECAL rhHNS
Adverse Events Due To Systemic Exposure To rhHNS
Although rhHNS is given intrathecally only, some proportion of the drug will diffuse from 
the CSF into the peripheral circulation.  The resulting systemic exposure may cause events 
that are typically seen in patients receiving ERT via an intravenous administration, known 
as infusion-related reactions.  An infusion-related reaction is defined as an adverse event 
that (1) begins either during or within 24 hours after the start of the infusion, and (2) is 
judged as possibly or probably related to study drug.  Other AEs that occur prior to the 
infusion, along with AEs associated with protocol-defined testing and assessments 
(laboratory testing and physical examinations) that were performed prior to the infusion 

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
78
will not be defined as infusion-related reactions.  
POTENTIAL ADVERSE EVENTS:  INTRATHECAL RECOMBINANT HUMAN HEPARAN N-
SULFATASE 
Adverse Events Due to Systemic Exposure to rhHNS
Although rhHNS is given intrathecally only, some proportion of the drug will diffuse from 
the CSF into the peripheral circulation.  The resulting systemic exposure may cause events 
that are typically seen in patients receiving ERT via an intravenous administration, known 
as infusion-related reactions.  An infusion-related reaction is defined as an adverse event 
that (1) begins either during or within 24 hours after the start of the infusion, and (2) is 
judged as possibly or probably related to study drug.  Other AEs that occur prior to the 
infusion, along with AEs associated with protocol-defined testing and assessments 
(laboratory testing and physical examinations) that were performed prior to the infusion 
will not be defined as infusion-related reactions.
No other sections were affected by this change.

Recombinant human heparan N-sulfatase (rhHNS)
Clinical Trial Protocol: HGT-SAN-067 Amendment 3
28 August 2012
Shire
Confidential
80
Appendix 6
The National Cancer Institute Common Toxicity Criteria 

Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, Version 3.0, DCTD, NCI, NIH, DHHS 
 
March 31, 2003 (http://ctep.cancer.gov), Publish Date: August 9, 2006 
Common Terminology Criteria for Adverse Events v3.0 (CTCAE) 
Publish Date: August 9, 2006 
Quick Reference 
The NCI Common Terminology Criteria for Adverse Events 
v3.0 is a descriptive terminology which can be utilized for 
Adverse Event (AE) reporting. A grading (severity) scale is 
provided for each AE term. 
Components and Organization  
CATEGORY 
A CATEGORY is a broad classification of AEs based on 
anatomy and/or pathophysiology. Within each CATEGORY, 
AEs are listed accompanied by their descriptions of severity 
(Grade). 
Adverse Event Terms 
An AE is any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medical treatment or procedure 
that may or may not be considered related to the medical 
treatment or procedure. An AE is a term that is a unique 
representation of a specific event used for medical 
documentation and scientific analyses. Each AE term is 
mapped to a MedDRA term and code. AEs are listed 
alphabetically within CATEGORIES. 
Short AE Name 
The ‘SHORT NAME’ column is new and it is used to simplify 
documentation of AE names on Case Report Forms.   
Supra-ordinate Terms  
A supra-ordinate term is located within a CATEGORY and is a 
grouping term based on disease process, signs, symptoms, 
or diagnosis. A supra-ordinate term is followed by the word 
‘Select’ and is accompanied by specific AEs that are all 
related to the supra-ordinate term. Supra-ordinate terms 
provide clustering and consistent representation of Grade for 
related AEs. Supra-ordinate terms are not AEs, are not 
mapped to a MedDRA term and code, cannot be graded and 
cannot be used for reporting. 
REMARK 
A ‘REMARK’ is a clarification of an AE. 
ALSO CONSIDER 
An ‘ALSO CONSIDER’ indicates additional AEs that are to be 
graded if they are clinically significant. 
NAVIGATION NOTE 
A ‘NAVIGATION NOTE’ indicates the location of an AE term 
within the CTCAE document. It lists signs/symptoms 
alphabetically and the CTCAE term will appear in the same 
CATEGORY unless the ‘NAVIGATION NOTE’ states differently. 
Grades 
Grade refers to the severity of the AE. The CTCAE v3.0 
displays Grades 1 through 5 with unique clinical descriptions 
of severity for each AE based on this general guideline: 
Grade 1 
Mild AE  
Grade 2 
Moderate AE 
Grade 3 
Severe AE 
Grade 4 
Life-threatening or disabling AE 
Grade 5 
Death related to AE 
A Semi-colon indicates ‘or’ within the description of the grade. 
An ‘Em dash’ (—) indicates a grade not available. 
Not all Grades are appropriate for all AEs. Therefore, some 
AEs are listed with fewer than five options for Grade 
selection. 
Grade 5 
Grade 5 (Death) is not appropriate for some AEs and 
therefore is not an option. 
The DEATH CATEGORY is new. Only one Supra-ordinate 
term is listed in this CATEGORY: ‘Death not associated with 
CTCAE term – Select’ with 4 AE options: Death NOS; 
Disease progression NOS; Multi-organ failure; Sudden death. 
Important: 
• 
Grade 5 is the only appropriate Grade 
• 
This AE is to be used in the situation where 
a death  
1. cannot be reported using a CTCAE v3.0 
term associated with Grade 5, or 
2. cannot be reported within a CTCAE 
CATEGORY as ‘Other (Specify)’ 
 
 
 
 
 
Contents 
ALLERGY/IMMUNOLOGY ............................................1 
AUDITORY/EAR............................................................2 
BLOOD/BONE MARROW .............................................4 
CARDIAC ARRHYTHMIA..............................................5 
CARDIAC GENERAL ....................................................7 
COAGULATION ..........................................................10 
CONSTITUTIONAL SYMPTOMS................................11 
DEATH ........................................................................13 
DERMATOLOGY/SKIN ...............................................14 
ENDOCRINE...............................................................17 
GASTROINTESTINAL.................................................19 
GROWTH AND DEVELOPMENT................................29 
HEMORRHAGE/BLEEDING ....................................... 30 
HEPATOBILIARY/PANCREAS ................................... 34 
INFECTION................................................................. 35 
LYMPHATICS ............................................................. 38 
METABOLIC/LABORATORY ...................................... 40 
MUSCULOSKELETAL/SOFT TISSUE........................ 43 
NEUROLOGY ............................................................. 47 
OCULAR/VISUAL........................................................ 52 
PAIN............................................................................ 55 
PULMONARY/UPPER RESPIRATORY...................... 56 
RENAL/GENITOURINARY.......................................... 60 
SECONDARY MALIGNANCY..................................... 63 
SEXUAL/REPRODUCTIVE FUNCTION ..................... 64 
SURGERY/INTRA-OPERATIVE INJURY ................... 66 
SYNDROMES............................................................. 68 
VASCULAR................................................................. 70 
 

 
ALLERGY/IMMUNOLOGY 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 1 - 
March 31, 2003, Publish Date: August 9, 2006 
Allergic reaction/ 
hypersensitivity  
(including drug fever) 
Allergic reaction 
Transient flushing or 
rash; drug fever <38°C 
(<100.4°F) 
Rash; flushing; urticaria; 
dyspnea; drug fever 
≥38°C (≥100.4°F) 
Symptomatic 
bronchospasm, with or 
without urticaria; 
parenteral medication(s) 
indicated; allergy-related 
edema/angioedema; 
hypotension 
Anaphylaxis 
Death 
REMARK: Urticaria with manifestations of allergic or hypersensitivity reaction is graded as Allergic reaction/hypersensitivity (including drug fever). 
ALSO CONSIDER: Cytokine release syndrome/acute infusion reaction. 
Allergic rhinitis  
(including sneezing, 
nasal stuffiness, 
postnasal drip) 
Rhinitis 
Mild, intervention not 
indicated  
Moderate, intervention 
indicated 
— 
— 
— 
REMARK: Rhinitis associated with obstruction or stenosis is graded as Obstruction/stenosis of airway – Select in the PULMONARY/UPPER RESPIRATORY CATEGORY. 
Autoimmune reaction 
Autoimmune reaction 
Asymptomatic and 
serologic or other 
evidence of autoimmune 
reaction, with normal 
organ function and 
intervention not indicated 
Evidence of autoimmune 
reaction involving a non-
essential organ or 
function (e.g., 
hypothyroidism) 
Reversible autoimmune 
reaction involving function 
of a major organ or other 
adverse event (e.g., 
transient colitis or 
anemia)  
Autoimmune reaction with 
life-threatening 
consequences 
Death 
ALSO CONSIDER: Colitis; Hemoglobin; Hemolysis (e.g., immune hemolytic anemia, drug-related hemolysis); Thyroid function, low (hypothyroidism). 
Serum sickness 
Serum sickness 
— 
— 
Present 
— 
Death 
NAVIGATION NOTE: Splenic function is graded in the BLOOD/BONE MARROW CATEGORY. 
NAVIGATION NOTE: Urticaria as an isolated symptom is graded as Urticaria (hives, welts, wheals) in the DERMATOLOGY/SKIN CATEGORY. 
Vasculitis 
Vasculitis 
Mild, intervention not 
indicated 
Symptomatic, non-
steroidal medical 
intervention indicated 
Steroids indicated 
Ischemic changes; 
amputation indicated 
Death 
Allergy/Immunology – 
Other (Specify, __) 
Allergy – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
AUDITORY/EAR 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 2 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Earache (otalgia) is graded as Pain – Select in the PAIN CATEGORY. 
Hearing:  
patients with/without 
baseline audiogram and 
enrolled in a monitoring 
program1 
Hearing (monitoring 
program) 
Threshold shift or loss of 
15 – 25 dB relative to 
baseline, averaged at 2 
or more contiguous test 
frequencies in at least 
one ear; or subjective 
change in the absence of 
a Grade 1 threshold shift 
Threshold shift or loss of 
>25 – 90 dB, averaged at 
2 contiguous test 
frequencies in at least 
one ear 
Adult only: Threshold shift 
of >25 – 90 dB, averaged 
at 3 contiguous test 
frequencies in at least 
one ear  
Pediatric:  
Hearing loss sufficient to 
indicate therapeutic 
intervention, including 
hearing aids (e.g., ≥20 dB 
bilateral HL in the speech 
frequencies; ≥30 dB 
unilateral HL; and 
requiring additional 
speech-language related 
services) 
Adult only: Profound 
bilateral hearing loss 
(>90 dB) 
Pediatric:  
Audiologic indication for 
cochlear implant and 
requiring additional 
speech-language related 
services  
— 
REMARK: Pediatric recommendations are identical to those for adults, unless specified. For children and adolescents (≤18 years of age) without a baseline test, pre-exposure/pre-
treatment hearing should be considered to be <5 dB loss. 
Hearing: 
patients without baseline 
audiogram and not 
enrolled in a monitoring 
program1  
Hearing (without 
monitoring program) 
— 
Hearing loss not requiring 
hearing aid or 
intervention (i.e., not 
interfering with ADL) 
Hearing loss requiring 
hearing aid or 
intervention (i.e., 
interfering with ADL) 
Profound bilateral hearing 
loss (>90 dB) 
— 
REMARK: Pediatric recommendations are identical to those for adults, unless specified. For children and adolescents (≤18 years of age) without a baseline test, pre-exposure/pre-
treatment hearing should be considered to be <5 dB loss. 
Otitis, external ear 
(non-infectious) 
Otitis, external  
External otitis with 
erythema or dry 
desquamation  
External otitis with moist 
desquamation, edema, 
enhanced cerumen or 
discharge; tympanic 
membrane perforation; 
tympanostomy 
External otitis with 
mastoiditis; stenosis or 
osteomyelitis 
Necrosis of soft tissue or 
bone 
Death 
ALSO CONSIDER: Hearing: patients with/without baseline audiogram and enrolled in a monitoring program1; Hearing: patients without baseline audiogram and not enrolled in a 
monitoring program1.  
Otitis, middle ear  
(non-infectious) 
Otitis, middle 
Serous otitis  
Serous otitis, medical 
intervention indicated 
Otitis with discharge; 
mastoiditis  
Necrosis of the canal soft 
tissue or bone 
Death 

 
AUDITORY/EAR 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 3 - 
March 31, 2003, Publish Date: August 9, 2006 
Tinnitus 
Tinnitus 
— 
Tinnitus not interfering 
with ADL 
Tinnitus interfering with 
ADL 
Disabling 
— 
ALSO CONSIDER: Hearing: patients with/without baseline audiogram and enrolled in a monitoring program1; Hearing: patients without baseline audiogram and not enrolled in a 
monitoring program1. 
Auditory/Ear – Other 
(Specify, __) 
Auditory/Ear – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
 
 
 
 
 
 
                                            
1 Drug-induced ototoxicity should be distinguished from age-related threshold decrements or unrelated cochlear insult. When considering whether an adverse event has occurred, it is 
first necessary to classify the patient into one of two groups. (1) The patient is under standard treatment/enrolled in a clinical trial <2.5 years, and has a 15 dB or greater threshold 
shift averaged across two contiguous frequencies; or (2) The patient is under standard treatment/enrolled in a clinical trial >2.5 years, and the difference between the expected age-
related and the observed threshold shifts is 15 dB or greater averaged across two contiguous frequencies. Consult standard references for appropriate age- and gender-specific 
hearing norms, e.g., Morrell, et al. Age- and gender-specific reference ranges for hearing level and longitudinal changes in hearing level. Journal of the Acoustical Society of America 
100:1949-1967, 1996; or Shotland, et al. Recommendations for cancer prevention trials using potentially ototoxic test agents. Journal of Clinical Oncology 19:1658-1663, 2001.  
In the absence of a baseline prior to initial treatment, subsequent audiograms should be referenced to an appropriate database of normals. ANSI. (1996) 
American National Standard: Determination of occupational noise exposure and estimation of noise-induced hearing impairment, ANSI S 3.44-1996. (Standard S 3.44). New York: 
American National Standards Institute. The recommended ANSI S3.44 database is Annex B. 

 
BLOOD/BONE MARROW 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 4 - 
March 31, 2003, Publish Date: August 9, 2006 
Bone marrow cellularity 
Bone marrow cellularity 
Mildly hypocellular or  
≤25% reduction from 
normal cellularity for age 
Moderately hypocellular 
or >25 – ≤50% reduction 
from normal cellularity for 
age  
Severely hypocellular or 
>50 – ≤75% reduction 
cellularity from normal for 
age  
— 
Death 
CD4 count  
CD4 count 
<LLN – 500/mm3 
<LLN – 0.5 x 109 /L 
<500 – 200/mm3  
<0.5 – 0.2 x 109 /L 
<200 – 50/mm3  
<0.2 x 0.05 – 109 /L 
<50/mm3  
<0.05 x 109 /L 
Death 
Haptoglobin  
Haptoglobin 
<LLN  
— 
Absent 
— 
Death 
Hemoglobin  
Hemoglobin 
<LLN – 10.0 g/dL  
<LLN – 6.2 mmol/L  
<LLN – 100 g/L 
<10.0 – 8.0 g/dL 
<6.2 – 4.9 mmol/L  
<100 – 80g/L 
<8.0 – 6.5 g/dL 
<4.9 – 4.0 mmol/L 
<80 – 65 g/L 
<6.5 g/dL 
<4.0 mmol/L  
<65 g/L 
Death 
Hemolysis (e.g., immune 
hemolytic anemia, drug-
related hemolysis) 
Hemolysis 
Laboratory evidence of 
hemolysis only (e.g., 
direct antiglobulin test 
[DAT, Coombs’] 
schistocytes) 
Evidence of red cell 
destruction and ≥2 gm 
decrease in hemoglobin, 
no transfusion 
Transfusion or medical 
intervention (e.g., 
steroids) indicated 
Catastrophic 
consequences of 
hemolysis (e.g., renal 
failure, hypotension, 
bronchospasm, 
emergency splenectomy) 
Death 
ALSO CONSIDER: Haptoglobin; Hemoglobin. 
Iron overload 
Iron overload 
— 
Asymptomatic iron 
overload, intervention not 
indicated  
Iron overload, 
intervention indicated  
Organ impairment (e.g., 
endocrinopathy, 
cardiopathy) 
Death 
Leukocytes (total WBC) 
Leukocytes 
<LLN – 3000/mm3 
<LLN – 3.0 x 109 /L  
<3000 – 2000/mm3 
<3.0 – 2.0 x 109 /L 
<2000 – 1000/mm3 
<2.0 – 1.0 x 109 /L 
<1000/mm3  
<1.0 x 109 /L 
Death 
Lymphopenia  
Lymphopenia 
<LLN – 800/mm3 
<LLN x 0.8 – 109 /L 
<800 – 500/mm3 
<0.8 – 0.5 x 109 /L 
<500 – 200 mm3 
<0.5 – 0.2 x 109 /L 
<200/mm3 
<0.2 x 109 /L 
Death 
Myelodysplasia 
Myelodysplasia 
— 
— 
Abnormal marrow 
cytogenetics (marrow 
blasts ≤5%)  
RAEB or RAEB-T 
(marrow blasts >5%) 
Death 
Neutrophils/granulocytes 
(ANC/AGC) 
Neutrophils 
<LLN – 1500/mm3  
<LLN – 1.5 x 109 /L 
<1500 – 1000/mm3 
<1.5 – 1.0 x 109 /L  
<1000 – 500/mm3 
<1.0 – 0.5 x 109 /L 
<500/mm3 
<0.5 x 109 /L 
Death 
Platelets 
Platelets 
<LLN – 75,000/mm3 
<LLN – 75.0 x 109 /L 
<75,000 – 50,000/mm3 
<75.0 – 50.0 x 109 /L 
<50,000 – 25,000/mm3  
<50.0 – 25.0 x 109 /L 
<25,000/mm3  
<25.0 x 109 /L 
Death 
Splenic function 
Splenic function 
Incidental findings (e.g., 
Howell-Jolly bodies) 
Prophylactic antibiotics 
indicated 
—  
Life-threatening 
consequences 
Death 
Blood/Bone Marrow – 
Other (Specify, __) 
Blood – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
CARDIAC ARRHYTHMIA 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 5 - 
March 31, 2003, Publish Date: August 9, 2006 
Conduction abnormality/ 
atrioventricular heart 
block  
– Select:  
Conduction abnormality 
– Select 
Asymptomatic, 
intervention not indicated 
– Asystole 
– AV Block-First degree 
– AV Block-Second degree Mobitz Type I (Wenckebach)  
– AV Block-Second degree Mobitz Type II 
– AV Block-Third degree (Complete AV block) 
– Conduction abnormality NOS 
– Sick Sinus Syndrome  
– Stokes-Adams Syndrome 
– Wolff-Parkinson-White Syndrome 
Non-urgent medical 
intervention indicated 
Incompletely controlled 
medically or controlled  
with device (e.g., 
pacemaker) 
Life-threatening (e.g., 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
Death 
Palpitations 
Palpitations 
Present 
Present with associated 
symptoms (e.g., 
lightheadedness, 
shortness of breath) 
— 
— 
— 
REMARK: Grade palpitations only in the absence of a documented arrhythmia. 
Prolonged QTc interval 
Prolonged QTc 
QTc >0.45 – 0.47 second 
 QTc >0.47 – 0.50 
second; ≥0.06 second 
above baseline 
QTc >0.50 second 
QTc >0.50 second; life-
threatening signs or 
symptoms (e.g., 
arrhythmia, CHF, 
hypotension, shock 
syncope); Torsade de 
pointes 
Death 
Supraventricular and 
nodal arrhythmia  
– Select: 
Supraventricular 
arrhythmia – Select 
Asymptomatic, 
intervention not indicated 
Non-urgent medical 
intervention indicated 
– Atrial fibrillation 
– Atrial flutter  
– Atrial tachycardia/Paroxysmal Atrial Tachycardia 
– Nodal/Junctional 
– Sinus arrhythmia  
– Sinus bradycardia 
– Sinus tachycardia  
– Supraventricular arrhythmia NOS 
– Supraventricular extrasystoles (Premature Atrial Contractions; Premature Nodal/Junctional Contractions) 
– Supraventricular tachycardia 
Symptomatic and 
incompletely controlled 
medically, or controlled 
with device (e.g., 
pacemaker) 
Life-threatening (e.g., 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
Death 
NAVIGATION NOTE: Syncope is graded as Syncope (fainting) in the NEUROLOGY CATEGORY. 

 
CARDIAC ARRHYTHMIA 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 6 - 
March 31, 2003, Publish Date: August 9, 2006 
Vasovagal episode 
Vasovagal episode 
— 
Present without loss of 
consciousness 
Present with loss of 
consciousness 
Life-threatening 
consequences  
Death 
Ventricular arrhythmia 
– Select: 
Ventricular arrhythmia 
– Select 
– Bigeminy 
– Idioventricular rhythm 
– PVCs 
– Torsade de pointes 
– Trigeminy 
– Ventricular arrhythmia NOS 
– Ventricular fibrillation  
– Ventricular flutter 
– Ventricular tachycardia 
Asymptomatic, no 
intervention indicated 
Non-urgent medical 
intervention indicated 
Symptomatic and 
incompletely controlled 
medically or controlled 
with device (e.g., 
defibrillator) 
Life-threatening (e.g., 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
Death 
Cardiac Arrhythmia  
– Other (Specify, __) 
Cardiac Arrhythmia – 
Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling  
Death 

 
CARDIAC GENERAL 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 7 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Angina is graded as Cardiac ischemia/infarction in the CARDIAC GENERAL CATEGORY. 
Cardiac 
ischemia/infarction 
Cardiac 
ischemia/infarction 
Asymptomatic arterial 
narrowing without 
ischemia 
Asymptomatic and testing 
suggesting ischemia; 
stable angina  
Symptomatic and testing 
consistent with ischemia; 
unstable angina; 
intervention indicated 
Acute myocardial 
infarction 
Death 
Cardiac troponin I (cTnI) 
cTnI 
— 
— 
Levels consistent with 
unstable angina as 
defined by the 
manufacturer 
Levels consistent with 
myocardial infarction as 
defined by the 
manufacturer 
Death 
Cardiac troponin T (cTnT) 
cTnT 
0.03 – <0.05 ng/mL 
0.05 – <0.1 ng/mL 
0.1 – <0.2 ng/mL 
0.2 ng/mL 
Death 
Cardiopulmonary arrest, 
cause unknown 
(non-fatal) 
Cardiopulmonary arrest 
— 
— 
— 
Life-threatening  
— 
REMARK: Grade 4 (non-fatal) is the only appropriate grade. CTCAE provides three alternatives for reporting Death: 
1. A CTCAE term associated with Grade 5.  
2. A CTCAE 'Other (Specify, __)’ within any CATEGORY. 
3. Death not associated with CTCAE term – Select in the DEATH CATEGORY. 
NAVIGATION NOTE: Chest pain (non-cardiac and non-pleuritic) is graded as Pain – Select in the PAIN CATEGORY. 
NAVIGATION NOTE: CNS ischemia is graded as CNS cerebrovascular ischemia in the NEUROLOGY CATEGORY. 
Hypertension 
Hypertension 
Asymptomatic, transient 
(<24 hrs) increase by >20 
mmHg (diastolic) or to 
>150/100 if previously 
WNL; intervention not 
indicated  
Pediatric: 
Asymptomatic, transient 
(<24 hrs) BP increase 
>ULN; intervention not 
indicated 
Recurrent or persistent 
(≥24 hrs) or symptomatic 
increase by >20 mmHg 
(diastolic) or to >150/100 
if previously WNL; 
monotherapy may be 
indicated  
Pediatric: 
Recurrent or persistent 
(≥24 hrs) BP >ULN; 
monotherapy may be 
indicated 
Requiring more than one 
drug or more intensive 
therapy than previously 
Pediatric: 
Same as adult 
Life-threatening 
consequences (e.g., 
hypertensive crisis) 
Pediatric: 
Same as adult 
Death 
REMARK: Use age and gender-appropriate normal values >95th percentile ULN for pediatric patients. 

 
CARDIAC GENERAL 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 8 - 
March 31, 2003, Publish Date: August 9, 2006 
Hypotension 
Hypotension 
Changes, intervention not 
indicated 
Brief (<24 hrs) fluid 
replacement or other 
therapy; no physiologic 
consequences 
Sustained (≥24 hrs) 
therapy, resolves without 
persisting physiologic 
consequences 
Shock (e.g., acidemia; 
impairment of vital organ 
function)  
Death 
ALSO CONSIDER: Syncope (fainting). 
Left ventricular diastolic 
dysfunction 
Left ventricular diastolic 
dysfunction 
Asymptomatic diagnostic 
finding; intervention not 
indicated 
Asymptomatic, 
intervention indicated 
Symptomatic CHF 
responsive to intervention 
Refractory CHF, poorly 
controlled; intervention 
such as ventricular assist 
device or heart transplant 
indicated  
Death 
Left ventricular systolic 
dysfunction 
Left ventricular systolic 
dysfunction 
Asymptomatic, resting 
ejection fraction (EF)  
<60 – 50%; shortening 
fraction (SF) <30 – 24% 
Asymptomatic, resting  
EF <50 – 40%; 
SF <24 – 15% 
Symptomatic CHF 
responsive to 
intervention; 
EF <40 – 20% 
SF <15% 
Refractory CHF or poorly 
controlled; EF <20%; 
intervention such as 
ventricular assist device, 
ventricular reduction 
surgery, or heart 
transplant indicated 
Death 
NAVIGATION NOTE: Myocardial infarction is graded as Cardiac ischemia/infarction in the CARDIAC GENERAL CATEGORY. 
Myocarditis 
Myocarditis 
— 
— 
CHF responsive to 
intervention 
Severe or refractory CHF 
Death 
Pericardial effusion 
(non-malignant) 
Pericardial effusion 
Asymptomatic effusion  
—  
Effusion with physiologic 
consequences 
Life-threatening 
consequences (e.g., 
tamponade); emergency 
intervention indicated 
Death 
Pericarditis 
Pericarditis 
Asymptomatic, ECG or 
physical exam (rub) 
changes consistent with 
pericarditis 
Symptomatic pericarditis 
(e.g., chest pain) 
Pericarditis with 
physiologic 
consequences (e.g., 
pericardial constriction) 
Life-threatening 
consequences; 
emergency intervention 
indicated 
Death 
NAVIGATION NOTE: Pleuritic pain is graded as Pain – Select in the PAIN CATEGORY. 
Pulmonary hypertension 
Pulmonary hypertension 
Asymptomatic without 
therapy 
Asymptomatic, therapy 
indicated 
Symptomatic 
hypertension, responsive 
to therapy 
Symptomatic 
hypertension, poorly 
controlled 
Death 
Restrictive 
cardiomyopathy  
Restrictive 
cardiomyopathy  
Asymptomatic, therapy 
not indicated 
Asymptomatic, therapy 
indicated 
Symptomatic CHF 
responsive to intervention 
Refractory CHF, poorly 
controlled; intervention 
such as ventricular assist 
device, or heart 
transplant indicated  
Death 

 
CARDIAC GENERAL 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 9 - 
March 31, 2003, Publish Date: August 9, 2006 
Right ventricular 
dysfunction 
(cor pulmonale) 
Right ventricular 
dysfunction 
Asymptomatic without 
therapy 
Asymptomatic, therapy 
indicated 
Symptomatic cor 
pulmonale, responsive to 
intervention 
Symptomatic cor 
pulmonale poorly 
controlled; intervention 
such as ventricular assist 
device, or heart 
transplant indicated  
Death 
Valvular heart disease 
Valvular heart disease 
Asymptomatic valvular 
thickening with or without 
mild valvular regurgitation 
or stenosis; treatment 
other than endocarditis 
prophylaxis not indicated 
Asymptomatic; moderate 
regurgitation or stenosis 
by imaging 
Symptomatic; severe 
regurgitation or stenosis; 
symptoms controlled with 
medical therapy 
Life-threatening; 
disabling; intervention 
(e.g., valve replacement, 
valvuloplasty) indicated 
Death 
Cardiac General – Other 
(Specify, __) 
Cardiac General – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
COAGULATION 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 10 - 
March 31, 2003, Publish Date: August 9, 2006 
DIC (disseminated 
intravascular coagulation) 
DIC 
— 
Laboratory findings with 
no bleeding 
Laboratory findings and 
bleeding 
Laboratory findings, life-
threatening or disabling 
consequences (e.g., CNS 
hemorrhage, organ 
damage, or 
hemodynamically 
significant blood loss) 
Death 
REMARK: DIC (disseminated intravascular coagulation) must have increased fibrin split products or D-dimer.  
ALSO CONSIDER: Platelets. 
 
Fibrinogen  
Fibrinogen 
<1.0 – 0.75 x LLN 
or <25% decrease from 
baseline 
<0.75 – 0.5 x LLN 
or 25 – <50% decrease 
from baseline 
<0.5 – 0.25 x LLN 
or 50 – <75% decrease 
from baseline 
<0.25 x LLN  
or 75% decrease from 
baseline or absolute 
value <50 mg/dL  
Death 
REMARK: Use % decrease only when baseline is <LLN (local laboratory value). 
INR (International 
Normalized Ratio of 
prothrombin time) 
INR 
 
>1 – 1.5 x ULN 
>1.5 – 2 x ULN 
>2 x ULN 
— 
— 
ALSO CONSIDER: Hemorrhage, CNS; Hemorrhage, GI – Select; Hemorrhage, GU – Select; Hemorrhage, pulmonary/upper respiratory – Select. 
PTT (Partial 
Thromboplastin Time)  
PTT 
>1 – 1.5 x ULN 
>1.5 – 2 x ULN 
>2 x ULN 
— 
— 
ALSO CONSIDER: Hemorrhage, CNS; Hemorrhage, GI – Select; Hemorrhage, GU – Select; Hemorrhage, pulmonary/upper respiratory – Select. 
Thrombotic 
microangiopathy (e.g., 
thrombotic 
thrombocytopenic 
purpura [TTP] or 
hemolytic uremic 
syndrome [HUS]) 
Thrombotic 
microangiopathy 
Evidence of RBC 
destruction 
(schistocytosis) without 
clinical consequences 
— 
Laboratory findings 
present with clinical 
consequences (e.g., renal 
insufficiency, petechiae) 
Laboratory findings and 
life-threatening or 
disabling consequences, 
(e.g., CNS hemorrhage/ 
bleeding or thrombosis/ 
embolism or renal failure) 
Death 
REMARK: Must have microangiopathic changes on blood smear (e.g., schistocytes, helmet cells, red cell fragments). 
ALSO CONSIDER: Creatinine; Hemoglobin; Platelets. 
Coagulation – Other 
(Specify, __) 
Coagulation – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
CONSTITUTIONAL SYMPTOMS 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 11 - 
March 31, 2003, Publish Date: August 9, 2006 
Fatigue  
(asthenia, lethargy, 
malaise) 
Fatigue 
Mild fatigue over baseline 
Moderate or causing 
difficulty performing some 
ADL 
Severe fatigue interfering 
with ADL 
Disabling 
— 
Fever  
(in the absence of 
neutropenia, where 
neutropenia is defined as 
ANC <1.0 x 109/L) 
Fever 
38.0 – 39.0°C  
(100.4 – 102.2°F) 
>39.0 – 40.0°C 
(102.3 – 104.0°F)  
>40.0°C 
(>104.0°F) for ≤24 hrs  
>40.0°C 
(>104.0°F) for >24 hrs 
Death 
REMARK: The temperature measurements listed are oral or tympanic. 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever).  
NAVIGATION NOTE: Hot flashes are graded as Hot flashes/flushes in the ENDOCRINE CATEGORY. 
Hypothermia 
Hypothermia 
— 
35 – >32°C 
95 – >89.6°F 
32 – >28°C  
89.6 – >82.4° F 
≤28 °C  
82.4°F or life-threatening 
consequences (e.g., 
coma, hypotension, 
pulmonary edema, 
acidemia, ventricular 
fibrillation) 
Death 
Insomnia 
Insomnia 
Occasional difficulty 
sleeping, not interfering 
with function 
Difficulty sleeping, 
interfering with function 
but not interfering with 
ADL 
Frequent difficulty 
sleeping, interfering with 
ADL 
Disabling 
— 
REMARK: If pain or other symptoms interfere with sleep, do NOT grade as insomnia. Grade primary event(s) causing insomnia. 
Obesity2 
Obesity 
— 
BMI 25 – 29.9 kg/m2 
BMI 30 – 39.99 kg/m2 
BMI ≥40 kg/m2 
— 
REMARK: BMI = (weight [kg]) / (height [m])2 
Odor  
(patient odor) 
Patient odor 
Mild odor 
Pronounced odor 
— 
— 
— 
Rigors/chills 
Rigors/chills 
Mild 
Moderate, narcotics 
indicated 
Severe or prolonged, not 
responsive to narcotics 
— 
— 
                                            
2 NHLBI Obesity Task Force. "Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults," The Evidence Report, Obes Res 6:51S-
209S, 1998.  

 
CONSTITUTIONAL SYMPTOMS 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 12 - 
March 31, 2003, Publish Date: August 9, 2006 
Sweating  
(diaphoresis) 
Sweating  
Mild and occasional 
Frequent or drenching 
— 
— 
— 
ALSO CONSIDER: Hot flashes/flushes.  
Weight gain  
Weight gain 
5 – <10% of baseline 
10 – <20% of baseline 
≥20% of baseline 
— 
— 
REMARK: Edema, depending on etiology, is graded in the CARDIAC GENERAL or LYMPHATICS CATEGORIES. 
ALSO CONSIDER: Ascites (non-malignant); Pleural effusion (non-malignant). 
Weight loss 
Weight loss 
5 to <10% from baseline; 
intervention not indicated 
10 – <20% from baseline; 
nutritional support 
indicated 
≥20% from baseline; tube 
feeding or TPN indicated 
— 
— 
Constitutional Symptoms 
– Other (Specify, __) 
Constitutional Symptoms 
– Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
DEATH 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 13 - 
March 31, 2003, Publish Date: August 9, 2006 
Death not associated with 
CTCAE term  
– Select: 
Death not associated with 
CTCAE term – Select 
– Death NOS 
– Disease progression NOS 
– Multi-organ failure 
– Sudden death 
— 
— 
— 
— 
Death 
REMARK: Grade 5 is the only appropriate grade. 'Death not associated with CTCAE term – Select' is to be used where a death: 
1. Cannot be attributed to a CTCAE term associated with Grade 5. 
2. Cannot be reported within any CATEGORY using a CTCAE 'Other (Specify, __)’.  

 
DERMATOLOGY/SKIN 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 14 - 
March 31, 2003, Publish Date: August 9, 2006 
Atrophy, skin 
Atrophy, skin 
Detectable 
Marked 
— 
— 
— 
Atrophy, subcutaneous 
fat 
Atrophy, subcutaneous 
fat 
Detectable 
Marked 
— 
— 
— 
ALSO CONSIDER: Induration/fibrosis (skin and subcutaneous tissue). 
Bruising  
(in absence of Grade 3 or 
4 thrombocytopenia) 
Bruising  
Localized or in a 
dependent area 
Generalized 
— 
— 
— 
Burn 
Burn 
Minimal symptoms; 
intervention not indicated  
Medical intervention; 
minimal debridement 
indicated  
Moderate to major 
debridement or 
reconstruction indicated  
Life-threatening 
consequences 
Death 
REMARK: Burn refers to all burns including radiation, chemical, etc. 
Cheilitis 
Cheilitis 
Asymptomatic 
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
— 
— 
Dry skin 
Dry skin 
Asymptomatic 
Symptomatic, not 
interfering with ADL 
Interfering with ADL 
— 
— 
Flushing 
Flushing 
Asymptomatic 
Symptomatic 
— 
— 
— 
Hair loss/alopecia 
(scalp or body) 
Alopecia 
Thinning or patchy 
Complete 
— 
— 
— 
Hyperpigmentation 
Hyperpigmentation 
Slight or localized 
Marked or generalized 
— 
— 
— 
Hypopigmentation 
Hypopigmentation 
Slight or localized 
Marked or generalized 
— 
— 
— 
Induration/fibrosis 
(skin and subcutaneous 
tissue) 
Induration  
Increased density on 
palpation 
Moderate impairment of 
function not interfering 
with ADL; marked 
increase in density and 
firmness on palpation 
with or without minimal 
retraction 
Dysfunction interfering 
with ADL; very marked 
density, retraction or 
fixation 
— 
— 
ALSO CONSIDER: Fibrosis-cosmesis; Fibrosis-deep connective tissue.  
Injection site reaction/ 
extravasation changes 
Injection site reaction 
Pain; itching; erythema 
Pain or swelling, with 
inflammation or phlebitis 
Ulceration or necrosis 
that is severe; operative 
intervention indicated  
— 
— 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever); Ulceration. 

 
DERMATOLOGY/SKIN 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 15 - 
March 31, 2003, Publish Date: August 9, 2006 
Nail changes 
Nail changes 
Discoloration; ridging 
(koilonychias); pitting 
Partial or complete loss of 
nail(s); pain in nailbed(s) 
Interfering with ADL  
— 
— 
NAVIGATION NOTE: Petechiae is graded as Petechiae/purpura (hemorrhage/bleeding into skin or mucosa) in the HEMORRHAGE/BLEEDING CATEGORY. 
Photosensitivity 
Photosensitivity 
Painless erythema 
Painful erythema 
Erythema with 
desquamation 
Life-threatening; disabling 
Death 
Pruritus/itching 
Pruritus 
Mild or localized 
Intense or widespread 
Intense or widespread 
and interfering with ADL  
— 
— 
ALSO CONSIDER: Rash/desquamation. 
Rash/desquamation  
Rash 
Macular or papular 
eruption or erythema 
without associated 
symptoms 
Macular or papular 
eruption or erythema with 
pruritus or other 
associated symptoms; 
localized desquamation 
or other lesions covering 
<50% of body surface 
area (BSA) 
Severe, generalized 
erythroderma or macular, 
papular or vesicular 
eruption; desquamation 
covering ≥50% BSA 
Generalized exfoliative, 
ulcerative, or bullous 
dermatitis 
Death 
REMARK: Rash/desquamation may be used for GVHD. 
Rash:  
acne/acneiform 
Acne 
Intervention not indicated  
Intervention indicated 
Associated with pain, 
disfigurement, ulceration, 
or desquamation 
— 
Death 
Rash:  
dermatitis associated with 
radiation  
– Select: 
– Chemoradiation 
– Radiation 
Dermatitis – Select  
Faint erythema or dry 
desquamation 
Moderate to brisk 
erythema; patchy moist 
desquamation, mostly 
confined to skin folds and 
creases; moderate 
edema 
Moist desquamation other 
than skin folds and 
creases; bleeding 
induced by minor trauma 
or abrasion 
Skin necrosis or 
ulceration of full thickness 
dermis; spontaneous 
bleeding from involved 
site  
Death 
Rash:  
erythema multiforme 
(e.g., Stevens-Johnson 
syndrome, toxic 
epidermal necrolysis) 
Erythema multiforme 
— 
Scattered, but not 
generalized eruption 
Severe (e.g., generalized 
rash or painful stomatitis); 
IV fluids, tube feedings, 
or TPN indicated 
Life-threatening; disabling 
Death 
Rash:  
hand-foot skin reaction 
Hand-foot 
Minimal skin changes or 
dermatitis (e.g., 
erythema) without pain  
Skin changes (e.g., 
peeling, blisters, 
bleeding, edema) or pain, 
not interfering with 
function  
Ulcerative dermatitis or 
skin changes with pain 
interfering with function  
— 
— 

 
DERMATOLOGY/SKIN 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 16 - 
March 31, 2003, Publish Date: August 9, 2006 
Skin breakdown/ 
decubitus ulcer 
Decubitus  
— 
Local wound care; 
medical intervention 
indicated 
Operative debridement or 
other invasive 
intervention indicated 
(e.g., hyperbaric oxygen)  
Life-threatening 
consequences; major 
invasive intervention 
indicated (e.g., tissue 
reconstruction, flap, or 
grafting) 
Death 
REMARK: Skin breakdown/decubitus ulcer is to be used for loss of skin integrity or decubitus ulcer from pressure or as the result of operative or medical intervention. 
Striae 
Striae 
Mild 
Cosmetically significant 
— 
— 
— 
Telangiectasia 
Telangiectasia 
Few 
Moderate number 
Many and confluent 
— 
— 
Ulceration 
Ulceration 
— 
Superficial ulceration  
<2 cm size; local wound 
care; medical intervention 
indicated 
Ulceration ≥2 cm size; 
operative debridement, 
primary closure or other 
invasive intervention 
indicated (e.g., hyperbaric 
oxygen)  
Life-threatening 
consequences; major 
invasive intervention 
indicated (e.g., complete 
resection, tissue 
reconstruction, flap, or 
grafting) 
Death 
Urticaria  
(hives, welts, wheals) 
Urticaria 
Intervention not indicated 
Intervention indicated for 
<24 hrs 
Intervention indicated for 
≥24 hrs 
— 
— 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever). 
Wound complication, 
non-infectious  
Wound complication, 
non-infectious 
Incisional separation of  
≤25% of wound, no 
deeper than superficial 
fascia 
Incisional separation 
>25% of wound with local 
care; asymptomatic 
hernia 
Symptomatic hernia 
without evidence of 
strangulation; fascial 
disruption/dehiscence 
without evisceration; 
primary wound closure or 
revision by operative 
intervention indicated; 
hospitalization or 
hyperbaric oxygen 
indicated 
Symptomatic hernia with 
evidence of strangulation; 
fascial disruption with 
evisceration; major 
reconstruction flap, 
grafting, resection, or 
amputation indicated 
Death 
REMARK: Wound complication, non-infectious is to be used for separation of incision, hernia, dehiscence, evisceration, or second surgery for wound revision. 
Dermatology/Skin – Other 
(Specify, __) 
Dermatology – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
ENDOCRINE 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 17 - 
March 31, 2003, Publish Date: August 9, 2006 
Adrenal insufficiency 
Adrenal insufficiency 
Asymptomatic, 
intervention not indicated 
Symptomatic, intervention 
indicated 
Hospitalization  
Life-threatening; disabling 
Death 
REMARK: Adrenal insufficiency includes any of the following signs and symptoms: abdominal pain, anorexia, constipation, diarrhea, hypotension, pigmentation of mucous membranes, 
pigmentation of skin, salt craving, syncope (fainting), vitiligo, vomiting, weakness, weight loss. Adrenal insufficiency must be confirmed by laboratory studies (low cortisol frequently 
accompanied by low aldosterone). 
ALSO CONSIDER: Potassium, serum-high (hyperkalemia); Thyroid function, low (hypothyroidism). 
Cushingoid appearance 
(e.g., moon face, buffalo 
hump, centripetal obesity, 
cutaneous striae) 
Cushingoid  
— 
Present 
— 
— 
— 
ALSO CONSIDER: Glucose, serum-high (hyperglycemia); Potassium, serum-low (hypokalemia). 
Feminization of male 
Feminization of male 
— 
— 
Present 
— 
— 
NAVIGATION NOTE: Gynecomastia is graded in the SEXUAL/REPRODUCTIVE FUNCTION CATEGORY. 
Hot flashes/flushes3 
Hot flashes 
Mild  
Moderate  
Interfering with ADL 
— 
— 
Masculinization of female 
Masculinization of female 
— 
— 
Present 
— 
— 
Neuroendocrine: 
ACTH deficiency 
ACTH  
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL; hospitalization 
indicated 
Life-threatening 
consequences (e.g., 
severe hypotension) 
Death 
Neuroendocrine: 
ADH secretion 
abnormality (e.g., SIADH 
or low ADH) 
ADH 
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL 
Life-threatening 
consequences 
Death 
Neuroendocrine: 
gonadotropin secretion 
abnormality 
Gonadotropin 
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL; osteopenia; 
fracture; infertility 
— 
— 
Neuroendocrine:  
growth hormone 
secretion abnormality 
Growth hormone  
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
— 
— 
— 
Neuroendocrine:  
prolactin hormone 
secretion abnormality 
Prolactin  
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL; amenorrhea; 
galactorrhea 
— 
Death 
                                            
3 Sloan JA, Loprinzi CL, Novotny PJ, Barton DL, Lavasseur BI, Windschitl HJ, "Methodologic Lessons Learned from Hot Flash Studies," J Clin Oncol 2001 Dec 1;19(23):4280-90 

 
ENDOCRINE 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 18 - 
March 31, 2003, Publish Date: August 9, 2006 
Pancreatic endocrine:  
glucose intolerance 
Diabetes 
Asymptomatic, 
intervention not indicated 
Symptomatic; dietary 
modification or oral agent 
indicated 
Symptoms interfering with 
ADL; insulin indicated 
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar non-ketotic 
coma)  
Death 
Parathyroid function, low 
(hypoparathyroidism) 
Hypoparathyroidism 
Asymptomatic, 
intervention not indicated 
Symptomatic; intervention 
indicated 
— 
— 
— 
Thyroid function, high 
(hyperthyroidism, 
thyrotoxicosis) 
Hyperthyroidism  
Asymptomatic, 
intervention not indicated 
Symptomatic, not 
interfering with ADL; 
thyroid suppression 
therapy indicated 
Symptoms interfering with 
ADL; hospitalization 
indicated  
Life-threatening 
consequences (e.g., 
thyroid storm) 
Death 
Thyroid function, low 
(hypothyroidism) 
Hypothyroidism 
Asymptomatic, 
intervention not indicated 
Symptomatic, not 
interfering with ADL; 
thyroid replacement 
indicated 
Symptoms interfering with 
ADL; hospitalization 
indicated  
Life-threatening 
myxedema coma 
Death 
Endocrine – Other  
(Specify, __) 
Endocrine – Other  
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
GASTROINTESTINAL 
Page 1 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 19 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Abdominal pain or cramping is graded as Pain – Select in the PAIN CATEGORY. 
Anorexia 
Anorexia 
Loss of appetite without 
alteration in eating habits 
Oral intake altered 
without significant weight 
loss or malnutrition; oral 
nutritional supplements 
indicated 
Associated with 
significant weight loss or 
malnutrition (e.g., 
inadequate oral caloric 
and/or fluid intake); IV 
fluids, tube feedings or 
TPN indicated 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Weight loss. 
Ascites (non-malignant) 
Ascites 
Asymptomatic 
Symptomatic, medical 
intervention indicated 
Symptomatic, invasive 
procedure indicated 
Life-threatening 
consequences 
Death 
REMARK: Ascites (non-malignant) refers to documented non-malignant ascites or unknown etiology, but unlikely malignant, and includes chylous ascites. 
Colitis 
Colitis 
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain; mucus 
or blood in stool 
Abdominal pain, fever, 
change in bowel habits 
with ileus; peritoneal 
signs 
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis, toxic 
megacolon) 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select.  
Constipation 
Constipation 
Occasional or intermittent 
symptoms; occasional 
use of stool softeners, 
laxatives, dietary 
modification, or enema 
Persistent symptoms with 
regular use of laxatives 
or enemas indicated 
Symptoms interfering 
with ADL; obstipation 
with manual evacuation 
indicated  
Life-threatening 
consequences (e.g., 
obstruction, toxic 
megacolon) 
Death 
ALSO CONSIDER: Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation); Obstruction, GI – Select. 
Dehydration 
Dehydration 
Increased oral fluids 
indicated; dry mucous 
membranes; diminished 
skin turgor 
IV fluids indicated <24 
hrs 
IV fluids indicated ≥24 hrs 
Life-threatening 
consequences (e.g., 
hemodynamic collapse) 
Death 
ALSO CONSIDER: Diarrhea; Hypotension; Vomiting. 
Dental:  
dentures or prosthesis 
Dentures  
Minimal discomfort, no 
restriction in activities  
Discomfort preventing 
use in some activities 
(e.g., eating), but not 
others (e.g., speaking) 
Unable to use dentures 
or prosthesis at any time 
— 
— 

 
GASTROINTESTINAL 
Page 2 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 20 - 
March 31, 2003, Publish Date: August 9, 2006 
Dental:  
periodontal disease  
Periodontal  
Gingival recession or 
gingivitis; limited bleeding 
on probing; mild local 
bone loss 
Moderate gingival 
recession or gingivitis; 
multiple sites of bleeding 
on probing; moderate 
bone loss 
Spontaneous bleeding; 
severe bone loss with or 
without tooth loss; 
osteonecrosis of maxilla 
or mandible  
— 
— 
REMARK: Severe periodontal disease leading to osteonecrosis is graded as Osteonecrosis (avascular necrosis) in the MUSCULOSKELETAL CATEGORY. 
Dental: 
teeth  
Teeth 
Surface stains; dental 
caries; restorable, without 
extractions 
Less than full mouth 
extractions; tooth fracture 
or crown amputation or 
repair indicated 
Full mouth extractions 
indicated 
— 
— 
Dental:  
teeth development 
Teeth development 
Hypoplasia of tooth or 
enamel not interfering 
with function 
Functional impairment 
correctable with oral 
surgery 
Maldevelopment with 
functional impairment not 
surgically correctable 
— 
— 
Diarrhea 
Diarrhea 
Increase of <4 stools per 
day over baseline; mild 
increase in ostomy output 
compared to baseline 
Increase of 4 – 6 stools 
per day over baseline; IV 
fluids indicated <24hrs; 
moderate increase in 
ostomy output compared 
to baseline; not 
interfering with ADL 
Increase of ≥7 stools per 
day over baseline; 
incontinence; IV fluids 
≥24 hrs; hospitalization; 
severe increase in 
ostomy output compared 
to baseline; interfering 
with ADL 
Life-threatening 
consequences (e.g., 
hemodynamic collapse) 
Death 
REMARK: Diarrhea includes diarrhea of small bowel or colonic origin, and/or ostomy diarrhea. 
ALSO CONSIDER: Dehydration; Hypotension. 
Distension/bloating, 
abdominal 
Distension 
Asymptomatic  
Symptomatic, but not 
interfering with GI 
function 
Symptomatic, interfering 
with GI function 
— 
— 
ALSO CONSIDER: Ascites (non-malignant); Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation); Obstruction, GI – Select.  

 
GASTROINTESTINAL 
Page 3 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 21 - 
March 31, 2003, Publish Date: August 9, 2006 
Dry mouth/salivary gland 
(xerostomia) 
Dry mouth 
Symptomatic (dry or thick 
saliva) without significant 
dietary alteration; 
unstimulated saliva flow 
>0.2 ml/min 
Symptomatic and 
significant oral intake 
alteration (e.g., copious 
water, other lubricants, 
diet limited to purees 
and/or soft, moist foods); 
unstimulated saliva 
0.1 to 0.2 ml/min 
Symptoms leading to 
inability to adequately 
aliment orally; IV fluids, 
tube feedings, or TPN 
indicated; unstimulated 
saliva <0.1 ml/min 
— 
— 
REMARK: Dry mouth/salivary gland (xerostomia) includes descriptions of grade using both subjective and objective assessment parameters. Record this event consistently throughout 
a patient’s participation on study. If salivary flow measurements are used for initial assessment, subsequent assessments must use salivary flow. 
ALSO CONSIDER: Salivary gland changes/saliva.  
Dysphagia 
(difficulty swallowing) 
Dysphagia 
Symptomatic, able to eat 
regular diet  
Symptomatic and altered 
eating/swallowing (e.g., 
altered dietary habits, 
oral supplements); IV 
fluids indicated <24 hrs 
Symptomatic and 
severely altered 
eating/swallowing (e.g., 
inadequate oral caloric or 
fluid intake); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences (e.g., 
obstruction, perforation) 
 
Death 
REMARK: Dysphagia (difficulty swallowing) is to be used for swallowing difficulty from oral, pharyngeal, esophageal, or neurologic origin. Dysphagia requiring dilation is graded as 
Stricture/stenosis (including anastomotic), GI – Select. 
ALSO CONSIDER: Dehydration; Esophagitis. 
Enteritis  
(inflammation of the small 
bowel) 
Enteritis 
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain; mucus 
or blood in stool 
Abdominal pain, fever, 
change in bowel habits 
with ileus; peritoneal 
signs 
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis) 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select; Typhlitis (cecal inflammation).  
Esophagitis 
Esophagitis 
Asymptomatic pathologic, 
radiographic, or 
endoscopic findings only 
Symptomatic; altered 
eating/swallowing (e.g., 
altered dietary habits, 
oral supplements); IV 
fluids indicated <24 hrs 
Symptomatic and 
severely altered 
eating/swallowing (e.g., 
inadequate oral caloric or 
fluid intake); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences 
Death 
REMARK: Esophagitis includes reflux esophagitis.  
ALSO CONSIDER: Dysphagia (difficulty swallowing). 

 
GASTROINTESTINAL 
Page 4 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 22 - 
March 31, 2003, Publish Date: August 9, 2006 
Fistula, GI 
– Select: 
Fistula, GI – Select  
– Abdomen NOS 
– Anus 
– Biliary tree  
– Colon/cecum/appendix 
– Duodenum 
– Esophagus 
– Gallbladder  
– Ileum 
– Jejunum 
– Oral cavity 
– Pancreas 
– Pharynx 
– Rectum 
– Salivary gland  
– Small bowel NOS 
– Stomach 
Asymptomatic, 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, diarrhea, 
or GI fluid loss); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered GI 
function (e.g., altered 
dietary habits, diarrhea, 
or GI fluid loss); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences  
Death 
REMARK: A fistula is defined as an abnormal communication between two body cavities, potential spaces, and/or the skin. The site indicated for a fistula should be the site from which 
the abnormal process is believed to have originated. For example, a tracheo-esophageal fistula arising in the context of a resected or irradiated esophageal cancer is graded as 
Fistula, GI – esophagus. 
Flatulence 
Flatulence 
Mild 
Moderate 
— 
— 
— 
Gastritis (including bile 
reflux gastritis) 
Gastritis 
Asymptomatic 
radiographic or 
endoscopic findings only 
Symptomatic; altered 
gastric function (e.g., 
inadequate oral caloric or 
fluid intake); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered gastric 
function (e.g., inadequate 
oral caloric or fluid 
intake); IV fluids, tube 
feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., gastrectomy)  
Death 
ALSO CONSIDER: Hemorrhage, GI – Select; Ulcer, GI – Select. 
NAVIGATION NOTE: Head and neck soft tissue necrosis is graded as Soft tissue necrosis – Select in the MUSCULOSKELETAL/SOFT TISSUE CATEGORY. 
Heartburn/dyspepsia 
Heartburn 
Mild 
Moderate 
Severe 
— 
— 
Hemorrhoids 
Hemorrhoids 
Asymptomatic 
Symptomatic; banding or 
medical intervention 
indicated 
Interfering with ADL; 
interventional radiology, 
endoscopic, or operative 
intervention indicated 
Life-threatening 
consequences 
Death 

 
GASTROINTESTINAL 
Page 5 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 23 - 
March 31, 2003, Publish Date: August 9, 2006 
Ileus, GI (functional 
obstruction of bowel, i.e., 
neuroconstipation) 
Ileus 
Asymptomatic, 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered GI 
function; IV fluids, tube 
feeding, or TPN indicated 
≥24 hrs 
Life-threatening 
consequences 
Death 
REMARK: Ileus, GI is to be used for altered upper or lower GI function (e.g., delayed gastric or colonic emptying). 
ALSO CONSIDER: Constipation; Nausea; Obstruction, GI – Select; Vomiting. 
Incontinence, anal 
Incontinence, anal 
Occasional use of pads 
required 
Daily use of pads 
required 
Interfering with ADL; 
operative intervention 
indicated 
Permanent bowel 
diversion indicated 
Death 
REMARK: Incontinence, anal is to be used for loss of sphincter control as sequelae of operative or therapeutic intervention. 
Leak (including 
anastomotic), GI 
– Select: 
– Biliary tree 
– Esophagus 
– Large bowel 
– Leak NOS 
– Pancreas 
– Pharynx 
– Rectum 
– Small bowel  
– Stoma 
– Stomach 
Leak, GI – Select  
Asymptomatic 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and 
interfering with GI 
function; invasive or 
endoscopic intervention 
indicated  
Life-threatening 
consequences 
Death 
REMARK: Leak (including anasomotic), GI – Select is to be used for clinical signs/symptoms or radiographic confirmation of anastomotic or conduit leak (e.g., biliary, esophageal, 
intestinal, pancreatic, pharyngeal, rectal), but without development of fistula. 
Malabsorption  
Malabsorption 
— 
Altered diet; oral 
therapies indicated (e.g., 
enzymes, medications, 
dietary supplements)  
Inability to aliment 
adequately via GI tract 
(i.e., TPN indicated) 
Life-threatening 
consequences 
Death 

 
GASTROINTESTINAL 
Page 6 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 24 - 
March 31, 2003, Publish Date: August 9, 2006 
Mucositis/stomatitis 
(clinical exam)  
– Select: 
– Anus 
– Esophagus 
– Large bowel 
– Larynx 
– Oral cavity 
– Pharynx 
– Rectum 
– Small bowel 
– Stomach 
– Trachea 
Mucositis (clinical exam) 
– Select  
Erythema of the mucosa 
Patchy ulcerations or 
pseudomembranes  
Confluent ulcerations or 
pseudomembranes; 
bleeding with minor 
trauma 
Tissue necrosis; 
significant spontaneous 
bleeding; life-threatening 
consequences 
Death 
REMARK: Mucositis/stomatitis (functional/symptomatic) may be used for mucositis of the upper aero-digestive tract caused by radiation, agents, or GVHD.  
Mucositis/stomatitis 
(functional/symptomatic)  
– Select: 
– Anus 
– Esophagus 
– Large bowel 
– Larynx 
– Oral cavity 
– Pharynx 
– Rectum 
– Small bowel 
– Stomach 
– Trachea 
Mucositis (functional/ 
symptomatic) – Select  
Upper aerodigestive tract 
sites: Minimal symptoms, 
normal diet; minimal 
respiratory symptoms but 
not interfering with 
function 
Lower GI sites: 
Minimal discomfort, 
intervention not indicated 
Upper aerodigestive tract 
sites: Symptomatic but 
can eat and swallow 
modified diet; respiratory 
symptoms interfering with 
function but not 
interfering with ADL 
Lower GI sites:  
Symptomatic, medical 
intervention indicated but 
not interfering with ADL 
Upper aerodigestive tract 
sites: Symptomatic and 
unable to adequately 
aliment or hydrate orally; 
respiratory symptoms 
interfering with ADL 
Lower GI sites: 
Stool incontinence or 
other symptoms 
interfering with ADL 
Symptoms associated 
with life-threatening 
consequences  
Death 
Nausea 
Nausea 
Loss of appetite without 
alteration in eating habits 
Oral intake decreased 
without significant weight 
loss, dehydration or 
malnutrition; IV fluids 
indicated <24 hrs 
Inadequate oral caloric or 
fluid intake; IV fluids, tube 
feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Anorexia; Vomiting. 

 
GASTROINTESTINAL 
Page 7 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 25 - 
March 31, 2003, Publish Date: August 9, 2006 
Necrosis, GI 
– Select:  
Necrosis, GI – Select  
– Anus 
– Colon/cecum/appendix 
– Duodenum 
– Esophagus 
– Gallbladder 
– Hepatic 
– Ileum 
– Jejunum 
– Oral 
– Pancreas 
– Peritoneal cavity 
– Pharynx  
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
— 
— 
Inability to aliment 
adequately by GI tract 
(e.g., requiring enteral or 
parenteral nutrition); 
interventional radiology, 
endoscopic, or operative 
intervention indicated  
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., total colectomy)  
Death 
ALSO CONSIDER: Visceral arterial ischemia (non-myocardial). 
Obstruction, GI 
– Select: 
– Cecum 
– Colon 
– Duodenum 
– Esophagus 
– Gallbladder 
– Ileum 
– Jejunum 
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
Obstruction, GI – Select 
Asymptomatic 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, vomiting, 
diarrhea, or GI fluid loss); 
IV fluids indicated <24 
hrs 
Symptomatic and 
severely altered GI 
function (e.g., altered 
dietary habits, vomiting, 
diarrhea, or GI fluid loss); 
IV fluids, tube feedings, 
or TPN indicated ≥24 hrs; 
operative intervention 
indicated 
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., total colectomy)  
Death 
NAVIGATION NOTE: Operative injury is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY CATEGORY. 
NAVIGATION NOTE: Pelvic pain is graded as Pain – Select in the PAIN CATEGORY. 

 
GASTROINTESTINAL 
Page 8 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 26 - 
March 31, 2003, Publish Date: August 9, 2006 
Perforation, GI 
– Select: 
– Appendix 
– Biliary tree 
– Cecum 
– Colon 
– Duodenum 
– Esophagus 
– Gallbladder 
– Ileum 
– Jejunum 
– Rectum 
– Small bowel NOS 
– Stomach 
Perforation, GI – Select 
Asymptomatic 
radiographic findings only 
Medical intervention 
indicated; IV fluids 
indicated <24 hrs 
IV fluids, tube feedings, 
or TPN indicated ≥24 hrs; 
operative intervention 
indicated 
Life-threatening 
consequences 
Death 
Proctitis  
Proctitis 
Rectal discomfort, 
intervention not indicated 
Symptoms not interfering 
with ADL; medical 
intervention indicated  
Stool incontinence or 
other symptoms 
interfering with ADL; 
operative intervention 
indicated 
Life-threatening 
consequences (e.g., 
perforation) 
Death 
Prolapse of stoma, GI 
Prolapse of stoma, GI 
Asymptomatic  
Extraordinary local care 
or maintenance; minor 
revision indicated 
Dysfunctional stoma; 
major revision indicated  
Life-threatening 
consequences 
Death 
REMARK: Other stoma complications may be graded as Fistula, GI – Select; Leak (including anastomotic), GI – Select; Obstruction, GI – Select; Perforation, GI – Select; 
Stricture/stenosis (including anastomotic), GI – Select. 
NAVIGATION NOTE: Rectal or perirectal pain (proctalgia) is graded as Pain – Select in the PAIN CATEGORY.  
Salivary gland 
changes/saliva 
Salivary gland changes 
Slightly thickened saliva; 
slightly altered taste (e.g., 
metallic) 
Thick, ropy, sticky saliva; 
markedly altered taste; 
alteration in diet 
indicated; secretion-
induced symptoms not 
interfering with ADL 
Acute salivary gland 
necrosis; severe 
secretion-induced 
symptoms interfering with 
ADL  
Disabling 
— 
ALSO CONSIDER: Dry mouth/salivary gland (xerostomia); Mucositis/stomatitis (clinical exam) – Select; Mucositis/stomatitis (functional/symptomatic) – Select; Taste alteration 
(dysgeusia). 
NAVIGATION NOTE: Splenic function is graded in the BLOOD/BONE MARROW CATEGORY. 

 
GASTROINTESTINAL 
Page 9 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 27 - 
March 31, 2003, Publish Date: August 9, 2006 
Stricture/stenosis 
(including anastomotic), 
GI 
– Select:  
Stricture, GI – Select  
– Anus 
– Biliary tree 
– Cecum 
– Colon  
– Duodenum  
– Esophagus 
– Ileum 
– Jejunum 
– Pancreas/pancreatic duct 
– Pharynx 
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
Asymptomatic 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, vomiting, 
bleeding, diarrhea); IV 
fluids indicated <24 hrs 
Symptomatic and 
severely altered GI 
function (e.g., altered 
dietary habits, diarrhea, 
or GI fluid loss); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs; 
operative intervention 
indicated 
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., total colectomy)  
Death 
Taste alteration 
(dysgeusia) 
Taste alteration 
Altered taste but no 
change in diet 
Altered taste with change 
in diet (e.g., oral 
supplements); noxious or 
unpleasant taste; loss of 
taste 
— 
— 
— 
Typhlitis 
(cecal inflammation) 
Typhlitis 
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain; mucus 
or blood in stool 
Abdominal pain, fever, 
change in bowel habits 
with ileus; peritoneal 
signs 
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis); 
operative intervention 
indicated 
Death 
ALSO CONSIDER: Colitis; Hemorrhage, GI – Select ; Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation).  

 
GASTROINTESTINAL 
Page 10 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 28 - 
March 31, 2003, Publish Date: August 9, 2006 
Ulcer, GI 
– Select: 
– Anus 
– Cecum 
– Colon 
– Duodenum 
– Esophagus 
– Ileum 
– Jejunum 
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
Ulcer, GI – Select 
Asymptomatic, 
radiographic or 
endoscopic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, oral 
supplements); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered GI 
function (e.g., inadequate 
oral caloric or fluid 
intake); IV fluids, tube 
feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select. 
Vomiting 
Vomiting 
1 episode in 24 hrs 
2 – 5 episodes in 24 hrs; 
IV fluids indicated  
<24 hrs 
≥6 episodes in 24 hrs; IV 
fluids, or TPN indicated 
≥24 hrs 
Life-threatening 
consequences  
Death 
ALSO CONSIDER: Dehydration. 
Gastrointestinal – Other 
(Specify, __) 
GI – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling 
Death 

 
GROWTH AND DEVELOPMENT 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 29 - 
March 31, 2003, Publish Date: August 9, 2006 
Bone age 
(alteration in bone age) 
Bone age 
— 
+2 SD (standard 
deviation) from normal 
— 
— 
— 
Bone growth: 
femoral head; slipped 
capital femoral epiphysis 
Femoral head growth 
Mild valgus/varus 
deformity 
Moderate valgus/varus 
deformity, symptomatic, 
interfering with function 
but not interfering with 
ADL 
Mild slipped capital 
femoral epiphysis; 
operative intervention 
(e.g., fixation) indicated; 
interfering with ADL 
Disabling; severe slipped 
capital femoral epiphysis 
>60%; avascular necrosis 
— 
Bone growth: 
limb length discrepancy 
Limb length  
Mild length discrepancy 
<2 cm 
Moderate length 
discrepancy 2 – 5 cm; 
shoe lift indicated 
Severe length 
discrepancy >5 cm; 
operative intervention 
indicated; interfering with 
ADL 
Disabling; epiphysiodesis 
— 
Bone growth: 
spine kyphosis/lordosis 
Kyphosis/lordosis 
Mild radiographic 
changes  
Moderate accentuation; 
interfering with function 
but not interfering with 
ADL 
Severe accentuation; 
operative intervention 
indicated; interfering with 
ADL 
Disabling (e.g., cannot lift 
head) 
— 
Growth velocity 
(reduction in growth 
velocity) 
Reduction in growth 
velocity 
10 – 29% reduction in 
growth from the baseline 
growth curve 
30 – 49% reduction in 
growth from the baseline 
growth curve 
≥50% reduction in growth 
from the baseline growth 
curve  
— 
— 
Puberty (delayed) 
Delayed puberty 
— 
No breast development 
by age 13 yrs for females; 
no Tanner Stage 2 
development by age 14.5 
yrs for males 
No sexual development 
by age 14 yrs for girls, 
age 16 yrs for boys; 
hormone replacement 
indicated 
— 
— 
REMARK: Do not use testicular size for Tanner Stage in male cancer survivors. 
Puberty (precocious)  
Precocious puberty 
— 
Physical signs of puberty 
<7 years for females,  
<9 years for males 
— 
— 
— 
Short stature 
Short stature 
Beyond two standard 
deviations of age and 
gender mean height 
Altered ADL 
— 
— 
— 
REMARK: Short stature is secondary to growth hormone deficiency. 
ALSO CONSIDER: Neuroendocrine: growth hormone secretion abnormality. 
Growth and Development 
– Other (Specify, __) 
Growth and Development 
– Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
HEMORRHAGE/BLEEDING 
Page 1 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 30 - 
March 31, 2003, Publish Date: August 9, 2006 
Hematoma  
Hematoma 
Minimal symptoms, 
invasive intervention not 
indicated  
Minimally invasive 
evacuation or aspiration 
indicated 
Transfusion, 
interventional radiology, 
or operative intervention 
indicated 
Life-threatening 
consequences; major 
urgent intervention 
indicated 
Death 
REMARK: Hematoma refers to extravasation at wound or operative site or secondary to other intervention. Transfusion implies pRBC.  
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Hemorrhage/bleeding 
associated with surgery, 
intra-operative or 
postoperative 
Hemorrhage with surgery 
— 
— 
Requiring transfusion of  
2 units non-autologous 
(10 cc/kg for pediatrics) 
pRBCs beyond protocol 
specification; 
postoperative 
interventional radiology, 
endoscopic, or operative 
intervention indicated 
Life-threatening 
consequences  
Death 
REMARK: Postoperative period is defined as ≤72 hours after surgery. Verify protocol-specific acceptable guidelines regarding pRBC transfusion. 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Hemorrhage, CNS 
CNS hemorrhage 
Asymptomatic, 
radiographic findings only 
Medical intervention 
indicated  
Ventriculostomy, ICP 
monitoring, 
intraventricular 
thrombolysis, or operative 
intervention indicated 
Life-threatening 
consequences; 
neurologic deficit or 
disability 
Death 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 

 
HEMORRHAGE/BLEEDING 
Page 2 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 31 - 
March 31, 2003, Publish Date: August 9, 2006 
Hemorrhage, GI  
– Select: 
– Abdomen NOS 
– Anus 
– Biliary tree  
– Cecum/appendix  
– Colon 
– Duodenum 
– Esophagus 
– Ileum 
– Jejunum 
– Liver 
– Lower GI NOS 
– Oral cavity 
– Pancreas 
– Peritoneal cavity 
– Rectum 
– Stoma 
– Stomach 
– Upper GI NOS 
– Varices (esophageal) 
– Varices (rectal) 
Hemorrhage, GI – Select 
Mild, intervention (other 
than iron supplements) 
not indicated 
Symptomatic and medical 
intervention or minor 
cauterization indicated 
Transfusion, 
interventional radiology, 
endoscopic, or operative 
intervention indicated; 
radiation therapy (i.e., 
hemostasis of bleeding 
site) 
Life-threatening 
consequences; major 
urgent intervention 
indicated  
Death 
REMARK: Transfusion implies pRBC. 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 

 
HEMORRHAGE/BLEEDING 
Page 3 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 32 - 
March 31, 2003, Publish Date: August 9, 2006 
Hemorrhage, GU  
– Select:  
– Bladder 
– Fallopian tube 
– Kidney 
– Ovary 
– Prostate  
– Retroperitoneum  
– Spermatic cord 
– Stoma 
– Testes 
– Ureter 
– Urethra 
– Urinary NOS 
– Uterus 
– Vagina 
– Vas deferens 
Hemorrhage, GU – Select 
Minimal or microscopic 
bleeding; intervention not 
indicated 
Gross bleeding, medical 
intervention, or urinary 
tract irrigation indicated 
Transfusion, 
interventional radiology, 
endoscopic, or operative 
intervention indicated; 
radiation therapy (i.e., 
hemostasis of bleeding 
site) 
Life-threatening 
consequences; major 
urgent intervention 
indicated 
Death 
REMARK: Transfusion implies pRBC. 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Hemorrhage, pulmonary/ 
upper respiratory  
– Select: 
Hemorrhage pulmonary  
– Select 
– Bronchopulmonary NOS 
– Bronchus  
– Larynx  
– Lung  
– Mediastinum 
– Nose 
– Pharynx 
– Pleura 
– Respiratory tract NOS 
– Stoma 
– Trachea 
Mild, intervention not 
indicated 
Symptomatic and 
medical intervention 
indicated 
Transfusion, 
interventional radiology, 
endoscopic, or operative 
intervention indicated; 
radiation therapy (i.e., 
hemostasis of bleeding 
site) 
Life-threatening 
consequences; major 
urgent intervention 
indicated 
Death 
REMARK: Transfusion implies pRBC.  
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Petechiae/purpura 
(hemorrhage/bleeding 
into skin or mucosa) 
Petechiae 
Few petechiae 
Moderate petechiae; 
purpura 
Generalized petechiae or 
purpura 
— 
— 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 

 
HEMORRHAGE/BLEEDING 
Page 4 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 33 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Vitreous hemorrhage is graded in the OCULAR/VISUAL CATEGORY. 
Hemorrhage/Bleeding – 
Other (Specify, __) 
Hemorrhage – Other 
(Specify) 
Mild without transfusion 
— 
Transfusion indicated 
Catastrophic bleeding, 
requiring major non-
elective intervention 
Death 

 
HEPATOBILIARY/PANCREAS 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 34 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Biliary tree damage is graded as Fistula, GI – Select; Leak (including anastomotic), GI – Select; Necrosis, GI – Select; Obstruction, GI – Select; Perforation, GI – 
Select; Stricture/stenosis (including anastomotic), GI – Select in the GASTROINTESTINAL CATEGORY. 
Cholecystitis 
Cholecystitis 
Asymptomatic, 
radiographic findings only 
Symptomatic, medical 
intervention indicated 
Interventional radiology, 
endoscopic, or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
sepsis or perforation)  
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection 
with unknown ANC – Select.  
Liver dysfunction/failure 
(clinical)  
Liver dysfunction  
— 
Jaundice  
Asterixis 
Encephalopathy or coma 
Death 
REMARK: Jaundice is not an AE, but occurs when the liver is not working properly or when a bile duct is blocked. It is graded as a result of liver dysfunction/failure or elevated bilirubin. 
ALSO CONSIDER: Bilirubin (hyperbilirubinemia). 
Pancreas, exocrine 
enzyme deficiency 
Pancreas, exocrine 
enzyme deficiency 
— 
Increase in stool 
frequency, bulk, or odor; 
steatorrhea 
Sequelae of absorption 
deficiency (e.g., weight 
loss)  
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Diarrhea. 
Pancreatitis  
Pancreatitis 
Asymptomatic, enzyme 
elevation and/or 
radiographic findings  
Symptomatic, medical 
intervention indicated 
Interventional radiology or 
operative intervention 
indicated 
Life-threatening 
consequences 
(e.g., circulatory failure, 
hemorrhage, sepsis) 
Death 
ALSO CONSIDER: Amylase. 
NAVIGATION NOTE: Stricture (biliary tree, hepatic or pancreatic) is graded as Stricture/stenosis (including anastomotic), GI – Select in the GASTROINTESTINAL CATEGORY. 
Hepatobiliary/Pancreas – 
Other (Specify, __) 
Hepatobiliary – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
INFECTION 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 35 - 
March 31, 2003, Publish Date: August 9, 2006 
Colitis, infectious 
(e.g., Clostridium difficile) 
Colitis, infectious  
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain with 
mucus and/or blood in 
stool 
IV antibiotics or TPN 
indicated  
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis or 
toxic megacolon); 
operative resection or 
diversion indicated 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select; Typhlitis (cecal inflammation).  
Febrile neutropenia 
(fever of unknown origin 
without clinically or 
microbiologically 
documented infection) 
(ANC <1.0 x 109/L, fever 
≥38.5°C) 
Febrile neutropenia 
— 
— 
Present 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
ALSO CONSIDER: Neutrophils/granulocytes (ANC/AGC). 
Infection  
(documented clinically or 
microbiologically) with 
Grade 3 or 4 neutrophils  
(ANC <1.0 x 109/L) 
– Select  
‘Select’ AEs appear at the 
end of the CATEGORY. 
Infection (documented 
clinically) with Grade 3 or 
4 ANC – Select 
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
REMARK: Fever with Grade 3 or 4 neutrophils in the absence of documented infection is graded as Febrile neutropenia (fever of unknown origin without clinically or microbiologically 
documented infection). 
ALSO CONSIDER: Neutrophils/granulocytes (ANC/AGC). 
Infection with normal 
ANC or Grade 1 or 2 
neutrophils  
– Select  
‘Select’ AEs appear at the 
end of the CATEGORY. 
Infection with normal 
ANC – Select 
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 

 
INFECTION 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 36 - 
March 31, 2003, Publish Date: August 9, 2006 
Infection with unknown 
ANC 
– Select  
‘Select’ AEs appear at the 
end of the CATEGORY. 
Infection with unknown 
ANC – Select 
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
REMARK: Infection with unknown ANC – Select is to be used in the rare case when ANC is unknown. 
Opportunistic infection 
associated with ≥Grade 2 
Lymphopenia 
Opportunistic infection  
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
ALSO CONSIDER: Lymphopenia. 
Viral hepatitis 
Viral hepatitis 
Present; transaminases 
and liver function normal 
Transaminases 
abnormal, liver function 
normal  
Symptomatic liver 
dysfunction; fibrosis by 
biopsy; compensated 
cirrhosis 
Decompensated liver 
function (e.g., ascites, 
coagulopathy, 
encephalopathy, coma) 
Death 
REMARK: Non-viral hepatitis is graded as Infection – Select. 
ALSO CONSIDER: Albumin, serum-low (hypoalbuminemia); ALT, SGPT (serum glutamic pyruvic transaminase); AST, SGOT (serum glutamic oxaloacetic transaminase); Bilirubin 
(hyperbilirubinemia); Encephalopathy. 
Infection – Other 
(Specify, __) 
Infection – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
INFECTION – SELECT 
Page 3 of 3 
CTCAE v3.0  
- 37 - 
March 31, 2003, Publish Date: August 9, 2006 
AUDITORY/EAR 
– External ear (otitis externa) 
– Middle ear (otitis media) 
CARDIOVASCULAR 
– Artery 
– Heart (endocarditis) 
– Spleen 
– Vein 
DERMATOLOGY/SKIN  
– Lip/perioral 
– Peristomal 
– Skin (cellulitis) 
– Ungual (nails) 
GASTROINTESTINAL  
– Abdomen NOS 
– Anal/perianal 
– Appendix 
– Cecum 
– Colon 
– Dental-tooth 
– Duodenum 
– Esophagus 
– Ileum 
– Jejunum 
– Oral cavity-gums (gingivitis) 
– Peritoneal cavity 
– Rectum 
– Salivary gland 
– Small bowel NOS 
– Stomach 
GENERAL 
– Blood 
– Catheter-related 
– Foreign body (e.g., graft, implant,  
prosthesis, stent) 
– Wound  
HEPATOBILIARY/PANCREAS 
– Biliary tree 
– Gallbladder (cholecystitis) 
– Liver 
– Pancreas 
LYMPHATIC 
– Lymphatic 
MUSCULOSKELETAL 
– Bone (osteomyelitis) 
– Joint 
– Muscle (infection myositis) 
– Soft tissue NOS 
NEUROLOGY 
– Brain (encephalitis, infectious) 
– Brain + Spinal cord (encephalomyelitis) 
– Meninges (meningitis) 
– Nerve-cranial 
– Nerve-peripheral 
– Spinal cord (myelitis) 
OCULAR 
– Conjunctiva 
– Cornea 
– Eye NOS 
– Lens 
PULMONARY/UPPER RESPIRATORY 
– Bronchus 
– Larynx 
– Lung (pneumonia) 
– Mediastinum NOS 
– Mucosa 
– Neck NOS 
– Nose 
– Paranasal 
– Pharynx 
– Pleura (empyema) 
– Sinus 
– Trachea 
– Upper aerodigestive NOS 
– Upper airway NOS  
RENAL/GENITOURINARY  
– Bladder (urinary) 
– Kidney 
– Prostate 
– Ureter 
– Urethra 
– Urinary tract NOS 
SEXUAL/REPRODUCTIVE FUNCTION 
– Cervix 
– Fallopian tube 
– Pelvis NOS 
– Penis 
– Scrotum 
– Uterus 
– Vagina 
– Vulva 
 

 
LYMPHATICS 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 38 - 
March 31, 2003, Publish Date: August 9, 2006 
Chyle or lymph leakage  
Chyle or lymph leakage 
Asymptomatic, clinical or 
radiographic findings 
Symptomatic, medical 
intervention indicated  
Interventional radiology 
or operative intervention 
indicated 
Life-threatening 
complications 
Death 
ALSO CONSIDER: Chylothorax. 
Dermal change 
lymphedema, 
phlebolymphedema  
Dermal change 
Trace thickening or faint 
discoloration 
Marked discoloration; 
leathery skin texture; 
papillary formation 
— 
— 
— 
REMARK: Dermal change lymphedema, phlebolymphedema refers to changes due to venous stasis. 
ALSO CONSIDER: Ulceration.  
Edema: 
head and neck 
Edema: head and neck 
Localized to dependent 
areas, no disability or 
functional impairment 
Localized facial or neck 
edema with functional 
impairment 
Generalized facial or 
neck edema with 
functional impairment 
(e.g., difficulty in turning 
neck or opening mouth 
compared to baseline) 
Severe with ulceration or 
cerebral edema; 
tracheotomy or feeding 
tube indicated 
Death 
Edema: 
limb 
Edema: limb 
5 – 10% inter-limb 
discrepancy in volume or 
circumference at point of 
greatest visible 
difference; swelling or 
obscuration of anatomic 
architecture on close 
inspection; pitting edema 
>10 – 30% inter-limb 
discrepancy in volume or 
circumference at point of 
greatest visible 
difference; readily 
apparent obscuration of 
anatomic architecture; 
obliteration of skin folds; 
readily apparent 
deviation from normal 
anatomic contour  
>30% inter-limb 
discrepancy in volume; 
lymphorrhea; gross 
deviation from normal 
anatomic contour; 
interfering with ADL 
Progression to 
malignancy (i.e., 
lymphangiosarcoma); 
amputation indicated; 
disabling 
Death 
Edema: 
trunk/genital 
Edema: trunk/genital 
Swelling or obscuration 
of anatomic architecture 
on close inspection; 
pitting edema 
Readily apparent 
obscuration of anatomic 
architecture; obliteration 
of skin folds; readily 
apparent deviation from 
normal anatomic contour 
Lymphorrhea; interfering 
with ADL; gross deviation 
from normal anatomic 
contour 
Progression to 
malignancy (i.e., 
lymphangiosarcoma); 
disabling  
Death 
Edema: 
viscera 
Edema: viscera 
Asymptomatic; clinical or 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and unable 
to aliment adequately 
orally; interventional 
radiology or operative 
intervention indicated  
Life-threatening 
consequences 
Death 

 
LYMPHATICS 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 39 - 
March 31, 2003, Publish Date: August 9, 2006 
Lymphedema-related 
fibrosis 
Lymphedema-related 
fibrosis 
Minimal to moderate 
redundant soft tissue, 
unresponsive to elevation 
or compression, with 
moderately firm texture or 
spongy feel 
Marked increase in 
density and firmness, 
with or without tethering 
Very marked density and 
firmness with tethering 
affecting ≥40% of the 
edematous area 
— 
— 
Lymphocele 
Lymphocele 
Asymptomatic, clinical or 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and 
interventional radiology 
or operative intervention 
indicated 
— 
— 
Phlebolymphatic cording  
Phlebolymphatic cording 
Asymptomatic, clinical 
findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and leading 
to contracture or reduced 
range of motion 
— 
— 
Lymphatics – Other  
(Specify, __) 
Lymphatics – Other  
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling 
Death 

 
METABOLIC/LABORATORY 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 40 - 
March 31, 2003, Publish Date: August 9, 2006 
Acidosis  
(metabolic or respiratory) 
Acidosis  
pH <normal, but ≥7.3 
— 
pH <7.3 
pH <7.3 with life-
threatening 
consequences 
Death 
Albumin, serum-low 
(hypoalbuminemia)  
Hypoalbuminemia 
<LLN – 3 g/dL  
<LLN – 30 g/L 
<3 – 2 g/dL 
<30 – 20 g/L  
<2 g/dL  
<20 g/L 
— 
Death 
Alkaline phosphatase 
Alkaline phosphatase 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Alkalosis  
(metabolic or respiratory) 
Alkalosis 
pH >normal, but ≤7.5 
— 
pH >7.5 
pH >7.5 with life-
threatening 
consequences 
Death 
ALT, SGPT  
(serum glutamic pyruvic 
transaminase) 
ALT 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Amylase 
Amylase 
>ULN – 1.5 x ULN 
>1.5 – 2.0 x ULN 
>2.0 – 5.0 x ULN 
>5.0 x ULN 
— 
AST, SGOT 
(serum glutamic 
oxaloacetic 
transaminase) 
AST 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Bicarbonate, serum-low  
Bicarbonate, serum-low 
<LLN – 16 mmol/L 
<16 – 11 mmol/L 
<11 – 8 mmol/L 
<8 mmol/L 
Death 
Bilirubin 
(hyperbilirubinemia) 
Bilirubin 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x ULN 
>3.0 – 10.0 x ULN 
>10.0 x ULN 
— 
REMARK: Jaundice is not an AE, but may be a manifestation of liver dysfunction/failure or elevated bilirubin. If jaundice is associated with elevated bilirubin, grade bilirubin. 
Calcium, serum-low 
(hypocalcemia) 
Hypocalcemia 
<LLN – 8.0 mg/dL 
<LLN – 2.0 mmol/L 
Ionized calcium: 
<LLN – 1.0 mmol/L 
<8.0 – 7.0 mg/dL 
<2.0 – 1.75 mmol/L 
Ionized calcium: 
<1.0 – 0.9 mmol/L 
<7.0 – 6.0 mg/dL 
<1.75 – 1.5 mmol/L 
Ionized calcium: 
<0.9 – 0.8 mmol/L 
<6.0 mg/dL 
<1.5 mmol/L 
Ionized calcium: 
<0.8 mmol/L 
Death 
REMARK: Calcium can be falsely low if hypoalbuminemia is present. Serum albumin is <4.0 g/dL, hypocalcemia is reported after the following corrective calculation has been 
performed: Corrected Calcium (mg/dL) = Total Calcium (mg/dL) – 0.8 [Albumin (g/dL) – 4] 4. Alternatively, direct measurement of ionized calcium is the definitive method to diagnose 
metabolically relevant alterations in serum calcium. 
                                            
4Crit Rev Clin Lab Sci 1984;21(1):51-97 

 
METABOLIC/LABORATORY 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 41 - 
March 31, 2003, Publish Date: August 9, 2006 
Calcium, serum-high 
(hypercalcemia) 
Hypercalcemia 
>ULN – 11.5 mg/dL 
>ULN – 2.9 mmol/L 
Ionized calcium: 
>ULN – 1.5 mmol/L 
>11.5 – 12.5 mg/dL 
>2.9 – 3.1 mmol/L 
Ionized calcium: 
>1.5 – 1.6 mmol/L 
>12.5 – 13.5 mg/dL 
>3.1 – 3.4 mmol/L 
Ionized calcium: 
>1.6 – 1.8 mmol/L 
>13.5 mg/dL 
>3.4 mmol/L 
Ionized calcium: 
>1.8 mmol/L 
Death 
Cholesterol, serum-high 
(hypercholesteremia) 
Cholesterol 
>ULN – 300 mg/dL 
>ULN – 7.75 mmol/L 
>300 – 400 mg/dL 
>7.75 – 10.34 mmol/L 
>400 – 500 mg/dL 
>10.34 – 12.92 mmol/L 
>500 mg/dL 
>12.92 mmol/L 
Death 
CPK (creatine 
phosphokinase) 
CPK 
>ULN – 2.5 x ULN 
>2.5 x ULN – 5 x ULN 
>5 x ULN – 10 x ULN 
>10 x ULN 
Death 
Creatinine 
Creatinine 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x ULN 
>3.0 – 6.0 x ULN 
>6.0 x ULN 
Death 
REMARK: Adjust to age-appropriate levels for pediatric patients.  
ALSO CONSIDER: Glomerular filtration rate. 
GGT (γ-Glutamyl 
transpeptidase) 
GGT 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Glomerular filtration rate  
GFR 
<75 – 50% LLN 
<50 – 25% LLN 
<25% LLN, chronic 
dialysis not indicated 
Chronic dialysis or renal 
transplant indicated 
Death 
ALSO CONSIDER: Creatinine. 
Glucose, serum-high 
(hyperglycemia)  
Hyperglycemia 
>ULN – 160 mg/dL 
>ULN – 8.9 mmol/L 
>160 – 250 mg/dL 
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL 
>13.9 – 27.8 mmol/L 
>500 mg/dL 
>27.8 mmol/L or acidosis 
Death 
REMARK: Hyperglycemia, in general, is defined as fasting unless otherwise specified in protocol. 
Glucose, serum-low 
(hypoglycemia) 
Hypoglycemia 
<LLN – 55 mg/dL 
<LLN – 3.0 mmol/L 
<55 – 40 mg/dL 
<3.0 – 2.2 mmol/L 
<40 – 30 mg/dL 
<2.2 – 1.7 mmol/L 
<30 mg/dL 
<1.7 mmol/L 
Death 
Hemoglobinuria 
Hemoglobinuria 
Present 
— 
— 
— 
Death 
Lipase 
Lipase 
>ULN – 1.5 x ULN 
>1.5 – 2.0 x ULN 
>2.0 – 5.0 x ULN 
>5.0 x ULN 
— 
Magnesium, serum-high 
(hypermagnesemia) 
Hypermagnesemia 
>ULN – 3.0 mg/dL 
>ULN – 1.23 mmol/L 
— 
>3.0 – 8.0 mg/dL 
>1.23 – 3.30 mmol/L 
>8.0 mg/dL 
>3.30 mmol/L 
Death 
Magnesium, serum-low 
(hypomagnesemia)  
Hypomagnesemia 
<LLN – 1.2 mg/dL 
<LLN – 0.5 mmol/L 
<1.2 – 0.9 mg/dL 
<0.5 – 0.4 mmol/L 
<0.9 – 0.7 mg/dL 
<0.4 – 0.3 mmol/L 
<0.7 mg/dL 
<0.3 mmol/L 
Death 
Phosphate, serum-low 
(hypophosphatemia)  
Hypophosphatemia 
<LLN – 2.5 mg/dL 
<LLN – 0.8 mmol/L 
<2.5 – 2.0 mg/dL  
<0.8 – 0.6 mmol/L 
<2.0 – 1.0 mg/dL 
<0.6 – 0.3 mmol/L 
<1.0 mg/dL 
<0.3 mmol/L 
Death 
Potassium, serum-high 
(hyperkalemia) 
Hyperkalemia 
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L 
>6.0 – 7.0 mmol/L 
>7.0 mmol/L 
Death 

 
METABOLIC/LABORATORY 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 42 - 
March 31, 2003, Publish Date: August 9, 2006 
Potassium, serum-low 
(hypokalemia)  
Hypokalemia 
<LLN – 3.0 mmol/L 
— 
<3.0 – 2.5 mmol/L 
<2.5 mmol/L 
Death 
Proteinuria 
Proteinuria 
1+ or 
0.15 – 1.0 g/24 hrs 
2+ to 3+ or 
>1.0 – 3.5 g/24 hrs  
4+ or 
>3.5 g/24 hrs 
Nephrotic syndrome 
Death 
Sodium, serum-high 
(hypernatremia) 
Hypernatremia 
>ULN – 150 mmol/L 
>150 – 155 mmol/L 
>155 – 160 mmol/L 
>160 mmol/L 
Death 
Sodium, serum-low 
(hyponatremia) 
Hyponatremia 
<LLN – 130 mmol/L 
— 
<130 – 120 mmol/L 
<120 mmol/L 
Death 
Triglyceride, serum-high 
(hypertriglyceridemia) 
Hypertriglyceridemia 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 10 x ULN 
>10 x ULN 
Death 
Uric acid, serum-high 
(hyperuricemia) 
Hyperuricemia 
>ULN – 10 mg/dL 
≤0.59 mmol/L without 
physiologic 
consequences 
— 
>ULN – 10 mg/dL 
≤0.59 mmol/L with 
physiologic 
consequences 
>10 mg/dL 
>0.59 mmol/L 
Death 
ALSO CONSIDER: Creatinine; Potassium, serum-high (hyperkalemia); Renal failure; Tumor lysis syndrome. 
Metabolic/Laboratory – 
Other (Specify, __) 
Metabolic/Lab – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
MUSCULOSKELETAL/SOFT TISSUE 
Page 1 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 43 - 
March 31, 2003, Publish Date: August 9, 2006 
Arthritis (non-septic) 
Arthritis 
Mild pain with 
inflammation, erythema, 
or joint swelling, but not 
interfering with function 
Moderate pain with 
inflammation, erythema, 
or joint swelling 
interfering with function, 
but not interfering with 
ADL 
Severe pain with 
inflammation, erythema, 
or joint swelling and 
interfering with ADL 
Disabling 
Death 
REMARK: Report only when the diagnosis of arthritis (e.g., inflammation of a joint or a state characterized by inflammation of joints) is made. Arthralgia (sign or symptom of pain in a 
joint, especially non-inflammatory in character) is graded as Pain – Select in the PAIN CATEGORY.  
Bone: 
spine-scoliosis 
Scoliosis  
≤20 degrees; clinically 
undetectable 
>20 – 45 degrees; visible 
by forward flexion; 
interfering with function 
but not interfering with 
ADL 
>45 degrees; scapular 
prominence in forward 
flexion; operative 
intervention indicated; 
interfering with ADL 
Disabling (e.g., interfering 
with cardiopulmonary 
function) 
Death 
Cervical spine-range of 
motion 
Cervical spine ROM 
Mild restriction of rotation 
or flexion between  
60 – 70 degrees 
Rotation <60 degrees to 
right or left; <60 degrees 
of flexion 
Ankylosed/fused over 
multiple segments with 
no C-spine rotation 
— 
— 
REMARK: 60 – 65 degrees of rotation is required for reversing a car; 60 – 65 degrees of flexion is required to tie shoes. 
Exostosis 
Exostosis 
Asymptomatic 
Involving multiple sites; 
pain or interfering with 
function  
Excision indicated 
Progression to 
malignancy (i.e., 
chondrosarcoma) 
Death 
Extremity-lower 
(gait/walking) 
Gait/walking 
Limp evident only to 
trained observer and able 
to walk ≥1 kilometer; 
cane indicated for 
walking 
Noticeable limp, or 
limitation of limb function, 
but able to walk ≥0.1 
kilometer (1 city block); 
quad cane indicated for 
walking 
Severe limp with stride 
modified to maintain 
balance (widened base of 
support, marked 
reduction in step length); 
ambulation limited to 
walker; crutches 
indicated 
Unable to walk 
— 
ALSO CONSIDER: Ataxia (incoordination); Muscle weakness, generalized or specific area (not due to neuropathy) – Select.  
Extremity-upper 
(function)  
Extremity-upper 
(function) 
Able to perform most 
household or work 
activities with affected 
limb 
Able to perform most 
household or work 
activities with 
compensation from 
unaffected limb 
Interfering with ADL  
Disabling; no function of 
affected limb 
— 
Fibrosis-cosmesis 
Fibrosis-cosmesis 
Visible only on close 
examination 
Readily apparent but not 
disfiguring 
Significant disfigurement; 
operative intervention 
indicated if patient 
chooses 
— 
— 

 
MUSCULOSKELETAL/SOFT TISSUE 
Page 2 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 44 - 
March 31, 2003, Publish Date: August 9, 2006 
Fibrosis-deep connective 
tissue 
Fibrosis-deep connective 
tissue  
Increased density, 
“spongy” feel 
Increased density with 
firmness or tethering 
Increased density with 
fixation of tissue; 
operative intervention 
indicated; interfering with 
ADL 
Life-threatening; 
disabling; loss of limb; 
interfering with vital organ 
function 
Death 
ALSO CONSIDER: Induration/fibrosis (skin and subcutaneous tissue); Muscle weakness, generalized or specific area (not due to neuropathy) – Select; Neuropathy: motor; Neuropathy: 
sensory. 
Fracture 
Fracture 
Asymptomatic, 
radiographic findings only 
(e.g., asymptomatic rib 
fracture on plain x-ray, 
pelvic insufficiency 
fracture on MRI, etc.) 
Symptomatic but non-
displaced; immobilization 
indicated 
Symptomatic and 
displaced or open wound 
with bone exposure; 
operative intervention 
indicated 
Disabling; amputation 
indicated 
Death 
Joint-effusion 
Joint-effusion 
Asymptomatic, clinical or 
radiographic findings only 
Symptomatic; interfering 
with function but not 
interfering with ADL 
Symptomatic and 
interfering with ADL 
Disabling 
Death 
ALSO CONSIDER: Arthritis (non-septic). 
Joint-function5 
Joint-function 
Stiffness interfering with 
athletic activity; ≤25% 
loss of range of motion 
(ROM) 
Stiffness interfering with 
function but not 
interfering with ADL;  
>25 – 50% decrease in 
ROM 
Stiffness interfering with 
ADL; >50 – 75% 
decrease in ROM  
Fixed or non-functional 
joint (arthrodesis); 
>75% decrease in ROM 
— 
ALSO CONSIDER: Arthritis (non-septic). 
Local complication –
device/prosthesis-related 
Device/prosthesis 
Asymptomatic  
Symptomatic, but not 
interfering with ADL; local 
wound care; medical 
intervention indicated 
Symptomatic, interfering 
with ADL; operative 
intervention indicated 
(e.g., hardware/device 
replacement or removal, 
reconstruction)  
Life-threatening; 
disabling; loss of limb or 
organ 
Death 
Lumbar spine-range of 
motion 
Lumbar spine ROM 
Stiffness and difficulty 
bending to the floor to 
pick up a very light object 
but able to do activity 
Some lumbar spine 
flexion but requires a 
reaching aid to pick up a 
very light object from the 
floor 
Ankylosed/fused over 
multiple segments with 
no L-spine flexion (i.e., 
unable to reach to floor to 
pick up a very light 
— 
— 
                                            
5 Adapted from the International SFTR Method of Measuring and Recording Joint Motion, International Standard Orthopedic Measurements (ISOM), Jon J. Gerhardt and Otto A. 
Russee, Bern, Switzerland, Han Huber 9 Publisher), 1975. 

 
MUSCULOSKELETAL/SOFT TISSUE 
Page 3 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 45 - 
March 31, 2003, Publish Date: August 9, 2006 
object) 
Muscle weakness, 
generalized or specific 
area (not due to 
neuropathy)  
– Select: 
Muscle weakness  
– Select  
– Extraocular 
– Extremity-lower  
– Extremity-upper 
– Facial 
– Left-sided 
– Ocular 
– Pelvic 
– Right-sided 
– Trunk 
– Whole body/generalized  
Asymptomatic, weakness 
on physical exam 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Life-threatening; disabling 
Death 
ALSO CONSIDER: Fatigue (asthenia, lethargy, malaise). 
Muscular/skeletal 
hypoplasia 
Muscular/skeletal 
hypoplasia 
Cosmetically and 
functionally insignificant 
hypoplasia  
Deformity, hypoplasia, or 
asymmetry able to be 
remediated by prosthesis 
(e.g., shoe insert) or 
covered by clothing  
Functionally significant 
deformity, hypoplasia, or 
asymmetry, unable to be 
remediated by prosthesis 
or covered by clothing  
Disabling 
— 
Myositis 
(inflammation/damage of 
muscle) 
Myositis 
Mild pain, not interfering 
with function 
Pain interfering with 
function, but not 
interfering with ADL 
Pain interfering with ADL 
Disabling 
Death 
REMARK: Myositis implies muscle damage (i.e., elevated CPK). 
ALSO CONSIDER: CPK (creatine phosphokinase); Pain – Select. 
Osteonecrosis  
(avascular necrosis) 
Osteonecrosis 
Asymptomatic, 
radiographic findings only 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL; minimal bone 
removal indicated (i.e., 
minor sequestrectomy)  
Symptomatic and 
interfering with ADL; 
operative intervention or 
hyperbaric oxygen 
indicated 
Disabling  
Death 

 
MUSCULOSKELETAL/SOFT TISSUE 
Page 4 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 46 - 
March 31, 2003, Publish Date: August 9, 2006 
Osteoporosis6 
Osteoporosis 
Radiographic evidence of 
osteoporosis or Bone 
Mineral Density (BMD) 
t-score –1 to –2.5 
(osteopenia) and no loss 
of height or therapy 
indicated 
BMD t-score < –2.5; loss 
of height <2 cm; anti-
osteoporotic therapy 
indicated 
Fractures; loss of height 
≥2 cm 
Disabling 
Death 
Seroma 
Seroma 
Asymptomatic 
Symptomatic; medical 
intervention or simple 
aspiration indicated 
Symptomatic, 
interventional radiology 
or operative intervention 
indicated 
— 
— 
Soft tissue necrosis 
– Select: 
– Abdomen 
– Extremity-lower 
– Extremity-upper  
– Head 
– Neck 
– Pelvic 
– Thorax 
Soft tissue necrosis 
– Select 
— 
Local wound care; 
medical intervention 
indicated 
Operative debridement or 
other invasive 
intervention indicated 
(e.g., hyperbaric oxygen)  
Life-threatening 
consequences; major 
invasive intervention 
indicated (e.g., tissue 
reconstruction, flap, or 
grafting) 
Death 
Trismus (difficulty, 
restriction or pain when 
opening mouth) 
Trismus 
Decreased range of 
motion without impaired 
eating  
Decreased range of 
motion requiring small 
bites, soft foods or 
purees 
Decreased range of 
motion with inability to 
adequately aliment or 
hydrate orally 
— 
— 
NAVIGATION NOTE: Wound-infectious is graded as Infection – Select in the INFECTION CATEGORY. 
NAVIGATION NOTE: Wound non-infectious is graded as Wound complication, non-infectious in the DERMATOLOGY/SKIN CATEGORY.  
Musculoskeletal/Soft 
Tissue – Other 
(Specify, __) 
Musculoskeletal – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
                                            
6 "Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis," Report of a WHO Study Group Technical Report Series, No. 843, 1994, v + 129 
pages [C*, E, F, R, S], ISBN 92 4 120843 0, Sw.fr. 22.-/US $19.80; in developing countries: Sw.fr. 15.40, Order no. 1100843 

 
NEUROLOGY 
Page 1 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 47 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: ADD (Attention Deficit Disorder) is graded as Cognitive disturbance. 
NAVIGATION NOTE: Aphasia, receptive and/or expressive, is graded as Speech impairment (e.g., dysphasia or aphasia). 
Apnea 
Apnea 
— 
— 
Present 
Intubation indicated  
Death 
Arachnoiditis/ 
meningismus/radiculitis 
Arachnoiditis 
Symptomatic, not 
interfering with function; 
medical intervention 
indicated 
Symptomatic (e.g., 
photophobia, nausea) 
interfering with function 
but not interfering with 
ADL  
Symptomatic, interfering 
with ADL 
Life-threatening; disabling 
(e.g., paraplegia) 
Death 
ALSO CONSIDER: Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 109/L); Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select; Pain – Select; Vomiting. 
Ataxia (incoordination) 
Ataxia 
Asymptomatic  
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL; mechanical 
assistance indicated  
Disabling 
Death 
REMARK: Ataxia (incoordination) refers to the consequence of medical or operative intervention. 
Brachial plexopathy 
Brachial plexopathy 
Asymptomatic 
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
Disabling 
Death 
CNS cerebrovascular 
ischemia 
CNS ischemia 
— 
Asymptomatic, 
radiographic findings only 
Transient ischemic event 
or attack (TIA) ≤24 hrs 
duration 
Cerebral vascular 
accident (CVA, stroke), 
neurologic deficit 
>24 hrs  
Death 
NAVIGATION NOTE: CNS hemorrhage/bleeding is graded as Hemorrhage, CNS in the HEMORRHAGE/BLEEDING CATEGORY.  
CNS necrosis/cystic 
progression 
CNS necrosis 
Asymptomatic, 
radiographic findings only 
Symptomatic, not 
interfering with ADL; 
medical intervention 
indicated 
Symptomatic and 
interfering with ADL; 
hyperbaric oxygen 
indicated 
Life-threatening; 
disabling; operative 
intervention indicated to 
prevent or treat CNS 
necrosis/cystic 
progression 
Death 
Cognitive disturbance 
Cognitive disturbance 
Mild cognitive disability; 
not interfering with 
work/school/life 
performance; specialized 
educational 
services/devices not 
indicated 
Moderate cognitive 
disability; interfering with 
work/school/life 
performance but capable 
of independent living; 
specialized resources on 
part-time basis indicated 
Severe cognitive 
disability; significant 
impairment of 
work/school/life 
performance 
Unable to perform ADL; 
full-time specialized 
resources or 
institutionalization 
indicated 
Death 
REMARK: Cognitive disturbance may be used for Attention Deficit Disorder (ADD). 

 
NEUROLOGY 
Page 2 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 48 - 
March 31, 2003, Publish Date: August 9, 2006 
Confusion 
Confusion 
Transient confusion, 
disorientation, or attention 
deficit 
Confusion, disorientation, 
or attention deficit 
interfering with function, 
but not interfering with 
ADL 
Confusion or delirium 
interfering with ADL 
Harmful to others or self; 
hospitalization indicated 
Death 
REMARK: Attention Deficit Disorder (ADD) is graded as Cognitive disturbance. 
NAVIGATION NOTE: Cranial neuropathy is graded as Neuropathy-cranial – Select. 
Dizziness  
Dizziness 
With head movements or 
nystagmus only; not 
interfering with function 
Interfering with function, 
but not interfering with 
ADL 
Interfering with ADL 
Disabling 
— 
REMARK: Dizziness includes disequilibrium, lightheadedness, and vertigo. 
ALSO CONSIDER: Neuropathy: cranial – Select; Syncope (fainting). 
NAVIGATION NOTE: Dysphasia, receptive and/or expressive, is graded as Speech impairment (e.g., dysphasia or aphasia). 
Encephalopathy 
Encephalopathy 
— 
Mild signs or symptoms; 
not interfering with ADL 
Signs or symptoms 
interfering with ADL; 
hospitalization indicated 
Life-threatening; disabling 
Death 
ALSO CONSIDER: Cognitive disturbance; Confusion; Dizziness; Memory impairment; Mental status; Mood alteration – Select; Psychosis (hallucinations/delusions); 
Somnolence/depressed level of consciousness. 
Extrapyramidal/ 
involuntary movement/ 
restlessness 
Involuntary movement 
Mild involuntary 
movements not 
interfering with function 
Moderate involuntary 
movements interfering 
with function, but not 
interfering with ADL 
Severe involuntary 
movements or torticollis 
interfering with ADL 
Disabling 
 
Death 
NAVIGATION NOTE: Headache/neuropathic pain (e.g., jaw pain, neurologic pain, phantom limb pain, post-infectious neuralgia, or painful neuropathies) is graded as Pain – Select in the 
PAIN CATEGORY. 
Hydrocephalus 
Hydrocephalus 
Asymptomatic, 
radiographic findings only 
Mild to moderate 
symptoms not interfering 
with ADL 
Severe symptoms or 
neurological deficit 
interfering with ADL 
Disabling  
Death 
Irritability (children <3 
years of age) 
Irritability 
Mild; easily consolable 
Moderate; requiring 
increased attention 
Severe; inconsolable 
— 
— 
Laryngeal nerve 
dysfunction  
Laryngeal nerve 
Asymptomatic, weakness 
on clinical 
examination/testing only 
Symptomatic, but not 
interfering with ADL; 
intervention not indicated 
Symptomatic, interfering 
with ADL; intervention 
indicated (e.g., 
thyroplasty, vocal cord 
injection) 
Life-threatening; 
tracheostomy indicated 
 
Death 

 
NEUROLOGY 
Page 3 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 49 - 
March 31, 2003, Publish Date: August 9, 2006 
Leak, cerebrospinal fluid 
(CSF) 
CSF leak 
Transient headache; 
postural care indicated 
Symptomatic, not 
interfering with ADL; 
blood patch indicated 
Symptomatic, interfering 
with ADL; operative 
intervention indicated 
Life-threatening; disabling 
Death 
REMARK: Leak, cerebrospinal fluid (CSF) may be used for CSF leak associated with operation and persisting >72 hours. 
Leukoencephalopathy 
(radiographic findings) 
Leukoencephalopathy  
Mild increase in 
subarachnoid space 
(SAS); mild 
ventriculomegaly; small 
(+/- multiple) focal T2 
hyperintensities, involving 
periventricular white 
matter or <1/3 of 
susceptible areas of 
cerebrum 
Moderate increase in 
SAS; moderate 
ventriculomegaly; focal 
T2 hyperintensities 
extending into centrum 
ovale or involving 1/3 to 
2/3 of susceptible areas 
of cerebrum 
Severe increase in SAS; 
severe ventriculomegaly; 
near total white matter T2 
hyperintensities or diffuse 
low attenuation (CT) 
— 
— 
REMARK: Leukoencephalopathy is a diffuse white matter process, specifically NOT associated with necrosis. Leukoencephalopathy (radiographic findings) does not include lacunas, 
which are areas that become void of neural tissue.  
Memory impairment 
Memory impairment 
Memory impairment not 
interfering with function 
Memory impairment 
interfering with function, 
but not interfering with 
ADL 
Memory impairment 
interfering with ADL 
Amnesia 
— 
Mental status7 
Mental status 
— 
1 – 3 point below age  
and educational norm in 
Folstein Mini-Mental 
Status Exam (MMSE) 
>3 point below age and 
educational norm in 
Folstein MMSE  
— 
— 
Mood alteration  
– Select: 
– Agitation 
– Anxiety 
– Depression 
– Euphoria 
Mood alteration – Select 
Mild mood alteration not 
interfering with function 
Moderate mood alteration 
interfering with function, 
but not interfering with 
ADL; medication 
indicated 
Severe mood alteration 
interfering with ADL 
Suicidal ideation; danger 
to self or others 
Death 
Myelitis 
Myelitis 
Asymptomatic, mild signs 
(e.g., Babinski’s or 
Lhermitte’s sign) 
Weakness or sensory 
loss not interfering with 
ADL 
Weakness or sensory 
loss interfering with ADL 
Disabling 
Death 
                                            
7 Folstein MF, Folstein, SE and McHugh PR (1975) "Mini-Mental State: A Practical Method for Grading the State of Patients for the Clinician," Journal of Psychiatric Research, 12: 
189-198 

 
NEUROLOGY 
Page 4 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 50 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Neuropathic pain is graded as Pain – Select in the PAIN CATEGORY.  
Neuropathy: 
cranial  
– Select: 
Neuropathy: cranial  
– Select 
Asymptomatic, detected 
on exam/testing only 
– CN I  
Smell 
– CN II  Vision 
– CN III  Pupil, upper eyelid, extra ocular movements 
– CN IV  Downward, inward movement of eye 
– CN V  Motor-jaw muscles; Sensory-facial 
– CN VI  Lateral deviation of eye 
– CN VII Motor-face; Sensory-taste 
– CN VIII Hearing and balance 
– CN IX Motor-pharynx; Sensory-ear, pharynx, tongue 
– CN X 
Motor-palate; pharynx, larynx 
– CN XI Motor-sternomastoid and trapezius 
– CN XII Motor-tongue 
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
Life-threatening; disabling 
Death 
Neuropathy: 
motor  
Neuropathy-motor 
Asymptomatic, weakness 
on exam/testing only 
Symptomatic weakness 
interfering with function, 
but not interfering with 
ADL 
Weakness interfering with 
ADL; bracing or 
assistance to walk (e.g., 
cane or walker) indicated 
Life-threatening; disabling 
(e.g., paralysis)  
Death 
REMARK: Cranial nerve motor neuropathy is graded as Neuropathy: cranial – Select. 
ALSO CONSIDER: Laryngeal nerve dysfunction; Phrenic nerve dysfunction.  
Neuropathy: 
sensory 
Neuropathy-sensory 
Asymptomatic; loss of 
deep tendon reflexes or 
paresthesia (including 
tingling) but not 
interfering with function 
Sensory alteration or 
paresthesia (including 
tingling), interfering with 
function, but not 
interfering with ADL 
Sensory alteration or 
paresthesia interfering 
with ADL  
Disabling  
Death 
REMARK: Cranial nerve sensory neuropathy is graded as Neuropathy: cranial – Select. 
Personality/behavioral 
Personality 
Change, but not 
adversely affecting 
patient or family 
Change, adversely 
affecting patient or family  
Mental health intervention 
indicated 
Change harmful to others 
or self; hospitalization 
indicated 
Death 
Phrenic nerve dysfunction  Phrenic nerve 
Asymptomatic weakness 
on exam/testing only 
Symptomatic but not 
interfering with ADL; 
intervention not indicated 
Significant dysfunction; 
intervention indicated 
(e.g., diaphragmatic 
plication) 
Life-threatening 
respiratory compromise; 
mechanical ventilation 
indicated 
Death 
Psychosis (hallucinations/ 
delusions) 
Psychosis 
— 
Transient episode 
Interfering with ADL; 
medication, supervision 
Harmful to others or self; 
life-threatening 
Death 

 
NEUROLOGY 
Page 5 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 51 - 
March 31, 2003, Publish Date: August 9, 2006 
or restraints indicated  
consequences 
Pyramidal tract 
dysfunction (e.g., ↑ tone, 
hyperreflexia, positive 
Babinski, ↓ fine motor 
coordination) 
Pyramidal tract 
dysfunction 
Asymptomatic, 
abnormality on exam or 
testing only  
Symptomatic; interfering 
with function but not 
interfering with ADL 
Interfering with ADL 
Disabling; paralysis 
Death 
Seizure 
Seizure 
— 
One brief generalized 
seizure; seizure(s) well 
controlled by 
anticonvulsants or 
infrequent focal motor 
seizures not interfering 
with ADL 
Seizures in which 
consciousness is altered; 
poorly controlled seizure 
disorder, with 
breakthrough generalized 
seizures despite medical 
intervention 
Seizures of any kind 
which are prolonged, 
repetitive, or difficult to 
control (e.g., status 
epilepticus, intractable 
epilepsy) 
Death 
Somnolence/depressed 
level of consciousness 
Somnolence 
— 
Somnolence or sedation 
interfering with function, 
but not interfering with 
ADL 
Obtundation or stupor; 
difficult to arouse; 
interfering with ADL 
Coma 
Death 
Speech impairment  
(e.g., dysphasia or 
aphasia)  
Speech impairment 
— 
Awareness of receptive 
or expressive dysphasia, 
not impairing ability to 
communicate 
Receptive or expressive 
dysphasia, impairing 
ability to communicate 
Inability to communicate 
— 
REMARK: Speech impairment refers to a primary CNS process, not neuropathy or end organ dysfunction. 
ALSO CONSIDER: Laryngeal nerve dysfunction; Voice changes/dysarthria (e.g., hoarseness, loss, or alteration in voice, laryngitis). 
Syncope (fainting) 
Syncope (fainting) 
— 
— 
Present 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: CNS cerebrovascular ischemia; Conduction abnormality/atrioventricular heart block – Select; Dizziness; Supraventricular and nodal arrhythmia – Select; Vasovagal 
episode; Ventricular arrhythmia – Select. 
NAVIGATION NOTE: Taste alteration (CN VII, IX) is graded as Taste alteration (dysgeusia) in the GASTROINTESTINAL CATEGORY. 
Tremor 
Tremor 
Mild and brief or 
intermittent but not 
interfering with function 
Moderate tremor 
interfering with function, 
but not interfering with 
ADL 
Severe tremor interfering 
with ADL 
Disabling 
— 
Neurology – Other 
(Specify, __) 
Neurology – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
OCULAR/VISUAL 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 52 - 
March 31, 2003, Publish Date: August 9, 2006 
Cataract 
Cataract 
Asymptomatic, detected 
on exam only  
Symptomatic, with 
moderate decrease in 
visual acuity  
(20/40 or better); 
decreased visual function 
correctable with glasses  
Symptomatic with marked 
decrease in visual acuity 
(worse than 20/40); 
operative intervention 
indicated (e.g., cataract 
surgery) 
— 
— 
Dry eye syndrome  
Dry eye 
Mild, intervention not 
indicated 
Symptomatic, interfering 
with function but not 
interfering with ADL; 
medical intervention 
indicated  
Symptomatic or decrease 
in visual acuity interfering 
with ADL; operative 
intervention indicated 
— 
— 
Eyelid dysfunction  
Eyelid dysfunction 
Asymptomatic  
Symptomatic, interfering 
with function but not ADL; 
requiring topical agents or 
epilation 
Symptomatic; interfering 
with ADL; surgical 
intervention indicated 
— 
— 
REMARK: Eyelid dysfunction includes canalicular stenosis, ectropion, entropion, erythema, madarosis, symblepharon, telangiectasis, thickening, and trichiasis. 
ALSO CONSIDER: Neuropathy: cranial – Select. 
Glaucoma  
Glaucoma 
Elevated intraocular 
pressure (EIOP) with 
single topical agent for 
intervention; no visual 
field deficit 
EIOP causing early visual 
field deficit (i.e., nasal 
step or arcuate deficit); 
multiple topical or oral 
agents indicated 
EIOP causing marked 
visual field deficits (i.e., 
involving both superior 
and inferior visual fields); 
operative intervention 
indicated 
EIOP resulting in 
blindness (20/200 or 
worse); enucleation 
indicated 
— 
Keratitis (corneal 
inflammation/corneal 
ulceration) 
Keratitis 
Abnormal ophthalmologic 
changes only; 
intervention not indicated 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL; 
operative intervention 
indicated 
Perforation or blindness 
(20/200 or worse)  
— 
NAVIGATION NOTE: Ocular muscle weakness is graded as Muscle weakness, generalized or specific area (not due to neuropathy) – Select in the MUSCULOSKELETAL/SOFT TISSUE 
CATEGORY.  
Night blindness 
(nyctalopia) 
Nyctalopia 
Symptomatic, not 
interfering with function 
Symptomatic and 
interfering with function 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL  
Disabling 
— 

 
OCULAR/VISUAL 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 53 - 
March 31, 2003, Publish Date: August 9, 2006 
Nystagmus 
Nystagmus 
Asymptomatic 
Symptomatic and 
interfering with function 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
ALSO CONSIDER: Neuropathy: cranial – Select; Ophthalmoplegia/diplopia (double vision). 
Ocular surface disease  
Ocular surface disease  
Asymptomatic or 
minimally symptomatic 
but not interfering with 
function 
Symptomatic, interfering 
with function but not 
interfering with ADL; 
topical antibiotics or other 
topical intervention 
indicated 
Symptomatic, interfering 
with ADL; operative 
intervention indicated 
— 
— 
REMARK: Ocular surface disease includes conjunctivitis, keratoconjunctivitis sicca, chemosis, keratinization, and palpebral conjunctival epithelial metaplasia. 
Ophthalmoplegia/ 
diplopia (double vision) 
Diplopia 
Intermittently 
symptomatic, intervention 
not indicated 
Symptomatic and 
interfering with function 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL; 
surgical intervention 
indicated 
Disabling 
— 
ALSO CONSIDER: Neuropathy: cranial – Select. 
Optic disc edema 
Optic disc edema 
Asymptomatic 
Decreased visual acuity 
(20/40 or better); visual 
field defect present 
Decreased visual acuity 
(worse than 20/40); 
marked visual field defect 
but sparing the central 20 
degrees 
Blindness  
(20/200 or worse) 
— 
ALSO CONSIDER: Neuropathy: cranial – Select.  
Proptosis/enophthalmos 
Proptosis/enophthalmos 
Asymptomatic, 
intervention not indicated 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
— 
— 
Retinal detachment 
Retinal detachment 
Exudative; no central 
vision loss; intervention 
not indicated 
Exudative and visual 
acuity 20/40 or better but 
intervention not indicated 
Rhegmatogenous or 
exudative detachment; 
operative intervention 
indicated 
Blindness 
(20/200 or worse) 
— 
Retinopathy  
Retinopathy 
Asymptomatic  
Symptomatic with 
moderate decrease in 
visual acuity 
(20/40 or better) 
Symptomatic with marked 
decrease in visual acuity 
(worse than 20/40) 
Blindness 
(20/200 or worse) 
— 

 
OCULAR/VISUAL 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 54 - 
March 31, 2003, Publish Date: August 9, 2006 
Scleral necrosis/melt 
Scleral necrosis 
Asymptomatic or 
symptomatic but not 
interfering with function 
Symptomatic, interfering 
with function but not 
interfering with ADL; 
moderate decrease in 
visual acuity (20/40 or 
better); medical 
intervention indicated 
Symptomatic, interfering 
with ADL; marked 
decrease in visual acuity 
(worse than 20/40); 
operative intervention 
indicated 
Blindness (20/200 or 
worse); painful eye with 
enucleation indicated 
— 
Uveitis  
Uveitis 
Asymptomatic 
Anterior uveitis; medical 
intervention indicated 
Posterior or pan-uveitis; 
operative intervention 
indicated 
Blindness 
(20/200 or worse) 
— 
Vision-blurred vision 
Blurred vision 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
Vision-flashing 
lights/floaters 
Flashing lights 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
Vision-photophobia 
Photophobia 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
Vitreous hemorrhage 
Vitreous hemorrhage 
Asymptomatic, clinical 
findings only 
Symptomatic, interfering 
with function, but not 
interfering with ADL; 
intervention not indicated 
Symptomatic, interfering 
with ADL; vitrectomy 
indicated  
— 
— 
Watery eye (epiphora, 
tearing) 
Watery eye 
Symptomatic, intervention 
not indicated 
Symptomatic, interfering 
with function but not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
— 
— 
Ocular/Visual – Other  
(Specify, __) 
Ocular – Other  
(Specify) 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Blindness 
(20/200 or worse) 
Death 

 
PAIN 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 55 - 
March 31, 2003, Publish Date: August 9, 2006 
Pain  
– Select: 
‘Select’ AEs appear at the 
end of the CATEGORY. 
Pain – Select  
Mild pain not interfering 
with function 
Moderate pain; pain or 
analgesics interfering with 
function, but not 
interfering with ADL 
Severe pain; pain or 
analgesics severely 
interfering with ADL 
Disabling 
— 
Pain – Other 
(Specify, __) 
Pain – Other (Specify) 
Mild pain not interfering 
with function 
Moderate pain; pain or 
analgesics interfering with 
function, but not 
interfering with ADL 
Severe pain; pain or 
analgesics severely 
interfering with ADL 
Disabling 
— 
PAIN – SELECT 
AUDITORY/EAR 
– External ear 
– Middle ear 
CARDIOVASCULAR 
– Cardiac/heart  
– Pericardium 
DERMATOLOGY/SKIN 
– Face 
– Lip 
– Oral-gums 
– Scalp 
– Skin 
GASTROINTESTINAL 
– Abdomen NOS 
– Anus 
– Dental/teeth/peridontal 
– Esophagus 
– Oral cavity 
– Peritoneum 
– Rectum 
– Stomach 
GENERAL 
– Pain NOS 
– Tumor pain  
HEPATOBILIARY/PANCREAS 
– Gallbladder 
– Liver  
LYMPHATIC 
– Lymph node 
MUSCULOSKELETAL 
– Back 
– Bone 
– Buttock 
– Extremity-limb 
– Intestine 
– Joint 
– Muscle 
– Neck 
– Phantom (pain associated with missing limb) 
NEUROLOGY 
– Head/headache 
– Neuralgia/peripheral nerve 
OCULAR 
– Eye 
PULMONARY/UPPER RESPIRATORY 
– Chest wall 
– Chest/thorax NOS 
PULMONARY/UPPER RESPIRATORY (continued) 
– Larynx 
– Pleura 
– Sinus 
– Throat/pharynx/larynx 
RENAL/GENITOURINARY 
– Bladder 
– Kidney 
SEXUAL/REPRODUCTIVE FUNCTION 
– Breast 
– Ovulatory 
– Pelvis 
– Penis 
– Perineum 
– Prostate 
– Scrotum 
– Testicle 
– Urethra 
– Uterus 
– Vagina 
 
 

 
PULMONARY/UPPER RESPIRATORY 
Page 1 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 56 - 
March 31, 2003, Publish Date: August 9, 2006 
Adult Respiratory 
Distress Syndrome 
(ARDS) 
ARDS 
— 
— 
Present, intubation not 
indicated  
Present, intubation 
indicated 
Death 
ALSO CONSIDER: Dyspnea (shortness of breath); Hypoxia; Pneumonitis/pulmonary infiltrates. 
Aspiration 
Aspiration 
Asymptomatic (“silent 
aspiration”); endoscopy 
or radiographic (e.g., 
barium swallow) findings  
Symptomatic (e.g., 
altered eating habits, 
coughing or choking 
episodes consistent with 
aspiration); medical 
intervention indicated 
(e.g., antibiotics, suction 
or oxygen) 
Clinical or radiographic 
signs of pneumonia or 
pneumonitis; unable to 
aliment orally 
Life-threatening (e.g., 
aspiration pneumonia or 
pneumonitis)  
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils 
– Select; Infection with unknown ANC – Select; Laryngeal nerve dysfunction; Neuropathy: cranial – Select; Pneumonitis/pulmonary infiltrates. 
Atelectasis  
Atelectasis  
Asymptomatic  
Symptomatic (e.g., 
dyspnea, cough), medical 
intervention indicated 
(e.g., bronchoscopic 
suctioning, chest 
physiotherapy, 
suctioning)  
Operative (e.g., stent, 
laser) intervention 
indicated  
Life-threatening 
respiratory compromise 
Death 
ALSO CONSIDER: Adult Respiratory Distress Syndrome (ARDS); Cough; Dyspnea (shortness of breath); Hypoxia; Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select; Obstruction/stenosis of airway – 
Select; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes). 
Bronchospasm, 
wheezing  
Bronchospasm 
Asymptomatic  
Symptomatic not 
interfering with function 
Symptomatic interfering 
with function 
Life-threatening 
Death 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever); Dyspnea (shortness of breath).  
Carbon monoxide 
diffusion capacity (DLCO) 
DLCO 
90 – 75% of predicted 
value 
<75 – 50% of predicted 
value 
<50 – 25% of predicted 
value 
<25% of predicted value 
Death 
ALSO CONSIDER: Hypoxia; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes). 
Chylothorax  
Chylothorax 
Asymptomatic 
Symptomatic; 
thoracentesis or tube 
drainage indicated  
Operative intervention 
indicated 
Life-threatening (e.g., 
hemodynamic instability 
or ventilatory support 
indicated) 
Death 
Cough 
Cough 
Symptomatic, non-
narcotic medication only 
indicated  
Symptomatic and 
narcotic medication 
indicated  
Symptomatic and 
significantly interfering 
with sleep or ADL 
— 
— 

 
PULMONARY/UPPER RESPIRATORY 
Page 2 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 57 - 
March 31, 2003, Publish Date: August 9, 2006 
Dyspnea (shortness of 
breath)  
Dyspnea  
Dyspnea on exertion, but 
can walk 1 flight of stairs 
without stopping 
Dyspnea on exertion but 
unable to walk 1 flight of 
stairs or 1 city block 
(0.1km) without stopping 
Dyspnea with ADL 
Dyspnea at rest; 
intubation/ventilator 
indicated  
Death 
ALSO CONSIDER: Hypoxia; Neuropathy: motor; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes). 
Edema, larynx  
Edema, larynx 
Asymptomatic edema by 
exam only 
Symptomatic edema, no 
respiratory distress  
Stridor; respiratory 
distress; interfering with 
ADL 
Life-threatening airway 
compromise; 
tracheotomy, intubation, 
or laryngectomy indicated 
Death 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever). 
FEV1  
FEV1 
90 – 75% of predicted 
value 
<75 – 50% of predicted 
value 
<50 – 25% of predicted 
value 
<25% of predicted 
Death 
Fistula, pulmonary/upper 
respiratory  
– Select: 
– Bronchus 
– Larynx 
– Lung 
– Oral cavity 
– Pharynx  
– Pleura 
– Trachea 
Fistula, pulmonary  
– Select  
Asymptomatic, 
radiographic findings only 
Symptomatic, tube 
thoracostomy or medical 
management indicated; 
associated with altered 
respiratory function but 
not interfering with ADL 
Symptomatic and 
associated with altered 
respiratory function 
interfering with ADL; or 
endoscopic (e.g., stent) 
or primary closure by 
operative intervention 
indicated 
Life-threatening 
consequences; operative 
intervention with 
thoracoplasty, chronic 
open drainage or multiple 
thoracotomies indicated 
Death 
REMARK: A fistula is defined as an abnormal communication between two body cavities, potential spaces, and/or the skin. The site indicated for a fistula should be the site from which 
the abnormal process is believed to have arisen. For example, a tracheo-esophageal fistula arising in the context of a resected or irradiated esophageal cancer should be graded as 
Fistula, GI – esophagus in the GASTROINTESTINAL CATEGORY. 
NAVIGATION NOTE: Hemoptysis is graded as Hemorrhage, pulmonary/upper respiratory – Select in the HEMORRHAGE/BLEEDING CATEGORY.  
Hiccoughs (hiccups, 
singultus) 
Hiccoughs 
Symptomatic, 
intervention not indicated 
Symptomatic, 
intervention indicated  
Symptomatic, 
significantly interfering 
with sleep or ADL 
— 
— 
Hypoxia 
Hypoxia 
— 
Decreased O2 saturation 
with exercise (e.g., pulse 
oximeter <88%); 
intermittent supplemental 
oxygen  
Decreased O2 saturation 
at rest; continuous 
oxygen indicated 
Life-threatening; 
intubation or ventilation 
indicated  
Death 

 
PULMONARY/UPPER RESPIRATORY 
Page 3 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 58 - 
March 31, 2003, Publish Date: August 9, 2006 
Nasal cavity/paranasal 
sinus reactions 
Nasal/paranasal 
reactions 
Asymptomatic mucosal 
crusting, blood-tinged 
secretions 
Symptomatic stenosis or 
edema/narrowing 
interfering with airflow 
Stenosis with significant 
nasal obstruction; 
interfering with ADL 
Necrosis of soft tissue or 
bone 
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils 
– Select; Infection with unknown ANC – Select. 
Obstruction/stenosis of 
airway 
– Select: 
– Bronchus 
– Larynx 
– Pharynx 
– Trachea 
Airway obstruction  
– Select  
Asymptomatic obstruction 
or stenosis on exam, 
endoscopy, or radiograph 
Symptomatic (e.g., noisy 
airway breathing), but 
causing no respiratory 
distress; medical 
management indicated 
(e.g., steroids)  
Interfering with ADL; 
stridor or endoscopic 
intervention indicated 
(e.g., stent, laser)  
Life-threatening airway 
compromise; tracheotomy 
or intubation indicated 
Death 
Pleural effusion 
(non-malignant)  
Pleural effusion 
Asymptomatic 
Symptomatic, 
intervention such as 
diuretics or up to 2 
therapeutic 
thoracenteses indicated 
Symptomatic and 
supplemental oxygen,  
>2 therapeutic 
thoracenteses, tube 
drainage, or pleurodesis 
indicated 
Life-threatening (e.g., 
causing hemodynamic 
instability or ventilatory 
support indicated)  
Death 
ALSO CONSIDER: Atelectasis; Cough; Dyspnea (shortness of breath); Hypoxia; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes).  
NAVIGATION NOTE: Pleuritic pain is graded as Pain – Select in the PAIN CATEGORY. 
Pneumonitis/pulmonary 
infiltrates  
Pneumonitis 
Asymptomatic, 
radiographic findings only 
Symptomatic, not 
interfering with ADL  
Symptomatic, interfering 
with ADL; O2 indicated  
Life-threatening; 
ventilatory support 
indicated 
Death 
ALSO CONSIDER: Adult Respiratory Distress Syndrome (ARDS); Cough; Dyspnea (shortness of breath); Hypoxia; Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select; Pneumonitis/pulmonary infiltrates; 
Pulmonary fibrosis (radiographic changes). 
Pneumothorax  
Pneumothorax  
Asymptomatic, 
radiographic findings only 
Symptomatic; 
intervention indicated 
(e.g., hospitalization for 
observation, tube 
placement without 
sclerosis) 
Sclerosis and/or 
operative intervention 
indicated 
Life-threatening, causing 
hemodynamic instability 
(e.g., tension 
pneumothorax); 
ventilatory support 
indicated 
Death 
Prolonged chest tube 
drainage or air leak after 
pulmonary resection 
Chest tube drainage or 
leak 
— 
Sclerosis or additional 
tube thoracostomy 
indicated 
Operative intervention 
indicated (e.g., 
thoracotomy with stapling 
or sealant application) 
Life-threatening; 
debilitating; organ 
resection indicated 
Death 

 
PULMONARY/UPPER RESPIRATORY 
Page 4 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 59 - 
March 31, 2003, Publish Date: August 9, 2006 
Prolonged intubation 
after pulmonary resection 
(>24 hrs after surgery)  
Prolonged intubation 
— 
Extubated within  
24 – 72 hrs 
postoperatively 
Extubated >72 hrs 
postoperatively, but 
before tracheostomy 
indicated 
Tracheostomy indicated 
Death 
NAVIGATION NOTE: Pulmonary embolism is graded as Grade 4 either as Thrombosis/embolism (vascular access-related) or Thrombosis/thrombus/embolism in the VASCULAR 
CATEGORY.  
Pulmonary fibrosis 
(radiographic changes)  
Pulmonary fibrosis 
Minimal radiographic 
findings (or patchy or bi-
basilar changes) with 
estimated radiographic 
proportion of total lung 
volume that is fibrotic of 
<25% 
Patchy or bi-basilar 
changes with estimated 
radiographic proportion of 
total lung volume that is 
fibrotic of 25 – <50% 
Dense or widespread 
infiltrates/consolidation 
with estimated 
radiographic proportion of 
total lung volume that is 
fibrotic of 50 – <75% 
Estimated radiographic 
proportion of total lung 
volume that is fibrotic is 
≥75%; honeycombing 
Death 
REMARK: Fibrosis is usually a “late effect” seen >3 months after radiation or combined modality therapy (including surgery). It is thought to represent scar/fibrotic lung tissue. It may be 
difficult to distinguish from pneumonitis that is generally seen within 3 months of radiation or combined modality therapy.  
ALSO CONSIDER: Adult Respiratory Distress Syndrome (ARDS); Cough; Dyspnea (shortness of breath); Hypoxia; Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select. 
NAVIGATION NOTE: Recurrent laryngeal nerve dysfunction is graded as Laryngeal nerve dysfunction in the NEUROLOGY CATEGORY. 
Vital capacity  
Vital capacity 
90 – 75% of predicted 
value 
<75 – 50% of predicted 
value 
<50 – 25% of predicted 
value 
<25% of predicted value 
Death 
Voice changes/dysarthria 
(e.g., hoarseness, loss or 
alteration in voice, 
laryngitis)  
Voice changes  
Mild or intermittent 
hoarseness or voice 
change, but fully 
understandable 
Moderate or persistent 
voice changes, may 
require occasional 
repetition but 
understandable on 
telephone 
Severe voice changes 
including predominantly 
whispered speech; may 
require frequent repetition 
or face-to-face contact for 
understandability; 
requires voice aid (e.g., 
electrolarynx) for ≤50% of 
communication 
Disabling; 
non-understandable voice 
or aphonic; requires voice 
aid (e.g., electrolarynx) 
for >50% of 
communication or 
requires >50% written 
communication 
Death 
ALSO CONSIDER: Laryngeal nerve dysfunction; Speech impairment (e.g., dysphasia or aphasia). 
Pulmonary/Upper 
Respiratory – Other 
(Specify, __) 
Pulmonary – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling 
Death 

 
RENAL/GENITOURINARY 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 60 - 
March 31, 2003, Publish Date: August 9, 2006 
Bladder spasms 
Bladder spasms 
Symptomatic, intervention 
not indicated 
Symptomatic, 
antispasmodics indicated 
Narcotics indicated 
Major surgical 
intervention indicated 
(e.g., cystectomy) 
— 
Cystitis 
Cystitis 
Asymptomatic 
Frequency with dysuria; 
macroscopic hematuria 
Transfusion; IV pain 
medications; bladder 
irrigation indicated 
Catastrophic bleeding; 
major non-elective 
intervention indicated 
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils 
– Select; Infection with unknown ANC – Select; Pain – Select. 
Fistula, GU 
– Select:  
– Bladder 
– Genital tract-female 
– Kidney 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
Fistula, GU – Select  
Asymptomatic, 
radiographic findings only 
Symptomatic; 
noninvasive intervention 
indicated  
Symptomatic interfering 
with ADL; invasive 
intervention indicated  
Life-threatening 
consequences; operative 
intervention requiring 
partial or full organ 
resection; permanent 
urinary diversion  
Death 
REMARK: A fistula is defined as an abnormal communication between two body cavities, potential spaces, and/or the skin. The site indicated for a fistula should be the site from which 
the abnormal process is believed to have originated. 
Incontinence, urinary  
Incontinence, urinary 
Occasional (e.g., with 
coughing, sneezing, etc.), 
pads not indicated 
Spontaneous, pads 
indicated  
Interfering with ADL; 
intervention indicated 
(e.g., clamp, collagen 
injections) 
Operative intervention 
indicated (e.g., 
cystectomy or permanent 
urinary diversion) 
— 
Leak (including 
anastomotic), GU 
– Select: 
– Bladder 
– Fallopian tube  
– Kidney 
– Spermatic cord 
– Stoma 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Leak, GU – Select  
Asymptomatic, 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic, interfering 
with GU function; invasive 
or endoscopic 
intervention indicated 
Life-threatening 
Death 
REMARK: Leak (including anastomotic), GU – Select refers to clinical signs and symptoms or radiographic confirmation of anastomotic leak but without development of fistula. 

 
RENAL/GENITOURINARY 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 61 - 
March 31, 2003, Publish Date: August 9, 2006 
Obstruction, GU  
– Select: 
– Bladder 
– Fallopian tube 
– Prostate 
– Spermatic cord 
– Stoma 
– Testes 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Obstruction, GU – Select  
Asymptomatic, 
radiographic or 
endoscopic findings only 
Symptomatic but no 
hydronephrosis, sepsis or 
renal dysfunction; dilation 
or endoscopic repair or 
stent placement indicated 
Symptomatic and altered 
organ function (e.g., 
sepsis or hydronephrosis, 
or renal dysfunction); 
operative intervention 
indicated  
Life-threatening 
consequences; organ 
failure or operative 
intervention requiring 
complete organ resection 
indicated  
Death 
NAVIGATION NOTE: Operative injury is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY CATEGORY.  
Perforation, GU  
– Select: 
– Bladder 
– Fallopian tube 
– Kidney  
– Ovary 
– Prostate 
– Spermatic cord 
– Stoma 
– Testes 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Perforation, GU – Select 
Asymptomatic 
radiographic findings only 
Symptomatic, associated 
with altered renal/GU 
function 
Symptomatic, operative 
intervention indicated 
Life-threatening 
consequences or organ 
failure; operative 
intervention requiring 
organ resection indicated 
Death 
Prolapse of stoma, GU 
Prolapse stoma, GU 
Asymptomatic; special 
intervention, 
extraordinary care not 
indicated 
Extraordinary local care 
or maintenance; minor 
revision under local 
anesthesia indicated 
Dysfunctional stoma; 
operative intervention or 
major stomal revision 
indicated 
Life-threatening 
consequences 
Death 
REMARK: Other stoma complications may be graded as Fistula, GU – Select; Leak (including anastomotic), GU – Select; Obstruction, GU – Select; Perforation, GU – Select; 
Stricture/stenosis (including anastomotic), GU – Select. 
Renal failure  
Renal failure 
— 
— 
Chronic dialysis not 
indicated 
Chronic dialysis or renal 
transplant indicated 
Death 
ALSO CONSIDER: Glomerular filtration rate. 

 
RENAL/GENITOURINARY 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 62 - 
March 31, 2003, Publish Date: August 9, 2006 
Stricture/stenosis 
(including anastomotic), 
GU 
– Select: 
– Bladder 
– Fallopian tube 
– Prostate 
– Spermatic cord 
– Stoma 
– Testes 
– Ureter  
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Stricture, anastomotic, 
GU – Select  
Asymptomatic, 
radiographic or 
endoscopic findings only 
Symptomatic but no 
hydronephrosis, sepsis or 
renal dysfunction; dilation 
or endoscopic repair or 
stent placement indicated 
Symptomatic and altered 
organ function (e.g., 
sepsis or hydronephrosis, 
or renal dysfunction); 
operative intervention 
indicated  
Life-threatening 
consequences; organ 
failure or operative 
intervention requiring 
organ resection indicated  
Death 
ALSO CONSIDER: Obstruction, GU – Select. 
Urinary electrolyte 
wasting (e.g., Fanconi’s 
syndrome, renal tubular 
acidosis) 
Urinary electrolyte 
wasting 
Asymptomatic, 
intervention not indicated 
Mild, reversible and 
manageable with 
replacement 
Irreversible, requiring 
continued replacement  
— 
— 
ALSO CONSIDER: Acidosis (metabolic or respiratory); Bicarbonate, serum-low; Calcium, serum-low (hypocalcemia); Phosphate, serum-low (hypophosphatemia). 
Urinary 
frequency/urgency 
Urinary frequency 
Increase in frequency or 
nocturia up to 2 x normal; 
enuresis 
Increase >2 x normal but 
<hourly 
≥1 x/hr; urgency; catheter 
indicated 
— 
— 
Urinary retention 
(including neurogenic 
bladder)  
Urinary retention 
Hesitancy or dribbling, no 
significant residual urine; 
retention occurring during 
the immediate 
postoperative period 
Hesitancy requiring 
medication; or operative 
bladder atony requiring 
indwelling catheter 
beyond immediate 
postoperative period but 
for <6 weeks 
More than daily 
catheterization indicated; 
urological intervention 
indicated (e.g., TURP, 
suprapubic tube, 
urethrotomy) 
Life-threatening 
consequences; organ 
failure (e.g., bladder 
rupture); operative 
intervention requiring 
organ resection indicated 
Death 
REMARK: The etiology of retention (if known) is graded as Obstruction, GU – Select; Stricture/stenosis (including anastomotic), GU – Select. 
ALSO CONSIDER: Obstruction, GU – Select; Stricture/stenosis (including anastomotic), GU – Select. 
Urine color change  
Urine color change 
Present 
— 
— 
— 
— 
REMARK: Urine color refers to change that is not related to other dietary or physiologic cause (e.g., bilirubin, concentrated urine, and hematuria). 
Renal/Genitourinary – 
Other (Specify, __) 
Renal – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
SECONDARY MALIGNANCY 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 63 - 
March 31, 2003, Publish Date: August 9, 2006 
Secondary Malignancy – 
possibly related to cancer 
treatment (Specify, __)  
Secondary Malignancy 
(possibly related to 
cancer treatment) 
— 
— 
Non-life-threatening basal 
or squamous cell 
carcinoma of the skin 
Solid tumor, leukemia or 
lymphoma  
Death 
REMARK: Secondary malignancy excludes metastasis from initial primary. Any malignancy possibly related to cancer treatment (including AML/MDS) should be reported via the routine 
reporting mechanisms outlined in each protocol. Important: Secondary Malignancy is an exception to NCI Expedited Adverse Event Reporting Guidelines. Secondary Malignancy is 
“Grade 4, present” but NCI does not require AdEERS Expedited Reporting for any (related or unrelated to treatment) Secondary Malignancy. A diagnosis of AML/MDS following 
treatment with an NCI-sponsored investigational agent is to be reported using the form available from the CTEP Web site at http://ctep.cancer.gov. Cancers not suspected of being 
treatment-related are not to be reported here. 

 
SEXUAL/REPRODUCTIVE FUNCTION 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 64 - 
March 31, 2003, Publish Date: August 9, 2006 
Breast function/lactation 
Breast function 
Mammary abnormality, 
not functionally significant 
Mammary abnormality, 
functionally significant 
— 
— 
— 
Breast nipple/areolar 
deformity  
Nipple/areolar 
Limited areolar 
asymmetry with no 
change in nipple/areolar 
projection 
Asymmetry of nipple 
areolar complex with 
slight deviation in nipple 
projection 
Marked deviation of 
nipple projection  
— 
— 
Breast volume/hypoplasia 
Breast 
Minimal asymmetry; 
minimal hypoplasia 
Asymmetry exists, ≤1/3 of 
the breast volume; 
moderate hypoplasia  
Asymmetry exists, >1/3 of 
the breast volume; severe 
hypoplasia 
— 
— 
REMARK: Breast volume is referenced with both arms straight overhead. 
NAVIGATION NOTE: Dysmenorrhea is graded as Pain – Select in the PAIN CATEGORY.  
NAVIGATION NOTE: Dyspareunia is graded as Pain – Select in the PAIN CATEGORY.  
NAVIGATION NOTE: Dysuria (painful urination) is graded as Pain – Select in the PAIN CATEGORY.  
Erectile dysfunction 
Erectile dysfunction 
Decrease in erectile 
function 
(frequency/rigidity of 
erections) but erectile 
aids not indicated 
Decrease in erectile 
function 
(frequency/rigidity of 
erections), erectile aids 
indicated 
Decrease in erectile 
function 
(frequency/rigidity of 
erections) but erectile 
aids not helpful; penile 
prosthesis indicated 
— 
— 
Ejaculatory dysfunction 
Ejaculatory dysfunction 
Diminished ejaculation 
Anejaculation or 
retrograde ejaculation 
— 
— 
— 
NAVIGATION NOTE: Feminization of male is graded in the ENDOCRINE CATEGORY. 
Gynecomastia 
Gynecomastia 
— 
Asymptomatic breast 
enlargement 
Symptomatic breast 
enlargement; intervention 
indicated 
— 
— 
ALSO CONSIDER: Pain – Select.  
Infertility/sterility 
Infertility/sterility 
— 
Male: oligospermia/low 
sperm count 
Female: diminished 
fertility/ovulation 
Male: sterile/azoospermia 
Female: infertile/ 
anovulatory 
— 
— 
Irregular menses  
(change from baseline) 
Irregular menses 
1 – 3 months without 
menses 
>3 – 6 months without 
menses but continuing 
menstrual cycles 
Persistent amenorrhea 
for >6 months 
— 
— 

 
SEXUAL/REPRODUCTIVE FUNCTION 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 65 - 
March 31, 2003, Publish Date: August 9, 2006 
Libido 
Libido 
Decrease in interest but 
not affecting relationship; 
intervention not indicated 
Decrease in interest and 
adversely affecting 
relationship; intervention 
indicated 
— 
— 
— 
NAVIGATION NOTE: Masculinization of female is graded in the ENDOCRINE CATEGORY. 
Orgasmic dysfunction 
Orgasmic function 
Transient decrease 
Decrease in orgasmic 
response requiring 
intervention 
Complete inability of 
orgasmic response; not 
responding to intervention 
— 
— 
NAVIGATION NOTE: Pelvic pain is graded as Pain – Select in the PAIN CATEGORY. 
NAVIGATION NOTE: Ulcers of the labia or perineum are graded as Ulceration in DERMATOLOGY/SKIN CATEGORY. 
Vaginal discharge  
(non-infectious) 
Vaginal discharge 
Mild 
Moderate to heavy; pad 
use indicated 
— 
— 
— 
Vaginal dryness 
Vaginal dryness 
Mild 
Interfering with sexual 
function; dyspareunia; 
intervention indicated 
— 
— 
— 
ALSO CONSIDER: Pain – Select. 
Vaginal mucositis 
Vaginal mucositis 
Erythema of the mucosa; 
minimal symptoms 
Patchy ulcerations; 
moderate symptoms or 
dyspareunia 
Confluent ulcerations; 
bleeding with trauma; 
unable to tolerate vaginal 
exam, sexual intercourse 
or tampon placement  
Tissue necrosis; 
significant spontaneous 
bleeding; life-threatening 
consequences 
— 
Vaginal stenosis/length 
Vaginal stenosis 
Vaginal narrowing and/or 
shortening not interfering 
with function  
Vaginal narrowing and/or 
shortening interfering with 
function  
Complete obliteration; not 
surgically correctable 
— 
— 
Vaginitis (not due to 
infection) 
Vaginitis 
Mild, intervention not 
indicated 
Moderate, intervention 
indicated 
Severe, not relieved with 
treatment; ulceration, but 
operative intervention not 
indicated 
Ulceration and operative 
intervention indicated 
— 
Sexual/Reproductive 
Function – Other 
(Specify, __) 
Sexual – Other (Specify) 
Mild 
Moderate 
Severe 
Disabling 
Death 

 
SURGERY/INTRA-OPERATIVE INJURY 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 66 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Intra-operative hemorrhage is graded as Hemorrhage/bleeding associated with surgery, intra-operative or postoperative in the HEMORRHAGE/BLEEDING 
CATEGORY.  
Intra-operative injury  
– Select Organ or 
Structure 
‘Select’ AEs appear at the 
end of the CATEGORY. 
Intraop injury – Select  
Primary repair of injured 
organ/structure indicated  
Partial resection of 
injured organ/structure 
indicated 
Complete resection or 
reconstruction of injured 
organ/structure indicated 
Life threatening 
consequences; disabling 
— 
REMARK: The ‘Select’ AEs are defined as significant, unanticipated injuries that are recognized at the time of surgery. These AEs do not refer to additional surgical procedures that 
must be performed because of a change in the operative plan based on intra-operative findings. Any sequelae resulting from the intra-operative injury that result in an adverse 
outcome for the patient must also be recorded and graded under the relevant CTCAE Term. 
Intra-operative Injury – 
Other (Specify, __) 
Intraop Injury – Other 
(Specify) 
Primary repair of injured 
organ/structure indicated  
Partial resection of 
injured organ/structure 
indicated 
Complete resection or 
reconstruction of injured 
organ/structure indicated 
Life threatening 
consequences; disabling 
— 
REMARK: Intra-operative Injury – Other (Specify, __) is to be used only to report an organ/structure not included in the ‘Select’ AEs found at the end of the CATEGORY. Any sequelae 
resulting from the intra-operative injury that result in an adverse outcome for the patient must also be recorded and graded under the relevant CTCAE Term. 

 
SURGERY/INTRA-OPERATIVE INJURY – SELECT  
Page 2 of 2 
CTCAE v3.0  
- 67 - 
March 31, 2003, Publish Date: August 9, 2006 
AUDITORY/EAR 
– Inner ear  
– Middle ear  
– Outer ear NOS  
– Outer ear-Pinna  
CARDIOVASCULAR 
– Artery-aorta  
– Artery-carotid  
– Artery-cerebral  
– Artery-extremity (lower)  
– Artery-extremity (upper)  
– Artery-hepatic  
– Artery-major visceral artery  
– Artery-pulmonary  
– Artery NOS 
– Heart  
– Spleen 
– Vein-extremity (lower)  
– Vein-extremity (upper)  
– Vein-hepatic  
– Vein-inferior vena cava  
– Vein-jugular  
– Vein-major visceral vein  
– Vein-portal vein  
– Vein-pulmonary  
– Vein-superior vena cava  
– Vein NOS 
DERMATOLOGY/SKIN 
– Breast  
– Nails  
– Skin 
ENDOCRINE 
– Adrenal gland 
– Parathyroid 
– Pituitary  
ENDOCRINE (continued) 
– Thyroid 
HEAD AND NECK 
– Gingiva  
– Larynx  
– Lip/perioral area  
– Face NOS  
– Nasal cavity  
– Nasopharynx  
– Neck NOS 
– Nose  
– Oral cavity NOS  
– Parotid gland  
– Pharynx  
– Salivary duct  
– Salivary gland  
– Sinus  
– Teeth  
– Tongue  
– Upper aerodigestive NOS 
GASTROINTESTINAL 
– Abdomen NOS  
– Anal sphincter  
– Anus 
– Appendix  
– Cecum  
– Colon  
– Duodenum  
– Esophagus  
– Ileum  
– Jejunum  
– Oral  
– Peritoneal cavity  
– Rectum 
– Small bowel NOS 
GASTROINTESTINAL (continued) 
– Stoma (GI)  
– Stomach  
HEPATOBILIARY/ PANCREAS 
– Biliary tree-common bile  
duct  
– Biliary tree-common hepatic 
duct  
– Biliary tree-left hepatic duct  
– Biliary tree-right hepatic duct  
– Biliary tree NOS  
– Gallbladder  
– Liver 
– Pancreas 
– Pancreatic duct 
MUSCULOSKELETAL 
– Bone  
– Cartilage  
– Extremity-lower 
– Extremity-upper 
– Joint  
– Ligament  
– Muscle  
– Soft tissue NOS 
– Tendon 
NEUROLOGY  
– Brain  
– Meninges  
– Spinal cord 
NERVES: 
– Brachial plexus 
– CN I (olfactory) 
– CN II (optic) 
– CN III (oculomotor) 
– CN IV (trochlear)  
NEUROLOGY (continued) 
NERVES: 
– CN V (trigeminal) motor  
– CN V (trigeminal) sensory  
– CN VI (abducens)  
– CN VII (facial) motor-face  
– CN VII (facial) sensory-
taste  
– CN VIII (vestibulocochlear)  
– CN IX (glossopharyngeal) 
motor pharynx  
– CN IX (glossopharyngeal) 
sensory ear-pharynx-
tongue  
– CN X (vagus)  
– CN XI (spinal accessory)  
– CN XII (hypoglossal)  
– Cranial nerve or branch 
NOS  
– Lingual  
– Lung thoracic  
– Peripheral motor NOS 
– Peripheral sensory NOS 
– Recurrent laryngeal  
– Sacral plexus  
– Sciatic 
– Thoracodorsal 
OCULAR 
– Conjunctiva  
– Cornea  
– Eye NOS 
– Lens 
– Retina 
PULMONARY/UPPER 
RESPIRATORY 
– Bronchus  
– Lung  
– Mediastinum  
– Pleura  
– Thoracic duct  
– Trachea 
– Upper airway NOS 
RENAL/GENITOURINARY 
– Bladder  
– Cervix  
– Fallopian tube  
– Kidney  
– Ovary  
– Pelvis NOS  
– Penis  
– Prostate  
– Scrotum  
– Testis  
– Ureter  
– Urethra  
– Urinary conduit  
– Urinary tract NOS  
– Uterus  
– Vagina  
– Vulva 
 
 

 
SYNDROMES 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 68 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Acute vascular leak syndrome is graded in the VASCULAR CATEGORY. 
NAVIGATION NOTE: Adrenal insufficiency is graded in the ENDOCRINE CATEGORY. 
NAVIGATION NOTE: Adult Respiratory Distress Syndrome (ARDS) is graded in the PULMONARY/UPPER RESPIRATORY CATEGORY. 
Alcohol intolerance 
syndrome (antabuse-like 
syndrome) 
Alcohol intolerance 
syndrome 
— 
— 
Present 
— 
Death 
REMARK: An antabuse-like syndrome occurs with some new anti-androgens (e.g., nilutamide) when patient also consumes alcohol. 
NAVIGATION NOTE: Autoimmune reaction is graded as Autoimmune reaction/hypersensitivity (including drug fever) in the ALLERGY/IMMUNOLOGY CATEGORY. 
Cytokine release 
syndrome/acute infusion 
reaction 
Cytokine release 
syndrome 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDS, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption of 
infusion); recurrence of 
symptoms following initial 
improvement; 
hospitalization indicated 
for other clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates) 
Life-threatening; pressor 
or ventilatory support 
indicated 
Death 
REMARK: Cytokine release syndromes/acute infusion reactions are different from Allergic/hypersensitive reactions, although some of the manifestations are common to both AEs. An 
acute infusion reaction may occur with an agent that causes cytokine release (e.g., monoclonal antibodies or other biological agents). Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hrs of completion of infusion. Signs/symptoms may include: Allergic reaction/hypersensitivity (including drug 
fever); Arthralgia (joint pain); Bronchospasm; Cough; Dizziness; Dyspnea (shortness of breath); Fatigue (asthenia, lethargy, malaise); Headache; Hypertension; Hypotension; Myalgia 
(muscle pain); Nausea; Pruritis/itching; Rash/desquamation; Rigors/chills; Sweating (diaphoresis); Tachycardia; Tumor pain (onset or exacerbation of tumor pain due to treatment); 
Urticaria (hives, welts, wheals); Vomiting.  
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever); Bronchospasm, wheezing; Dyspnea (shortness of breath); Hypertension; Hypotension; Hypoxia; Prolonged 
QTc interval; Supraventricular and nodal arrhythmia – Select; Ventricular arrhythmia – Select.  
NAVIGATION NOTE: Disseminated intravascular coagulation (DIC) is graded in the COAGULATION CATEGORY. 
NAVIGATION NOTE: Fanconi’s syndrome is graded as Urinary electrolyte wasting (e.g., Fanconi’s syndrome, renal tubular acidosis) in the RENAL/GENITOURINARY CATEGORY. 
Flu-like syndrome 
Flu-like syndrome 
Symptoms present but 
not interfering with 
function 
Moderate or causing 
difficulty performing some 
ADL 
Severe symptoms 
interfering with ADL 
Disabling 
Death 
REMARK: Flu-like syndrome represents a constellation of symptoms which may include cough with catarrhal symptoms, fever, headache, malaise, myalgia, prostration, and is to be 
used when the symptoms occur in a cluster consistent with one single pathophysiological process. 
NAVIGATION NOTE: Renal tubular acidosis is graded as Urinary electrolyte wasting (e.g., Fanconi’s syndrome, renal tubular acidosis) in the RENAL/GENITOURINARY CATEGORY. 

 
SYNDROMES 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 69 - 
March 31, 2003, Publish Date: August 9, 2006 
“Retinoic acid syndrome”  
“Retinoic acid syndrome” 
Fluid retention; less than 
3 kg of weight gain; 
intervention with fluid 
restriction and/or diuretics 
indicated 
Mild to moderate signs/ 
symptoms; steroids 
indicated 
Severe signs/symptoms; 
hospitalization indicated 
Life-threatening; 
ventilatory support 
indicated 
Death 
REMARK: Patients with acute promyelocytic leukemia may experience a syndrome similar to “retinoic acid syndrome” in association with other agents such as arsenic trioxide. The 
syndrome is usually manifested by otherwise unexplained fever, weight gain, respiratory distress, pulmonary infiltrates and/or pleural effusion, with or without leukocytosis.  
ALSO CONSIDER: Acute vascular leak syndrome; Pleural effusion (non-malignant); Pneumonitis/pulmonary infiltrates. 
NAVIGATION NOTE: SIADH is graded as Neuroendocrine: ADH secretion abnormality (e.g., SIADH or low ADH) in the ENDOCRINE CATEGORY.  
NAVIGATION NOTE: Stevens-Johnson syndrome is graded as Rash: erythema multiforme (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis) in the DERMATOLOGY/SKIN 
CATEGORY. 
NAVIGATION NOTE: Thrombotic microangiopathy is graded as Thrombotic microangiopathy (e.g., thrombotic thrombocytopenic purpura [TTP] or hemolytic uremic syndrome [HUS]) in 
the COAGULATION CATEGORY. 
Tumor flare 
Tumor flare 
Mild pain not interfering 
with function 
Moderate pain; pain or 
analgesics interfering with 
function, but not 
interfering with ADL 
Severe pain; pain or 
analgesics interfering with 
function and interfering 
with ADL 
Disabling 
Death 
REMARK: Tumor flare is characterized by a constellation of signs and symptoms in direct relation to initiation of therapy (e.g., anti-estrogens/androgens or additional hormones). The 
symptoms/signs include tumor pain, inflammation of visible tumor, hypercalcemia, diffuse bone pain, and other electrolyte disturbances.  
ALSO CONSIDER: Calcium, serum-high (hypercalcemia). 
Tumor lysis syndrome 
Tumor lysis syndrome 
— 
— 
Present 
— 
Death 
ALSO CONSIDER: Creatinine; Potassium, serum-high (hyperkalemia). 
Syndromes – Other 
(Specify, __) 
Syndromes – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
VASCULAR 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 70 - 
March 31, 2003, Publish Date: August 9, 2006 
Acute vascular leak 
syndrome 
Acute vascular leak 
syndrome 
— 
Symptomatic, fluid 
support not indicated 
Respiratory compromise 
or fluids indicated 
Life-threatening; pressor 
support or ventilatory 
support indicated  
Death 
Peripheral arterial 
ischemia 
Peripheral arterial 
ischemia 
— 
Brief (<24 hrs) episode of 
ischemia managed non-
surgically and without 
permanent deficit 
Recurring or prolonged 
(≥24 hrs) and/or invasive 
intervention indicated 
Life-threatening, disabling 
and/or associated with 
end organ damage 
(e.g., limb loss) 
Death 
Phlebitis (including 
superficial thrombosis) 
Phlebitis 
— 
Present 
— 
— 
— 
ALSO CONSIDER: Injection site reaction/extravasation changes. 
Portal vein flow 
Portal flow 
— 
Decreased portal vein 
flow 
Reversal/retrograde 
portal vein flow 
— 
— 
Thrombosis/embolism 
(vascular access-related) 
Thrombosis/embolism 
(vascular access) 
— 
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
not indicated 
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
indicated 
Embolic event including 
pulmonary embolism or 
life-threatening thrombus 
Death 
Thrombosis/thrombus/ 
embolism 
Thrombosis/thrombus/ 
embolism 
— 
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
not indicated  
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
indicated  
Embolic event including 
pulmonary embolism or 
life-threatening thrombus 
Death 
Vessel injury-artery  
– Select:  
– Aorta 
– Carotid 
– Extremity-lower 
– Extremity-upper  
– Other NOS 
– Visceral 
Artery injury – Select 
Asymptomatic diagnostic 
finding; intervention not 
indicated 
Symptomatic (e.g., 
claudication); not 
interfering with ADL; 
repair or revision not 
indicated 
Symptomatic interfering 
with ADL; repair or 
revision indicated 
Life-threatening; 
disabling; evidence of 
end organ damage (e.g., 
stroke, MI, organ or limb 
loss) 
Death 
NAVIGATION NOTE: Vessel injury to an artery intra-operatively is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY 
CATEGORY. 

 
VASCULAR 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 71 - 
March 31, 2003, Publish Date: August 9, 2006 
Vessel injury-vein  
– Select: 
– Extremity-lower  
– Extremity-upper 
– IVC 
– Jugular 
– Other NOS 
– SVC 
– Viscera 
Vein injury – Select 
Asymptomatic diagnostic 
finding; intervention not 
indicated 
Symptomatic (e.g., 
claudication); not 
interfering with ADL; 
repair or revision not 
indicated  
Symptomatic interfering 
with ADL; repair or 
revision indicated 
Life-threatening; 
disabling; evidence of 
end organ damage  
Death 
NAVIGATION NOTE: Vessel injury to a vein intra-operatively is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY CATEGORY. 
Visceral arterial ischemia 
(non-myocardial) 
Visceral arterial ischemia 
— 
Brief (<24 hrs) episode of 
ischemia managed 
medically and without 
permanent deficit 
Prolonged (≥24 hrs) or 
recurring symptoms 
and/or invasive 
intervention indicated 
Life-threatening; 
disabling; evidence of 
end organ damage  
Death 
ALSO CONSIDER: CNS cerebrovascular ischemia.  
Vascular – Other  
(Specify, __) 
Vascular – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
 

Clinical Trial Protocol:  HGT-SAN-067
Study Title:
An Open-Label Extension of Study HGT-SAN-055 Evaluating 
Long-Term Safety and Clinical Outcomes of Intrathecal 
Administration of rhHNS in Patients with Sanfilippo Syndrome
Type A (MPS IIIA)
Study Number:
HGT-SAN-067
Study Phase:
I/II
Product Name:
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Device Names:
SOPH-A-PORT® Mini S, Implantable Access Port, Spinal, Mini 
Unattached, with Guidewire
and
PORT-A-CATH® II Low Profile™Intrathecal Implantable Access 
System (Smiths device)
EudraCT 
Number:
2010-021348-16
Indication:
Sanfilippo Syndrome A
Investigators:
Multicenter
Sponsor:
Shire Human Genetic Therapies, Inc. 
300 Shire Way
Lexington, MA  02421, United States
Medical Monitor:
MD,
Date
Original Protocol:
21 June 2010
Amendment 1:
27 January 2011
Amendment 2:
13 January 2012
Amendment 3:
28 August 2012
Amendment 4:
3 May 2013
Confidentiality Statement
This document is the proprietary and confidential property of 
Shire Human Genetic Therapies, Inc.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
2
TABLE OF CONTENTS
TABLE OF CONTENTS...........................................................................................................2
SYNOPSIS.................................................................................................................................7
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..........................................14
1
INTRODUCTION ...........................................................................................................18
1.1
Disease Background...............................................................................................18
1.2
Nonclinical Overview............................................................................................20
1.2.1
Toxicology in Monkeys ...............................................................................20
1.2.2
Efficacy in Murine and Canine Models of MPS IIIA..................................21
1.3
HGT-SAN-067 Study Rationale............................................................................21
2
STUDY OBJECTIVES....................................................................................................23
2.1
Primary Objective..................................................................................................23
2.2
Secondary Objectives.............................................................................................23
2.3
Exploratory Objective............................................................................................23
3
STUDY ENDPOINTS.....................................................................................................24
3.1
Primary Endpoint...................................................................................................24
3.2
Secondary Endpoints .............................................................................................24
3.3
SOPH-A-PORT Mini S Assessments....................................................................24
4
INVESTIGATIONAL PLAN..........................................................................................25
4.1
Overall Study Design and Plan..............................................................................25
4.2
Rationale for Study Design and Control Group.....................................................27
4.3
Study Duration and Dates......................................................................................27
5
STUDY POPULATION SELECTION ...........................................................................28
5.1
Study Population....................................................................................................28
5.2
Inclusion Criteria ...................................................................................................28
5.3
Exclusion Criteria ..................................................................................................28
6
STUDY TREATMENT(S)..............................................................................................30
6.1
Description of Treatment(s)...................................................................................30
6.1.1
Study Drug...................................................................................................30
6.1.2
Intrathecal Drug Delivery Device................................................................30
6.1.3
Placebo or Control .......................................................................................30
6.2
Treatment Administered ........................................................................................30
6.3
Selection and Timing of Dose for Each Patient.....................................................31
6.3.1
Cerebral Spinal Fluid Sample Procedure.....................................................31
6.3.2
Intrathecal Administration of HGT-1410 ....................................................32
6.3.3
Administration of HGT-1410 via Lumbar Puncture....................................32
6.4
Method of Assigning Patients to Treatment Groups..............................................33
6.5
Blinding..................................................................................................................33

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
3
6.6
Concomitant Therapy.............................................................................................33
6.7
Restrictions ............................................................................................................33
6.7.1
Prior Therapy ...............................................................................................33
6.7.2
Fluid and Food Intake..................................................................................34
6.7.3
Patient Activity Restrictions ........................................................................34
6.8
Treatment Compliance...........................................................................................34
6.9
Packaging and Labeling.........................................................................................34
6.9.1
Drug Product................................................................................................34
6.9.2
SOPH-A-PORT Mini S Access Port............................................................34
6.10
Storage and Accountability....................................................................................34
6.10.1
Investigational Product ................................................................................34
6.10.2
Intrathecal Drug Delivery Device................................................................35
6.10.2.1
PORT-A-CATH IDDD......................................................................35
6.10.2.2
SOPH-A-PORT Mini S IDDD...........................................................35
6.11
Investigational Product Retention at Study Site ....................................................35
7
STUDY PROCEDURES .................................................................................................36
7.1
Informed Consent...................................................................................................36
7.2
Physical Examination.............................................................................................36
7.3
Height and Weight .................................................................................................36
7.4
Head Circumference ..............................................................................................36
7.5
Vital Signs..............................................................................................................37
7.6
Electrocardiography...............................................................................................37
7.6.1
Electrocardiograms ......................................................................................37
7.7
Clinical Laboratory Tests.......................................................................................37
7.7.1
Hematology..................................................................................................37
7.7.2
Serum Chemistry .........................................................................................38
7.7.3
Pregnancy Test.............................................................................................38
7.7.4
Urinalysis .....................................................................................................38
7.7.4.1
Standard Urinalysis............................................................................38
7.7.4.2
Urine Heparan Sulfate and Heparan Sulfate Derivatives...................38
7.7.5
Cerebrospinal Fluid Assessments ................................................................39
7.7.5.1
Cerebrospinal Fluid Cell Counts........................................................39
7.7.5.2
Cerebrospinal Fluid Heparan Sulfate Levels and Heparan Sulfate 
Derivatives .........................................................................................39
7.7.5.3
Anti-rhHNS Antibodies .....................................................................39
7.7.5.4
Cerebrospinal Fluid Biomarkers........................................................39
7.7.6
Sample Collection, Storage, and Shipping ..................................................39
7.8
Anesthesia..............................................................................................................39
7.9
Audiometry and Auditory Brainstem Response ....................................................40

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
4
7.10
Magnetic Resonance Imaging of the Head ............................................................40
7.11
Device Data............................................................................................................40
7.12
Surgical Re-implantation of the IDDD..................................................................40
7.12.1
Restrictions on the Number of Revision and/or re-implantation of the 
IDDD ...........................................................................................................41
7.13
Device Related Study Procedures..........................................................................41
7.13.1
IDDD Implantation or Revision Procedures................................................41
7.13.2
X-ray Verification of Intrathecal Drug Delivery Device Placement ...........41
7.13.3
CSF Sampling Procedure.............................................................................42
7.13.4
Device Removal...........................................................................................42
7.14
Cerebrospinal Fluid Opening Pressure Measurement............................................42
7.15
Dispensing Study Drug..........................................................................................42
7.16
Pharmacokinetic Assessments ...............................................................................43
7.17
Neurological Examination .....................................................................................43
7.18
Anti-rhHNS Antibody, Heparan Sulfate, and Heparan Sulfate Derivative 
Determination ........................................................................................................43
7.19
Neurocognitive and Developmental Assessments.................................................43
7.20
Sleep Questionnaire:  Children’s Sleep Habits Rating Scale.................................45
7.21
Age-Dependent, Health-Related Quality of Life in Children................................45
7.21.1
Quality of Life Indicator:  CHQ-50 .............................................................45
7.21.2
Quality of Life Indicator:  CHQ-87 .............................................................45
7.21.3
Quality of Life Indicator:  ITQOL...............................................................45
7.22
Concomitant Medications, Therapies and Medical/Surgical Procedures ..............45
7.23
Adverse Events ......................................................................................................46
7.23.1
Definitions of Adverse Events and Serious Adverse Events.......................46
7.23.1.1
Adverse Event....................................................................................46
7.23.1.2
Potential Adverse Events:  Intrathecal recombinant human heparan 
N-sulfatase .........................................................................................47
7.23.1.3
IDDD-related Adverse Events ...........................................................47
7.23.1.4
Serious Adverse Event.......................................................................48
7.23.2
Device-Associated Definitions ....................................................................48
7.23.2.1
Device Revision (Partial and Full).....................................................48
7.23.2.2
Device Malfunction ...........................................................................49
7.23.2.3
Device Failure....................................................................................49
7.23.3
Classification of Adverse Events and Serious Adverse Events...................49
7.23.4
Relatedness of Adverse Events and Serious Adverse Events......................50
7.23.5
Procedures for Recording and Reporting Adverse Events ..........................50
7.23.5.1
Reporting Serious Adverse Events Related to Study Procedures......50
7.23.5.2
Eliciting Adverse Events....................................................................52
7.23.5.3
Protocol Deviations for Medical Emergency or Adverse Event........52

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
5
7.24
Abuse, Overdose and Medication Errors...............................................................53
7.25
Safety-related Study Stopping Rules .....................................................................53
7.26
Pregnancy...............................................................................................................53
7.27
Removal of Patients from the Trial or Study Drug................................................54
7.28
Other Study Procedures .........................................................................................55
7.29
Appropriateness of Measurements.........................................................................55
8
STUDY ACTIVITIES .....................................................................................................56
8.1
Screening Visit/Study Start Visit...........................................................................56
8.2
Treatment:  Drug Administration and Weekly Assessments.................................57
8.2.1
Week 1 .........................................................................................................57
8.2.1.1
Day 1 (Pre-treatment) Assessments Performed Prior to Each Dose..57
8.2.1.2
Day 2 (±2 days) Assessments and Administration of HGT-1410 .....58
8.3
End of Study/Early Termination Procedures:  Month 55 ......................................58
8.4
Safety Follow-up (by Telephone or Visit) Month 56 ............................................59
9
QUALITY CONTROL AND ASSURANCE .................................................................61
10
PLANNED STATISTICAL METHODS ........................................................................62
10.1
General Statistical Methodology............................................................................62
10.2
Determination of Sample Size ...............................................................................62
10.3
Analysis Populations..............................................................................................62
10.4
Demographics and Baseline Characteristics..........................................................62
10.5
Statistical Analysis of Pharmacokinetic Variables ................................................63
10.6
Efficacy, Safety, and Pharmacodynamic Evaluations ...........................................63
10.6.1
Primary Analyses.........................................................................................63
10.6.1.1
Safety Analysis ..................................................................................63
10.6.2
Other Observations Related to Safety..........................................................64
10.6.2.1
IDDD Performance ............................................................................64
10.6.3
Secondary Analysis......................................................................................65
10.6.3.1
Clinical Assessments .........................................................................65
10.6.3.2
Pharmacodynamic Analyses ..............................................................65
11
ADMINISTRATIVE CONSIDERATIONS....................................................................66
11.1
Investigators and Study Administrative Structure.................................................66
11.2
Institutional Review Board or Independent Ethics Committee Approval .............66
11.3
Ethical Conduct of the Study.................................................................................66
11.4
Patient Information and Consent ...........................................................................66
11.5
Patient Confidentiality...........................................................................................67
11.6
Study Monitoring...................................................................................................67
11.7
Case Report Forms and Study Records .................................................................68
11.7.1
Critical Documents ......................................................................................68
11.8
Device Failure Adjudication Process.....................................................................69

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
6
11.9
Protocol Violations/Deviations..............................................................................69
11.10 Access to Source Documentation ..........................................................................69
11.11 Data Generation and Analysis ...............................................................................69
11.12 Premature Closure of the Study.............................................................................70
11.12.1
Study Termination .......................................................................................70
11.12.2
Site Termination...........................................................................................70
11.13 Retention of Data...................................................................................................70
11.14 Financial Disclosure...............................................................................................70
11.15 Publication and Disclosure Policy .........................................................................70
12
LIST OF REFERENCES.................................................................................................72
LIST OF IN-TEXT TABLES
Table 7-1.  Neurodevelopmental Assessments Tests.........................................................44
Table 7-2.  Sanfilippo-Specific Disability Assessment And Behavior Rating Scales.......44
Table 7-3.  Adverse Event Severity...................................................................................49
Table 7-4.  Adverse Event Relatedness .............................................................................50
Table 4-1. Summary of Neurodevelopmental Outcome Measures....................................77
Table 4-2. Summary of Sanfilippo-specific Assessments .................................................77
LIST OF APPENDICES
Appendix 1
Schedule of Events .....................................................................................74
Appendix 2
Neurodevelopmental and Behavioral Assessments....................................77
Appendix 3
Expected Adverse Device Effects ..............................................................81
Appendix 4
Protocol Amendment Summary of Changes..............................................83
Appendix 5
Protocol Signature Page .............................................................................89
Appendix 6
The National Cancer Institute Common Terminology Criteria version 
3.0...............................................................................................................90

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
7
SYNOPSIS
Sponsor:
Shire Human Genetic Therapies, Inc.
300 Shire Way
Lexington, MA  02421, United States
Name of Finished Product:
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Name of Active Ingredient:
rhHNS, HGT-1410
Name of Inactive Ingredient:
N/A
Names of Devices:  
SOPH-A-PORTMini S, Implantable Access Port, Spinal, Mini Unattached, with 
Guidewire (SOPH-A-PORT Mini S)
and
PORT-A-CATHII Low ProfileIntrathecal Implantable Access System 
(PORT-A-CATH)
Study Title:
An Open-Label Extension of Study HGT-SAN-055 Evaluating Long-Term Safety and 
Clinical Outcomes of Intrathecal Administration of rhHNS in Patients with Sanfilippo 
Syndrome Type A (MPS IIIA)
Study Number:
HGT-SAN-067
Study Phase:  I/II
Device, Intended Use
The SOPH-A-PORT Mini S is a system intended for implantation by physicians. The 
SOPH-A-PORT Mini S, once implanted, allows healthcare personnel to administer 
HGT-1410 indicated for intrathecal delivery intermittently over a long period of time.
Prior to approval of Amendment 4 patients were implanted with a PORT-A-CATH 
(Smith’s device). After approval of Amendment 4 all PORT-A-CATH IDDDs requiring 
revision or replacement will be replaced with a SOPH-A-PORT at a time judged 
appropriate by the Investigator.
Study Objectives:
Primary Objective: 
The primary objective of this study is:

To collect long-term safety and tolerability data in patients with Sanfilippo Syndrome 
Type A (MPS IIIA) who received HGT-1410 via a surgically implanted intrathecal 
drug delivery device (IDDD) in study HGT-SAN-055 and elected to continue therapy 
in study HGT-SAN-067.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
8
Secondary Objectives:
The secondary objectives of this study are:

To collect as measures of drug efficacy, over an extended treatment period (as change 
from baseline), the following:  clinical, neurological, cognitive, behavioral, 
functional, and quality of life (QoL) assessments, together with potential imaging and 
biochemical biomarkers.
Study Endpoints: 
Primary Endpoints:
The primary endpoints of this study are related to the long-term safety of intrathecal 
HGT-1410 administration. There safety endpoints are:

adverse events (type and severity)

changes in clinical laboratory testing (serum chemistry including  liver function tests, 
hematology, and urinalysis)

electrocardiograms (ECG)

cerebrospinal fluid (CSF) chemistries (including cell counts and inflammatory 
markers)

anti-rhHNS antibodies (in CSF and serum).
Secondary Endpoints:
The secondary endpoints of this study are to collect over an extended treatment period (as 
change from baseline) clinical and potential surrogate biomarker efficacy data:

Standardized neurocognitive and behavioral assessments, Sanfilippo-specific 
behavioral rating scales, gross and fine motor assessments, functional adaptive rating 
scales, quality of life questionnaires, and Children’s Sleep Habits Rating Scale.

Concentration of inflammatory cytokines in serum and CSF.

Concentration of safety and potential surrogate efficacy biomarkers in CSF, urine, 
and serum.

Concentration of heparan sulfate and heparan sulfate derivatives in urine and/or CSF, 
and if possible, in serum and/or plasma.

Brain magnetic resonance imaging (MRI) and auditory brainstem response (ABR), 
Brainstem Auditory Evoked Potentials).
Study Design:
This study, HGT-SAN-067, is an open-label, long term, multicenter, extension of 
Study HGT-SAN-055.  The study is designed to evaluate the long-term safety, clinical 
activity, and biomarker outcomes of intrathecal (IT) administration of 3 dose levels 
(10 mg, 45 mg, and 90 mg once per month [Q4W]) of HGT-1410 via an IDDD in patients 
with MPS IIIA who successfully complete the Phase I/II study HGT-SAN-055 (including 
end of study [EOS] assessments) and elect to continue to receive HGT-1410 treatment.  
Initially, patients will continue in the same treatment group they were assigned to in the 
HGT-SAN-055 study. Following approval of protocol Amendment 4, patients in the 10 
mg group will have their dose increased to 45 mg per month.
For nomenclature of chronology purposes, the Baseline Visit for this extension study will 
be considered to be the first day the patient received his/her IT dose of HGT-1410 in 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
9
Study HGT-SAN-055.  The HGT-SAN-055 EOS assessment information will provide the 
screening/start of study information for patients who continue into the HGT-SAN-067 
extension study.  Note:  HGT-SAN-055 EOS data must be recorded in the context of the 
HGT-SAN-055 trial, and a copy of those data can be used for HGT-SAN-067 screening.  
Once eligibility is confirmed, informed consent must be obtained prior to performing any 
study-related procedures that are specific to HGT-SAN-067.  
Informed consent will be provided by the patient’s parent(s)/legally authorized 
representative(s) prior to the start of the extension study procedures.  Informed consent 
may be obtained anytime from week 20 in HGT-SAN-055.  This would allow a patient to 
have a nonfunctional IDDD replaced or revised prior to the first HGT-1410 dose in 
HGT-SAN-067.
Enrolled patients will check in to the study center 1 day before each of the scheduled 
HGT-1410 dosing days for safety assessments (designated Day 1). If no safety concerns 
exist, the patient will subsequently receive IT administration of HGT-1410 on Day 2 
(±2 days). However, if feasible and there are no safety concerns in the opinion of the 
investigator, the Day 1 and Day 2 assessments may be combined and performed on 
Day 2; if this is done the results will be recorded as Day 2. Patients will remain in the 
study center for at least 4 hours following dosing with HGT-1410 and will be discharged 
from the unit when deemed clinically stable by the Investigator.
All patients will have received a series of standardized neurodevelopment assessments in 
the HGT-SAN-055 study.  These assessments will have occurred at Baseline and either 
prior to or at the 6-month time point. Patients will continue in HGT-SAN-067 with 
whichever age specific assessment they began with in HGT-SAN-055. If, however, a 
patient’s capability improves and they become capable of completing assessments at a 
higher level, such additional assessments may be added. Any additional assessments 
would be performed after the original assessments (those previously used in study 
HGT-SAN-055) have been carried out. A MRI of the head and ABR testing will be 
performed at Months 12, 24, 36, and 54 (note that assessment time point nomenclature 
includes the 6 months in the HGT-SAN-055 study). Note: X-rays may be performed to 
investigate device malfunction, and to verify correct catheter and port placement 
following surgical implantation or revision. In addition, fluoroscopy should be employed 
intraoperatively to guide catheter placement. Thus, patients may undergo 3 X-ray 
examinations in association with each episode of IDDD malfunction and subsequent 
IDDD revision or replacement. Since the number of IDDD revisions/replacements is 
limited to 2 in any 6-month period (including the time in the HGT-SAN-055 study), the 
number of protocol-associated X-ray evaluations is limited to 6 exposures in any 6-month 
period (including time in the HGT-SAN-055). Patients will also have X-ray examinations 
of the device performed at the EOS visit if the patient is to continue to receive intrathecal 
HGT-1410 beyond the end of the study.
Patients will be evaluated for safety throughout the study.  Adverse events that occur in 
HGT-SAN-055 and that are ongoing at enrollment in HGT-SAN-067 will be captured in 
the case report forms (CRFs) for study HGT-SAN-067.  Specific safety stopping criteria 
will be applied and will be based on the types and severity of adverse events (AEs) 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
10
reported while on-study.  These data will be reviewed to inform the decision to 
discontinue a patient, a dose group, or the study as a whole. 
All patients will have an EOS visit 30 (±7) days following their last administration of 
HGT-1410 (ie, Month 55).  The EOS procedures will include standard clinical laboratory 
tests (serum chemistry, hematology, and urinalysis) in CSF and blood, protocol specific 
laboratory testing (eg, anti-rhHNS antibody testing), neurodevelopmental testing, ABR, 
child health questionnaires, MRI and an X-ray examination of the device.  
Use of concomitant medications, therapies, and procedures will be recorded and AEs will 
be monitored. 
All patients will be contacted by telephone or will have a visit for a Final Safety 
Follow-up, to be conducted at 30 (±7) days after the EOS visit (ie, Month 56) to collect 
updated information on AEs and concomitant medications, therapies, and procedures. 
It is anticipated that the IDDD will be used to obtain CSF samples and to deliver 
administrations of HGT-1410.  However, if a patient’s IDDD appears nonfunctional or if 
its use is precluded on a scheduled day of dosing, site personnel will refer to the 
operations manual (for PORT-A-CATH) or the IDDD Manual (for SOPH-A-PORT), 
which describes the investigation and management of IDDD-related issues.  This will 
include possible partial revision or complete replacement of the IDDD.  As noted above, 
a maximum of 2 partial revisions and/or complete replacements can occur in any 6 month 
period.  If revision or replacement of the IDDD cannot be scheduled in time to avoid a 
delay of the next scheduled dose of HGT-1410, or if the patient experiences more than 
2 IDDD malfunctions in a 6 month period (including participation in study 
HGT-SAN-055), HGT-1410 will be administered via lumbar puncture (LP).  Study drug 
may be administered via LP for a maximum of 5 successive monthly doses, after which, 
IDDD re-implantation or revision must occur. 
If there is no significant safety risk in the opinion of the Investigator, a non-functional 
IDDD may be left in situ for up to 3 months.
In light of the higher than expected complications experienced with the PORT-A-CATH 
IDDD, the SOPH-A-PORT Mini S device will be introduced for those patients requiring 
replacement or revision.  This new device has design features anticipated to reduce 
complications encountered with the PORT-A-CATH IDDD device.  Specific device 
assessments are included in the protocol to collect information with respect to 
information specific to SOPH-A-PORT Mini S device safety and function.  
Patients who discontinue or are withdrawn before receiving 3 monthly IT injections will 
not have to undergo the EOS evaluations but will have their IDDD removed.  
Patients will have the IDDD removed when they discontinue from the study, unless the 
patient is continuing to receive treatment through another mechanism (eg, extension 
study, expanded access, commercially available).

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
11
An overview of the study appears in the Schedule of Events.
Study Population: 
A maximum of 12 patients are planned for this study.  To be eligible for participation 
patients will have completed all study requirements in Study HGT-SAN-055, including 
the EOS visit, and will have elected to continue treatment with HGT-1410. 
Test Product; Dose; and Mode of Administration: Recombinant human heparan 
N-sulfatase (rhHNS, HGT-1410) will be administered via an IDDD according to the same 
dose to which the patient was assigned in HGT-SAN-055 (ie, 10 mg, 45 mg, or 90 mg 
monthly). Patients assigned to the 10 mg monthly dose will have their dose increased to 
45 mg once per month (Q4W) at the first administration of HGT-1410 following full 
approval of the protocol amendment.
Reference Therapy; Dose; and Mode of Administration: 
N/A
Diagnosis and Main Criteria for Inclusion
Inclusion Criteria:
Each patient must meet the following criteria to be enrolled in this study.
1. The patient must have completed Study HGT-SAN-055 and, in the opinion of the 
investigator, have no safety or medical issues that contraindicate participation. 
2. The patient, patient’s parent(s) or legally authorized representative(s) has voluntarily 
signed an Institutional Review Board/Independent Ethics Committee-approved 
informed consent (and assent, if applicable) form after all relevant aspects of the 
study have been explained and discussed with them.  Informed consent/assent must be 
obtained prior to any study specific procedures.
3. The patient received at least 5 of the 6 planned infusions of HGT-1410 in the 
HGT-SAN-055 study. 
4. The patient must be medically stable, in the opinion of the Investigator, to 
accommodate the protocol requirements, including travel, assessments, and IDDD 
surgery (if necessary for replacement purposes), without placing an undue burden on 
the patient/patient's family.
Exclusion Criteria: 
Patients will be excluded from the study if there is evidence of any of the following:
1. The patient has experienced an adverse reaction to study drug in Study 
HGT-SAN-055 that contraindicates further treatment withHGT-1410.
5. The patient has a known hypersensitivity to the active ingredient or any excipients in 
HGT-1410 drug product.
6. The patient has non-MPS IIIA related central nervous system (CNS) impairment or 
behavioral disturbances that would confound the scientific integrity or interpretation 
of study assessments, as determined by the Investigator.
7. The patient has MPS IIIA behavioral-related issues, as determined by the 
Investigator, which would preclude performance of study neurocognitive and 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
12
developmental testing procedures.
8. The patient is pregnant, breast feeding, or is a patient of childbearing potential who 
will not or cannot comply with the use of an acceptable method of birth control, such 
as condoms, barrier method, oral contraception, etc.
9. The patient has any known or suspected hypersensitivity to anesthesia or is thought to 
have an unacceptably high risk for anesthesia due to airway compromise or other 
conditions.
10. The patient has a history of a poorly controlled seizure disorder. 
11. The patient is currently receiving psychotropic or other medications, which in the 
Investigator’s opinion, would be likely to substantially confound test results and the 
dose and regimen of which cannot be kept constant throughout the study.
12. The patient cannot sustain absence from aspirin, non-steroidal medications, or 
medications that affect blood clotting within 1 week prior to a relevant study-related 
procedure (eg, device re-implantation if applicable), or has ingested such medications 
within 1 week before any procedures in which any change in clotting activity would 
be deleterious.
13. The patient has received treatment with any investigational drug (other than 
HGT-1410) intended as a treatment for MPS IIIA within the 30 days prior to, during 
the study, or is currently enrolled in another study that involves an investigational 
drug or device (screening through safety follow-up contact).
14. The patient has received a hematopoietic stem cell or bone marrow transplant.
For patients to be implanted with the SOPH-A-PORT Mini S IDDD the following 
conditions are contraindicated, as described in the Instructions for Use: 
1. The patient has had, or may have, an allergic reaction to the materials of construction 
of the SOPH-A-PORT Mini S device
1. The patient’s body size is too small to support the size of the SOPH-A-PORT Mini S 
Access Port, as judged by the Investigator 
1. The patient has a known or suspected local or general infection
1. The patient is at risk of abnormal bleeding due to a medical condition or therapy
1. The patient has one or more spinal abnormalities that could complicate safe 
implantation or fixation
1. The patient has a functioning CSF shunt device
1. The patient has shown an intolerance to an implanted device
Duration of Treatment: 
The study duration will be 4 years.
Pharmacokinetic Variables:
N/A.
Safety Assessments: 
Safety evaluations will include vital signs, physical examinations, AE assessments, 
electrocardiograms (ECG); serum chemistry, hematology, urine laboratory tests, and 
screening for antibodies to rhHNS (in CSF and serum).  

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
13
Statistical Methods: The statistical methodology supporting the trial will focus on
descriptive rather than inferential approaches, given the early phase and objectives of the 
trial. Data will be plotted and the mean, standard deviation, median, minimum, and 
maximum for each variable will be tabulated by dose group to look for gross trends over 
time, which may be attributed to treatment. For continuous data, 95% confidence interval 
(CI) around the mean will also be estimated and presented.
The analysis population consists of all eligible patients from HGT-SAN-055 who have 
completed Study HGT-SAN-055 and agreed to participate in this extension study.  Safety 
analyses will be performed using the above mentioned population.  The data will be 
presented by dose group.
Date of Original Protocol: 21 June 2010
Date of Amendment 4: 3 May 2013

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
14
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
ABR
auditory brainstem response
AE
adverse event
ALB
albumin
ALK-P
alkaline phosphatase
ALT
alanine aminotransferase (SGPT)
AST
aspartate aminotransferase (SGOT)
βhCG
human chorionic gonadotropin
BSID-III
Bayley Scales of Infant Development, Third Edition
BBB
blood brain barrier
BUN
blood urea nitrogen
Ca
calcium
CE
Conformité Européenne
CFR
Code of Federal Regulations
CHQ-50
Child Health Questionnaire™ Parent Form 50
CHQ-87
Child Health Questionnaire™ Child Form 87
CK
creatine kinase
Cl
chloride
CNS
central nervous system
CO2
carbon dioxide
CTCAE
Common Terminology Criteria for Adverse Events
CRO
contract research organization
CRIM
cross-reacting immunologic material 
CS
clinically significant
CSF
cerebrospinal fluid
ECG
electrocardiogram
eCRF
electronic case report form
EDC
Electronic Data Capture 
ERT
enzyme replacement therapy

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
15
EOS
end of study
EOW
every other week
EU
European Union
FDA
Food and Drug Administration
FPSS/TDS
Four-Point Scoring System/Total Disability Score
GAG
glycosaminoglycan
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
H
High
Hct
hematocrit
Hgb
hemoglobin
HS
heparan sulfate
ICH
International Conference on Harmonization 
IDDD
intrathecal drug delivery device
IEC
Independent Ethics Committee
IFU
instructions for use
IND
Investigational New Drug 
IRB
Institutional Review Board
IT
intrathecal
ITQOL
Infant Toddler Quality of Life Questionnaire™
IV
intravenous
K
potassium
KABC-II
Kaufman Assessment Battery for Children, Second Edition
L
Low 
LDH
lactic dehydrogenase
LP
lumbar puncture 
LSD
lysosomal storage disease
M6P
mannose-6-phosphate
MABC-2
Movement Assessment Battery for Children

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
16
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MABC-2
Movement Assessment Battery for Children, Second Edition
MPS
Mucopolysaccharidosis 
MPS IIIA
Mucopolysaccharidosis IIIA or Sanfilippo syndrome Type A
MRI
magnetic resonance imaging
Na
sodium 
NCI
National Cancer Institute
NCS
not clinically significant
PE
pressure-equalization
QoL
quality of life
Q4W
once per month
RBC
red blood cell (count)
rhHNS
recombinant human heparan N-sulfatase
RNA
ribonucleic acid
SAE
serious adverse event
SAP
Statistical Analysis Plan
SBRS
The Sanfilippo Behavior Rating Scale
SGOT
serum glutamic oxaloacetic transaminase (AST)
SGPT
serum glutamic pyruvic transaminase (ALT)
Shire HGT
Shire Human Genetic Therapies, Inc.
SOC
system organ class
TMF
Trial Master File
TX
treatment
UADE
unanticipated adverse device effect
US
United States
VABS-II
Vineland Adaptive Behavior Scales 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
17
WBC
white blood cell (count)
WHO-DD
WHO Drug Dictionary 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
18
1
INTRODUCTION 
The progressive and irreversible nature of lysosomal storage diseases (LSDs) present a challenge 
in the interpretation of clinical benefit derived from treatment in studies using enzyme 
replacement therapy (ERT).  Any short-term improvement and/or stabilization of clinically 
important manifestations of the disease may be viewed as clinically meaningful.  However, the 
demonstration of the different aspects of a long-term, clinically-meaningful improvement may be 
limited by the short duration of treatment in clinical studies.  Extended access to treatment 
through extension studies provides an opportunity for further evaluation of long-term safety and 
clinical outcomes for treated patients.  In this extension study, patients who completed study 
HGT-SAN-055, a phase I/II safety and dose-escalation trial, and elected to continue to receive 
recombinant human heparan N-sulfatase (rhHNS), will receive treatment through this extension 
protocol.  Initially, the patient’s treatment group and dosing regimen will be the same as that 
employed in study HGT-SAN-055. Following the analysis of data from HGT-SAN-055, patients 
in the lowest dose group will have their dose increased to 45 mg, as outlined in section 1.3, 
below. 
1.1
Disease Background 
Sanfilippo syndrome, or Mucopolysaccharidosis (MPS) III, is LSD caused by loss in activity of 1 
of 4 enzymes necessary for degradation of the glycosaminoglycan (GAG) heparan sulfate (HS) 
in lysosomes.  Four different subtypes (A, B, C, and D) have been identified and are each due to 
a specific enzyme deficiency involved in the lysosomal catabolism of HS.  
Mucopolysaccharidosis IIIA or Sanfilippo syndrome Type A (MPS IIIA) results from deficiency 
of the enzyme heparan N-sulfatase (sulfamidase).  In the absence of this enzyme, intermediates 
of the HS degradation process accumulate in the lysosomes of neurons and glial cells, with lesser 
accumulation outside the brain.  
MPS III is the most prevalent of all mucopolysaccharidoses, with subtype A the most common of 
these.1 The birth prevalence of MPS IIIA has been estimated as 1.28 in 100,000 in Australia, 
1.16 in 100,000 in the Netherlands, and 0.88 in 100,000 in Germany.1-3 In summary, MPS IIIA 
is a rare genetic disorder with apparently widespread geographic distribution and an average 
global birth incidence of approximately 1 in 100,000. 
In a recent detailed review of all MPS IIIA patients diagnosed in the Netherlands, it was reported 
that among 81 patients in whom information was available, first symptoms arose at a median of 
2.5 years (range 0.5 to 7 years).4  Owing to the rarity of the disease and the non-specific and 
often subtle nature of its initial manifestations, diagnosis is usually delayed until an average age 
of 4 to 4.5 years.4, 5 Patients present a wide spectrum and severity of clinical symptoms.  The 
central nervous system (CNS) is the most severely affected organ system in patients with MPS 
IIIA, evidenced by deficits in language development, motor skills, and intellectual development.5  
In addition, there are abnormal behaviors including, but not limited to, aggression and excess 
motor activity/hyperactivity that contribute to disturbances in sleep.5 - 7 In contrast with other 
MPS types, the viscera are mildly affected, with transient enlargement of liver and spleen during 
childhood with no evidence of dysfunction.  There are also reports of unexplained, recurrent and 
severe diarrhea.8  Overall, individuals with MPS IIIA have a marked developmental delay and 
significantly reduced lifespan of 15 years of age on average.8  

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
19
A milder variant has recently been identified with slower progression and survival to later age in 
approximately 10% of German patients with MPS IIIA.9
No effective, disease-modifying therapies are currently approved as treatments for this rare, 
devastating and disabling disease.  
A long-range goal of Shire Human Genetic Therapies, Inc. (Shire HGT) is to develop a 
recombinant human sulfamidase ERT for patients with MPS IIIA.  A particular problem for 
LSDs that damage the brain such as MPS III is how to target ERT to the brain.10  In animal 
studies, ERT was administered into the cerebrospinal fluid (CSF) via an intrathecal (IT) route, 
because when administered intravenously (IV), it was shown to not cross the blood brain barrier 
(BBB) after the immediate postnatal period of life.11, 12  
As the CNS in patients with MPS IIIA is the most severely affected body system, the main focus 
of the HGT-1410 clinical development program has been the development of ERT specifically 
for delivery directly to the CNS.  Recombinant human heparan N-sulfatase has been developed 
specifically for delivery into the CSF via an intrathecal drug delivery device (IDDD) due to the 
acknowledged impermeability of the BBB to macromolecules. 
Heparan N-sulfatase is a highly purified recombinant form of the naturally occurring human 
lysosomal enzyme sulfamidase.  It is expressed from the well characterized continuous human 
HT-1080 cell line as a 482 amino acid peptide, following cleavage of the 20 amino acid 
N-terminal signal peptide.  The mature protein in solution is a homodimeric glycoprotein of 
approximately 122 kDa, which undergoes post-translational modifications by conversion of 
Cys50 to formylglycine, required for enzyme activity, and glycosylation at 4 of the 5 potential 
N-linked glycosylation sites.  The rhHNS glycans contain mannose-6-phosphate (M6P) residues 
which target the protein for cellular uptake and internalization in its lysosomal site of action via 
the membrane-bound M6P receptors.13, 14, 16
The first precedent for intraspinal ERT was recently published and has been shown to be both 
safe and effective for spinal cord compression in MPS I.17   In this study, a patient with MPS I 
received 4 IT doses of enzyme (Laronidase [recombinant α-L-Idurunonidase]) at 1-month 
intervals.  Safety evaluations included CSF opening pressure, serum chemistry and CSF protein, 
glucose and cell count, in addition to clinical efficacy studies.  No changes in safety evaluations 
were observed.
In another recent study, a patient with MPS VI and spinal cord compression received IT 
injections of enzyme (Galsulfase) monthly, for 4 months.  CSF analysis revealed no 
inflammatory reaction; no other side effects were noted.18
Several MPS I patients have been treated since 2005 with IT Laronidase in 2 ongoing clinical 
trials (clinicaltrials.gov identifiers NCT00215527 and NCT00786968) studying efficacy on 
spinal cord compression. No results of these trials have yet been published. However, in 
June 2009 a study further investigating the effectiveness of IT ERT as a treatment for another 
neurological symptom in MPS I, cognitive decline, was initiated (clinicaltrials.gov identifier 
NCT00852358). 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
20
This study is a 24-month, open label, prospective, randomized trial in 16 patients with 
MPS I, 6 years of age or older, who have documented evidence of cognitive decline. In this 
study, the clinical safety of the regimen will be assessed by AE monitoring, CSF laboratory 
assessments, and clinical evaluations.  This study is ongoing; no efficacy or safety data have yet 
been published as of October 2011.19 
In addition, there are 4 ongoing Shire HGT-sponsored studies that are evaluating IT 
administration of ERT:  A Phase I/II safety and dose escalation study of monthly idursulfase-IT 
injection for cognitively impaired patients with Hunter syndrome (Study HGT HIT-045; 
NCT00920647), the open-label extension to this study (HGT-HIT-046); a Phase I/II ascending 
dose and dose frequency study of monthly IT injection of HGT-1410 in patients with Sanfilippo 
Syndrome Type A (Study HGT-SAN-055; NCT01155778), and the open-label extension to this 
study (HGT-SAN-067; NCT 01299727).
In light of the higher than expected complications experienced with the PORT-A-CATH IDDD, 
the SOPH-A-PORT Mini S device will be introduced for those patients requiring replacement or 
revision.  This new device has design features anticipated to reduce complications encountered 
with the PORT-A-CATH IDDD device.  Specific device assessments are included in the protocol 
to collect information with respect to information specific to SOPH-A-PORT Mini S device 
safety and function.  
1.2
Nonclinical Overview
To circumvent the restriction of the BBB, HGT-1410 was administered into the CSF of rats and 
monkeys via an IT route.  The non-clinical data demonstrate that IT administration of HGT-1410 
leads to uptake by target CNS tissues with appropriate efficacy and distribution.  In addition, 
there were no findings noted in the toxicity studies, allowing for a 6.2-fold safety margin from 
the results in the juvenile cynomolgus monkey.  Intermittent bolus injection of HGT-1410 to the 
brain via the IT route of administration is hypothesized to be of benefit in stabilizing, improving, 
or preventing the CNS manifestations of disease. 
The doses tested in the non-clinical studies adequately support the efficacy of the planned doses 
(10, 45 or 90 mg/month, normalized to the brain weight of the human) in the ongoing Phase I/II 
study, HGT-SAN-055.  Specifically, in the San A mouse, the 100 μg dose corresponds to a 
2.2-fold increase (per kg brain weight) from the highest anticipated human dose (90 mg) (human 
brain = 1 kg).  The 20 μg dose given IT every-other-week (EOW) or monthly, for which efficacy 
was also observed, corresponds to a 40 mg (per kg brain weight) human dose.  In the Huntaway 
(Sanfilippo A) dogs, the 3 mgHGT-1410 given IT weekly (corresponding to a 33 mg/kg of brain 
weight in man), was not only well tolerated but resulted in significant effects on biomarkers of 
disease activity and improved histopathology. 
1.2.1
Toxicology in Monkeys
In the pivotal, 6-month IT toxicity study in juvenile cynomolgus monkeys, and the highest dose 
of HGT-1410 was 8.3 mg given EOW.  This translates into a 138 mg/kg brain-weight dose (ie, 
based on a 60 g juvenile monkey brain).  Since no HGT-1410-related adverse effects were noted, 
the nonclinical study provides for the proposed Phase I/II clinical trial a ~13.8 × safety margin 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
21
relative to the starting clinical dose (10 mg), and a 1.5× safety margin relative to the highest 
clinical dose (90 mg).    
1.2.2
Efficacy in Murine and Canine Models of MPS IIIA
Non-clinical proof of concept efficacy studies were conducted using mouse and dog models of 
MPS IIIA, both of which contain naturally-occurring mutations in the HNS gene.  
In the MPS IIIA mouse, direct injection into the CNS had a beneficial effect on clinical signs, 
impaired neurobehavioral, and the biochemical and histopathologic markers of disease activity.  
In Huntaway (Sanfilippo A) dogs,,HGT-1410 (3 mg) given IT weekly had a significant effect on 
biomarkers of disease activity and improved histopathology.
Efficacy has been demonstrated at a range of doses in nonclinical mouse and canine models.  In 
MPS IIIA mice, a dose-dependent reduction in the level of a heparan sulfate-derived monosulfate 
disaccharide was observed within the brain (up to 62% reduction compared with vehicle-treated 
mice) and spinal cord (up to 71% reduction).  An ultrastructural examination revealed a 
reduction in lysosomal vesicle formation in various cell types and fewer (ubiquitin-positive) 
axonal spheroids in several brain regions after repeated injections (5 to 20 µg) of HGT-1410 into 
the CSF of MPS III mutant mice via the cisterna magna (ie, IT).  The biochemical changes were 
accompanied by improved behavior, particularly in mice treated more frequently.20
In the MPS IIIA mutant mouse model, intracisternal (ie, IT) injection of a single dose of 100 µg 
HGT-1410 resulted in a substantial (and sustained) reduction of biomarkers of disease activity 
(heparan sulfate-derived disaccharides, microgliosis and astrogliosis).21  Equally impressive was 
the improvement in neurobehavioral parameters (learning in the Morris water maze, 
normalization of aggression) in these mice post-dose.21  One-hundred µg HGT-1410 per mouse 
translates into 200 mg/kg brain weight (ie, based on a 0.5 g mutant mouse brain).  Efficacy at 
lower doses of HGT-1410 (eg, 20 µg, given IT, EOW or monthly) has been demonstrated.11  A 
20 µg injection translates into a 40 mg human dose (ie, 40 mg per kilogram of brain weight).  
Thus, this data further suggests that efficacy will be seen at the highest clinical dose (90 mg, per 
month) in the proposed Phase I/II study. 
In the tolerized Huntaway (San A) dogs, 3 mg HGT-1410 was initially given IT on a weekly 
basis, then EOW, and had a significant effect on biomarkers of disease activity.22 The 3 mg dose 
in the dog translates into a 33 mg (per kg brain weight) human dose (based on a 90 g Huntaway 
dog brain). 
1.3
HGT-SAN-067 Study Rationale
This extension study (Study HGT-SAN-067) will evaluate the effects of long-term HGT-1410 
administration on safety, clinical activity, and biomarker outcomes in patients who completed 
Study HGT-SAN-055 and elected to continue therapy with HGT-1410.
Patients who were enrolled in Study HGT-SAN-055 through Week 26 and completed the end of 
study (EOS) evaluations are eligible for enrollment in this open-label extension study. All 
patients enrolled in this study will initially receive HGT-1410 at the same dose and schedule as 
they received in Study HGT-SAN-055. Patients assigned to 10 mg monthly will have their dose 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
22
increased to 45 mg monthly once per month (Q4W) at the first administration of HGT-1410 
following full approval of protocol Amendment 4. Based on analyses performed at the 
completion of Study HGT-SAN-055 a decline in the primary pharmacodynamic parameter, CSF 
heparan sulfate, was observed. This response to therapy was exhibited at all dose levels, 
however, the greatest impact was at the 2 higher dose levels. An effect on CSF heparan sulfate 
demonstrated in vivo activity of HGT-1410 in the target anatomical compartment. This effect is 
thought to have central importance in mediating the potential therapeutic benefit of HGT-1410. 
As no apparent difference in safety profile was observed between the 3 dose groups, it was 
believed that the increase in the potential therapeutic benefit of the higher dose outweighed any 
potential increase in risks for this lowest dose group.  
Please refer to the current edition of the Investigator’s Brochure for further information 
concerning the safety and clinical development of HGT-1410 and PORT-A-CATH IDDD and 
SOPH-A-PORT Mini S device.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
23
2
STUDY OBJECTIVES
2.1
Primary Objective 
The primary objective of this study is:

To collect long-term safety and tolerability data in patients with Sanfilippo Syndrome 
Type A (MPS IIIA) who received HGT-1410 via a surgically implanted IDDD in study 
HGT-SAN-055 and elect to continue therapy in study HGT-SAN-067.
2.2
Secondary Objectives 
The secondary objectives of this study are:

To collect, as measures of drug efficacy, over an extended treatment period (as change from 
baseline), the following:  clinical, neurological, cognitive, behavioral, functional, and quality 
of life (QoL) assessments, together with potential imaging and biochemical biomarkers.
2.3
Exploratory Objective
An exploratory objective of this study is:


Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
24
3
STUDY ENDPOINTS
3.1
Primary Endpoint
The primary endpoints of this study are related to the long-term safety of intrathecal HGT-1410 
administration. There safety endpoints are:

adverse events (type and severity)

changes in clinical laboratory testing (serum chemistry including  liver function tests, 
hematology, and urinalysis)

electrocardiograms (ECG)

cerebrospinal fluid (CSF) chemistries (including cell counts and inflammatory markers)

anti-rhHNS antibodies (in CSF and serum).
3.2
Secondary Endpoints 
The secondary endpoints of this study are to collect over an extended treatment period (as the 
change from baseline [defined as the start of the HGT-SAN-055 study]) clinical and potential 
surrogate biomarker efficacy data: 

Measures of standardized neurocognitive and behavioral assessments, Sanfilippo-specific 
behavioral rating scales, gross and fine motor assessments, functional adaptive rating scales, 
QoL questionnaires, and Children’s Sleep Habits Rating Scale.

Concentration of inflammatory cytokines in serum and CSF.

Concentration of safety and potential surrogate efficacy biomarkers in CSF, urine, and 
serum.

Concentration of heparan sulfate and heparan sulfate derivatives in urine, plasma, and serum. 

Brain MRI and ABR, (also known as Brainstem Auditory Evoked Potentials).
3.3
SOPH-A-PORT Mini S Assessments

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
25
4
INVESTIGATIONAL PLAN
4.1
Overall Study Design and Plan
Study HGT-SAN-067, is an open-label, long term, multicenter, extension of Study 
HGT-SAN-055.  This study is designed to evaluate the long-term safety, clinical activity, and 
biomarker outcomes of IT administration of 3 dose levels (10 mg, 45 mg, and 90 mg once per 
month [Q4W]) of HGT-1410 via an IDDD in patients with MPS IIIA who successfully 
completed HGT-SAN-055 (including the EOS assessments) and elect to continue to receive 
uninterrupted HGT-1410 treatment.  Patients will initially continue in the same treatment group 
they were assigned to in the HGT-SAN-055 study: 

Group 1:  HGT-1410 administered by IT injection 10 mg once per month (Q4W) 

Group 2:  HGT-1410 administered by IT injection 45 mg once per month (Q4W)

Group 3:  HGT-1410 administered by IT injection 90 mg once per month (Q4W) 
Patients assigned to Group 1 will initially receive 10 mg monthly but will have their dose 
increased to 45 mg monthly (Q4W) at the first administration of HGT-1410 following full 
approval of protocol Amendment 4.
In order to maintain a nomenclature system based on study chronology across the original 
HGT-SAN-055 study and this extension study, the Baseline Visit for this extension study will be 
considered to be the day the patient received their first IT dose of HGT-1410 in 
Study HGT-SAN-055.  The HGT-SAN-055 EOS assessment information will provide the 
screening/start of study information for patients who continue into the HGT-SAN-067 extension 
study.  Note: HGT-SAN-055 EOS data must be recorded in the context of the HGT-SAN-055 
trial, and a copy of those data can be used for HGT-SAN-067 screening.  Once eligibility is 
confirmed, informed consent (and assent, if applicable), provided by the patient’s 
parent(s)/legally authorized representative(s), must be obtained prior to performing any 
HGT-SAN-067 study-related procedures.  Informed consent may be obtained anytime from 
Week 20 in HGT-SAN-055.  This would allow a patient to have a nonfunctional IDDD replaced 
or revised prior to the first HGT-1410 dose in HGT-SAN-067.
Enrolled patients will check in to the study center 1 day before each of the scheduled HGT-1410 
dosing days for safety assessments (designated Day 1).  If no safety concerns exist, the patient 
will subsequently receive IT administration of HGT-1410 on Day 2 (±2 days).  However, if 
feasible and there are no safety concerns in the opinion of the investigator, the Day 1 and Day 2 
assessments may be combined and performed on Day 2; if this is done the results will be 
recorded as Day 2.  Patients will remain in the study center for at least 4 hours following dosing 
with HGT-1410 and will be discharged from the unit when deemed clinically stable by the 
Investigator.  
All patients will have received a series of standardized neurodevelopment assessments; in the 
HGT-SAN-055 study, these will have occurred at Baseline and either prior to or at the 6-month 
time point.  Patients will continue in HGT-SAN-067 with whichever age specific assessment 
they began with in HGT-SAN-055.  If, however, a patient’s capability improves and they 
become capable of completing assessments at a higher level, such additional assessments may be 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
26
added.  Any additional assessments are to be performed after the original assessments (those 
used in study HGT-SAN-055) have been carried out.  
A MRI of the head and ABR testing will be performed at Months 12, 24, 36, and 54 (note that 
assessment time point nomenclature includes the 6 months in the HGT-SAN-055 study). 
In the event of a device malfunction, X-rays may be performed to investigate, as well as to verify
correct catheter and port placement following surgical IDDD implantation or revision.  In 
addition, fluoroscopy may be employed intra-operatively to guide catheter placement.  Patients 
may undergo 3 X-ray examinations in association with each episode of IDDD malfunction and 
subsequent IDDD revision or replacement.  The number of IDDD revisions/replacements is 
limited to 2 in any 6-month period (including the time in the HGT-SAN-055 study), and the 
number of protocol-associated X-ray evaluations is limited to 6 exposures in any 6-month period 
(including time in study HGT-SAN-055). If patients are to continue to receive HGT-1410 using 
the IDDD beyond the duration of this study, they will also have X-ray examinations of the 
device performed at the EOS visit, to document correct positioning.
Patients will be evaluated for safety throughout the study.  Adverse events that occur in 
HGT-SAN-055 and are ongoing at enrollment in HGT-SAN-067 will be captured as ongoing in 
the HGT-SAN-055 study and also be reported as a concurrent condition in the HGT-SAN-067 
electronic case report forms (eCRFs).  Specific safety stopping criteria will be applied and will 
be based on the types and severity of AEs reported while on-study.  These data will be reviewed 
to inform the decision to discontinue a patient, a dose group, or the study as a whole. 
All patients will have an EOS visit 30 (±7) days following their last administration of HGT-1410 
(ie, Month 55).  The EOS procedures will include standard clinical laboratory tests (serum
chemistry, hematology, and urinalysis) in CSF and blood, protocol specific laboratory testing 
(eg, anti-rhHNS antibody testing), neurodevelopmental testing, ABR, child health 
questionnaires, MRI and X-ray examination of the device.  Use of concomitant medications, 
therapies, and procedures will be recorded and AEs will be monitored. 
All patients will be contacted by telephone or will have a visit for a Final Safety Follow-up, 
conducted at 30 (±7) days after the EOS visit (ie, Month 56) to collect updated information on 
AEs and concomitant medications, therapies, and procedures. 
It is anticipated that the IDDD will be used to obtain CSF samples and to administer HGT-1410. 
However, if a patient’s PORT-A-CATH IDDD appears nonfunctional or if its use is precluded 
on a scheduled day of dosing, site personnel will refer to the PORT-A-CATH instructions for use 
(IFU),  which describes the investigation and management of IDDD-related issues with this 
device. This will include possible partial revision or complete replacement of the PORT-A-
CATH IDDD with a SOPH-A-PORT IDDD. For malfunctions involving the SOPH-A-PORT 
Mini S, site personnel will refer to the SOPH-A-PORT Instructions for Use (IFU).  For either 
IDDD, a maximum of 2 partial revisions and/or complete replacements are permitted in any 
6 month period (including participation in study HGT-SAN-055). If a revision or replacement of
the IDDD cannot be scheduled in time to avoid a delay of the next scheduled dose of HGT-1410, 
or if the patient experiences more than 2 IDDD malfunctions in a 6 month period, HGT-1410 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
27
will be administered via LP. Drug may be administered via LP for a maximum of 5 successive 
monthly doses, after which, IDDD re-implantation or revision must occur. 
If there is no significant safety risk in the opinion of the Investigator, a non-functional IDDD 
may be left in situ for up to 3 months.
Patients who discontinue or are withdrawn before receiving 3 monthly IT injections will not have 
to undergo the EOS evaluations but will have their IDDD removed.  
If a patient discontinues, or withdraws from the study, or the study is stopped by the Sponsor, the 
IDDD will be removed as part of the EOS Procedures. 
An overview of the study appears in the Schedule of Events (Appendix 1).
4.2
Rationale for Study Design and Control Group
The original study, Study HGT-SAN-055, is an ongoing Phase I/II safety and ascending dose 
ranging study of IT administration of HGT-1410 via an IDDD, in patients 3 years of age and 
older with MPS IIIA and early cognitive impairment.  This extension study is proposed to 
continue evaluation of the effects of IT HGT-1410 administration on long-term safety and 
clinical outcomes for patients who completed Study HGT-SAN-055 and elected to continue
treatment with HGT-1410 in the HGT-SAN-067 study. 
In order to traverse the blood-brain barrier, Shire HGT is evaluating HGT-1410 delivered 
directly to the CNS using an IDDD. The advantage of using an IDDD is that it obviates the need 
for multiple lumbar punctures for drug delivery. Drug products will be administered through this 
port or, if the IDDD is non functional, via lumbar puncture.
If patients in the study require revision and/or replacement of the PORT-A-CATH IDDD, it will 
be removed and replaced with the SOPH-A-PORT Mini S device at a time judged appropriate by 
the Investigator.
4.3
Study Duration and Dates
The study duration will be 4 years.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
28
5
STUDY POPULATION SELECTION
5.1
Study Population
Patients who have completed all study requirements in Study-HGT-SAN-055 and who elected to 
continue HGT-1410 treatment will be eligible to participate; a maximum of 12 patients are 
planned for this study. 
5.2
Inclusion Criteria
Each patient must meet the following criteria to be considered eligible for enrollment in this 
study.
1. The patient must have completed Study HGT-SAN-055 and, in the opinion of the 
investigator, have no safety or medical issues that contraindicate participation. 
2. The patient, patient’s parent(s) or legally authorized representative(s) has voluntarily signed 
an Institutional Review Board/Independent Ethics Committee-approved informed consent 
(and assent, if applicable) form after all relevant aspects of the study have been explained and 
discussed with them.  Informed consent/assent must be obtained prior to any study specific 
procedures.
3. The patient has received at least 5 of the 6 planned infusions of HGT-1410 in the 
HGT-SAN-055 study. 
4. The patient must be medically stable, in the opinion of the Investigator, to accommodate the 
protocol requirements, including travel, assessments, and IDDD surgery (if necessary for 
replacement purposes), without placing an undue burden on the patient/patient's family.
5.3
Exclusion Criteria
Patients will be excluded from the study if there is evidence of any of the following:
1. The patient has experienced an adverse reaction to study drug in Study HGT-SAN-055 that 
contraindicates further treatment with HGT-1410.
2. The patient has a known hypersensitivity to the active ingredient or any excipients in 
HGT-1410 drug product.
3. The patient has significant non-MPS IIIA related central nervous system impairment or 
behavioral disturbances that would confound the scientific integrity or interpretation of study 
assessments, as determined by the Investigator.
4. The patient has MPS IIIA behavioral-related issues, as determined by the Investigator, which 
would preclude performance of study neurocognitive and developmental testing procedures.
5. The patient is pregnant, breast feeding, or is of childbearing potential who will not or cannot 
comply with the use of an acceptable method of birth control, such as condoms, barrier 
method, oral contraception, etc.
6. The patient has any known or suspected hypersensitivity to anesthesia or is thought to have 
an unacceptably high risk for anesthesia due to airway compromise or other conditions.
7. The patient has a history of a poorly controlled seizure disorder. 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
29
8. The patient is currently receiving psychotropic or other medications, which in the 
Investigator’s opinion, would be likely to substantially confound test results and the dose and 
regimen of which cannot be kept constant throughout the study.
9. The patient cannot sustain absence of aspirin, non-steroidal medications, or medications that 
affect blood clotting within 1 week prior to a relevant study-related procedure (eg, device 
re-implantation if applicable), or has ingested such medications within 1 week before any 
procedures in which any change in clotting activity would be deleterious.
10. The patient has received treatment with any investigational drug (other than HGT-1410) 
intended as a treatment for MPS IIIA within the 30 days prior to, during the study, or is 
currently enrolled in another study that involves an investigational drug or device (screening 
through safety follow-up contact).
11. The patient has received a hematopoietic stem cell or bone marrow transplant.
For patients to be implanted with the SOPH-A-PORT Mini S IDDD the following conditions are 
contraindicated, as described in the Instructions for Use: 
1. The patient has had, or may have, an allergic reaction to the materials of construction of the 
SOPH-A-PORT Mini S device
2. The patient’s body size is too small to support the size of the SOPH-A-PORT Mini S Access 
Port, as judged by the Investigator 
3. The patient has a known or suspected local or general infection
4. The patient is at risk of abnormal bleeding due to a medical condition or therapy
5. The patient has one or more spinal abnormalities that could complicate safe implantation or 
fixation
6. The patient has a functioning CSF shunt device
7. The patient has shown an intolerance to an implanted device

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
30
6
STUDY TREATMENT(S)
6.1
Description of Treatment(s)
6.1.1
Study Drug
Recombinant human heparan N-sulfatase (HGT-1410 drug product) formulation is a sterile 
solution for injection in single-use vials for IT administration.  It is formulated in an aqueous 
isotonic solution containing 15.0 mg/mL HGT-1410 in 145 mM sodium chloride, 0.02% (v/v) 
polysorbate 20, 5 mM sodium phosphate at pH 7.0.
6.1.2
Intrathecal Drug Delivery Device
The PORT-A-CATH will continue to be used for the administration of drug product for each 
patient until such time as an IDDD replacement may be required. Following implementation of 
protocol Amendment 4, any replacements will be performed using the SOPH-A-PORT Mini S.   
After IDDD replacement the drug product will be administered via the SOPH-A-PORT Mini S 
Implantable Access Port.  The SOPH-A-PORT Mini S device is intended for long-term, 
intermittent access to the IT space for the delivery of investigational drug.
The SOPH-A-PORT Mini S is comprised of the following 7 components:

One SOPH-A-PORT Mini S Access Port

One intrathecal port closed-tip catheter

One guidewire

Two suture wings

One 14-gauge Tuohy needle

One 22-gauge non-coring Huber needle

One Luer lock Connector.
Further details are provided in the Instructions for Use.
6.1.3
Placebo or Control
This study will not employ a placebo or control.  
6.2
Treatment Administered
HGT-1410 for IT administration will be provided by Shire HGT.  HGT-1410 will be 
administered by an IDDD.  Following the review and signing of informed consent (and assent, if 
applicable), eligible patients will initially receive the same dose of HGT-1410 they received in 
Study HGT-SAN-055:

Group 1:  HGT-1410 administered by IT injection 10 mg once per month (Q4W) 

Group 2:  HGT-1410 administered by IT injection 45 mg once per month (Q4W)

Group 3:  HGT-1410 administered by IT injection 90 mg once per month (Q4W)

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
31
Patients assigned to Group 1 will have their dose increased to 45 mg once per month (Q4W) at 
the first administration of HGT-1410 following full approval of protocol Amendment 4.
The study drug will be administered through an IDDD.
The initial implantation and revision and/or explantation of the PORT-A-CATH IDDD or 
SOPH-A-PORT Mini S will be performed by pediatric or general neurosurgeons or 
anesthesiologists who have experience in port and catheter implant procedures and 
intrathecal-access procedures. Please refer to the relevant IFU for further details.
Drug administration will be performed in a clinical setting by appropriately trained and skilled 
healthcare providers (nurses or physicians) with knowledge of the patient’s drug regimen and 
experienced in accessing vascular or CNS ports or CNS infusion pumps. Patients and patients’ 
families will not be directly using the device to administer drugs and will have limited direct 
interaction with the device as there is minimal care required during the immediate postoperative 
period as the implant site heals, or at times of drug administration.
6.3
Selection and Timing of Dose for Each Patient
Patients will check into the study center 1 day prior to IT HGT-1410 dosing for safety 
assessments, designated Day 1, on each HGT-1410 treatment week, and if no safety concerns 
exist, will receive IT administration of HGT-1410 on Day 2 (±2 days).  However, if feasible and 
there are no safety concerns in the opinion of the Investigator, the Day 1 and Day 2 assessments 
and dosing may be combined and performed on Day 2; if this is done the results will be recorded 
as Day 2.  Patients will remain in the study center for at least 4 hours following dosing with 
HGT-1410 and will be discharged from the unit when deemed clinically stable by the 
Investigator.  
The IT injections are to be administered every 28 days (±7 days).  If a patient’s IDDD becomes 
nonfunctional, it may be revised (partial or complete) (a maximum of twice in a 6 month period) 
so that the patient can remain on study (see Section 7.12 for details).  In the event of a 
non-functional IDDD, HGT-1410 may be administered by LP, for up to 5 successive months (see 
Section 6.3.3). 
6.3.1
Cerebral Spinal Fluid Sample Procedure
CSF samples will be obtained prior to each injection for safety evaluation and biomarker studies.  
The IDDD will be used for CSF sampling and a topical anesthetic agent may be applied over the 
skin covering the IDDD reservoir prior to sampling. Site personnel should refer to the operations 
manual for instructions on the use of topical anesthesia prior to accessing the IDDD reservoir.
If use of the IDDD is precluded on a scheduled day of dosing, CSF samples may be obtained by 
LP, as described in the Study Operations Manual.  CSF opening pressure will be measured 
whenever a LP is performed, and at the time of IDDD revision (partial or replacement).  
Additional CSF samples may be taken during this time.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
32
6.3.2
Intrathecal Administration of HGT-1410
A visual examination of both the port and catheter track will be performed before each IT 
injection
HGT-1410 will be administered using an IDDD.  After appropriate pre-procedure assessments 
are completed, anesthesia cream will be applied to the skin over the port.  Patients may receive 
sedation as necessary to alleviate anxiety and/or to facilitate drug delivery.
Patients will receive HGT-1410 via slow push/injection through an appropriately sized syringe 
(see the Pharmacy Manual).  Replacement of fluid, including drug, to the CSF will be an 
approximate equal volume to that removed.  The patient’s vital signs will be continuously 
monitored.  The patient will also be monitored closely during study drug administration and 
through the next 4 hours for any adverse clinical reactions.  The patient will be encouraged to lie 
down comfortably for 1 to 3 hours post injection, although this may be difficult for the most 
hyperactive patients.
For the Soph-A-Port Mini S, a 22-gauge Huber non-coring needle is to be used for access to the 
implanted port; standard hypodermic needles would damage the septum and may cause leakage. 
If no needle-free connector is present, either a stopcock of the Huber needle infusion set’s clamp 
is to be used to prevent CSF backflow and to mitigate the risk of air entering the system. It is 
possible to use other brands of Huber non-coring needles, provided that their specifications are 
identical to that of the Huber needle supplied by Sophysa in the SOPH-A-PORT Mini S (22G).
The injection date, injection start/stop time, planned dose, injection volume, and flush volume 
will be recorded on the patient’s eCRF.  
In the event of IDDD malfunction, CSF collection and study drug administration may be 
performed via LP (see Section 6.3.3).  The investigation and management of a malfunctioning 
IDDD is detailed in the PORT-A-CATH or SOPH-A-PORT IFUs. Partial or complete 
replacement of the IDDD may be necessary (only permitted twice in a 6-month period, including 
the time a patient was in study HGT-SAN-055), and will require scheduling of the appropriate 
procedure.  The definitive diagnosis of the cause of IDDD failure may not be possible until the 
time of exploratory surgery.  Surgery will take place at the earliest convenience, so the patient 
may remain on, or as close as possible to their treatment schedule. 
6.3.3
Administration of HGT-1410 via Lumbar Puncture
In the event of a non functional IDDD, HGT-1410 may be administered by LP, for up to 
5 successive months.  The performance of a LP is at the discretion of the Investigator.
If a LP is to be performed, the patient may require general anesthesia with appropriate airway 
management.  Once the patient is anesthetized, a LP will be performed and a CSF sample will be 
obtained.  Some cases may be managed with conscious sedation, if this is considered by the 
investigator to be adequate for the safe and expeditious performance of a LP.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
33
6.4
Method of Assigning Patients to Treatment Groups
This is an open-label, non-randomized study; all patients enrolled in this study will be treated 
with HGT-1410. Patients will initially receive the same dose of HGT-1410 they received in 
Study HGT-SAN-055.  Patients assigned to Group 1 (10 mg once per month [Q4W]) will have 
their dose increased to 45 mg once per month (Q4W) at the first administration of HGT-1410 
following full approval of protocol Amendment 4.
6.5
Blinding
Not applicable; as this trial is not blinded.
6.6
Concomitant Therapy
All non-protocol treatments and procedures that occur from the time of informed consent (and 
assent, if applicable) through the safety follow-up contact are regarded as concomitant and will 
be documented on the appropriate pages of the eCRF.  Concomitant therapy includes 
medications (including Genistein), therapies/interventions administered to patients, and 
medical/surgical procedures performed on the patients. 
Every effort should be made to keep the patient’s symptomatic Sanfilippo syndrome Type A 
treatment constant throughout the study.  However, changes in medications are acceptable if 
necessary according to clinical judgment.  All changes will be recorded on the appropriate eCRF.  
Concomitant medication will be coded using World Health Organization Drug Dictionary 
(WHO-DD).
6.7
Restrictions
6.7.1
Prior Therapy
Prior therapy excluded for this study consists of the following:

Psychotropic or other medications, which in the Investigator’s opinion would be likely to 
substantially confound test results, and the dose and regimen of which cannot be kept 
constant throughout the study.

The patient cannot sustain absence from aspirin, non-steroidal medications, or medications 
that affect blood clotting within 1 week prior to a relevant study related procedure (eg, device 
implantation if applicable) or medications within 1 week before any procedures in which any 
change in clotting activity would be deleterious.

The patient has received any investigational drug or device intended as a treatment for 
MPS IIIA within the 30 days prior to the study other than HGT-1410 or is enrolled in another 
study that involves an investigational drug or device.

Hematopoietic stem cell or bone marrow transplant.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
34
6.7.2
Fluid and Food Intake 
Food and fluid intake are not restricted over the course of the study, with the exception of 
hospital standard pre-anesthesia dietary restrictions.
6.7.3
Patient Activity Restrictions
For patients implanted with the SOPH-A-PORT Mini S please refer to the SOPH-A-PORT Mini 
S IFU for details regarding patient activity restrictions for patients to be implanted with this 
device.
6.8
Treatment Compliance
HGT-1410 is administered under controlled conditions by the Investigator; therefore, full patient 
compliance with study treatment is anticipated in this study. 
6.9
Packaging and Labeling
6.9.1
Drug Product
Drug product will be supplied in a 3 mL clear, colorless glass (Type 1) vial. Each vial holds an 
extractable volume of 1 mL of HGT-1410. The closure is a gray, 13 mm stopper composed of 
butyl rubber with a fluoro resin lamination. The overseal is an aluminium seal with a flip-off, 
plastic, tamper evident cap. 
See the Pharmacy Manual for additional details.
6.9.2
SOPH-A-PORT Mini S Access Port
The SOPH-A-PORT Mini S Access Port is available in one size, individually packaged, with 
other SOPH-A-PORT Mini S components in double peel-off, sterile, pyrogen-free packaging, 
sterilized with Ethylene Oxide.  Instructions for use are also included in the packaging. A 
guidewire is provided in separate double pouch, sterile, pyrogen-free packaging.
Labels are provided on the outer carton, and on both the SOPH-A-PORT Mini S box and 
guidewire/cannula package inside.
6.10
Storage and Accountability
6.10.1
Investigational Product
Drug product should be stored refrigerated (2 to 8°C); drug product may not be stored beyond 
the expiration date on the vial.
All HGT-1410 study drug delivered to an Investigator will be recorded and accounted for 
throughout the study.  All HGT-1410 study drug must be recorded on a patient-by-patient basis.  
The lot number of the IDDD and the date and time of administration of the study medication will 
be documented on the appropriate eCRF.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
35
All unused study medication and other study materials are to be returned to the Sponsor or its 
designee or disposed of after Sponsor approval per site policy after study completion.
6.10.2
Intrathecal Drug Delivery Device
6.10.2.1
PORT-A-CATH IDDD
Please refer to the operations manual for return instructions.
6.10.2.2
SOPH-A-PORT Mini S IDDD
The disposition of all SOPH-A-PORT Mini S intrathecal drug delivery devices delivered to a 
Principal Investigator must be recorded on a patient-by-patient basis by completing the 
Accountability Log.  The date and time of administration of the investigational product and use 
of the SOPH-A-PORT Mini S device must be documented on the patient’s appropriate eCRF.
The Principal Investigator, Clinical Research Coordinator, or designee (eg, Pharmacist) must 
ensure that all documentation regarding receipt, storage, dispensing, loss/damaged 
SOPH-A-PORT Mini S intrathecal drug delivery devices and return of used/unused intrathecal 
drug delivery devices) is complete, accurate, and ready for review at each monitoring visit and/or 
audit.  The sites must ensure that the SOPH-A-PORT Mini S devices are available for the 
monitor to inventory and prepare for return shipment to the Sponsor or designee, if required.
The SOPH-A-PORT Mini S and its components are sterile, single-use devices.
Please refer to the relevant IDDD Manual for device return instructions.
6.11
Investigational Product Retention at Study Site
All HGT-1410 study drug delivered to an Investigator will be recorded and accounted for 
throughout the study.  All HGT-1410 study drug must be recorded on a patient-by-patient basis.  
The lot number of the IDDD and the date and time of administration of the study medication will 
be documented on the appropriate eCRF.
All unused study medication and other study materials are to be returned to the Sponsor or its 
designee or disposed of after Sponsor approval per site policy after study completion.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
36
7
STUDY PROCEDURES
7.1
Informed Consent
Study procedures will be conducted only after written informed consent for the patient to 
participate in this study is provided by the parent(s) or the patient’s legally authorized 
representative(s) and assent from the patient (if applicable).  Detailed descriptions of patient 
evaluations required for this protocol are described in this section.  These evaluations will be 
performed during the indicated days and weeks of each study month (see Appendix 1 Schedule 
of Events).
All data collected are to be recorded on the appropriate eCRF.  Blood, urine and CSF volumes to 
be collected for each clinical laboratory measurement are described in detail in the Laboratory 
and/or Study Operations Manual.
7.2
Physical Examination
A physical examination of each patient will be performed as detailed in Appendix 1 Schedule of 
Events.
Note:  if the patient’s hearing cannot be assessed during the physical examination, the patient 
will have an Ears, Nose, and Throat Evaluation performed under anesthesia at the screening/start 
of study visit.  If it is determined that the patient requires pressure-equalization (PE) tubes, they 
may be implanted during that evaluation (see Section 7.9).  Note:  PE tubes may be re-implanted 
if they fall out during this study.
The physical examination findings will be recorded on the eCRF and will include a review of the 
patient’s general appearance as well as the following evaluations:
-
Head and neck
-
Eyes, ears, nose, and throat
-
Chest and lungs
-
Cardiovascular
-
Abdomen
-
Skin
-
Lymphatic
-
Musculoskeletal
-
Neurological
-
Endocrine
-
Genitourinary
7.3
Height and Weight
Height or length (cm), and weight (kg) will be measured once and recorded on the eCRF.
7.4
Head Circumference
Head circumference (cm) will be measured and recorded on the eCRF.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
37
7.5
Vital Signs
Vital signs (blood pressure, heart rate, respiratory rate, and temperature measurements) will be 
measured and recorded on the eCRF.
7.6
Electrocardiography
7.6.1
Electrocardiograms
An ECG will be performed.  Each ECG will include an assessment of heart rate, sinus rhythm, 
atrial or ventricular hypertrophy, PR, QRS, QT, and QTc intervals.  The ECGs will be conducted 
in accordance with the clinical site’s standard practice(s), and will be read locally at the clinical 
site.  Identification of any clinically significant findings and/or conduction abnormalities will be 
recorded on the eCRF. 
7.7
Clinical Laboratory Tests
Blood, urine, and CSF samples will be collected as described below for clinical laboratory 
testing.  Procedures for collection and handling of samples are included in the Laboratory and/or 
Study Operations Manual. 
Patients will be in a seated or supine position during blood collection.  Clinical laboratory tests 
will include hematology, serum chemistry, and urinalysis.
Laboratory Parameters 
Clinical laboratory tests will be performed at a central laboratory.  Clinical laboratory tests will 
include the following:
7.7.1
Hematology

Hematocrit (Hct)

Hemoglobin (Hgb)

Mean corpuscular hemoglobin (MCH)

Mean corpuscular hemoglobin 
concentration (MCHC)

Mean corpuscular volume (MCV)

Platelet count

Red blood cell (RBC) count 

White blood cell (WBC) count with 
differential 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
38
7.7.2
Serum Chemistry

Albumin (ALB)

Alkaline phosphatase (ALK-P)

Alanine aminotransferase (ALT; SGPT)

Aspartate aminotransferase (AST; 
SGOT)

Blood urea nitrogen (BUN)

Calcium (Ca)

Carbon dioxide (CO2)

Chloride (Cl)

Creatinine

Creatine kinase (CK) and subtypes

Gamma-glutamyl transferase (GGT)

Globulin

Glucose

Lactate dehydrogenase (LDH)

Phosphorus

Potassium (K)

Sodium (Na)

Total bilirubin

Direct bilirubin

Total cholesterol

Total protein

Triglycerides

Uric acid

Human Chorionic Gonadotropin
(βhCG) Pregnancy Test
In addition a leukocyte pellet will be prepared, stored frozen, and will be used for additional 
disease-related laboratory studies, including possible assessment of cross-reactive immunologic 
material (CRIM).
7.7.3
Pregnancy Test
A pregnancy test will be performed on Day 1 of each dosing week.  Pregnancy testing will be 
performed using either a serum or urine sample (at the discretion of the site), and only on 
females who have reached menarche.  All pregnancy testing and the reporting of results will be 
performed locally by the clinical site staff.  Study drug must not be administered in the event of a 
positive or inconclusive pregnancy result. 
7.7.4
Urinalysis 
Patient catheterization may be required for obtaining urine samples (if deemed necessary by the 
Investigator).  
7.7.4.1
Standard Urinalysis
The following urinalysis parameters will be performed at a central laboratory:  pH, macroscopic 
and microscopic evaluations.
7.7.4.2
Urine Heparan Sulfate and Heparan Sulfate Derivatives
A urine sample will be collected for the determination of heparan sulfate and heparan sulfate 
derivatives and the analysis will be performed at Shire HGT or designated laboratories.  A urine 
sample from each visit will be reserved for possible exploratory biomarker studies that may
provide new indicators or markers of MPS IIIA disease severity or progression.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
39
7.7.5
Cerebrospinal Fluid Assessments
Cerebrospinal fluid sample collection, processing, and shipping instructions will be provided in 
the Laboratory and/or Study Operations Manual. A CSF sample will be reserved for possible 
exploratory biomarker studies for MPS IIIA disease.
Each CSF sample collected will be assessed for appearance and will be analyzed using the assays 
listed in Sections 7.7.5.1, 7.7.5.2, and 7.7.5.4.  In addition, as more is learned about Sanfilippo 
CNS pathology and etiology, future exploratory assays of CSF metabolites, protein or RNA may 
become used as they become available in the future.
7.7.5.1
Cerebrospinal Fluid Cell Counts
An aliquot of each CSF sample collected will be evaluated for CSF standard chemistries, 
glucose, protein, and cell counts.  These assessments will be performed at the local laboratory.
7.7.5.2
Cerebrospinal Fluid Heparan Sulfate Levels and Heparan Sulfate Derivatives
An aliquot of each CSF sample collected will be quick frozen as per the Laboratory and/or Study 
Operations Manual for subsequent determination of CSF heparan sulfate and heparan sulfate 
derivatives at Shire HGT laboratories.
7.7.5.3
Anti-rhHNS Antibodies
An aliquot of each CSF sample collected will be quick frozen as per the Laboratory and/or Study 
Operations Manual for subsequent determination of anti-rhHNS antibodies at Shire HGT or 
Shire HGT designated laboratories.
7.7.5.4
Cerebrospinal Fluid Biomarkers 
An aliquot of each CSF sample collected will be quick frozen as per the Laboratory and/or Study 
Operations Manual for subsequent determination of MPS exploratory biomarkers at Shire HGT 
laboratories.
7.7.6
Sample Collection, Storage, and Shipping
Sample collection, processing, and shipping instructions will be provided in the Laboratory 
and/or Study Operations Manual to be provided by Shire HGT.
CSF, urine, and serum samples may be reserved for potential, future, biomarker studies.  
Samples will be stored securely to ensure patient confidentiality.  
7.8
Anesthesia
Administration of anesthesia/sedation will be given prior to obtaining CSF (when the use of the 
IDDD is precluded), prior to performing a MRI of the head, the ABR, the CSF opening pressure, 
and the partial revision or replacement of the IDDD (if applicable).  

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
40
See Appendix 1 for the Schedule of Events. When logistically feasible, the MRI, ABR, and 
surgical implantation of the IDDD may be performed together to reduce exposure to 
general anesthesia.
Note:  The neurologic exam and the neurocognitive and developmental assessments must be 
performed prior to the administration of anesthesia.
7.9
Audiometry and Auditory Brainstem Response
The rare attenuated patients with MPS IIIA with high levels of cognitive functioning will have 
hearing tests via clinical audiometry measurement performed using age-appropriate testing 
methods based on the child’s developmental age at the time of the testing.  It is anticipated that 
most of the cognitively-impaired and/or behaviorally-deteriorated patients with Sanfilippo A will 
be unable to cooperate with a (conscious) hearing evaluation.  In these instances, the Investigator 
will utilize his best clinical judgment to estimate the extent of hearing loss (if any) during the 
physical examination.  In this situation, a specific evaluation of hearing loss will occur during an 
examination of waveforms in the ABR (see below).  If the patient has a history of multiple 
instances of otitis media or evidence of clinically-significant otitis media on physical 
examination, which the Investigator believes causes significant conductive hearing loss and 
impairment of daily living, the Investigator will discuss and offer the parent or legally authorized 
representative(s) placement of PE tubes as part of the scheduled anesthesia.  A patient’s PE tubes 
may be replaced if they fall out during the course of this study.
The ABR will be conducted under anesthesia.  The ABR findings will be considered within 
normal limits if, after applying appropriate correction factors, the waveforms reveal normal 
morphology. 
7.10
Magnetic Resonance Imaging of the Head
The regional brain volume will be assessed through a MRI, of the head.  The patient will be 
under general anesthesia for this assessment.  All MRIs will be centrally read by the University 
of Minnesota Medical Center.  Refer to the Study Operations Manual for specific procedures and 
precautions.
7.11
Device Data
7.12
Surgical Re-implantation of the IDDD
If a patient’s IDDD becomes nonfunctional or infected, it will be replaced or revised so that the 
patient can remain on study. After full approval of protocol Amendment 4, all IDDD 
replacements will be made with the SOPH-A-PORT IDDD. If the IDDD device is a 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
41
PORT-A-CATH IDDD, it will be replaced by a SOPH-A PORT IDDD. Management details for 
the PORT-A- CATH IDDD or for the SOPH-A PORT IDDD are provided in the respective 
device's IFU. Procedures for implantation are detailed in the relevant device’s Instructions for 
Use Manual and in the training materials provided by Shire HGT. The patient will be under 
general anesthesia for this procedure. The CSF opening pressure will be recorded when the 
intrathecal space is first entered at the time of the IDDD re-implantation. Standard hospital 
procedure for surgery will be followed and will include an X-ray to confirm that the device has 
been (1) surgically implanted correctly, and (2) positioned so that the intrathecal catheter tip is at 
the mid-thoracic level (a check list is provided in the Study Operations Manual). 
A post-operative check of the IDDD and incision will be performed on Day 4 following surgery.  
X-rays may be performed to check placement of the device, as needed, throughout the study (see 
Section 7.12.1 for limits on the number of x-rays and IDDD revisions and or replacement).
7.12.1
Restrictions on the Number of Revision and/or re-implantation of the IDDD
A non-functional IDDD can be replaced or revised twice in a 6-month period, including the time 
a patient was in study HGT-SAN-055.  Similarly, 6 X-rays may be taken in a 6-month period 
(including the time in HGT-SAN-055).
7.13
Device Related Study Procedures
7.13.1
IDDD Implantation or Revision Procedures
The IDDD will be surgically implanted or revised at the clinical site. Procedures for implantation 
and revision are detailed in the device’s IFU. Standard hospital procedures for surgery will be 
followed; the patient will be under general anesthesia for this procedure.
An additional medical device, the catheter passer, is necessary for the implantation procedure, 
for patients receiving the SOPH-A-PORT Mini S.  The catheter passer is a sterile, single use 
device that will be used in the subcutaneous placement of the catheter.  The Phoenix Neuro 
Disposable Catheter Passer, manufactured by Sophysa is CE marked in the EU and cleared under 
K853370 in the US. 
Details of the implantation/revision and malfunctions/failure for the SOPH-A-PORT will be 
documented on the patient’s eCRF.
7.13.2
X-ray Verification of Intrathecal Drug Delivery Device Placement 
A postoperative x-ray check of the IDDD will be performed following surgery to verify proper 
installation and confirmation of IDDD placement at the mid-thoracic level. The x-rays may be 
performed to check placement of the device, as needed, throughout the study. If the patient is to 
receive intrathecal HGT-1410 beyond the end of the study, an X-ray will be performed at the end 
of the study to verify that the IDDD is in the correct position. At a minimum, the date of the 
x-ray verifying correct IDDD placement will be documented on the patient’s eCRF. If the device 
requires revision or replacement during the study, additional x-rays will be taken to document 
proper positioning of the device. If an IDDD malfunctions, an X-ray may be performed to assess 
the potential cause of malfunction

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
42
7.13.3
CSF Sampling Procedure
Cerebrospinal fluid will be sampled via the device. If this is not possible, and if CSF sampling is 
necessary, either for adherence to the protocol, or to investigate clinical concerns, an LP may be 
performed to sample CSF, either with or without administration of drug afterwards.
7.13.4
Device Removal
If at the time of a scheduled dosing it is not possible to administer a full medication dosage as 
per the standard administration steps detailed in the device’s IFU due to a device-related issue, 
the IDDD will be declared a device malfunction. If the device malfunction is irreversible and 
cannot be corrected without a device surgical intervention, the IDDD will be declared a device 
failure, starting from the date of the initial malfunction. 
The IDDD will then be surgically removed or revised and a new device and/or device 
components will be re-implanted at the earliest possible opportunity, preferably at the same time. 
Patients who have a PORT-A-CATH IDDD device failure will have this device replaced by a 
SOPH-A-PORT Mini S.
Details of the device removal will be recorded in the patient’s eCRF. Refer to the relevant IFU 
for further details.
If the IT space is not accessible via the IDDD, study drug may be administered by LP up to 
5 times.
Patients will have the IDDD removed when they discontinue from the study, unless the patient is 
continuing to receive treatment through another mechanism (eg, extension study, expanded 
access, commercially available).
7.14
Cerebrospinal Fluid Opening Pressure Measurement
A CSF opening pressure measurement (cm of H2O) will be conducted as per standard hospital 
practice.  The measurement will be obtained whenever a LP is performed and an IDDD revision 
or replacement is done.
7.15
Dispensing Study Drug
A visual examination of both the port and catheter track will be performed before each IT 
injection.
HGT-1410 will be administered IT by means of an IDDD (or via LP if necessary) to patients on 
Day 2 (±2 days) of Week 1 of each treatment month. 
The patient may be sedated for this procedure.  HGT-1410 will be administered through an 
appropriately sized syringe (see the Pharmacy Manual).  If the IT space is not accessible via the 
IDDD, HGT-1410 may be administered via LP.  See Section 6.3.3 for details.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
43
For the Soph-A-Port Mini S, a 22-gauge Huber non-coring needle is to be used for access to the 
implanted port; standard hypodermic needles would damage the septum and may cause leakage. 
If no needle-free connector is present, either a stopcock or the Huber needle infusion set’s clamp 
is to be used to prevent CSF backflow and to mitigate the risk of air entering the system. It is 
possible to use other brands of Huber non-coring needles, provided that their specifications are 
identical to that of the Huber needle supplied by Sophysa in the SOPH-A-PORT Mini S (22G).
7.16
Pharmacokinetic Assessments
Pharmacokinetic assessments are not included in this study.
7.17
Neurological Examination
A neurological examination to monitor CNS changes in a patient’s neurological status will be 
conducted during this study.  See Appendix 2 for a complete list of the neurological 
examinations.
The neurological exam should not occur sooner than 4 hours after study drug administration or 
before the patient has fully recovered from any anesthesia administered for the dosing, 
whichever occurs later.
7.18
Anti-rhHNS Antibody, Heparan Sulfate, and Heparan Sulfate Derivative 
Determination
Blood samples will be collected and evaluated at Shire HGT laboratories for the determination of 
anti-rhHNS antibodies, and plasma and serum heparan sulfate and heparan sulfate derivatives.  
Samples will be reserved in accordance with local regulations for potential future MPS IIIA 
research that may determine biomarkers of disease severity and progression. 
Two blood samples will be collected from each patient at each designated time point.  One 
sample will be collected in tubes intended for serum specimens, while the second sample will be 
collected in tubes intended for plasma specimens.  Blood sample collection, processing, and 
shipping instructions will be provided in the Laboratory and/or Study Operations Manual.
7.19
Neurocognitive and Developmental Assessments
Patients will undergo neurocognitive and neurobehavioral development testing.  The assessments 
are estimated to last between 2 and 4 hours and must be conducted prior to sedation or 
anesthesia. 
A full neurodevelopmental assessment, including global development, cognition, adaptive 
behavior, receptive and expressive language, and gross motor function, will be evaluated using 
standardized developmental and behavioral tests to provide a surrogate and quantifiable measure 
of global CNS neurodevelopmental/neurobehavioral function. 
All patients will have received a series of standardized neurodevelopment assessments; in the 
HGT-SAN-055 study, patients in HGT-SAN-067 will continue with the age specific assessment 
they began with in HGT-SAN-055.  If, however, a patient’s capability improves and they 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
44
become capable of completing assessments at a higher level, any such additional assessments 
may be added.  Any additional assessments would be performed after the original assessments 
have been carried out.  
For this study, outcome measures will be computed for each patient enrolled.  The psychometric 
instruments and Sanfilippo-specific assessments are summarized below in Table 7-1 and 
Table 7-2, respectively.  See Appendix 2 for details on these assessments.
Table 7-1.  Neurodevelopmental Assessments Tests 
Developmental or Cognitive 
Domain(s)
Patient Age:  Representative Cognitive Test or 
Scale
COGNITIVE DEVELOPMENT ASSESSMENT
Summary score and sub-domains:
- Cognitive
- Motor
- Social/emotional
0 to 42 months:  Bayley Scales of Infant Development-III 
Bayley Scales of Infant Development, Third Edition
(BSID-III)23
- Cognitive 
- Processing skills
3 to 18 years:  Kaufman Assessment Battery for Children, 
Second Edition (KABC-II)24  
GROSS AND FINE MOTOR SKILLS ASSESSMENT AND VOLUNTARY MOVEMENT
Motor
3.0 to 16:11 years:  Movement Assessment Battery for 
Children II (MABC-2)25
- Cognitive
- Motor
0 to 5 ½ years:  Bayley Scales of Infant Development III 
(BSID-III)23
ADAPTIVE BEHAVIOR
Communication
Daily Living
Socialization
Motor Skills
0 to 90 years:  Vineland Adaptive Behavior Scales (VABS-II)  
Second Edition26
Table 7-2.  Sanfilippo-Specific Disability Assessment And Behavior Rating Scales
DEVELOPMENTAL OR COGNITIVE 
DOMAIN(S)
SANFILIPPO SPECIFIC ASSESSMENTS
Parent-scored behavioral inventory
- communication:  understanding
- communication:  expression
- tantrums
- specific behaviors inventory
- mood & emotions inventory
Sanfilippo Behavior Rating Scale (SBRS)
MPS-specific disability score 
- cognitive functioning
- expressive language
- motor score
Four-Point Scoring System/Total Disability Score 
(FPSS/TDS)5

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
45
7.20
Sleep Questionnaire:  Children’s Sleep Habits Rating Scale 
A sleep questionnaire, Children’s Sleep Habits Rating Scale, will be administered to the patient's 
parent(s)/legally authorized representative(s).
7.21
Age-Dependent, Health-Related Quality of Life in Children
The Quality of Life questionnaires will be administered as outlined in Sections 7.21.1, 7.21.2, 
and 7.21.3.
7.21.1
Quality of Life Indicator:  CHQ-50
The Child Health Questionnaire™ Parent Form 50 Questions (CHQ-50) will be administered 
during the study.  The questionnaire is a generic quality of life instrument, measuring 14 unique 
physical and psychosocial concepts, which was developed for children from 5 to 18 years of age.
7.21.2
Quality of Life Indicator:  CHQ-87
The Child Health Questionnaire™ Child Form 87 (CHQ-87) will be administered during the 
study.  The CHQ-87 is a child and adolescent self-report, developed for ages 10 and older, which 
assesses the child’s self-perceived physical and psychosocial well-being.
7.21.3
Quality of Life Indicator:  ITQOL
The Infant Toddler Quality of Life Questionnaire™ (ITQOL) will be administered during the 
study.  The ITQOL was developed for children at least 2 months of age up to 5 years and 
assesses the physical, mental, and social well being of the child and assesses the quality of the 
parent/legally authorized representative(s) life.  
7.22
Concomitant Medications, Therapies and Medical/Surgical Procedures
All non-protocol treatments that occur from the time of informed consent (and assent, if 
applicable) through the safety follow-up contact are regarded as concomitant and will be 
documented on the appropriate pages of the eCRF.  Concomitant therapy includes medication 
(including Genistein), therapies/interventions administered to patients, and medical/surgical 
procedures performed on the patients.
Every effort should be made to keep symptomatic Sanfilippo syndrome Type A treatment 
constant throughout the study.  However, changes in medications are acceptable if necessary 
according to clinical judgment.  All changes will be recorded on the appropriate eCRF.  
Concomitant medication will be coded using WHO-DD.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
46
7.23
Adverse Events
7.23.1
Definitions of Adverse Events and Serious Adverse Events
7.23.1.1
Adverse Event
An adverse event (AE) is any noxious, pathologic, or unintended change in anatomical, 
physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory 
changes occurring in any phase of a clinical study, whether or not considered study drug-related.  
This includes an exacerbation of a pre-existing condition.  Once the informed consent is signed 
and dated, any adverse event prior to the start of study drug must be reported. 
AEs include:

Worsening (change in nature, severity, or frequency) of conditions present at the onset of the 
study

Intercurrent illnesses

Drug interactions

Events related to or possibly related to concomitant medications

Abnormal laboratory values (this includes significant shifts from baseline  within the range 
of normal that the Investigator considers to be clinically important)

Clinically significant abnormalities in physical examination, vital signs, and weight
Throughout the study, the Investigator must record all AEs on the AE eCRF, regardless of the 
severity or relationship to study drug.  The Investigator should treat patients with AEs 
appropriately and observe them at suitable intervals until the events stabilize or resolve.  AEs 
may be discovered through observation or examination of the patient, questioning of the patient, 
complaint by the patient, or by abnormal clinical laboratory values.
In addition, AEs may also include laboratory values that become significantly out of range.  In 
the event of an out-of-range value, the laboratory test should be repeated until it returns to 
normal or can be explained and the patient’s safety is not at risk.  
All AEs should be recorded with causality assessment.
The information presented below is intended to provide issues to consider for AEs associated 
with intrathecal injections of HGT-1410.  In general, these AEs can be classified as follows: 

Adverse events due to systemic exposure to HGT-1410 caused by the drug diffusion from the 
CSF to the peripheral circulation; 

Adverse events related to the direct delivery of HGT-1410 to the intrathecal CSF space and 
meninges, and subsequent diffusion into brain parenchyma, via an intrathecal route 

IDDD–related AEs  
Note:  the classification of potential AEs and the examples presented below are based on purely 
theoretical considerations and/or published literature as there is limited human experience with 
intrathecal HGT-1410 therapy to date.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
47
7.23.1.2
Potential Adverse Events:  Intrathecal recombinant human heparan 
N-sulfatase 
ADVERSE EVENTS RELATED TO THE DIRECT DELIVERY OF HGT-1410 TO THE CNS THROUGH 
INTRATHECAL ADMINISTRATION
Examples of AEs observed in other published clinical trials with intrathecally-administered 
peptides or proteins, include, but are not limited to the following:  headache, fever, feeling of 
warmth, sensory parathesias (including feelings of warmth, tingling, or pain) or autonomic 
symptoms such as dry mouth or gustatory abnormalities (including loss of smell and metallic 
taste).  Changes in mental cognitive status or level of consciousness that are not caused by pre-
medication may either occur acutely or develop post-injection, over time
ADVERSE EVENTS DUE TO SYSTEMIC EXPOSURE TO HGT-1410
Although HGT-1410 is given intrathecally only, some proportion of the drug will diffuse from 
the CSF into the peripheral circulation. The resulting systemic exposure may cause events that 
are typically seen in patients receiving ERT via an intravenous administration, known as 
infusion-related reactions.  An infusion-related reaction is defined as an adverse event that 
(1) begins either during or within 24 hours after the start of the infusion, and (2) is judged as 
possibly or probably related to study drug.  Other AEs that occur prior to the infusion, along with 
AEs associated with protocol-defined testing and assessments (laboratory testing and physical 
examinations) that were performed prior to the infusion will not be defined as infusion-related 
reactions.
7.23.1.3
IDDD-related Adverse Events 
IDDD ADVERSE EVENTS
Examples of AEs related to use of the IDDD include, but are not limited to, the following: device 
failure, device malfunction, incorrect connection of IDDD components, erosion of the 
portal/catheter through the skin, fibrin sheath formation around the catheter tip, hematoma, 
implant rejection, migration of the portal/catheter, occlusion of the portal/catheter, portal site or 
subcutaneous tract infection. The device may also need to be replaced or repaired as needed. A 
list of the more common IDDD AEs is included in Appendix 3.
If the patient is admitted to the hospital in association with an IDDD event (eg for subsequent 
revision or replacement) the surgery will be recorded as a SAE.
DEVICE SURGICAL PROCEDURE-RELATED ADVERSE EVENTS
Examples of AEs related to surgical procedures include, but are not limited to, the following: 
IDDD implant/explant, IDDD adjustment, full revision, partial revision, IDDD removal, and 
delayed re-implantation after previous IDDD removal.
IT ADMINISTRATION PROCESS ADVERSE EVENTS 
In studies that include administration of investigational drug with an IDDD, potential AEs 
related to the IT Administration process include AEs that are caused by anesthesia during drug 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
48
administration, drug administration issues (eg, extravasation during infusion or hematoma due to 
Huber needle), etc.
7.23.1.4
Serious Adverse Event
1. A serious AE (SAE) is any AE occurring at any dose of investigational drug or at any 
procedure that results in any of the following outcomes:

Death

Is life-threatening

Requires inpatient hospitalization

Requires prolongation of existing hospitalization

A persistent or significant disability or incapacity 

A congenital anomaly or birth defect
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization. Hospitalizations, which are the 
result of elective or previously scheduled surgery for pre-existing conditions, which have not
worsened after initiation of treatment, should not be classified as SAEs. For example, an 
admission for a previously scheduled ventral hernia repair would not be classified as an SAE; 
however, complication(s) resulting from a hospitalization for an elective or previously scheduled 
surgery that meet(s) serious criteria must be reported as SAE(s). Furthermore, this does not 
apply to device failures resulting in scheduled surgical revisions, which should be reported as 
SAEs.”
2.  Unanticipated Adverse Device Effect (UADE) - Any serious adverse effect on health or
safety or any life-threatening problem or death caused by, or associated with, a device, if that 
effect, problem, or death was not previously identified in nature, severity, or degree of incidence 
in the investigational plan or application (including a supplementary plan or application), or any 
other unanticipated serious problem associated with a device that relates to the rights, safety, or 
welfare of patients. (21CFR812.3[s] or other regulatory requirements, as applicable).
7.23.2
Device-Associated Definitions
7.23.2.1
Device Revision (Partial and Full)
Partial device revision: surgical revision/replacement of one or more component(s) of the device; 
other component(s) of the original device remain implanted and are not affected (eg, port 
revision).
Full device revision: the device is removed (explanted) in its entirety and a completely new 
device is implanted.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
49
7.23.2.2
Device Malfunction
The device does not perform as intended, based on the description in the device’s IFU, but does 
not require either a partial or full device revision.
7.23.2.3
Device Failure
The device irreversibly fails to perform as intended and requires either a partial or full device 
revision or removal.
7.23.3
Classification of Adverse Events and Serious Adverse Events
The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) 
version 3.0 grading scale should be referenced when assessing the severity of an AE (see 
Appendix 6).  If an AE is not described in the NCI CTC, the severity should be recorded based 
on the scale provided in Table 7-3. The severity of all AEs/SAEs should be recorded on the 
appropriate eCRF page. Adverse events are graded as Grade 1, 2, 3, 4, or 5 corresponding, 
respectively, to a severity of mild, moderate, severe, life-threatening, or death. 
Table 7-3.  Adverse Event Severity
Severity
Definition
Grade 1 (Mild)
No limitation of usual activities.
Grade 2 (Moderate)
Some limitation of usual activities.
Grade 3 (Severe)
Inability to carry out usual activities.
Grade 4 (Life-threatening)
Immediate risk of death.
Grade 5 (Death related to an AE)
Death

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
50
7.23.4
Relatedness of Adverse Events and Serious Adverse Events
Relationship of an AE or SAE to investigational product, device, device surgical procedure, or 
IT administration process is to be determined by the Investigator based on the definitions in 
Table 7-4:
Table 7-4.  Adverse Event Relatedness
Relationship to Product(s)
Definition
Not Related
Unrelated to study drug, device, device surgical procedure, or IT 
administration process..
Possibly Related
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of study drug, device, device surgical 
procedure, or IT administration process but which could also be 
explained by concurrent disease or other drugs or chemicals.
Probably Related
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of study drug, device, device surgical 
procedure, or IT administration process unlikely to be attributable to 
concurrent disease or other drugs and chemicals and which follows a 
clinically reasonable response on de-challenge.  The association of the 
clinical event or laboratory abnormality must also have some biologic 
plausibility, at least on theoretical grounds.
Definitely Related
The event follows a reasonable temporal sequence from administration 
of the medication,  device, device surgical procedure, or IT 
administration process follows a known or suspected response pattern 
to the medication, is confirmed by improvement upon stopping the 
medication (dechallenge) and reappears upon repeated exposure 
(rechallenge).  
Note that this is not to be construed as requiring re-exposure of the 
patient to study drug; however, the determination of definitely related 
can only be used when recurrence of event is observed.
7.23.5
Procedures for Recording and Reporting Adverse Events
7.23.5.1
Reporting Serious Adverse Events Related to Study Procedures
Any SAE regardless of relationship to investigational product, device, device surgical procedure, 
or IT administration process that occurs in a patient after informed consent (and assent if 
applicable) should be recorded by the clinical site on an SAE form that is to be transmitted to the 
Shire HGT Medical Monitor and to the Shire Pharmacovigilance and Risk Management 
Department at the contact number provided below.  The SAE must be completely described on 
the patient’s eCRF, including the judgment of the Investigator as to the relationship of the SAE 
to the study procedure.  The Investigator will promptly supply all information identified and 
requested by the Sponsor (and/or contract research organization [CRO]) regarding the SAE as to 
the relationship of the SAE to study drug, device, or procedure. 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
51
The SAE form must be completed and FAXED or scanned and EMAILED (PDF sent by e-mail) 
within 24 hours of the Investigator’s learning of the event to: 
Any follow-up information must also be completed on an SAE form and faxed or scanned to the 
same numbers or e-mail address listed above.
In the event of a severe and unexpected, fatal, or life-threatening SAE, the clinical site must 
contact the Shire HGT Medical Monitor by telephone; this is in addition to completing and 
transmitting the SAE form as stated above.  The following provides contact information for the 
Shire HGT Medical Monitor.
If an SAE is assessed as severe and unexpected, or life-threatening, contact:
 MD 
Shire Human Genetic Therapies, Inc.
300 Shire Way
Lexington, MA  02421,  United States
Telephone: 
Fax:  
(United States)
Mobile: 
(24-hour access)
Shire Pharmacovigilance and Risk Management Department:
International FAX: 
United Kingdom OR 
United States FAX:  
Email: 
AND
Shire HGT Medical Monitor:
FAX: 
 (United States)
The Investigator may also call the Medical Monitor directly (optional):
Shire HGT Medical Monitor: 
 MD
Shire HGT
Work:
Cell:
 (24 hour access)
Email: 
AND
Clinical Project Manager CC’d: 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
52
The Investigator must promptly report all required information to the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC).  It is the responsibility of the Sponsor to ensure that 
each Investigator receives a copy of any CIOMS I/MedWatch report that has been submitted to 
the appropriate regulatory agencies notifying them of an unexpected related SAE.  The 
Investigator or Sponsor must ensure that the IRB/IEC receives a copy of the report and that a 
copy is also filed within their study files.  In addition, the Sponsor will also notify the 
Investigators and IRBs/IECs of all deaths that occur during the study, irrespective of relationship 
to study medication
7.23.5.2
Eliciting Adverse Events
Patients should be asked non-leading questions (eg, “How do you feel?”) and further questions 
should be posed if there is indication of an AE.  The questioning should be conducted with due 
regard for objectivity and, in particular, the questioner should gather information regarding AEs 
from questioning the patient, the patient’s parent/guardian, spontaneous report by the patient or 
parent/guardian, laboratory reports, and any health care provider’s observations.
The onset date, resolution date, treatment administered, and outcome of each AE must be 
recorded on the appropriate eCRF. The relationship of each AE to study medication must be 
recorded. In addition AEs may be considered to be related to the IDDD, the IDDD surgical 
procedure, or the IT administration process. Since the AE may be deemed to be related to more 
than one of these factors, as many of these IDDD-related options as apply should be indicated on 
the eCRF.
7.23.5.3
Protocol Deviations for Medical Emergency or Adverse Event
During and following a patient’s participation in the study, the Investigator should ensure that 
adequate medical care is provided to a patient for any AEs, including clinically significant 
laboratory test results.  
The Investigator should inform the patient, the patient’s parent(s), or the patient’s legally 
authorized representative when medical care is needed for intercurrent illness(es) of which the 
Investigator becomes aware.  In an emergency situation, the Investigator should contact the Shire 
HGT Medical Monitor (see Section 7.23.5.1).
Only when an emergency occurs that requires an immediate deviation from the protocol for the 
safety of a patient, will there be such a deviation and this will be only for that patient.  
The Investigator or other physician in attendance in such an emergency must contact the Shire 
HGT Medical Monitor as soon as possible.  
The Investigator, along with the Shire HGT Medical Monitor, will make a decision as to whether 
or not the patient should continue in the study prior to the next scheduled dose.  The departure 
from the protocol and the grounds for it should be stated in the eCRF.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
53
7.24
Abuse, Overdose and Medication Errors
Abuse, misuse, overdose or medication error must be reported to the Sponsor according to the 
SAE reporting procedure whether or not they result in an AE/SAE as described in Section 7.23.

Abuse – Persistent or sporadic intentional intake of investigational medicinal product at a 
dose higher than prescribed per protocol (but below the dose defined for overdose) or when 
used for non-medical purpose (eg, altering one’s state of consciousness)

Misuse – Intentional or unintentional use of investigational medicinal product other than as 
directed or indicated at any dose, which is at or below the dose defined for overdose (Note: 
This includes a situation where the test article is not used as directed at the dose prescribed 
by the protocol)

Overdose – Overdosage with adverse clinical consequences is not anticipated with the use of 
HGT-1410. Additionally, HGT-1410 will be given in a clinical setting by a health care 
provider. 

Medication Error – A mistake made in prescribing, dispensing, administration and/or use of 
the investigational medicinal product.
7.25
Safety-related Study Stopping Rules
If any patient experiences a life-threatening (Grade 4) adverse event or death which is considered 
by the sponsor to be possibly, probably, or definitely related to study drug or the IDDD, or if 
2 or more patients experience a Grade 3 adverse event during the trial that is considered by the 
sponsor to be possibly, probably, or definitely related to the study drug or the IDDD, then the 
site will be instructed to halt further HGT-1410 administration to all patients and the safety data 
reviewed. Following a review of safety data, the study will be either:

Resumed unchanged

Resumed with modifications to the protocol or

Terminated
Patient safety will be monitored on a continuous basis during this study until the last patient 
completes his or her last scheduled study visit/assessment.  
7.26
Pregnancy
Pregnancy and breast feeding are exclusion criteria.  Only female patients who have 
reached menarche will be tested for pregnancy in HGT-SAN-067.  If applicable, this will occur 
at study start and before each dose of HGT-1410 throughout the study.  Pregnancy testing will be 
performed on a blood or urine sample.  Patients with a positive or inconclusive result will not be 
eligible for this study.
At study start, a pregnancy test will be performed if more than 30 days have passed since the 
initial screening sample.  Throughout the study pregnancy testing will occur prior to each dose of 
HGT-1410.  The clinical site’s local laboratory will analyze and report all pregnancy testing 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
54
results.  If a pregnancy test is positive the patient will be discontinued from the study, and the 
Investigator must contact the Shire HGT Medical Monitor. 
Pregnancy is not to be reported as an AE; the Pregnancy Reporting Form, found in the Study 
Operations Manual along with instructions for completion, should be used to report the 
pregnancy.  The pregnancy will be followed up through delivery or final outcome.
7.27
Removal of Patients from the Trial or Study Drug
The patient's parent or legally authorized representative acting on behalf of the patient is free to 
withdraw consent and discontinue participation in the study at any time without prejudice to 
further treatment.  Since this is an extension trial, there will be no replacement of patients who 
discontinue the study for any reason.
A patient’s participation in the study may be discontinued at any time at the discretion of the 
Investigator, Sponsor, or Medical Monitor.  The following may be justifiable reasons for the 
Investigator, Sponsor, or Medical Monitor to remove a patient from the study:

Adverse Event:  If a patient experiences an AE which, in the judgment of the investigator, the 
sponsor, or the medical monitor, presents an unacceptable consequence or risk to the patient.

Adverse Laboratory Experience:  If a patient has an adverse laboratory experience which, in 
the judgment of the investigator, the Sponsor, or the medical monitor, presents an 
unacceptable consequence or risk to the patient, the patient may be withdrawn from the 
study.

Comorbidity:  If a patient develops comorbidity during the course of the study that is 
independent of the study indication, and treatment is required that is not consistent with 
protocol requirements. 

Intercurrent Illness:  If a patient develops an illness during the course of the study that is not 
associated with the condition under study, and which requires treatment that is not consistent 
with protocol requirements.

Refusal of Treatment:  If the patient, the patient’s parent(s) or legally authorized 
representative(s) discontinues participation in the study, or the patient is discontinued by the 
Investigator, reasonable efforts will be made to follow the patient through the end of study 
assessments.  The reason for refusal will be documented on the eCRF.  

Withdrawal of Informed Consent:  A patient’s parent or legally authorized representative 
may withdraw his informed consent to participate in the study at any time.

Cerebrospinal fluid leukocyte count >100 cells per cubic millimeter for 2 consecutive 
months.

New onset seizure.

Anaphylactic reaction beyond reasonable management as described in the Investigator’s 
Brochure.

Clinically problematic intubations or extubations, which may preclude safe airway 
management and anesthesia.

Development of refractory spinal fluid leakage. 

Clinically significant prolonged (eg, greater than 24 to 48 hours) worsening in mental status, 
including development of new focal or non-focal neurological symptoms, or recurrence of a 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
55
previously stable prior medical problem judged due to study drug or participation that is 
exclusive of effects from anesthesia.

Non-compliance, including failure to appear at 1 or more study visits.

The patient was erroneously included in the study.

The patient develops an exclusion criterion.

The study is terminated by the Sponsor.

The patient becomes pregnant during the trial.
If a patient discontinues the study the Patient Completion/Discontinuation eCRF describing the 
reason for discontinuation must be completed.  Any AE’s experienced up to the point of 
discontinuation must be documented on the AE eCRF.  
If AEs are present when the patient withdraws from the study, the patient will be re-evaluated 
within 30 days of withdrawal.  All ongoing SAEs at the time of withdrawal will be followed until 
resolution.
At the time of discontinuation or withdrawal, patients will be asked to participate in all safety 
and efficacy evaluations required for the end of study visit and for the safety follow-up visit.  
Participation in these EOS procedures will be strongly encouraged, but is voluntary for those 
patients electing to discontinue from the study.  The patient will be scheduled for the removal of 
the IDDD. 
7.28
Other Study Procedures
This section is not applicable.
7.29
Appropriateness of Measurements
The neurocognitive and developmental assessments are intended to gauge which domains can be 
accurately measured, with which specific tools, despite the considerable behavioral and cognitive 
challenges in Sanfilippo syndrome.  The evaluation of these domains and the analysis of CSF, 
serum, and urine biomarkers may provide the pivotal data necessary to inform the clinical 
assessments and biomarkers used in possible future Sanfilippo syndrome ERT trials.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
56
8
STUDY ACTIVITIES
Patients who participated in Study HGT-SAN-055 through Week 26 and completed the EOS 
evaluations may be eligible for enrollment in this open-label extension study.  Informed consent 
(and assent, if applicable) must be obtained prior to performing any study related procedures that 
are specific to HGT-SAN-067.  Informed consent may be obtained anytime from Week 20 in 
HGT-SAN-055.  This would allow a patient to have a nonfunctional IDDD replaced or revised 
prior to the first HGT-1410 dose in HGT-SAN-067.
8.1
Screening Visit/Study Start Visit 
All Screening assessments for this study are to have been performed during the Week 26 EOS 
procedures in HGT-SAN-055 (ie, 30 [±7] days after the last HGT-1410 administration).  If less 
than 60 days have elapsed since completion of the EOS assessments for HGT-SAN-055, and the 
start of HGT-SAN-067, the assessments detailed in this Screening visit do not need to be 
repeated.  The Baseline visit for this study will be the first day the patient received their first 
dose of HGT-1410 in the HGT-SAN-055 Study.  
If more than 60 days have elapsed following the HGT-SAN-055 EOS procedures, patients will 
be evaluated for enrollment in HGT-SAN-067 on a case-by-case basis by the Investigator.  A 
decision about enrollment will be made following discussion with the Medical Monitor.  If the 
patient is enrolled, the following assessments are to be repeated within 30 days prior to the first 
scheduled intrathecal HGT-1410 dose:

Physical examination

Height and weight

Head circumference

ECG

Vital signs

Hematology 

Leukocyte pellet preparation to be used for additional disease-related laboratory studies, 
including possible assessment of cross-reactive immunologic material (if this is not collected 
at baseline, it can be collected at any subsequent pre-dosing time point)

Serum chemistry 

Pregnancy testing (for post menarche premenopausal females only)

Urinalysis 

Urine heparan sulfate and heparan sulfate derivatives

Plasma and serum heparan sulfate and heparan sulfate derivatives

Anti-rhHNS antibody testing

General anesthesia:  administration of anesthesia will be given prior to the following 
assessments:

ABR

MRI of the head

Neurological examination (performed prior to the administration of anesthesia)

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
57

Full Neurodevelopmental assessments, including Vineland Adaptive Behavior Scales, 
Second Edition (VABS-II; all assessments performed prior to the administration of 
anesthesia)

CSF sample collection (chemistry, cell count, heparan sulfate and heparan sulfate derivatives, 
and other MPS exploratory biomarkers) via the IDDD

Children’s Sleep Habits Rating Scale 

CHQ-50

CHQ-87

ITQOL

Concomitant medications, therapies, and procedures

AE assessments
8.2
Treatment:  Drug Administration and Weekly Assessments
Patients will receive HGT-1410 IDDD monthly (Q4W), on Day 2 (±2 days), Week 1.  
Patient assessments for safety, biochemical, and neurological baseline measures (Day 1, Week 1) 
will occur on the day before the first IT injection.  Note:  Day 1 assessments may be performed 
on the same day as the administration of study drug (Day 2).  This can occur if it is feasible for 
the patient to arrive at the study site early in the day, and if it is deemed clinically appropriate by 
the Investigator.  If the procedures on Day 1 and Day 2 are combined in this way, the 
assessments will be recorded as occurring on Day 2.
CSF samples will be obtained from these patients on Day 2, immediately prior to the first IT 
study drug injection.  Note:  Patients will not receive study drug if the pre-dose CSF contains 
>100 WBC per cubic millimeter.
8.2.1
Week 1 
8.2.1.1
Day 1 (Pre-treatment) Assessments Performed Prior to Each Dose

Physical examination

Height and weight

Vital signs

Hematology

Serum chemistry

Urinalysis

Pregnancy testing (applicable females only)

Neurological examination (performed prior to the administration of anesthesia and the 
HGT-1410 IT injection)

Concomitant medications, therapies, and procedures

AE assessments

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
58
Note: If the HGT-SAN-055 EOS (or HGT-SAN-067 Screening) assessments were performed 
within 7 days of first intrathecal HGT-1410 treatment in this study, the pre-treatment 
assessments described in this section do not need to be completed prior to the first treatment in 
study HGT-SAN-067.
DAY 1 (PRE-TREATMENT) ADDITIONAL ASSESSMENTS PERFORMED AT MONTHS 12, 24, 36, AND 54

Head circumference

Visual and hearing assessments 

Urine heparan sulfate and heparan sulfate derivatives 

Plasma and /or serum heparan sulfate and heparan sulfate derivatives 

Anti-rhHNS antibody testing

ABR

MRI of the head 

Full neurodevelopmental testing, including VABS-II (performed prior to the administration 
of anesthesia and the HGT-1410 IT injection)

Children’s Sleep Habits Rating Scale 

Child health questionnaire-50 

Child health questionnaire-87 

Infant toddler QOL Questionnaire 
8.2.1.2
Day 2 (±2 days) Assessments and Administration of HGT-1410
Patients may be discharged from the clinical site 4 hours after dosing, if deemed stable by the 
Investigator.

Physical examination

ECG (performed following IT study drug injection)

Vital signs

CSF sample collection (obtained prior to IT study drug injection)

HGT-1410 IT injection (Day 2 ±2 days)

Neurological examination 

Concomitant medications, therapies, and procedures

AE assessments
The neurological exam should not occur sooner than 4 hours after study drug administration or 
before the patient has fully recovered from any anesthesia administered for the dosing, 
whichever occurs later.
8.3
End of Study/Early Termination Procedures:  Month 55
Patients who complete the study or who discontinue prior to the end of the study, will have EOS 
assessments performed 30 (±7 days) after their last dose of HGT-1410.  

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
59
Patients who discontinue or are withdrawn prior to study completion will be asked to participate 
in the EOS procedures at the time of discontinuation.  Participation in these EOS procedures will 
be strongly encouraged, but is voluntary for those patients electing to discontinue from the study.  
Note:  Patients will have the IDDD removed when they discontinue from the study, unless the 
patient is continuing to receive treatment through another mechanism (eg, expanded access, 
commercially available).

Physical examination

Height and weight

Head circumference

Visual and hearing assessment

ECG

Vital signs

Hematology

Serum chemistries

Urinalysis

Urine heparan sulfate and heparan sulfate derivatives 

Plasma and serum heparan sulfate and heparan sulfate derivatives 

Anti-rhHNS antibody testing

ABR (unless performed at Month 54)

MRI of the head (unless performed at Month 54)

CSF sample collection (unless performed at Month 54)

Neurological examination

Full neurodevelopmental testing, including VABS-II 

Children’s Sleep Habits Rating Scale 

Child health questionnaire-50 

Child health questionnaire-87 

Infant toddler QOL Questionnaire 

Concomitant medications, therapies, and procedures

AE assessments

X-ray of device, if the patient is to continue to receive intrathecal HGT-1410 beyond the end 
of the study
All patients who discontinue the study early will have their IDDD removed.  
Patients who withdraw or discontinue after having received fewer than 3 IT injections will not 
need to complete the EOS visit.  
Patients who withdraw or discontinue from the study after having received 3 or more IT 
injections, will be asked to complete the EOS visit and undergo all the scheduled assessments.
8.4
Safety Follow-up (by Telephone or Visit) Month 56
Patients who complete the study or withdraw early will have a safety follow-up telephone call or 
visit 30 Days (±7 days) after the last study visit.  This will assess:

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
60

Concomitant medications, therapies, and procedures

AE assessments

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
61
9
QUALITY CONTROL AND ASSURANCE
Training will occur at an investigator meeting or at the site initiation visit or both, and instruction 
manuals (eg, laboratory manuals and pharmacy manuals) will be provided to aid consistency in 
data collection and reporting across sites.
Clinical sites will be monitored by Shire HGT or its designee to ensure the accuracy of data 
against source documents.  The required data will be captured in a validated clinical data 
management system that is compliant with the Food and Drug Administration (FDA) 21 Code of 
Federal Regulations (CFR) Part 11 Guidance.  The clinical trial database will include an audit 
trail to document any evidence of data processing or activity on each data field by each user.  
Users will be trained and given restricted access, based on their role in the study, through a 
password protected environment.  
Data entered in the system will be reviewed manually for validity and completeness against the 
source documents by a clinical monitor from Shire HGT or its designee.  If necessary, the study 
site will be contacted for corrections or clarifications; all missing data will be accounted for.
SAE information captured in the clinical trial database will be reconciled with the information 
captured in the Pharmacovigilance database.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
62
10 PLANNED STATISTICAL METHODS
10.1
General Statistical Methodology
This is an open-label extension of study HGT-SAN-055 to evaluate the long-term safety and 
clinical outcomes of intrathecal administration of HGT-1410 in patients with MPS IIIA.  The 
statistical methodology supporting the trial will focus on descriptive rather than inferential 
approaches, given the early phase and objectives of this trial. 
Data will be summarized by dose group (10 mg, 45 mg, and 90 mg) with respect to demographic 
and baseline characteristics, efficacy variables, and safety variables. Summary statistics for 
continuous variables will include the n, mean, standard deviation, median, minimum and 
maximum. Categorical variables will be summarized in a contingency table by the frequency and 
percentage of patients in each category. Data will be plotted to assess trends across time as 
appropriate.
No a priori hypotheses will be tested.  Exploratory hypotheses may emerge from the data 
analysis, in which case, appropriate testing methods will be applied and specified in the 
statistical analysis plan.
There are no formal hypotheses associated with the evaluation of the safety and performance of 
the IDDD device (SOPH-A-PORT Mini S). All analyses of device safety and performance will 
be descriptive and no statistical testing will be performed. Device related analyses will be based 
on patients for whom the device implant procedure was performed and are described in the 
sections below.
10.2
Determination of Sample Size
Since this is an extension study, sample size is determined by the number of patients who 
completed HGT-SAN-055 (maximum of 12 patients) and elected to continue treatment with 
HGT-1410 in this study. Hence no statistical estimation of the sample size was performed.
10.3
Analysis Populations
The primary analysis population consists of all eligible patients from HGT-SAN-055 who have 
agreed to participate in the extension study. This population will be used to perform both safety 
and efficacy analyses. The collection of detailed data pertaining to the SOPH-A-PORT mini S 
will permit device-related analyses to be conducted in the subset of patients in the primary 
analysis population who had the SOPH-A-PORT Mini S implant procedure performed.
10.4
Demographics and Baseline Characteristics
Patient disposition for those enrolled will be presented in a summary table using number and 
percentage of patients enrolled, completed or discontinued/withdrew. The reasons for 
discontinuation/withdrawal will also be presented.
Demographic and baseline characteristics (eg, age, race, ethnicity, medical history, and surgical 
history) will be reported in summary tables.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
63
10.5
Statistical Analysis of Pharmacokinetic Variables
Not applicable.
10.6
Efficacy, Safety, and Pharmacodynamic Evaluations    
10.6.1
Primary Analyses
10.6.1.1
Safety Analysis
In general, safety assessments will be based on all assessments post-baseline.  The assessment of 
safety will be based primarily on the frequency of AEs, and on the frequency of clinically 
notable abnormal vital sign and laboratory values.  Changes from baseline will be calculated by 
subtracting the baseline value from the post-baseline value.
All enrolled patients who had an IDDD surgical procedure and/or received administration of 
HGT-1410 will be included in the safety analysis.  
Adverse events will be recorded throughout the study and at early termination.  Adverse events 
and medical conditions will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). 
Adverse events will be summarized by presenting, for each dose group, the number and 
percentage of patients having any AE, having an AE in system organ class, and having each 
individual AE. In addition, those events which resulted in death or were otherwise classified as 
serious will be presented in a separate listing. The incidence of treatment-emergent adverse 
events , defined as all AEs from the time of the surgery for IDDD implantation to the last follow 
up contact, ie, 30 days after the last HGT-1410 administration, (new or worsened from baseline) 
will be summarized by system organ class, severity, type of adverse event and relationship to 
trial medication/procedure. 
Treatment-emergent AEs deemed related to HGT-1410 administration will be summarized 
separately.
IDDD, and procedure-related AEs will be summarized within system organ class by preferred 
term. IDDD and procedure-related AEs will be tabulated by severity (mild, moderate, severe) 
and degree of relatedness.  Separate tabulations will be provided for adverse events related to the 
IDDD, device surgical procedure (including post-implant infections) and IT administration 
process.  These summaries will be presented by device and overall, as appropriate. 
Descriptive summaries of clinical laboratory evaluations (hematology, serum chemistry, 
urinalysis and CSF) results will be presented in summary tables by evaluation visit.  Changes 
from baseline will be summarized for each post-baseline visit.  Each laboratory result will be 
categorized as a patient having had (1) an Abnormal and Clinically Significant (CS) value at any 
time, (2) no CS values at any time but had at least one Abnormal and not CS (NCS) value, and 
(3) no CS or NCS values at any time; the number and percentage in each category will be 
presented.  For any patient who experiences a CS laboratory result at any time that was not CS at 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
64
baseline (or the most recent non-missing value prior to the start of the treatment), their entire 
profile for that particular laboratory parameter will be presented as a listing.
The observed values and changes from baseline for vital sign data will be summarized for each 
dose group.  Shift tables may be presented, utilizing reference ranges.  Patients with notably 
abnormal values will be identified and listed separately along with their values.
The observed values and changes from baseline for ECG data will be summarized for each dose 
group.  Patients with any clinically significant findings and/or conduction abnormalities will be 
listed separately along with their values. 
Anti-rhHNS antibody formation will be monitored throughout the study.  Results will be 
presented in summary tables by number and percentage of positive and negative specimens by 
evaluation visit, and number and percentage of positive and negative specimens overall.  The 
effect of antibodies on other safety parameters will be assessed by presenting summary tables by 
antibody status.  
For those patients who fail to complete the study, the reason for discontinuation will be listed by 
patient and dose group. 
Listings of all study safety data will be presented.
10.6.2
Other Observations Related to Safety
10.6.2.1
IDDD Performance
IDDD safety and performance will be summarized in detail for patients implanted with the 
SOPH-A-PORT Mini S. Difficulties associated with the implant procedure (e.g. excessive 
bleeding, CSF leakage, etc.) will be summarized.  A summary of abnormal findings from the 
IDDD radiological assessments will also be presented.  
The proportion of patients with at least one IDDD failure and/or malfunction, as well as the 
number of and reasons for IDDD failures/malfunctions and actions taken will be summarized.  
The rate of IDDD failures/malfunctions and 95% confidence interval will also be estimated.  The 
time from initial implant surgery to first IDDD failure and/or malfunction will be summarized.  
Patients without an IDDD failure/malfunction will be censored at their last study drug injection 
date.  A by-patient listing of the device failure/malfunction data will be displayed.
The proportion of patients for whom a successful first injection of study drug occurred will be 
reported among those for whom a first injection was attempted (i.e. those who had an apparently 
successful implantation and did not suffer a device removal or revision prior to first scheduled 
injection).  The proportion of patients who had no failed injection attempts during the study will 
also be summarized. The corresponding 95% confidence intervals of the proportion of interest 
will be estimated, where appropriate. Injections not given for patient reasons (e.g. patient 
uncooperative, competing medical issue, etc) will not be included in the determination of these 
success proportions.  The frequency and reasons for unsuccessful injection attempts will be 
reported.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
65
10.6.3
Secondary Analysis
10.6.3.1
Clinical Assessments
The change from baseline in neurocognitive assessment based scores will be examined by dose 
group.  Furthermore, the effect of HGT-1410 administration on QoL measures will be examined 
by presenting mean change from baseline by dose groups.  Other relevant assessments which 
might help in the understanding of clinical activity will also be analyzed.
10.6.3.2
Pharmacodynamic Analyses
To determine the effects of HGT-1410 administration on biomarkers, mean change from baseline 
will be assessed at selected time points.  The heparan sulfate reduction (in CSF and urine) will be 
examined using mean change and the corresponding 95% confidence interval.  The concentration 
of inflammatory cytokines in serum and CSF will also be examined.  Other exploratory 
biomarkers in CSF, serum, and urine may also be examined.
The effect of anti- rhHNS antibodies on the changes in CSF biomarkers may also be examined 
by presenting summary tables by antibody status.
The planned analyses and presentations will be defined in the Statistical Analysis Plan (SAP).

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
66
11 ADMINISTRATIVE CONSIDERATIONS
11.1
Investigators and Study Administrative Structure
Before initiation of the study, the Investigators must provide the Sponsor with a completed Form 
FDA 1572 or Investigator Agreement.  Study medications may be administered only under the 
supervision of the Investigators listed on this form.  Curriculum vitae must be provided for the 
Investigators and sub-investigators listed on Form FDA 1572 or Investigator Agreement.
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, any amendments to the protocol, the study treatments, and their study related 
duties and functions.  The Investigator must maintain a list of sub-investigators and other 
appropriately qualified persons to whom he or she has delegated significant study related duties.
11.2
Institutional Review Board or Independent Ethics Committee Approval
Before initiation of the study, the Investigator must provide the Sponsor with a copy of the 
written IRB or IEC approval of the protocol and the informed consent form.  This approval must 
refer to the informed consent form and to the study title, study number, and version and date of 
issue of the study protocol, as given by the Sponsor on the cover page of the protocol.  
Status reports must be submitted to the IRB/IEC at least once per year.  The IRB/IEC must be 
notified of completion of the study.  Within 3 months of study completion or termination, a final 
report must be provided to the IRB/IEC.  A copy of these reports will be sent to the study clinical 
monitor.  The Investigators must maintain an accurate and complete record of all submissions 
made to the IRB/IEC, including a list of all reports and documents submitted.  AEs which are 
reported to the US FDA or other Regulatory agencies (Investigational New Drug [IND] Safety 
Reports) must be submitted promptly to the IRB/IEC.
11.3
Ethical Conduct of the Study
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor and Investigators abide by 
good clinical practice (GCP) as described in the 21 CFR Parts 50, 56, and 312 and the 
International Conference on Harmonization (ICH) GCP Guidelines. 
11.4
Patient Information and Consent
Before enrolling in the clinical study, the patient’s parent(s), or the patient’s legally authorized 
representative(s) must consent to participate after the nature, scope, and possible consequences 
of the clinical study have been explained in a form understandable to him or her.  An informed 
consent form that includes information about the study will be prepared and given to the 
patient’s parent(s), or the patient’s legally authorized representative(s).  This document will 
contain all FDA and ICH-required elements.  

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
67
The informed consent form must be in a language understandable to the patient’s parent(s), or 
the patient’s legally authorized representative(s) and must specify who informed the patient’s 
parent(s) or the patient’s legally authorized representative.
After reading the informed consent document, the patient, patient’s parent(s), or the patient’s 
legally authorized representative(s) must give consent in writing.  The patient’s consent must be 
confirmed at the time of consent by the personally dated signature of the patient, patient’s 
parent(s) or the patient’s legally authorized representative(s) and by the personally dated 
signature of the person conducting the informed consent discussions.  If the patient, patient’s 
parent(s), or the patient’s legally authorized representative(s) is unable to read, oral presentation 
and explanation of the written informed consent form and information to be supplied must take 
place in the presence of an impartial witness.  Consent (or assent) must be confirmed at the time 
of consent orally and by the personally dated signature of the patient, patient’s parent(s) or by the 
patient’s legally authorized representative(s).  The witness and the person conducting the 
informed consent discussions must also sign and personally date the informed consent document.  
It should also be recorded and dated in the source document that consent was given.
A copy of the signed and dated consent document(s) must be given to the patient’s parent(s), or 
the patient’s legally authorized representative(s).  The original signed and dated consent 
document will be retained by the Investigator.
The Investigator will not undertake any measures specifically required solely for the clinical 
study until valid consent has been obtained.
A model of the informed consent form to be used in this study will be provided to the sites 
separately from this protocol.  
Where applicable, signed assent(s) to participate in the study must be obtained.
11.5
Patient Confidentiality
Patient names will not be supplied to the Sponsor.  Only the patient number and patient initials 
will be recorded in the eCRF, and if the patient name appears on any other document, it must be 
obliterated before a copy of the document is supplied to the Sponsor.  Study findings stored on a 
computer will be stored in accordance with local data protection laws.  The patients will be told 
that representatives of the Sponsor, a designated Clinical Research Organization (CRO), the 
IRB/IEC, or regulatory authorities may inspect their medical records to verify the information 
collected, and that all personal information made available for inspection will be handled in 
strictest confidence and in accordance with local data protection laws.  The Investigator will 
maintain a personal patient identification list (patient numbers with the corresponding patient 
names) to enable records to be identified.
11.6
Study Monitoring
Monitoring procedures that comply with current GCP guidelines will be followed.  On-site 
review of the eCRFs for completeness and clarity, cross-checking with source documents, and 
clarification of administrative matters will be performed.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
68
The study will be monitored by the Sponsor or its designee.  On site monitoring will be 
performed by a representative of the Sponsor (Clinical Study Monitor) who will review the CRFs 
and source documents.  The site monitor will ensure that the investigation is conducted 
according to protocol design and regulatory requirements by frequent site visits and 
communications (letter, telephone, and facsimile).
11.7
Case Report Forms and Study Records
Case report forms are provided for each patient in electronic format.  Electronic Data Capture 
(EDC) will be used for this study.  The study data will be recorded from the source documents 
into the eCRF.  The electronic files will be considered as the CRFs. 
All forms must be filled out by authorized study personnel.  All corrections to the original eCRF 
entry must indicate the reason for change.  The Investigator is required to sign the eCRF after all 
data have been captured for each patient.  If corrections are made after review and signature by 
the Investigator, he or she must be made aware of the changes, and his or her awareness 
documented by re-signing the eCRF.   
11.7.1
Critical Documents
Before Shire HGT initiates the trial (ie, obtains informed consent [assent if applicable] from the 
first patient), it is the responsibility of the Investigator to ensure that the following documents are 
available to Shire HGT or their designee:

Curricula vitae of Investigator and sub-investigator(s) (current, dated and signed or supported 
by an official regulatory document)

Current medical license of Investigator and sub investigator(s)

Signed and dated agreement of the final protocol

Signed and dated agreement of any amendment(s), if applicable

Approval/favorable opinion from the IRB/IEC clearly identifying the documents reviewed:  
protocol, any amendments, Patient Information/Informed Consent Form (Assent form if 
applicable), and any other written information to be provided regarding patients recruitment 
procedures

Copy of IRB/IEC approved Patient Information/Informed Consent Form (Assent Form if 
applicable)/any other written information/advertisement

Any additional regulatory approvals, ie national regulatory approvals

List of IRB/IEC Committee members/constitution

Financial agreement(s)

Documentation from central or local laboratory as applicable
•
Reference ranges
•
Certification/QA scheme/other documentation
Regulatory approval and notification as required must also be available; these are the 
responsibility of Shire HGT.  All trial documents will be available in a Trial Master File (TMF) 
at the Investigator/trial site and at Shire HGT.     

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
69
11.8
Device Failure Adjudication Process
The final cause for device failures will be adjudicated by a Shire team by examining the clinical 
database, safety database, and manufacturer investigation of returned devices.
11.9
Protocol Violations/Deviations
The Investigator will conduct the study in compliance with the protocol.  The protocol will not 
be initiated until the IRB/IEC and the appropriate regulatory authorities have given 
approval/favorable opinion.  Modifications to the protocol will not be made without agreement 
of the Sponsor.  Changes to the protocol will require written IRB/IEC approval/favorable opinion 
prior to implementation, except when the modification is needed to eliminate an immediate 
hazard(s) to patients.  The IRB/IEC may provide, if applicable regulatory authorities permit, 
expedited review and approval/favorable opinion for minor change(s) in ongoing studies that 
have the approval/favorable opinion of the IRB/IEC.  The Sponsor will submit all protocol 
modifications to the regulatory authorities in accordance with the governing regulations.  A 
record of patients screened, but not entered into the study, is also to be maintained.  There will be 
no protocol exemptions granted for this study.
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
patients, the Investigator will contact the Sponsor or its designee, if circumstances permit, to 
discuss the planned course of action.  Any departures from the protocol must be fully 
documented as a protocol deviation.  Protocol deviations will need to be reviewed by the medical 
monitor and may also be required to be submitted to the IRB/IEC.
Protocol modifications will only be initiated by the Sponsor and must be approved by the 
IRB/IEC and submitted to the FDA or other applicable international regulatory authority before 
initiation.
11.10 Access to Source Documentation
Regulatory authorities, the IEC/IRB, or the Sponsor may request access to all source documents, 
CRFs, and other study documentation for on-site audit or inspection.  Direct access to these 
documents must be guaranteed by the Investigator, who must provide support at all times for 
these activities.  Monitoring and auditing procedures that comply with current GCP guidelines 
will be followed.  On-site review of the CRFs for completeness and clarity, crosschecking with 
source documents, and clarification of administrative matters will be performed.
11.11 Data Generation and Analysis
The clinical database will be developed and maintained by a contract research organization or an 
electronic data capture technology provider as designated by Shire HGT.  Shire HGT or its 
designee will be responsible for performing study data management activities. 
Adverse events will be coded using MedDRA.  Concomitant medication will be coded using 
WHO-DD.  Centralized laboratories will be employed as described in the study manual to aid in 
consistent measurement of efficacy and safety parameters.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
70
11.12 Premature Closure of the Study
11.12.1
Study Termination
If the Sponsor or an Investigator discovers conditions arising during the study which indicate that 
the clinical investigation should be halted due to an unacceptable patient risk, the study may be
terminated after appropriate consultation between Shire HGT and the Investigators.  In addition, 
a decision on the part of Shire HGT to suspend or discontinue development of the study material 
may be made at any time.
11.12.2
Site Termination
A specific site may be terminated separate from the general study for, but not limited to, the 
following conditions:

The discovery of an unexpected, significant, or unacceptable risk to the patients enrolled at 
the site.

Failure of the Investigator to enter patients at an acceptable rate.

Insufficient adherence by the Investigator to protocol requirements.
11.13 Retention of Data
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application and until there are no pending or contemplated marketing applications or 
at least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product.  The Sponsor will notify the Investigator if these documents must be 
retained for a longer period of time.  It is the responsibility of the Sponsor to inform the 
Investigator or institution as to when these documents no longer need to be retained. 
Biological samples may be reserved for potential, future, biomarker studies (see Section 7.7.6).  
11.14 Financial Disclosure
The Investigator should disclose any financial interests in the Sponsor as described in 21 CFR 
Part 54 prior to beginning this study.  The appropriate form will be provided to the Investigator 
by the Sponsor, which will be signed and dated by the Investigator, prior to the start of the study. 
11.15 Publication and Disclosure Policy
All information concerning the study material, such as patent applications, manufacturing 
processes, basic scientific data, and formulation information supplied by the Sponsor and not 
previously published are considered confidential and will remain the sole property of the 
Sponsor.  The Investigator agrees to use this information only in accomplishing this study and 
will not use it for other purposes.
It is understood by the Investigator that the information developed in the clinical study may be 
disclosed as required to the authorized regulatory authorities and governmental agencies.  

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
71
In order to allow for the use of the information derived from the clinical studies, it is understood 
that there is an obligation to provide the Sponsor with complete test results and all data 
developed in the study in a timely manner.
The Investigator and any other clinical personnel associated with this study will not publish the 
results of the study, in whole or in part, at any time, unless they have consulted with Shire HGT, 
provided Shire HGT a copy of the draft document intended for publication, and obtained Shire 
HGT’s written consent for such publication.  All information obtained during the conduct of this 
study will be regarded as confidential.  Shire HGT will use the information for registration 
purposes and for the general development of the drug.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
72
12 LIST OF REFERENCES
1. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. 
JAMA : the journal of the American Medical Association 1999;281:249-54.
2. Poorthuis BJ, Wevers RA, Kleijer WJ, et al. The frequency of lysosomal storage diseases in 
The Netherlands. Human genetics 1999;105:151-6.
3. Baehner F, Schmiedeskamp C, Krummenauer F, et al. Cumulative incidence rates of the 
mucopolysaccharidoses in Germany. J Inherit Metab Dis 2005;28:1011-7.
4. Valstar MJ, Bruggenwirth HT, Olmer R, et al. Mucopolysaccharidosis type IIIB may 
predominantly present with an attenuated clinical phenotype. Journal of inherited metabolic 
disease 2010;33:759-67.
5. Meyer A, Kossow K, Gal A, et al. Scoring evaluation of the natural course of 
mucopolysaccharidosis type IIIA (Sanfilippo syndrome type A). Pediatrics 
2007;120:e1255-61.
6. Cleary MA, Wraith JE. Management of mucopolysaccharidosis type III. Arch Dis Child 
1993;69:403-6.
7. Fraser J, Wraith JE, Delatycki MB. Sleep disturbance in mucopolysaccharidosis type III 
(Sanfilippo syndrome): a survey of managing clinicians. Clin Genet 2002;62:418-21.
8. Neufeld E, Muenzer J. The Mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, 
Valle D, eds. The metabolic and molecular bases of inherited disease. 8th ed. New York: 
McGraw-Hill; 2001:4 v. (xivii, 6338, I-104 p.).
9. Meyer A, Kossow K, Gal A, et al. The mutation p.Ser298Pro in the sulphamidase gene 
(SGSH) is associated with a slowly progressive clinical phenotype in mucopolysaccharidosis 
type IIIA (Sanfilippo A syndrome). Hum Mutat 2008;29:770.
10. Vellodi A. Lysosomal storage disorders. Br J Haematol 2005;128:413-31.
11. Hemsley KM, Beard H, King BM, Hopwood JJ. Effect of high dose, repeated intra-CSF 
injection of sulphamidase on neuropathology in MPS IIIA mice. Genes Brain Behav 2008.
12. Urayama A, Grubb JH, Sly WS, Banks WA. Mannose 6-phosphate receptor-mediated 
transport of sulfamidase across the blood-brain barrier in the newborn mouse. Mol Ther 
2008;16:1261-6.
13. Bielicki J, Hopwood JJ, Melville EL, Anson DS. Recombinant human sulphamidase: 
expression, amplification, purification and characterization. Biochem J 1998;329 ( Pt 
1):145-50.
14. Di Natale P, Vanacore B, Daniele A, Esposito S. Heparan N-sulfatase: in vitro mutagenesis 
of potential N-glycosylation sites. Biochem Biophys Res Commun 2001;280:1251-7.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
73
15. Daniele A, Di Natale P. Heparan N-sulfatase: cysteine 70 plays a role in the enzyme catalysis 
and processing. FEBS Lett 2001;505:445-8.
16. Perkins KJ, Byers S, Yogalingam G, Weber B, Hopwood JJ. Expression and characterization 
of wild type and mutant recombinant human sulfamidase. Implications for Sanfilippo 
(Mucopolysaccharidosis IIIA) syndrome. J Biol Chem 1999;274:37193-9.
17. Munoz-Rojas MV, Vieira T, Costa R, et al. Intrathecal enzyme replacement therapy in a 
patient with mucopolysaccharidosis type I and symptomatic spinal cord compression. Am J 
Med Genet A 2008;146A:2538-44.
18. Muñoz-Rojas M, Dain D, Horovitz G, et al. Intrathecal administration of recombinant human 
N-acetylgalactosamine 4-sulfatase to a MPS VI patient with pachymeningitis cervicalis. 
Molecular Genetics and Metabolism 2010;99:346-50.
19. Chen A, Dickson P, Shapiro E, Lyons B, Kan S, Guillaume D. A study of intrathecal enzyme 
replacement for cognitivedecline in mucopolysaccharidosis. Mol Genet Metab 
2010;99:S13-S4.
20. Hemsley K, King B, Hopwood J. Injection of recombinant human sulfamidase into the CSF 
via the cerebellomedullary cistern in MPS IIIA mice. Mol Genet Metab 2007;90:313-28.
21. Hemsley KM, Luck AJ, Crawley AC, et al. Examination of intravenous and intra-CSF 
protein delivery for treatment of neurological disease. Eur J Neurosci 2009;29:1197-214.
22. Hemsley KM, Norman EJ, Crawley AC, et al. Effect of cisternal sulfamidase delivery in 
MPS IIIA Huntaway dogs-A proof of principle study. Mol Genet Metab 2009.
23. Bayley N. Bayley Scales of Infant and Toddler Development: Third Edition. San Antonio, 
TX The Psychological Corporation; 2005.
24. Kaufman S, Kaufman N. Kaufman Assessment Battery for Children (KABC-II). 2nd ed.
25. Henderson S, Sugden D, Barnett A. Movement Assessment Battery for Children (second 
ed.). London: Harcourt Assessment; 2007.
26. Sparrow S, Balla D, Cicchetti D. Vineland Adaptive Behavior Scales (Second Edition). 4201 
Woodland Road Circle Pines, MN 55014-1796: American Guidance Service, Inc; 2005.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
74
Appendix 1
Schedule of Events 
HGT-SAN-067 Study Assessments for Patients Who Have Received 6 Months of HGT-1410 Treatment in Study HGT-SAN-
055
Dosed every 28 (±7) days 
(ie, Q4W)
Assessment
Screening/or HGT-SAN-055 
EOS Visitk
(Month 6 from the start of 
HGT-SAN-055)
Pre-Tx
Day 1a
IT dosing
Day 2 (±2)
Months 12, 24, 36, 
and 54 
(from the start of 
HGT-SAN-055)
EOSf Month 55
(from the start of 
HGT-SAN-055)
Month 56
Safety 
Follow-upj
Informed Consent/Enrollment
●
Physical Examination
●
●
●
●
Height and Weight
●
●
●
Head Circumference
●
●
●
Visual and Hearing Assessment
●
●
ECG
●
●b
●
Vital Signs
●
●
●
●
Hematology
●
●
●
Serum Chemistry
●
●
●
Pregnancy Testingn
●
●
Urinalysis
●
●
●
Leukocyte pellet preparationo
●
Urine Heparan Sulfate and Heparan 
Sulfate Derivatives 
●
●e
●
Plasma and serum Heparan Sulfate and 
Heparan Sulfate Derivatives
●
●e
●
Anti-rhHNS antibody testing (serum and 
CSF)l
●
●
●
Auditory Brainstem Response (ABR)
●
●
●p
MRI of the Head
●
●
●p
CSF Sample Collectionm
●
●c
●c, p
HGT-1410 dosing: every 28 (7) days d, g , 
●
Neurological Examinationh
●
●
●
●
Full Neurodevelopmental Testingi
●
●
●
Children’s Sleep Habits Rating Scale
●
●
●
Child Health Questionnaire-50
●
●
●

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
75
HGT-SAN-067 Study Assessments for Patients Who Have Received 6 Months of HGT-1410 Treatment in Study HGT-SAN-
055
Dosed every 28 (±7) days 
(ie, Q4W) 
Assessment 
Screening/or HGT-SAN-055 
EOS Visitk 
(Month 6 from the start of 
HGT-SAN-055) 
Pre-Tx 
Day 1a 
IT dosing 
Day 2 (±2) 
Months 12, 24, 36, 
and 54 
(from the start of 
HGT-SAN-055) 
EOSf Month 55 
(from the start of 
HGT-SAN-055) 
Month 56 
Safety 
Follow-upj 
Child Health Questionnaire-87
●
●
● 
Infant Toddler QOL Questionnaire
●
●
● 
Concomitant Medications, Therapies, and 
Procedures 
● 
●
●
●
● 
Adverse Event Monitoring
●
●
●
●
● 
X-ray examination of device (if treatment 
is to continue beyond end of study) 
● 
Removal of IDDD
●q
●q 
Abbreviations:
ABR = Auditory brainstem response; CSF = cerebrospinal fluid; EOS  = end of study ; ECG = electrocardiogram; IT = intrathecal; 
MRI = Magnetic resonance imaging; TX = treatment 
Note: The timing of assessments is calculated from the start of HGT-SAN-055.  Therefore, for example, the end-of-study visit, as presented here at Month 54, 
corresponds to Month 48 in HGT-SAN-067, but represents a total of 54 months of study treatment (48 months in HGT-SAN-067 + 6 months in 
HGT-SAN-055). 
a
Week 1 only, and only performed  if >7 days have elapsed since  HGT-SAN-055 EOS visit assessments. 
b
ECG to be performed following administration of study drug. 
c
CSF samples will be obtained according to the process with in the study operations manual).  An attempt will be made to obtain a CSF sample via the IDDD 
prior to each administration of HGT-1410 and at the End of Study visit.  If it is not possible to obtain a CSF using the IDDD, the IDDD may be replaced (up 
to twice in a 6 month period [including the time in the HGT-SAN-055 study]) or a LP may be performed (can occur up to 5 times in a 6 month period). 
d
Patients may be discharged as early as 4 hours post HGT-1410 infusion (ie, on Day 2) when deemed clinically stable by the Investigator. 
e
Specimens collected once a month, at Day 1 of the first treatment week. 
f
All patients who complete the study will have end of study assessments performed 30 (±7 days) after their last dose of study drug. 
g
If a patient’s IDDD becomes nonfunctional or infected; it will be replaced (up to 2 times in a 6 month period; including the time in Study HGT-SAN-055).  
h
The neurological exam should not occur sooner than 4 hours after administration of study drug or before the patient has fully recovered from any anesthesia 
administered for the dosing, whichever occurs later. 
i
Full neurodevelopmental testing includes an assessment with the Vineland Adaptive Behavior Scales, Second Edition (VABS-II) 
j
A safety follow up telephone call will be made 30 (±7 days) after End of Study Procedures. 
k
Assessments will be required only if more than 60 days have elapsed following the HGT-SAN-055 procedures.  These assessments would be repeated 
within 30 days prior to the first scheduled HGT-1410 IT dose. 
l
Blood sample drawn before IT injection of HGT-1410. 
m
CSF will be tested for standard chemistries, heparan sulfate and heparan sulfate derivatives, anti-rhHNS antibodies, and MPS exploratory biomarkers. 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
76
HGT-SAN-067 Study Assessments for Patients Who Have Received 6 Months of HGT-1410 Treatment in Study HGT-SAN-
055
Dosed every 28 (±7) days 
(ie, Q4W) 
Assessment 
Screening/or HGT-SAN-055 
EOS Visitk 
(Month 6 from the start of 
HGT-SAN-055) 
Pre-Tx 
Day 1a 
IT dosing 
Day 2 (±2) 
Months 12, 24, 36, 
and 54 
(from the start of 
HGT-SAN-055) 
EOSf Month 55 
(from the start of 
HGT-SAN-055) 
Month 56 
Safety 
Follow-upj 
n
A pregnancy test will be carried out on pre-treatment Day 1 in females who are postmenarche to premenopause (childbearing).  The results must be negative 
before study drug can be administered. 
o
A blood sample for leukocyte pellet preparation is to be taken at baseline, before dosing.  This pellet should be stored frozen, and will be used for additional 
disease-related laboratory studies, including possible assessment of cross-reactive immunologic material.  If this is not drawn at baseline, it can be drawn at 
any subsequent visit, but it must be taken before dosing.  This only needs to be taken once during the study. 
P    These assessments are not to be performed at an EOS visit conducted at Month 55 if they were performed at the Month 54 visit 
q   The IDDD will be removed at the Month 54 visit, or at the EOS visit if the patient discontinues the study prior to the Month 54 visit 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
77
Appendix 2
Neurodevelopmental and Behavioral Assessments 
Table 4-1 and Table 4-2 detail the specific psychometric instruments that will be used to provide 
measures of each of relevant neurobehavioral or developmental domain assessed.  The tables 
also summarize the rules used to select a test for a patient, the subtests included in each test, and 
the subscales generated by the test battery.
Table 4-1. Summary of Neurodevelopmental Outcome Measures
Domain
Age
Test
Summary score and 
subdomains:
- Cognitive
- Motor
- Social/Emotional
0 to 42 months
Bayley Scales of Infant Development, Third 
Edition (BSID-III)23
- Cognitive 
- Processing skills
3 to 18 years
Kaufman Assessment Battery for Children, 
Second Edition (KABC-II)24  
Motor
3.0 to 16:11 
years
Movement Assessment Battery for Children, 
Second Edition (MABC-2)25  
Communication
Daily Living
Socialization
Motor Skills
0 to 90 years
Vineland Adaptive Behavior Scales, Second 
Edition (VABS-II)26
Table 4-2. Summary of Sanfilippo-specific Assessments
Domain
Assessment
Parent-scored behavioral inventory
- communication:  understanding
- communication:  expression
- tantrums
- specific behaviors inventory
- mood & emotions inventory
Sanfilippo Behavior Rating Scale
MPS-specific four-point scoring 
system/total disability score
- cognition
- expressive language
- motor score
Four-Point Scoring System/Total Disability 
Score (FPSS/TDS)5
The term “neurodevelopmental” refers to the process by which the neurological system matures 
and changes over time.  Assessing these changes in a population of children whose neurological 
system is progressively more affected can be very challenging.  
Typically, neurodevelopmental progress is reflected by the child’s abilities to perform certain 
skills (sitting, walking, and talking).  

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
78
However, a child with a neurological disorder may be able to perform age appropriate skills, but 
with atypical patterns.  For example, the child may be able to walk, but his gait is not normal.  
Most assessments will therefore measure the skills, but are not designed to capture the 
abnormalities in pattern or quality of the skill.  
These qualitative differences will be evident to the skilled test administrator/clinician who is 
familiar with the disorder.  However, only longitudinal tracking and repeated measures will 
reveal the significance of these abnormalities in overall function to the less experienced clinician.   
The rate at which different skills develop or regress over time will give insight into the disease 
process.  The next step is to determine how the learned skills are used for daily functional 
activities so that as the children grow up they become independent from caregivers.  These 
functional skills can be tracked to reflect quality of life issues for both parents and children. 
Neurodevelopmental assessments described below will be scheduled for administration in the 
morning and estimated to last between 2 and 4 hours. 
The list of assessments and algorithm is discussed in detail in the Study Operations Manual and 
includes: 
Bayley Scales of Infant Development, Third Edition (BSID-III) 23 
The Bayley Scales of Infant Development is a standard series of measurements used primarily to 
assess the motor (fine and gross), language (receptive and expressive), and cognitive 
development of infants and toddlers, ages 0 to 42 months.  This measure consists of a series of 
developmental play tasks and takes between 45 and 60 minutes to administer.  Raw scores of 
successfully completed items are converted to scale scores and to composite scores.  These 
scores are used to determine the child's performance compared with norms taken from typically 
developing children of their age (in months).  The assessment is often used in conjunction with 
the Social-Emotional Adaptive Behavior Questionnaire.  Completed by the parent or caregiver, 
this questionnaire establishes the range of adaptive behaviors that the child can currently achieve 
and enables comparison with age norms. 
Kaufman Assessment Battery for Children, Second Edition (KABC-II) 24 
Purpose: 
The KABC-II measures a child’s cognitive ability and processing skills and was designed to 
minimize verbal instructions and responses.  In addition, the assessment contains little cultural 
content to provide a more accurate assessment of children from diverse backgrounds.  Thus 
language difficulties or cultural differences are minimized in the test battery’s results. 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
79
Description:
Investigators may choose either the Cattell-Horn-Carroll or the Luria model for a patient’s 
assessment.  
The Cattell-Horn-Carroll model is used with children from a mainstream cultural and language 
background and the Luria model is used for children with significantly limited verbal ability.  
Subtests are administered on four or five ability scales and interpreted using the chosen model. 
Movement Assessment Battery for Children, Second Edition (MABC-2)25
Purpose:
The Movement Assessment Battery for Children, Second Edition identifies, describes and guides 
treatment of motor impairment in children from 3.0 to 16:11 years of age.
Description:
The MABC-2 checklist is administered individually over approximately 30 minutes.  It yields 
both normative and qualitative measures of movement competence, manual dexterity, ball skills, 
static and dynamic balance.
Vineland Adaptive Behavior Scales, Second Edition (VABS-II) 26
Purpose:
The test measures adaptive behaviors, including the ability to cope with environmental changes, 
to learn new everyday skills and to demonstrate independence.  It is an instrument that supports 
the diagnosis of intellectual and developmental disabilities.  It encompasses ages from birth to 
90 years. 
Description:
Adaptive behavior is a composite of various dimensions.  This test measures 5 domains:  
communication, daily living skills, socialization, motor skills, and maladaptive behavior 
(optional) and is administered in a semi-structured interview in through a questionnaire.  The 
scales of the VABS-II were organized within a 3-domain structure:  Communication, Daily 
Living, and Socialization.  This structure corresponds to the 3 broad domains of adaptive 
functioning by the American Association of Intellectual and Developmental Disabilities:  
Conceptual, Practical, and Social.  In addition, VABS-II offers a Motor Skills Domain and an 
optional Maladaptive Behavior Index.  The scores are interpreted by means of score equivalents 
for the raw scores in each domain, percentile ranks, age equivalents, adaptive levels, and 
maladaptive levels.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
80
Sanfilippo Behavior Rating Scale (SBRS)
The Sanfilippo Behavior Rating Scale (SBRS) is a newly-developed scale designed by Drs. Elsa 
Shapiro and Michael Potegal to measure a cluster of behaviors known to occur in Sanfilippo 
syndrome.  The SBRS is a parent-scored behavioral inventory measuring (1) comprehensive 
language skills, (2) expressive language skills, (3) tantrums, (4) mood and emotions, and 
(5) other behaviors not otherwise classified.
Four-Point Scoring System/Total Disability Score (FPSS/TDS) 5
The FPSS assesses motor function, expressive language, and cognitive function on a 0 to 3 point 
scale and can be used for individuals of all ages.  The total disability score is the average of the 
motor function, speech, and cognitive function scores.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
81
Appendix 3
Expected Adverse Device Effects
Procedure-Related Complications

Components handled improperly before, during, or after implantation 

Access port implanted incorrectly

Catheter positioned improperly

Injection through septum performed incorrectly

Injection of incorrect medication through access port

Injection outside the access port into pocket or subcutaneous tissue or extravasation

Pocket seroma, hematoma, erosion, or infection
Intrathecal Access Complications

Surgical complications such as hemorrhage or hematoma

Infection of the implant site or catheter track

Radiculitis or arachnoiditis

Intrathecal space infection resulting in meningitis or encephalitis

Bleeding 

Spinal cord damage or trauma to the spinal cord or nerve roots

Post-lumbar puncture, cerebrospinal fluid (CSF) leak, leading to headache, or  subcutaneous 
CSF collection

Epidural instead of intrathecal placement of catheter

Inflammatory mass resulting in neurological impairment, including paralysis

Pain on injection

Complications of anesthesia

Pseudomeningocele

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
82
System-Related Complications

Improperly positioned access port

Erosion of the skin because of the underlying access port or the catheter

Wound dehiscence

Access port migration, fracture, breakage or occlusion

Catheter damage, dislodgement, migration, disconnection, kinking or occlusion, fibrosis, or 
hygroma, resulting in tissue damage or a loss of or change in therapy, or other potentially 
serious adverse health consequences

Catheter breakage and migration of residual catheter fragments, potentially resulting in 
serious adverse health consequences and the need for surgical removal 

Local immunological or fibrous reaction to the presence of a foreign body (the device)

End of device service life or component failure, requiring surgical replacement

Component failure, resulting in loss of therapy

Access port inversion (“flipping”), rotation, or extrusion

Access port or catheter rejection 

Fibrin sheath formation around catheter tip

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
83
Appendix 4
Protocol Amendment Summary of Changes
AMENDMENT SUMMARY AND RATIONALE
Clinical protocol HGT-SAN-067 has been amended to include language to indicate that patients 
in the lowest dose group (10 mg Q4W) are to have the dose increased to that of the mid-dose, ie, 
45 mg at the first visit following the full approval of this protocol. A decline in the primary 
pharmacodynamic parameter, CSF heparan sulfate, was observed in data collected during the 
6-month study, HGT-SAN-055.  This response to therapy was exhibited at all dose levels, 
however, the greatest impact was at the 2 higher dose levels An effect on CSF heparan sulfate 
demonstrated in vivo activity of HGT-1410 in the target anatomical compartment, and is thought 
to have central importance in mediating the potential therapeutic benefit of HGT-1410. As no 
apparent differences in safety profile was observed between the 3 dose groups it was believed 
that the increase in the potential therapeutic benefit of the higher dose outweighed any potential 
increase in risks for this lowest dose group. 
The protocol has also been amended to reduce the number of hours a patient is monitored at the 
site after administration of HGT-1410 from 8 hours to 4 hours.  The monitoring time after each 
administration of HGT-1410 was reconsidered based on experience with IT administration of 
HGT-1410, ie a lack of injection-associated safety issues occurring between 4 and 8 hours after 
administration. 
The protocol has also been amended to include a description of a new intrathecal drug delivery 
device, the SOPH A PORT® Mini S, Implantable Access Port, Spinal, Mini Unattached, with 
Guidewire. In light of the higher than expected complications experienced with the previous 
IDDD the SOPH-A-PORT Mini S device will be introduced for those patients requiring 
replacement or revision.  This new device has design features anticipated to reduce 
complications encountered with the PORT-A-CATH IDDD device.  Specific device assessments 
are included in the protocol to collect information with respect to information specific to SOPH-
A-PORT Mini S device safety and function.  
Changes in grammar, spelling, punctuation, format, minor editorial changes (including changes 
for consistency and clarity), and updates to the list of abbreviations and cross-references are not 
reflected in the change summary.
Previous Amendment:  Amendment 3; 28 August 2012
DETAILED SUMMARY OF CHANGES FOR THE AMENDMENT 
This is a section that has been updated to describe the changes from the previous protocol 
version.  Significant changes and additions to the protocol text are captured below.  Bold text 
indicates new text.  Strikethrough text indicates deleted text.
Change:  Dose of the 10 mg Q4W group increased to 45 mg Q4W
Section impacted by this change: Section 6.4
Patients will initially receive the same dose of HGT-1410 they received in Study 
HGT-SAN-055.  Patients assigned to Group 1 (10 mg once per month [Q4W]) will have 
their dose increased to 45 mg once per month (Q4W) at the first administration of 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
84
HGT-1410 following full approval of the protocol amendment.
Other sections impacted by this change: Synopsis; Sections 1.3; 4.1;and 6.2
Change: The number of hours a patient is monitored in the clinic after each administration of 
HGT-1410 is reduced from 8 hours to xx 
Section impacted by this change: Section 4.1;
Enrolled patients will check in to the study center 1 day before each of the scheduled HGT-1410 
dosing days for safety assessments (designated Day 1).  If no safety concerns exist, the patient 
will subsequently receive IT administration of HGT-1410 on Day 2 (±2 days).  However, if 
feasible and there are no safety concerns in the opinion of the investigator, the Day 1 and Day 2 
assessments may be combined and performed on Day 2; if this is done the results will be
recorded as Day 2.  Patients will remain in the study centre for at least 4 hours following dosing 
with HGT-1410 and will be discharged from the unit when deemed clinically stable by the 
Investigator.
Other sections impacted by this change:  Synopsis; Sections 6.3; 6.3.2; and 8.2; Appendix 1
Schedule of Events
Change: Introduction of the SOPH-A-PORT to replace the PORT-A-CATH for those patients 
requiring a replacement or revision. 
Section impacted by this change: Section 1.1
In light of the higher than expected complications experienced with the PORT-A-CATH 
IDDD, due primarily to device design features, the SOPH-A-PORT Mini S device will be 
introduced for those patients requiring replacement or revision.  This new device was 
designed with the intention of minimizing the complications encountered with the 
PORT-A-CATH IDDD device.  Provisions are made in the protocol to collect information 
with respect to information specific to SOPH-A-PORT Mini S device safety and function. 
Other sections impacted by this change:  Sections 1.3; 4.2; 6.1.2; and 6.9.2
Change: Three categories of adverse events associated with the device are defined.
Section impacted by this change: 
7.23.1.3 IDDD-related Adverse Events
IDDD ADVERSE EVENTS
Examples of AEs related to use of the IDDD include, but are not limited to, the following: 
device failure, device malfunction, incorrect connection of IDDD components, erosion of 
the portal/catheter through the skin, fibrin sheath formation around the catheter tip, 
hematoma, implant rejection, migration of the portal/catheter, occlusion of the
portal/catheter, portal site or subcutaneous tract infection. The device may also need to be 
replaced or repaired as needed. A list of the more common IDDD AEs is included in 
Appendix 4.
DEVICE SURGICAL PROCEDURE-RELATED ADVERSE EVENTS
Examples of AEs related to surgical procedures include, but are not limited to, the 
following: IDDD implant/explant, IDDD adjustment, full revision, partial revision, IDDD 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
85
removal, and delayed re-implantation after previous IDDD removal.
IT ADMINISTRATION PROCESS ADVERSE EVENTS 
In studies that include administration of investigational drug with an IDDD, potential AEs 
that are caused by anesthesia during drug administration, drug administration issues (eg, 
extravasation during infusion or hematoma due to Huber needle), etc.
Other sections impacted by this change:  None
Change: Severity grading of device-associated adverse events specified
Section impacted by this change: Section7.23.3
The severity of all AEs/SAEs should be recorded on the appropriate eCRF page. Adverse events 
are to be graded as Grade 1, 2, or 3.  All other AEs are graded as Grade 1, 2, 3, 4, or 5 
corresponding, respectively, to a severity of mild, moderate, severe, life-threatening, or death.
Other sections impacted by this change: None
Change: Device revisions and malfunctions defined
Section impacted by this change: Section 7.23.2
7.23.2 Device-Associated Definitions
7.23.2.1 Device Revisions (Partial and Full)
Partial device revision: surgical revision/replacement of one or more component(s) of the 
device; other component(s) of the original device remain implanted and are not affected 
(eg, port revision)
Full device revision: the device is removed (explanted) in its entirety and a completely new 
device is implanted.
7.23.2.2  Device Malfunction
The device does not perform as intended, based on the description in the device’s IFU, but 
does not require either a partial or full device revision.
7.23.2.3  Device Failure
The device irreversibly fails to perform as intended and requires either a partial or full 
device revision or removal.
Other sections impacted by this change: None

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
86
Change: Clarification that AEs may be considered related to the IDDD in addition to the study 
drug
Section impacted by this change: Section 7.23.5.2
The onset date, resolution date, treatment administered, and outcome of each AE must be 
recorded on the appropriate eCRF.  The relationship of each AE to study medication must 
be recorded. In addition AEs may be considered to be related to the IDDD, the IDDD 
surgical procedure or the IT administration process.  As many of these IDDD-related 
options as apply will be indicated on the eCRF.
Other sections impacted by this change:  None
Change: Standard Abuse, Overdose and Medication Error
Section impacted by this change: Section 7.24
7.24  Abuse, Overdose and Medication Error

Abuse – Persistent or sporadic intentional intake of investigational medicinal product at a 
dose higher than prescribed per protocol (but below the dose defined for overdose) or when 
used for non-medical purpose (eg, altering one’s state of consciousness)

Misuse – Intentional or unintentional use of investigational medicinal product other than as 
directed or indicated at any dose, which is at or below the dose defined for overdose (Note: 
This includes a situation where the test article is not used as directed at the dose prescribed 
by the protocol)

Overdose – Overdosage with adverse clinical consequences is not anticipated with the use of 
HGT-1410. Additionally, HGT-1410 will be given in a clinical setting by a health care 
provider. 

Medication Error – A mistake made in prescribing, dispensing, administration and/or use of 
the investigational medicinal product.
Other sections impacted by this change: None
Change: Clarifications were made within the statistical analysis section. Section 10.1 clarified 
exploratory hypotheses, Section 10.3 clarified that SOPH-A-PORT device-related analyses 
would be conducted in the subset of patients in the primary analysis population who had the 
SOPH-A-PORT Mini S implant procedure performed, and Section 10.6.1.1. detailed 
analyses for IDDD-related AEs.
Section impacted by this change: Sections 10.1, 10.3 and 10.6.1.1

Other sections impacted by this change: None
Change: Modifications to the Statistical Methodology Section, particularly the analysis of 
device-related AEs
Section impacted by this change: Section 10.6.2.1
10.6.2.1  IDDD Performance

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
87
IDDD safety and performance will be summarized for patients implanted with the SOPH-
A-PORT Mini S. Difficulties associated with the implant procedure (e.g. excessive bleeding, 
CSF leakage, etc.) will be summarized.  A summary of abnormal findings from the IDDD 
radiological assessments will also be presented.  
The proportion of patients with at least one IDDD failure and/or malfunction, as well as the 
number of and reasons for IDDD failures/malfunctions and actions taken will be 
summarized.  The rate of IDDD failures/malfunctions and 95% confidence interval will 
also be estimated.  The time from initial implant surgery to first IDDD failure and/or 
malfunction will be summarized.  Patients without an IDDD failure/malfunction will be 
censored at their last study drug injection date.  A by-patient listing of the device 
failure/malfunction data will be displayed.
The proportion of patients for whom a successful first injection of study drug occurred will 
be reported among those for whom a first injection was attempted (i.e. those who had an 
apparently successful implantation and did not suffer a device removal or revision prior to 
first scheduled injection).  The proportion of patients who had no failed injection attempts 
during the study will also be summarized. The corresponding 95% confidence intervals of 
the proportion of interest will be estimated, where appropriate. Injections not given for 
patient reasons (e.g. patient uncooperative, competing medical issue, etc) will not be 
included in the determination of these success proportions.  The frequency and reasons for 
unsuccessful injection attempts will be reported.
Other sections impacted by this change:  Sections 10.3; and 10.6.1.1
Change: Clarification that an x-ray of the device was to be performed at the EOS visit. This had 
been included in Section 7.13.2 but not other appropriate sections.
Section impacted by this change: Section 4.1
All patients will have an EOS visit 30 (±7) days following their last administration of HGT-1410 
(ie, Month 55).  The EOS procedures will include standard clinical laboratory tests (serum 
chemistry, hematology, and urinalysis) in CSF and blood, protocol specific laboratory testing 
(eg, anti-rhHNS antibody testing), neurodevelopmental testing, ABR, child health 
questionnaires, MRI and X-ray examination of the device.  
Other sections impacted by this change:  Synopsis, Section 8.3, Appendix 1 Schedule of Events
Change: Implementation of a Device Failure Adjudication Process
Section impacted by this change: Section 11.8
11.8   Device Failure Adjudication Process
The final cause for device failures will be adjudicated by a Shire team by examining the 
clinical database, safety database, and manufacturer investigation of returned devices.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
88
Other sections impacted by this change:  None  
Change: Addition of a list of expected adverse device effects
Section impacted by this change: Appendix 3
All Appendix 3 is new.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410) 
Clinical Trial Protocol: HGT -SAN-067 Amendment 4 
3 May 2013 
Appendix 5 
Protocol Signature Page 
Study Title: 
An Open-Label Extension of Study HGT-SAN-055 Evaluating 
Long-Term Safety and Clinical Outcomes of Intrathecal 
Administration of rhHNS in Patients with Sanfilippo Syndrome 
Type A (MPS IlIA) 
Study Number: 
HGT-SAN-067 Amendment 4 
Final Date: 
21 June 2010 
Amendment 1 Date: 
22 January 2011 
Amendment 2 Date: 
13 January 2012 
Amendment 3 Date: 
28 August 2012 
Amendment 4 Date: 
3 May 2013 
I have read the protocol described above. I agree to comply with all applicable regulations 
and to conduct the study as described in the protocol. 
Signatory: 
Investigator 
Signature 
Printed Name 
I have read and approve the protocol described above. 
Signatory: 
ShireHGT 
Medical 
Monitor 
Shire 
Signa
 MD 
Printed Name 
Confidential 
Date 
Date 
89

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 4
3 May 2013
Shire
Confidential
90
Appendix 6
The National Cancer Institute Common Terminology Criteria 
version 3.0

Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, Version 3.0, DCTD, NCI, NIH, DHHS 
 
March 31, 2003 (http://ctep.cancer.gov), Publish Date: August 9, 2006 
Common Terminology Criteria for Adverse Events v3.0 (CTCAE) 
Publish Date: August 9, 2006 
Quick Reference 
The NCI Common Terminology Criteria for Adverse Events 
v3.0 is a descriptive terminology which can be utilized for 
Adverse Event (AE) reporting. A grading (severity) scale is 
provided for each AE term. 
Components and Organization  
CATEGORY 
A CATEGORY is a broad classification of AEs based on 
anatomy and/or pathophysiology. Within each CATEGORY, 
AEs are listed accompanied by their descriptions of severity 
(Grade). 
Adverse Event Terms 
An AE is any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medical treatment or procedure 
that may or may not be considered related to the medical 
treatment or procedure. An AE is a term that is a unique 
representation of a specific event used for medical 
documentation and scientific analyses. Each AE term is 
mapped to a MedDRA term and code. AEs are listed 
alphabetically within CATEGORIES. 
Short AE Name 
The ‘SHORT NAME’ column is new and it is used to simplify 
documentation of AE names on Case Report Forms.   
Supra-ordinate Terms  
A supra-ordinate term is located within a CATEGORY and is a 
grouping term based on disease process, signs, symptoms, 
or diagnosis. A supra-ordinate term is followed by the word 
‘Select’ and is accompanied by specific AEs that are all 
related to the supra-ordinate term. Supra-ordinate terms 
provide clustering and consistent representation of Grade for 
related AEs. Supra-ordinate terms are not AEs, are not 
mapped to a MedDRA term and code, cannot be graded and 
cannot be used for reporting. 
REMARK 
A ‘REMARK’ is a clarification of an AE. 
ALSO CONSIDER 
An ‘ALSO CONSIDER’ indicates additional AEs that are to be 
graded if they are clinically significant. 
NAVIGATION NOTE 
A ‘NAVIGATION NOTE’ indicates the location of an AE term 
within the CTCAE document. It lists signs/symptoms 
alphabetically and the CTCAE term will appear in the same 
CATEGORY unless the ‘NAVIGATION NOTE’ states differently. 
Grades 
Grade refers to the severity of the AE. The CTCAE v3.0 
displays Grades 1 through 5 with unique clinical descriptions 
of severity for each AE based on this general guideline: 
Grade 1 
Mild AE  
Grade 2 
Moderate AE 
Grade 3 
Severe AE 
Grade 4 
Life-threatening or disabling AE 
Grade 5 
Death related to AE 
A Semi-colon indicates ‘or’ within the description of the grade. 
An ‘Em dash’ (—) indicates a grade not available. 
Not all Grades are appropriate for all AEs. Therefore, some 
AEs are listed with fewer than five options for Grade 
selection. 
Grade 5 
Grade 5 (Death) is not appropriate for some AEs and 
therefore is not an option. 
The DEATH CATEGORY is new. Only one Supra-ordinate 
term is listed in this CATEGORY: ‘Death not associated with 
CTCAE term – Select’ with 4 AE options: Death NOS; 
Disease progression NOS; Multi-organ failure; Sudden death. 
Important: 
• 
Grade 5 is the only appropriate Grade 
• 
This AE is to be used in the situation where 
a death  
1. cannot be reported using a CTCAE v3.0 
term associated with Grade 5, or 
2. cannot be reported within a CTCAE 
CATEGORY as ‘Other (Specify)’ 
 
 
 
 
 
Contents 
ALLERGY/IMMUNOLOGY ............................................1 
AUDITORY/EAR............................................................2 
BLOOD/BONE MARROW .............................................4 
CARDIAC ARRHYTHMIA..............................................5 
CARDIAC GENERAL ....................................................7 
COAGULATION ..........................................................10 
CONSTITUTIONAL SYMPTOMS................................11 
DEATH ........................................................................13 
DERMATOLOGY/SKIN ...............................................14 
ENDOCRINE...............................................................17 
GASTROINTESTINAL.................................................19 
GROWTH AND DEVELOPMENT................................29 
HEMORRHAGE/BLEEDING ....................................... 30 
HEPATOBILIARY/PANCREAS ................................... 34 
INFECTION................................................................. 35 
LYMPHATICS ............................................................. 38 
METABOLIC/LABORATORY ...................................... 40 
MUSCULOSKELETAL/SOFT TISSUE........................ 43 
NEUROLOGY ............................................................. 47 
OCULAR/VISUAL........................................................ 52 
PAIN............................................................................ 55 
PULMONARY/UPPER RESPIRATORY...................... 56 
RENAL/GENITOURINARY.......................................... 60 
SECONDARY MALIGNANCY..................................... 63 
SEXUAL/REPRODUCTIVE FUNCTION ..................... 64 
SURGERY/INTRA-OPERATIVE INJURY ................... 66 
SYNDROMES............................................................. 68 
VASCULAR................................................................. 70 
 

 
ALLERGY/IMMUNOLOGY 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 1 - 
March 31, 2003, Publish Date: August 9, 2006 
Allergic reaction/ 
hypersensitivity  
(including drug fever) 
Allergic reaction 
Transient flushing or 
rash; drug fever <38°C 
(<100.4°F) 
Rash; flushing; urticaria; 
dyspnea; drug fever 
≥38°C (≥100.4°F) 
Symptomatic 
bronchospasm, with or 
without urticaria; 
parenteral medication(s) 
indicated; allergy-related 
edema/angioedema; 
hypotension 
Anaphylaxis 
Death 
REMARK: Urticaria with manifestations of allergic or hypersensitivity reaction is graded as Allergic reaction/hypersensitivity (including drug fever). 
ALSO CONSIDER: Cytokine release syndrome/acute infusion reaction. 
Allergic rhinitis  
(including sneezing, 
nasal stuffiness, 
postnasal drip) 
Rhinitis 
Mild, intervention not 
indicated  
Moderate, intervention 
indicated 
— 
— 
— 
REMARK: Rhinitis associated with obstruction or stenosis is graded as Obstruction/stenosis of airway – Select in the PULMONARY/UPPER RESPIRATORY CATEGORY. 
Autoimmune reaction 
Autoimmune reaction 
Asymptomatic and 
serologic or other 
evidence of autoimmune 
reaction, with normal 
organ function and 
intervention not indicated 
Evidence of autoimmune 
reaction involving a non-
essential organ or 
function (e.g., 
hypothyroidism) 
Reversible autoimmune 
reaction involving function 
of a major organ or other 
adverse event (e.g., 
transient colitis or 
anemia)  
Autoimmune reaction with 
life-threatening 
consequences 
Death 
ALSO CONSIDER: Colitis; Hemoglobin; Hemolysis (e.g., immune hemolytic anemia, drug-related hemolysis); Thyroid function, low (hypothyroidism). 
Serum sickness 
Serum sickness 
— 
— 
Present 
— 
Death 
NAVIGATION NOTE: Splenic function is graded in the BLOOD/BONE MARROW CATEGORY. 
NAVIGATION NOTE: Urticaria as an isolated symptom is graded as Urticaria (hives, welts, wheals) in the DERMATOLOGY/SKIN CATEGORY. 
Vasculitis 
Vasculitis 
Mild, intervention not 
indicated 
Symptomatic, non-
steroidal medical 
intervention indicated 
Steroids indicated 
Ischemic changes; 
amputation indicated 
Death 
Allergy/Immunology – 
Other (Specify, __) 
Allergy – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
AUDITORY/EAR 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 2 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Earache (otalgia) is graded as Pain – Select in the PAIN CATEGORY. 
Hearing:  
patients with/without 
baseline audiogram and 
enrolled in a monitoring 
program1 
Hearing (monitoring 
program) 
Threshold shift or loss of 
15 – 25 dB relative to 
baseline, averaged at 2 
or more contiguous test 
frequencies in at least 
one ear; or subjective 
change in the absence of 
a Grade 1 threshold shift 
Threshold shift or loss of 
>25 – 90 dB, averaged at 
2 contiguous test 
frequencies in at least 
one ear 
Adult only: Threshold shift 
of >25 – 90 dB, averaged 
at 3 contiguous test 
frequencies in at least 
one ear  
Pediatric:  
Hearing loss sufficient to 
indicate therapeutic 
intervention, including 
hearing aids (e.g., ≥20 dB 
bilateral HL in the speech 
frequencies; ≥30 dB 
unilateral HL; and 
requiring additional 
speech-language related 
services) 
Adult only: Profound 
bilateral hearing loss 
(>90 dB) 
Pediatric:  
Audiologic indication for 
cochlear implant and 
requiring additional 
speech-language related 
services  
— 
REMARK: Pediatric recommendations are identical to those for adults, unless specified. For children and adolescents (≤18 years of age) without a baseline test, pre-exposure/pre-
treatment hearing should be considered to be <5 dB loss. 
Hearing: 
patients without baseline 
audiogram and not 
enrolled in a monitoring 
program1  
Hearing (without 
monitoring program) 
— 
Hearing loss not requiring 
hearing aid or 
intervention (i.e., not 
interfering with ADL) 
Hearing loss requiring 
hearing aid or 
intervention (i.e., 
interfering with ADL) 
Profound bilateral hearing 
loss (>90 dB) 
— 
REMARK: Pediatric recommendations are identical to those for adults, unless specified. For children and adolescents (≤18 years of age) without a baseline test, pre-exposure/pre-
treatment hearing should be considered to be <5 dB loss. 
Otitis, external ear 
(non-infectious) 
Otitis, external  
External otitis with 
erythema or dry 
desquamation  
External otitis with moist 
desquamation, edema, 
enhanced cerumen or 
discharge; tympanic 
membrane perforation; 
tympanostomy 
External otitis with 
mastoiditis; stenosis or 
osteomyelitis 
Necrosis of soft tissue or 
bone 
Death 
ALSO CONSIDER: Hearing: patients with/without baseline audiogram and enrolled in a monitoring program1; Hearing: patients without baseline audiogram and not enrolled in a 
monitoring program1.  
Otitis, middle ear  
(non-infectious) 
Otitis, middle 
Serous otitis  
Serous otitis, medical 
intervention indicated 
Otitis with discharge; 
mastoiditis  
Necrosis of the canal soft 
tissue or bone 
Death 

 
AUDITORY/EAR 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 3 - 
March 31, 2003, Publish Date: August 9, 2006 
Tinnitus 
Tinnitus 
— 
Tinnitus not interfering 
with ADL 
Tinnitus interfering with 
ADL 
Disabling 
— 
ALSO CONSIDER: Hearing: patients with/without baseline audiogram and enrolled in a monitoring program1; Hearing: patients without baseline audiogram and not enrolled in a 
monitoring program1. 
Auditory/Ear – Other 
(Specify, __) 
Auditory/Ear – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
 
 
 
 
 
 
                                            
1 Drug-induced ototoxicity should be distinguished from age-related threshold decrements or unrelated cochlear insult. When considering whether an adverse event has occurred, it is 
first necessary to classify the patient into one of two groups. (1) The patient is under standard treatment/enrolled in a clinical trial <2.5 years, and has a 15 dB or greater threshold 
shift averaged across two contiguous frequencies; or (2) The patient is under standard treatment/enrolled in a clinical trial >2.5 years, and the difference between the expected age-
related and the observed threshold shifts is 15 dB or greater averaged across two contiguous frequencies. Consult standard references for appropriate age- and gender-specific 
hearing norms, e.g., Morrell, et al. Age- and gender-specific reference ranges for hearing level and longitudinal changes in hearing level. Journal of the Acoustical Society of America 
100:1949-1967, 1996; or Shotland, et al. Recommendations for cancer prevention trials using potentially ototoxic test agents. Journal of Clinical Oncology 19:1658-1663, 2001.  
In the absence of a baseline prior to initial treatment, subsequent audiograms should be referenced to an appropriate database of normals. ANSI. (1996) 
American National Standard: Determination of occupational noise exposure and estimation of noise-induced hearing impairment, ANSI S 3.44-1996. (Standard S 3.44). New York: 
American National Standards Institute. The recommended ANSI S3.44 database is Annex B. 

 
BLOOD/BONE MARROW 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 4 - 
March 31, 2003, Publish Date: August 9, 2006 
Bone marrow cellularity 
Bone marrow cellularity 
Mildly hypocellular or  
≤25% reduction from 
normal cellularity for age 
Moderately hypocellular 
or >25 – ≤50% reduction 
from normal cellularity for 
age  
Severely hypocellular or 
>50 – ≤75% reduction 
cellularity from normal for 
age  
— 
Death 
CD4 count  
CD4 count 
<LLN – 500/mm3 
<LLN – 0.5 x 109 /L 
<500 – 200/mm3  
<0.5 – 0.2 x 109 /L 
<200 – 50/mm3  
<0.2 x 0.05 – 109 /L 
<50/mm3  
<0.05 x 109 /L 
Death 
Haptoglobin  
Haptoglobin 
<LLN  
— 
Absent 
— 
Death 
Hemoglobin  
Hemoglobin 
<LLN – 10.0 g/dL  
<LLN – 6.2 mmol/L  
<LLN – 100 g/L 
<10.0 – 8.0 g/dL 
<6.2 – 4.9 mmol/L  
<100 – 80g/L 
<8.0 – 6.5 g/dL 
<4.9 – 4.0 mmol/L 
<80 – 65 g/L 
<6.5 g/dL 
<4.0 mmol/L  
<65 g/L 
Death 
Hemolysis (e.g., immune 
hemolytic anemia, drug-
related hemolysis) 
Hemolysis 
Laboratory evidence of 
hemolysis only (e.g., 
direct antiglobulin test 
[DAT, Coombs’] 
schistocytes) 
Evidence of red cell 
destruction and ≥2 gm 
decrease in hemoglobin, 
no transfusion 
Transfusion or medical 
intervention (e.g., 
steroids) indicated 
Catastrophic 
consequences of 
hemolysis (e.g., renal 
failure, hypotension, 
bronchospasm, 
emergency splenectomy) 
Death 
ALSO CONSIDER: Haptoglobin; Hemoglobin. 
Iron overload 
Iron overload 
— 
Asymptomatic iron 
overload, intervention not 
indicated  
Iron overload, 
intervention indicated  
Organ impairment (e.g., 
endocrinopathy, 
cardiopathy) 
Death 
Leukocytes (total WBC) 
Leukocytes 
<LLN – 3000/mm3 
<LLN – 3.0 x 109 /L  
<3000 – 2000/mm3 
<3.0 – 2.0 x 109 /L 
<2000 – 1000/mm3 
<2.0 – 1.0 x 109 /L 
<1000/mm3  
<1.0 x 109 /L 
Death 
Lymphopenia  
Lymphopenia 
<LLN – 800/mm3 
<LLN x 0.8 – 109 /L 
<800 – 500/mm3 
<0.8 – 0.5 x 109 /L 
<500 – 200 mm3 
<0.5 – 0.2 x 109 /L 
<200/mm3 
<0.2 x 109 /L 
Death 
Myelodysplasia 
Myelodysplasia 
— 
— 
Abnormal marrow 
cytogenetics (marrow 
blasts ≤5%)  
RAEB or RAEB-T 
(marrow blasts >5%) 
Death 
Neutrophils/granulocytes 
(ANC/AGC) 
Neutrophils 
<LLN – 1500/mm3  
<LLN – 1.5 x 109 /L 
<1500 – 1000/mm3 
<1.5 – 1.0 x 109 /L  
<1000 – 500/mm3 
<1.0 – 0.5 x 109 /L 
<500/mm3 
<0.5 x 109 /L 
Death 
Platelets 
Platelets 
<LLN – 75,000/mm3 
<LLN – 75.0 x 109 /L 
<75,000 – 50,000/mm3 
<75.0 – 50.0 x 109 /L 
<50,000 – 25,000/mm3  
<50.0 – 25.0 x 109 /L 
<25,000/mm3  
<25.0 x 109 /L 
Death 
Splenic function 
Splenic function 
Incidental findings (e.g., 
Howell-Jolly bodies) 
Prophylactic antibiotics 
indicated 
—  
Life-threatening 
consequences 
Death 
Blood/Bone Marrow – 
Other (Specify, __) 
Blood – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
CARDIAC ARRHYTHMIA 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 5 - 
March 31, 2003, Publish Date: August 9, 2006 
Conduction abnormality/ 
atrioventricular heart 
block  
– Select:  
Conduction abnormality 
– Select 
Asymptomatic, 
intervention not indicated 
– Asystole 
– AV Block-First degree 
– AV Block-Second degree Mobitz Type I (Wenckebach)  
– AV Block-Second degree Mobitz Type II 
– AV Block-Third degree (Complete AV block) 
– Conduction abnormality NOS 
– Sick Sinus Syndrome  
– Stokes-Adams Syndrome 
– Wolff-Parkinson-White Syndrome 
Non-urgent medical 
intervention indicated 
Incompletely controlled 
medically or controlled  
with device (e.g., 
pacemaker) 
Life-threatening (e.g., 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
Death 
Palpitations 
Palpitations 
Present 
Present with associated 
symptoms (e.g., 
lightheadedness, 
shortness of breath) 
— 
— 
— 
REMARK: Grade palpitations only in the absence of a documented arrhythmia. 
Prolonged QTc interval 
Prolonged QTc 
QTc >0.45 – 0.47 second 
 QTc >0.47 – 0.50 
second; ≥0.06 second 
above baseline 
QTc >0.50 second 
QTc >0.50 second; life-
threatening signs or 
symptoms (e.g., 
arrhythmia, CHF, 
hypotension, shock 
syncope); Torsade de 
pointes 
Death 
Supraventricular and 
nodal arrhythmia  
– Select: 
Supraventricular 
arrhythmia – Select 
Asymptomatic, 
intervention not indicated 
Non-urgent medical 
intervention indicated 
– Atrial fibrillation 
– Atrial flutter  
– Atrial tachycardia/Paroxysmal Atrial Tachycardia 
– Nodal/Junctional 
– Sinus arrhythmia  
– Sinus bradycardia 
– Sinus tachycardia  
– Supraventricular arrhythmia NOS 
– Supraventricular extrasystoles (Premature Atrial Contractions; Premature Nodal/Junctional Contractions) 
– Supraventricular tachycardia 
Symptomatic and 
incompletely controlled 
medically, or controlled 
with device (e.g., 
pacemaker) 
Life-threatening (e.g., 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
Death 
NAVIGATION NOTE: Syncope is graded as Syncope (fainting) in the NEUROLOGY CATEGORY. 

 
CARDIAC ARRHYTHMIA 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 6 - 
March 31, 2003, Publish Date: August 9, 2006 
Vasovagal episode 
Vasovagal episode 
— 
Present without loss of 
consciousness 
Present with loss of 
consciousness 
Life-threatening 
consequences  
Death 
Ventricular arrhythmia 
– Select: 
Ventricular arrhythmia 
– Select 
– Bigeminy 
– Idioventricular rhythm 
– PVCs 
– Torsade de pointes 
– Trigeminy 
– Ventricular arrhythmia NOS 
– Ventricular fibrillation  
– Ventricular flutter 
– Ventricular tachycardia 
Asymptomatic, no 
intervention indicated 
Non-urgent medical 
intervention indicated 
Symptomatic and 
incompletely controlled 
medically or controlled 
with device (e.g., 
defibrillator) 
Life-threatening (e.g., 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
Death 
Cardiac Arrhythmia  
– Other (Specify, __) 
Cardiac Arrhythmia – 
Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling  
Death 

 
CARDIAC GENERAL 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 7 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Angina is graded as Cardiac ischemia/infarction in the CARDIAC GENERAL CATEGORY. 
Cardiac 
ischemia/infarction 
Cardiac 
ischemia/infarction 
Asymptomatic arterial 
narrowing without 
ischemia 
Asymptomatic and testing 
suggesting ischemia; 
stable angina  
Symptomatic and testing 
consistent with ischemia; 
unstable angina; 
intervention indicated 
Acute myocardial 
infarction 
Death 
Cardiac troponin I (cTnI) 
cTnI 
— 
— 
Levels consistent with 
unstable angina as 
defined by the 
manufacturer 
Levels consistent with 
myocardial infarction as 
defined by the 
manufacturer 
Death 
Cardiac troponin T (cTnT) 
cTnT 
0.03 – <0.05 ng/mL 
0.05 – <0.1 ng/mL 
0.1 – <0.2 ng/mL 
0.2 ng/mL 
Death 
Cardiopulmonary arrest, 
cause unknown 
(non-fatal) 
Cardiopulmonary arrest 
— 
— 
— 
Life-threatening  
— 
REMARK: Grade 4 (non-fatal) is the only appropriate grade. CTCAE provides three alternatives for reporting Death: 
1. A CTCAE term associated with Grade 5.  
2. A CTCAE 'Other (Specify, __)’ within any CATEGORY. 
3. Death not associated with CTCAE term – Select in the DEATH CATEGORY. 
NAVIGATION NOTE: Chest pain (non-cardiac and non-pleuritic) is graded as Pain – Select in the PAIN CATEGORY. 
NAVIGATION NOTE: CNS ischemia is graded as CNS cerebrovascular ischemia in the NEUROLOGY CATEGORY. 
Hypertension 
Hypertension 
Asymptomatic, transient 
(<24 hrs) increase by >20 
mmHg (diastolic) or to 
>150/100 if previously 
WNL; intervention not 
indicated  
Pediatric: 
Asymptomatic, transient 
(<24 hrs) BP increase 
>ULN; intervention not 
indicated 
Recurrent or persistent 
(≥24 hrs) or symptomatic 
increase by >20 mmHg 
(diastolic) or to >150/100 
if previously WNL; 
monotherapy may be 
indicated  
Pediatric: 
Recurrent or persistent 
(≥24 hrs) BP >ULN; 
monotherapy may be 
indicated 
Requiring more than one 
drug or more intensive 
therapy than previously 
Pediatric: 
Same as adult 
Life-threatening 
consequences (e.g., 
hypertensive crisis) 
Pediatric: 
Same as adult 
Death 
REMARK: Use age and gender-appropriate normal values >95th percentile ULN for pediatric patients. 

 
CARDIAC GENERAL 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 8 - 
March 31, 2003, Publish Date: August 9, 2006 
Hypotension 
Hypotension 
Changes, intervention not 
indicated 
Brief (<24 hrs) fluid 
replacement or other 
therapy; no physiologic 
consequences 
Sustained (≥24 hrs) 
therapy, resolves without 
persisting physiologic 
consequences 
Shock (e.g., acidemia; 
impairment of vital organ 
function)  
Death 
ALSO CONSIDER: Syncope (fainting). 
Left ventricular diastolic 
dysfunction 
Left ventricular diastolic 
dysfunction 
Asymptomatic diagnostic 
finding; intervention not 
indicated 
Asymptomatic, 
intervention indicated 
Symptomatic CHF 
responsive to intervention 
Refractory CHF, poorly 
controlled; intervention 
such as ventricular assist 
device or heart transplant 
indicated  
Death 
Left ventricular systolic 
dysfunction 
Left ventricular systolic 
dysfunction 
Asymptomatic, resting 
ejection fraction (EF)  
<60 – 50%; shortening 
fraction (SF) <30 – 24% 
Asymptomatic, resting  
EF <50 – 40%; 
SF <24 – 15% 
Symptomatic CHF 
responsive to 
intervention; 
EF <40 – 20% 
SF <15% 
Refractory CHF or poorly 
controlled; EF <20%; 
intervention such as 
ventricular assist device, 
ventricular reduction 
surgery, or heart 
transplant indicated 
Death 
NAVIGATION NOTE: Myocardial infarction is graded as Cardiac ischemia/infarction in the CARDIAC GENERAL CATEGORY. 
Myocarditis 
Myocarditis 
— 
— 
CHF responsive to 
intervention 
Severe or refractory CHF 
Death 
Pericardial effusion 
(non-malignant) 
Pericardial effusion 
Asymptomatic effusion  
—  
Effusion with physiologic 
consequences 
Life-threatening 
consequences (e.g., 
tamponade); emergency 
intervention indicated 
Death 
Pericarditis 
Pericarditis 
Asymptomatic, ECG or 
physical exam (rub) 
changes consistent with 
pericarditis 
Symptomatic pericarditis 
(e.g., chest pain) 
Pericarditis with 
physiologic 
consequences (e.g., 
pericardial constriction) 
Life-threatening 
consequences; 
emergency intervention 
indicated 
Death 
NAVIGATION NOTE: Pleuritic pain is graded as Pain – Select in the PAIN CATEGORY. 
Pulmonary hypertension 
Pulmonary hypertension 
Asymptomatic without 
therapy 
Asymptomatic, therapy 
indicated 
Symptomatic 
hypertension, responsive 
to therapy 
Symptomatic 
hypertension, poorly 
controlled 
Death 
Restrictive 
cardiomyopathy  
Restrictive 
cardiomyopathy  
Asymptomatic, therapy 
not indicated 
Asymptomatic, therapy 
indicated 
Symptomatic CHF 
responsive to intervention 
Refractory CHF, poorly 
controlled; intervention 
such as ventricular assist 
device, or heart 
transplant indicated  
Death 

 
CARDIAC GENERAL 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 9 - 
March 31, 2003, Publish Date: August 9, 2006 
Right ventricular 
dysfunction 
(cor pulmonale) 
Right ventricular 
dysfunction 
Asymptomatic without 
therapy 
Asymptomatic, therapy 
indicated 
Symptomatic cor 
pulmonale, responsive to 
intervention 
Symptomatic cor 
pulmonale poorly 
controlled; intervention 
such as ventricular assist 
device, or heart 
transplant indicated  
Death 
Valvular heart disease 
Valvular heart disease 
Asymptomatic valvular 
thickening with or without 
mild valvular regurgitation 
or stenosis; treatment 
other than endocarditis 
prophylaxis not indicated 
Asymptomatic; moderate 
regurgitation or stenosis 
by imaging 
Symptomatic; severe 
regurgitation or stenosis; 
symptoms controlled with 
medical therapy 
Life-threatening; 
disabling; intervention 
(e.g., valve replacement, 
valvuloplasty) indicated 
Death 
Cardiac General – Other 
(Specify, __) 
Cardiac General – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
COAGULATION 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 10 - 
March 31, 2003, Publish Date: August 9, 2006 
DIC (disseminated 
intravascular coagulation) 
DIC 
— 
Laboratory findings with 
no bleeding 
Laboratory findings and 
bleeding 
Laboratory findings, life-
threatening or disabling 
consequences (e.g., CNS 
hemorrhage, organ 
damage, or 
hemodynamically 
significant blood loss) 
Death 
REMARK: DIC (disseminated intravascular coagulation) must have increased fibrin split products or D-dimer.  
ALSO CONSIDER: Platelets. 
 
Fibrinogen  
Fibrinogen 
<1.0 – 0.75 x LLN 
or <25% decrease from 
baseline 
<0.75 – 0.5 x LLN 
or 25 – <50% decrease 
from baseline 
<0.5 – 0.25 x LLN 
or 50 – <75% decrease 
from baseline 
<0.25 x LLN  
or 75% decrease from 
baseline or absolute 
value <50 mg/dL  
Death 
REMARK: Use % decrease only when baseline is <LLN (local laboratory value). 
INR (International 
Normalized Ratio of 
prothrombin time) 
INR 
 
>1 – 1.5 x ULN 
>1.5 – 2 x ULN 
>2 x ULN 
— 
— 
ALSO CONSIDER: Hemorrhage, CNS; Hemorrhage, GI – Select; Hemorrhage, GU – Select; Hemorrhage, pulmonary/upper respiratory – Select. 
PTT (Partial 
Thromboplastin Time)  
PTT 
>1 – 1.5 x ULN 
>1.5 – 2 x ULN 
>2 x ULN 
— 
— 
ALSO CONSIDER: Hemorrhage, CNS; Hemorrhage, GI – Select; Hemorrhage, GU – Select; Hemorrhage, pulmonary/upper respiratory – Select. 
Thrombotic 
microangiopathy (e.g., 
thrombotic 
thrombocytopenic 
purpura [TTP] or 
hemolytic uremic 
syndrome [HUS]) 
Thrombotic 
microangiopathy 
Evidence of RBC 
destruction 
(schistocytosis) without 
clinical consequences 
— 
Laboratory findings 
present with clinical 
consequences (e.g., renal 
insufficiency, petechiae) 
Laboratory findings and 
life-threatening or 
disabling consequences, 
(e.g., CNS hemorrhage/ 
bleeding or thrombosis/ 
embolism or renal failure) 
Death 
REMARK: Must have microangiopathic changes on blood smear (e.g., schistocytes, helmet cells, red cell fragments). 
ALSO CONSIDER: Creatinine; Hemoglobin; Platelets. 
Coagulation – Other 
(Specify, __) 
Coagulation – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
CONSTITUTIONAL SYMPTOMS 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 11 - 
March 31, 2003, Publish Date: August 9, 2006 
Fatigue  
(asthenia, lethargy, 
malaise) 
Fatigue 
Mild fatigue over baseline 
Moderate or causing 
difficulty performing some 
ADL 
Severe fatigue interfering 
with ADL 
Disabling 
— 
Fever  
(in the absence of 
neutropenia, where 
neutropenia is defined as 
ANC <1.0 x 109/L) 
Fever 
38.0 – 39.0°C  
(100.4 – 102.2°F) 
>39.0 – 40.0°C 
(102.3 – 104.0°F)  
>40.0°C 
(>104.0°F) for ≤24 hrs  
>40.0°C 
(>104.0°F) for >24 hrs 
Death 
REMARK: The temperature measurements listed are oral or tympanic. 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever).  
NAVIGATION NOTE: Hot flashes are graded as Hot flashes/flushes in the ENDOCRINE CATEGORY. 
Hypothermia 
Hypothermia 
— 
35 – >32°C 
95 – >89.6°F 
32 – >28°C  
89.6 – >82.4° F 
≤28 °C  
82.4°F or life-threatening 
consequences (e.g., 
coma, hypotension, 
pulmonary edema, 
acidemia, ventricular 
fibrillation) 
Death 
Insomnia 
Insomnia 
Occasional difficulty 
sleeping, not interfering 
with function 
Difficulty sleeping, 
interfering with function 
but not interfering with 
ADL 
Frequent difficulty 
sleeping, interfering with 
ADL 
Disabling 
— 
REMARK: If pain or other symptoms interfere with sleep, do NOT grade as insomnia. Grade primary event(s) causing insomnia. 
Obesity2 
Obesity 
— 
BMI 25 – 29.9 kg/m2 
BMI 30 – 39.99 kg/m2 
BMI ≥40 kg/m2 
— 
REMARK: BMI = (weight [kg]) / (height [m])2 
Odor  
(patient odor) 
Patient odor 
Mild odor 
Pronounced odor 
— 
— 
— 
Rigors/chills 
Rigors/chills 
Mild 
Moderate, narcotics 
indicated 
Severe or prolonged, not 
responsive to narcotics 
— 
— 
                                            
2 NHLBI Obesity Task Force. "Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults," The Evidence Report, Obes Res 6:51S-
209S, 1998.  

 
CONSTITUTIONAL SYMPTOMS 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 12 - 
March 31, 2003, Publish Date: August 9, 2006 
Sweating  
(diaphoresis) 
Sweating  
Mild and occasional 
Frequent or drenching 
— 
— 
— 
ALSO CONSIDER: Hot flashes/flushes.  
Weight gain  
Weight gain 
5 – <10% of baseline 
10 – <20% of baseline 
≥20% of baseline 
— 
— 
REMARK: Edema, depending on etiology, is graded in the CARDIAC GENERAL or LYMPHATICS CATEGORIES. 
ALSO CONSIDER: Ascites (non-malignant); Pleural effusion (non-malignant). 
Weight loss 
Weight loss 
5 to <10% from baseline; 
intervention not indicated 
10 – <20% from baseline; 
nutritional support 
indicated 
≥20% from baseline; tube 
feeding or TPN indicated 
— 
— 
Constitutional Symptoms 
– Other (Specify, __) 
Constitutional Symptoms 
– Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
DEATH 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 13 - 
March 31, 2003, Publish Date: August 9, 2006 
Death not associated with 
CTCAE term  
– Select: 
Death not associated with 
CTCAE term – Select 
– Death NOS 
– Disease progression NOS 
– Multi-organ failure 
– Sudden death 
— 
— 
— 
— 
Death 
REMARK: Grade 5 is the only appropriate grade. 'Death not associated with CTCAE term – Select' is to be used where a death: 
1. Cannot be attributed to a CTCAE term associated with Grade 5. 
2. Cannot be reported within any CATEGORY using a CTCAE 'Other (Specify, __)’.  

 
DERMATOLOGY/SKIN 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 14 - 
March 31, 2003, Publish Date: August 9, 2006 
Atrophy, skin 
Atrophy, skin 
Detectable 
Marked 
— 
— 
— 
Atrophy, subcutaneous 
fat 
Atrophy, subcutaneous 
fat 
Detectable 
Marked 
— 
— 
— 
ALSO CONSIDER: Induration/fibrosis (skin and subcutaneous tissue). 
Bruising  
(in absence of Grade 3 or 
4 thrombocytopenia) 
Bruising  
Localized or in a 
dependent area 
Generalized 
— 
— 
— 
Burn 
Burn 
Minimal symptoms; 
intervention not indicated  
Medical intervention; 
minimal debridement 
indicated  
Moderate to major 
debridement or 
reconstruction indicated  
Life-threatening 
consequences 
Death 
REMARK: Burn refers to all burns including radiation, chemical, etc. 
Cheilitis 
Cheilitis 
Asymptomatic 
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
— 
— 
Dry skin 
Dry skin 
Asymptomatic 
Symptomatic, not 
interfering with ADL 
Interfering with ADL 
— 
— 
Flushing 
Flushing 
Asymptomatic 
Symptomatic 
— 
— 
— 
Hair loss/alopecia 
(scalp or body) 
Alopecia 
Thinning or patchy 
Complete 
— 
— 
— 
Hyperpigmentation 
Hyperpigmentation 
Slight or localized 
Marked or generalized 
— 
— 
— 
Hypopigmentation 
Hypopigmentation 
Slight or localized 
Marked or generalized 
— 
— 
— 
Induration/fibrosis 
(skin and subcutaneous 
tissue) 
Induration  
Increased density on 
palpation 
Moderate impairment of 
function not interfering 
with ADL; marked 
increase in density and 
firmness on palpation 
with or without minimal 
retraction 
Dysfunction interfering 
with ADL; very marked 
density, retraction or 
fixation 
— 
— 
ALSO CONSIDER: Fibrosis-cosmesis; Fibrosis-deep connective tissue.  
Injection site reaction/ 
extravasation changes 
Injection site reaction 
Pain; itching; erythema 
Pain or swelling, with 
inflammation or phlebitis 
Ulceration or necrosis 
that is severe; operative 
intervention indicated  
— 
— 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever); Ulceration. 

 
DERMATOLOGY/SKIN 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 15 - 
March 31, 2003, Publish Date: August 9, 2006 
Nail changes 
Nail changes 
Discoloration; ridging 
(koilonychias); pitting 
Partial or complete loss of 
nail(s); pain in nailbed(s) 
Interfering with ADL  
— 
— 
NAVIGATION NOTE: Petechiae is graded as Petechiae/purpura (hemorrhage/bleeding into skin or mucosa) in the HEMORRHAGE/BLEEDING CATEGORY. 
Photosensitivity 
Photosensitivity 
Painless erythema 
Painful erythema 
Erythema with 
desquamation 
Life-threatening; disabling 
Death 
Pruritus/itching 
Pruritus 
Mild or localized 
Intense or widespread 
Intense or widespread 
and interfering with ADL  
— 
— 
ALSO CONSIDER: Rash/desquamation. 
Rash/desquamation  
Rash 
Macular or papular 
eruption or erythema 
without associated 
symptoms 
Macular or papular 
eruption or erythema with 
pruritus or other 
associated symptoms; 
localized desquamation 
or other lesions covering 
<50% of body surface 
area (BSA) 
Severe, generalized 
erythroderma or macular, 
papular or vesicular 
eruption; desquamation 
covering ≥50% BSA 
Generalized exfoliative, 
ulcerative, or bullous 
dermatitis 
Death 
REMARK: Rash/desquamation may be used for GVHD. 
Rash:  
acne/acneiform 
Acne 
Intervention not indicated  
Intervention indicated 
Associated with pain, 
disfigurement, ulceration, 
or desquamation 
— 
Death 
Rash:  
dermatitis associated with 
radiation  
– Select: 
– Chemoradiation 
– Radiation 
Dermatitis – Select  
Faint erythema or dry 
desquamation 
Moderate to brisk 
erythema; patchy moist 
desquamation, mostly 
confined to skin folds and 
creases; moderate 
edema 
Moist desquamation other 
than skin folds and 
creases; bleeding 
induced by minor trauma 
or abrasion 
Skin necrosis or 
ulceration of full thickness 
dermis; spontaneous 
bleeding from involved 
site  
Death 
Rash:  
erythema multiforme 
(e.g., Stevens-Johnson 
syndrome, toxic 
epidermal necrolysis) 
Erythema multiforme 
— 
Scattered, but not 
generalized eruption 
Severe (e.g., generalized 
rash or painful stomatitis); 
IV fluids, tube feedings, 
or TPN indicated 
Life-threatening; disabling 
Death 
Rash:  
hand-foot skin reaction 
Hand-foot 
Minimal skin changes or 
dermatitis (e.g., 
erythema) without pain  
Skin changes (e.g., 
peeling, blisters, 
bleeding, edema) or pain, 
not interfering with 
function  
Ulcerative dermatitis or 
skin changes with pain 
interfering with function  
— 
— 

 
DERMATOLOGY/SKIN 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 16 - 
March 31, 2003, Publish Date: August 9, 2006 
Skin breakdown/ 
decubitus ulcer 
Decubitus  
— 
Local wound care; 
medical intervention 
indicated 
Operative debridement or 
other invasive 
intervention indicated 
(e.g., hyperbaric oxygen)  
Life-threatening 
consequences; major 
invasive intervention 
indicated (e.g., tissue 
reconstruction, flap, or 
grafting) 
Death 
REMARK: Skin breakdown/decubitus ulcer is to be used for loss of skin integrity or decubitus ulcer from pressure or as the result of operative or medical intervention. 
Striae 
Striae 
Mild 
Cosmetically significant 
— 
— 
— 
Telangiectasia 
Telangiectasia 
Few 
Moderate number 
Many and confluent 
— 
— 
Ulceration 
Ulceration 
— 
Superficial ulceration  
<2 cm size; local wound 
care; medical intervention 
indicated 
Ulceration ≥2 cm size; 
operative debridement, 
primary closure or other 
invasive intervention 
indicated (e.g., hyperbaric 
oxygen)  
Life-threatening 
consequences; major 
invasive intervention 
indicated (e.g., complete 
resection, tissue 
reconstruction, flap, or 
grafting) 
Death 
Urticaria  
(hives, welts, wheals) 
Urticaria 
Intervention not indicated 
Intervention indicated for 
<24 hrs 
Intervention indicated for 
≥24 hrs 
— 
— 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever). 
Wound complication, 
non-infectious  
Wound complication, 
non-infectious 
Incisional separation of  
≤25% of wound, no 
deeper than superficial 
fascia 
Incisional separation 
>25% of wound with local 
care; asymptomatic 
hernia 
Symptomatic hernia 
without evidence of 
strangulation; fascial 
disruption/dehiscence 
without evisceration; 
primary wound closure or 
revision by operative 
intervention indicated; 
hospitalization or 
hyperbaric oxygen 
indicated 
Symptomatic hernia with 
evidence of strangulation; 
fascial disruption with 
evisceration; major 
reconstruction flap, 
grafting, resection, or 
amputation indicated 
Death 
REMARK: Wound complication, non-infectious is to be used for separation of incision, hernia, dehiscence, evisceration, or second surgery for wound revision. 
Dermatology/Skin – Other 
(Specify, __) 
Dermatology – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
ENDOCRINE 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 17 - 
March 31, 2003, Publish Date: August 9, 2006 
Adrenal insufficiency 
Adrenal insufficiency 
Asymptomatic, 
intervention not indicated 
Symptomatic, intervention 
indicated 
Hospitalization  
Life-threatening; disabling 
Death 
REMARK: Adrenal insufficiency includes any of the following signs and symptoms: abdominal pain, anorexia, constipation, diarrhea, hypotension, pigmentation of mucous membranes, 
pigmentation of skin, salt craving, syncope (fainting), vitiligo, vomiting, weakness, weight loss. Adrenal insufficiency must be confirmed by laboratory studies (low cortisol frequently 
accompanied by low aldosterone). 
ALSO CONSIDER: Potassium, serum-high (hyperkalemia); Thyroid function, low (hypothyroidism). 
Cushingoid appearance 
(e.g., moon face, buffalo 
hump, centripetal obesity, 
cutaneous striae) 
Cushingoid  
— 
Present 
— 
— 
— 
ALSO CONSIDER: Glucose, serum-high (hyperglycemia); Potassium, serum-low (hypokalemia). 
Feminization of male 
Feminization of male 
— 
— 
Present 
— 
— 
NAVIGATION NOTE: Gynecomastia is graded in the SEXUAL/REPRODUCTIVE FUNCTION CATEGORY. 
Hot flashes/flushes3 
Hot flashes 
Mild  
Moderate  
Interfering with ADL 
— 
— 
Masculinization of female 
Masculinization of female 
— 
— 
Present 
— 
— 
Neuroendocrine: 
ACTH deficiency 
ACTH  
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL; hospitalization 
indicated 
Life-threatening 
consequences (e.g., 
severe hypotension) 
Death 
Neuroendocrine: 
ADH secretion 
abnormality (e.g., SIADH 
or low ADH) 
ADH 
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL 
Life-threatening 
consequences 
Death 
Neuroendocrine: 
gonadotropin secretion 
abnormality 
Gonadotropin 
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL; osteopenia; 
fracture; infertility 
— 
— 
Neuroendocrine:  
growth hormone 
secretion abnormality 
Growth hormone  
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
— 
— 
— 
Neuroendocrine:  
prolactin hormone 
secretion abnormality 
Prolactin  
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL; amenorrhea; 
galactorrhea 
— 
Death 
                                            
3 Sloan JA, Loprinzi CL, Novotny PJ, Barton DL, Lavasseur BI, Windschitl HJ, "Methodologic Lessons Learned from Hot Flash Studies," J Clin Oncol 2001 Dec 1;19(23):4280-90 

 
ENDOCRINE 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 18 - 
March 31, 2003, Publish Date: August 9, 2006 
Pancreatic endocrine:  
glucose intolerance 
Diabetes 
Asymptomatic, 
intervention not indicated 
Symptomatic; dietary 
modification or oral agent 
indicated 
Symptoms interfering with 
ADL; insulin indicated 
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar non-ketotic 
coma)  
Death 
Parathyroid function, low 
(hypoparathyroidism) 
Hypoparathyroidism 
Asymptomatic, 
intervention not indicated 
Symptomatic; intervention 
indicated 
— 
— 
— 
Thyroid function, high 
(hyperthyroidism, 
thyrotoxicosis) 
Hyperthyroidism  
Asymptomatic, 
intervention not indicated 
Symptomatic, not 
interfering with ADL; 
thyroid suppression 
therapy indicated 
Symptoms interfering with 
ADL; hospitalization 
indicated  
Life-threatening 
consequences (e.g., 
thyroid storm) 
Death 
Thyroid function, low 
(hypothyroidism) 
Hypothyroidism 
Asymptomatic, 
intervention not indicated 
Symptomatic, not 
interfering with ADL; 
thyroid replacement 
indicated 
Symptoms interfering with 
ADL; hospitalization 
indicated  
Life-threatening 
myxedema coma 
Death 
Endocrine – Other  
(Specify, __) 
Endocrine – Other  
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
GASTROINTESTINAL 
Page 1 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 19 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Abdominal pain or cramping is graded as Pain – Select in the PAIN CATEGORY. 
Anorexia 
Anorexia 
Loss of appetite without 
alteration in eating habits 
Oral intake altered 
without significant weight 
loss or malnutrition; oral 
nutritional supplements 
indicated 
Associated with 
significant weight loss or 
malnutrition (e.g., 
inadequate oral caloric 
and/or fluid intake); IV 
fluids, tube feedings or 
TPN indicated 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Weight loss. 
Ascites (non-malignant) 
Ascites 
Asymptomatic 
Symptomatic, medical 
intervention indicated 
Symptomatic, invasive 
procedure indicated 
Life-threatening 
consequences 
Death 
REMARK: Ascites (non-malignant) refers to documented non-malignant ascites or unknown etiology, but unlikely malignant, and includes chylous ascites. 
Colitis 
Colitis 
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain; mucus 
or blood in stool 
Abdominal pain, fever, 
change in bowel habits 
with ileus; peritoneal 
signs 
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis, toxic 
megacolon) 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select.  
Constipation 
Constipation 
Occasional or intermittent 
symptoms; occasional 
use of stool softeners, 
laxatives, dietary 
modification, or enema 
Persistent symptoms with 
regular use of laxatives 
or enemas indicated 
Symptoms interfering 
with ADL; obstipation 
with manual evacuation 
indicated  
Life-threatening 
consequences (e.g., 
obstruction, toxic 
megacolon) 
Death 
ALSO CONSIDER: Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation); Obstruction, GI – Select. 
Dehydration 
Dehydration 
Increased oral fluids 
indicated; dry mucous 
membranes; diminished 
skin turgor 
IV fluids indicated <24 
hrs 
IV fluids indicated ≥24 hrs 
Life-threatening 
consequences (e.g., 
hemodynamic collapse) 
Death 
ALSO CONSIDER: Diarrhea; Hypotension; Vomiting. 
Dental:  
dentures or prosthesis 
Dentures  
Minimal discomfort, no 
restriction in activities  
Discomfort preventing 
use in some activities 
(e.g., eating), but not 
others (e.g., speaking) 
Unable to use dentures 
or prosthesis at any time 
— 
— 

 
GASTROINTESTINAL 
Page 2 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 20 - 
March 31, 2003, Publish Date: August 9, 2006 
Dental:  
periodontal disease  
Periodontal  
Gingival recession or 
gingivitis; limited bleeding 
on probing; mild local 
bone loss 
Moderate gingival 
recession or gingivitis; 
multiple sites of bleeding 
on probing; moderate 
bone loss 
Spontaneous bleeding; 
severe bone loss with or 
without tooth loss; 
osteonecrosis of maxilla 
or mandible  
— 
— 
REMARK: Severe periodontal disease leading to osteonecrosis is graded as Osteonecrosis (avascular necrosis) in the MUSCULOSKELETAL CATEGORY. 
Dental: 
teeth  
Teeth 
Surface stains; dental 
caries; restorable, without 
extractions 
Less than full mouth 
extractions; tooth fracture 
or crown amputation or 
repair indicated 
Full mouth extractions 
indicated 
— 
— 
Dental:  
teeth development 
Teeth development 
Hypoplasia of tooth or 
enamel not interfering 
with function 
Functional impairment 
correctable with oral 
surgery 
Maldevelopment with 
functional impairment not 
surgically correctable 
— 
— 
Diarrhea 
Diarrhea 
Increase of <4 stools per 
day over baseline; mild 
increase in ostomy output 
compared to baseline 
Increase of 4 – 6 stools 
per day over baseline; IV 
fluids indicated <24hrs; 
moderate increase in 
ostomy output compared 
to baseline; not 
interfering with ADL 
Increase of ≥7 stools per 
day over baseline; 
incontinence; IV fluids 
≥24 hrs; hospitalization; 
severe increase in 
ostomy output compared 
to baseline; interfering 
with ADL 
Life-threatening 
consequences (e.g., 
hemodynamic collapse) 
Death 
REMARK: Diarrhea includes diarrhea of small bowel or colonic origin, and/or ostomy diarrhea. 
ALSO CONSIDER: Dehydration; Hypotension. 
Distension/bloating, 
abdominal 
Distension 
Asymptomatic  
Symptomatic, but not 
interfering with GI 
function 
Symptomatic, interfering 
with GI function 
— 
— 
ALSO CONSIDER: Ascites (non-malignant); Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation); Obstruction, GI – Select.  

 
GASTROINTESTINAL 
Page 3 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 21 - 
March 31, 2003, Publish Date: August 9, 2006 
Dry mouth/salivary gland 
(xerostomia) 
Dry mouth 
Symptomatic (dry or thick 
saliva) without significant 
dietary alteration; 
unstimulated saliva flow 
>0.2 ml/min 
Symptomatic and 
significant oral intake 
alteration (e.g., copious 
water, other lubricants, 
diet limited to purees 
and/or soft, moist foods); 
unstimulated saliva 
0.1 to 0.2 ml/min 
Symptoms leading to 
inability to adequately 
aliment orally; IV fluids, 
tube feedings, or TPN 
indicated; unstimulated 
saliva <0.1 ml/min 
— 
— 
REMARK: Dry mouth/salivary gland (xerostomia) includes descriptions of grade using both subjective and objective assessment parameters. Record this event consistently throughout 
a patient’s participation on study. If salivary flow measurements are used for initial assessment, subsequent assessments must use salivary flow. 
ALSO CONSIDER: Salivary gland changes/saliva.  
Dysphagia 
(difficulty swallowing) 
Dysphagia 
Symptomatic, able to eat 
regular diet  
Symptomatic and altered 
eating/swallowing (e.g., 
altered dietary habits, 
oral supplements); IV 
fluids indicated <24 hrs 
Symptomatic and 
severely altered 
eating/swallowing (e.g., 
inadequate oral caloric or 
fluid intake); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences (e.g., 
obstruction, perforation) 
 
Death 
REMARK: Dysphagia (difficulty swallowing) is to be used for swallowing difficulty from oral, pharyngeal, esophageal, or neurologic origin. Dysphagia requiring dilation is graded as 
Stricture/stenosis (including anastomotic), GI – Select. 
ALSO CONSIDER: Dehydration; Esophagitis. 
Enteritis  
(inflammation of the small 
bowel) 
Enteritis 
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain; mucus 
or blood in stool 
Abdominal pain, fever, 
change in bowel habits 
with ileus; peritoneal 
signs 
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis) 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select; Typhlitis (cecal inflammation).  
Esophagitis 
Esophagitis 
Asymptomatic pathologic, 
radiographic, or 
endoscopic findings only 
Symptomatic; altered 
eating/swallowing (e.g., 
altered dietary habits, 
oral supplements); IV 
fluids indicated <24 hrs 
Symptomatic and 
severely altered 
eating/swallowing (e.g., 
inadequate oral caloric or 
fluid intake); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences 
Death 
REMARK: Esophagitis includes reflux esophagitis.  
ALSO CONSIDER: Dysphagia (difficulty swallowing). 

 
GASTROINTESTINAL 
Page 4 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 22 - 
March 31, 2003, Publish Date: August 9, 2006 
Fistula, GI 
– Select: 
Fistula, GI – Select  
– Abdomen NOS 
– Anus 
– Biliary tree  
– Colon/cecum/appendix 
– Duodenum 
– Esophagus 
– Gallbladder  
– Ileum 
– Jejunum 
– Oral cavity 
– Pancreas 
– Pharynx 
– Rectum 
– Salivary gland  
– Small bowel NOS 
– Stomach 
Asymptomatic, 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, diarrhea, 
or GI fluid loss); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered GI 
function (e.g., altered 
dietary habits, diarrhea, 
or GI fluid loss); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences  
Death 
REMARK: A fistula is defined as an abnormal communication between two body cavities, potential spaces, and/or the skin. The site indicated for a fistula should be the site from which 
the abnormal process is believed to have originated. For example, a tracheo-esophageal fistula arising in the context of a resected or irradiated esophageal cancer is graded as 
Fistula, GI – esophagus. 
Flatulence 
Flatulence 
Mild 
Moderate 
— 
— 
— 
Gastritis (including bile 
reflux gastritis) 
Gastritis 
Asymptomatic 
radiographic or 
endoscopic findings only 
Symptomatic; altered 
gastric function (e.g., 
inadequate oral caloric or 
fluid intake); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered gastric 
function (e.g., inadequate 
oral caloric or fluid 
intake); IV fluids, tube 
feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., gastrectomy)  
Death 
ALSO CONSIDER: Hemorrhage, GI – Select; Ulcer, GI – Select. 
NAVIGATION NOTE: Head and neck soft tissue necrosis is graded as Soft tissue necrosis – Select in the MUSCULOSKELETAL/SOFT TISSUE CATEGORY. 
Heartburn/dyspepsia 
Heartburn 
Mild 
Moderate 
Severe 
— 
— 
Hemorrhoids 
Hemorrhoids 
Asymptomatic 
Symptomatic; banding or 
medical intervention 
indicated 
Interfering with ADL; 
interventional radiology, 
endoscopic, or operative 
intervention indicated 
Life-threatening 
consequences 
Death 

 
GASTROINTESTINAL 
Page 5 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 23 - 
March 31, 2003, Publish Date: August 9, 2006 
Ileus, GI (functional 
obstruction of bowel, i.e., 
neuroconstipation) 
Ileus 
Asymptomatic, 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered GI 
function; IV fluids, tube 
feeding, or TPN indicated 
≥24 hrs 
Life-threatening 
consequences 
Death 
REMARK: Ileus, GI is to be used for altered upper or lower GI function (e.g., delayed gastric or colonic emptying). 
ALSO CONSIDER: Constipation; Nausea; Obstruction, GI – Select; Vomiting. 
Incontinence, anal 
Incontinence, anal 
Occasional use of pads 
required 
Daily use of pads 
required 
Interfering with ADL; 
operative intervention 
indicated 
Permanent bowel 
diversion indicated 
Death 
REMARK: Incontinence, anal is to be used for loss of sphincter control as sequelae of operative or therapeutic intervention. 
Leak (including 
anastomotic), GI 
– Select: 
– Biliary tree 
– Esophagus 
– Large bowel 
– Leak NOS 
– Pancreas 
– Pharynx 
– Rectum 
– Small bowel  
– Stoma 
– Stomach 
Leak, GI – Select  
Asymptomatic 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and 
interfering with GI 
function; invasive or 
endoscopic intervention 
indicated  
Life-threatening 
consequences 
Death 
REMARK: Leak (including anasomotic), GI – Select is to be used for clinical signs/symptoms or radiographic confirmation of anastomotic or conduit leak (e.g., biliary, esophageal, 
intestinal, pancreatic, pharyngeal, rectal), but without development of fistula. 
Malabsorption  
Malabsorption 
— 
Altered diet; oral 
therapies indicated (e.g., 
enzymes, medications, 
dietary supplements)  
Inability to aliment 
adequately via GI tract 
(i.e., TPN indicated) 
Life-threatening 
consequences 
Death 

 
GASTROINTESTINAL 
Page 6 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 24 - 
March 31, 2003, Publish Date: August 9, 2006 
Mucositis/stomatitis 
(clinical exam)  
– Select: 
– Anus 
– Esophagus 
– Large bowel 
– Larynx 
– Oral cavity 
– Pharynx 
– Rectum 
– Small bowel 
– Stomach 
– Trachea 
Mucositis (clinical exam) 
– Select  
Erythema of the mucosa 
Patchy ulcerations or 
pseudomembranes  
Confluent ulcerations or 
pseudomembranes; 
bleeding with minor 
trauma 
Tissue necrosis; 
significant spontaneous 
bleeding; life-threatening 
consequences 
Death 
REMARK: Mucositis/stomatitis (functional/symptomatic) may be used for mucositis of the upper aero-digestive tract caused by radiation, agents, or GVHD.  
Mucositis/stomatitis 
(functional/symptomatic)  
– Select: 
– Anus 
– Esophagus 
– Large bowel 
– Larynx 
– Oral cavity 
– Pharynx 
– Rectum 
– Small bowel 
– Stomach 
– Trachea 
Mucositis (functional/ 
symptomatic) – Select  
Upper aerodigestive tract 
sites: Minimal symptoms, 
normal diet; minimal 
respiratory symptoms but 
not interfering with 
function 
Lower GI sites: 
Minimal discomfort, 
intervention not indicated 
Upper aerodigestive tract 
sites: Symptomatic but 
can eat and swallow 
modified diet; respiratory 
symptoms interfering with 
function but not 
interfering with ADL 
Lower GI sites:  
Symptomatic, medical 
intervention indicated but 
not interfering with ADL 
Upper aerodigestive tract 
sites: Symptomatic and 
unable to adequately 
aliment or hydrate orally; 
respiratory symptoms 
interfering with ADL 
Lower GI sites: 
Stool incontinence or 
other symptoms 
interfering with ADL 
Symptoms associated 
with life-threatening 
consequences  
Death 
Nausea 
Nausea 
Loss of appetite without 
alteration in eating habits 
Oral intake decreased 
without significant weight 
loss, dehydration or 
malnutrition; IV fluids 
indicated <24 hrs 
Inadequate oral caloric or 
fluid intake; IV fluids, tube 
feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Anorexia; Vomiting. 

 
GASTROINTESTINAL 
Page 7 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 25 - 
March 31, 2003, Publish Date: August 9, 2006 
Necrosis, GI 
– Select:  
Necrosis, GI – Select  
– Anus 
– Colon/cecum/appendix 
– Duodenum 
– Esophagus 
– Gallbladder 
– Hepatic 
– Ileum 
– Jejunum 
– Oral 
– Pancreas 
– Peritoneal cavity 
– Pharynx  
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
— 
— 
Inability to aliment 
adequately by GI tract 
(e.g., requiring enteral or 
parenteral nutrition); 
interventional radiology, 
endoscopic, or operative 
intervention indicated  
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., total colectomy)  
Death 
ALSO CONSIDER: Visceral arterial ischemia (non-myocardial). 
Obstruction, GI 
– Select: 
– Cecum 
– Colon 
– Duodenum 
– Esophagus 
– Gallbladder 
– Ileum 
– Jejunum 
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
Obstruction, GI – Select 
Asymptomatic 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, vomiting, 
diarrhea, or GI fluid loss); 
IV fluids indicated <24 
hrs 
Symptomatic and 
severely altered GI 
function (e.g., altered 
dietary habits, vomiting, 
diarrhea, or GI fluid loss); 
IV fluids, tube feedings, 
or TPN indicated ≥24 hrs; 
operative intervention 
indicated 
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., total colectomy)  
Death 
NAVIGATION NOTE: Operative injury is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY CATEGORY. 
NAVIGATION NOTE: Pelvic pain is graded as Pain – Select in the PAIN CATEGORY. 

 
GASTROINTESTINAL 
Page 8 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 26 - 
March 31, 2003, Publish Date: August 9, 2006 
Perforation, GI 
– Select: 
– Appendix 
– Biliary tree 
– Cecum 
– Colon 
– Duodenum 
– Esophagus 
– Gallbladder 
– Ileum 
– Jejunum 
– Rectum 
– Small bowel NOS 
– Stomach 
Perforation, GI – Select 
Asymptomatic 
radiographic findings only 
Medical intervention 
indicated; IV fluids 
indicated <24 hrs 
IV fluids, tube feedings, 
or TPN indicated ≥24 hrs; 
operative intervention 
indicated 
Life-threatening 
consequences 
Death 
Proctitis  
Proctitis 
Rectal discomfort, 
intervention not indicated 
Symptoms not interfering 
with ADL; medical 
intervention indicated  
Stool incontinence or 
other symptoms 
interfering with ADL; 
operative intervention 
indicated 
Life-threatening 
consequences (e.g., 
perforation) 
Death 
Prolapse of stoma, GI 
Prolapse of stoma, GI 
Asymptomatic  
Extraordinary local care 
or maintenance; minor 
revision indicated 
Dysfunctional stoma; 
major revision indicated  
Life-threatening 
consequences 
Death 
REMARK: Other stoma complications may be graded as Fistula, GI – Select; Leak (including anastomotic), GI – Select; Obstruction, GI – Select; Perforation, GI – Select; 
Stricture/stenosis (including anastomotic), GI – Select. 
NAVIGATION NOTE: Rectal or perirectal pain (proctalgia) is graded as Pain – Select in the PAIN CATEGORY.  
Salivary gland 
changes/saliva 
Salivary gland changes 
Slightly thickened saliva; 
slightly altered taste (e.g., 
metallic) 
Thick, ropy, sticky saliva; 
markedly altered taste; 
alteration in diet 
indicated; secretion-
induced symptoms not 
interfering with ADL 
Acute salivary gland 
necrosis; severe 
secretion-induced 
symptoms interfering with 
ADL  
Disabling 
— 
ALSO CONSIDER: Dry mouth/salivary gland (xerostomia); Mucositis/stomatitis (clinical exam) – Select; Mucositis/stomatitis (functional/symptomatic) – Select; Taste alteration 
(dysgeusia). 
NAVIGATION NOTE: Splenic function is graded in the BLOOD/BONE MARROW CATEGORY. 

 
GASTROINTESTINAL 
Page 9 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 27 - 
March 31, 2003, Publish Date: August 9, 2006 
Stricture/stenosis 
(including anastomotic), 
GI 
– Select:  
Stricture, GI – Select  
– Anus 
– Biliary tree 
– Cecum 
– Colon  
– Duodenum  
– Esophagus 
– Ileum 
– Jejunum 
– Pancreas/pancreatic duct 
– Pharynx 
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
Asymptomatic 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, vomiting, 
bleeding, diarrhea); IV 
fluids indicated <24 hrs 
Symptomatic and 
severely altered GI 
function (e.g., altered 
dietary habits, diarrhea, 
or GI fluid loss); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs; 
operative intervention 
indicated 
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., total colectomy)  
Death 
Taste alteration 
(dysgeusia) 
Taste alteration 
Altered taste but no 
change in diet 
Altered taste with change 
in diet (e.g., oral 
supplements); noxious or 
unpleasant taste; loss of 
taste 
— 
— 
— 
Typhlitis 
(cecal inflammation) 
Typhlitis 
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain; mucus 
or blood in stool 
Abdominal pain, fever, 
change in bowel habits 
with ileus; peritoneal 
signs 
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis); 
operative intervention 
indicated 
Death 
ALSO CONSIDER: Colitis; Hemorrhage, GI – Select ; Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation).  

 
GASTROINTESTINAL 
Page 10 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 28 - 
March 31, 2003, Publish Date: August 9, 2006 
Ulcer, GI 
– Select: 
– Anus 
– Cecum 
– Colon 
– Duodenum 
– Esophagus 
– Ileum 
– Jejunum 
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
Ulcer, GI – Select 
Asymptomatic, 
radiographic or 
endoscopic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, oral 
supplements); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered GI 
function (e.g., inadequate 
oral caloric or fluid 
intake); IV fluids, tube 
feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select. 
Vomiting 
Vomiting 
1 episode in 24 hrs 
2 – 5 episodes in 24 hrs; 
IV fluids indicated  
<24 hrs 
≥6 episodes in 24 hrs; IV 
fluids, or TPN indicated 
≥24 hrs 
Life-threatening 
consequences  
Death 
ALSO CONSIDER: Dehydration. 
Gastrointestinal – Other 
(Specify, __) 
GI – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling 
Death 

 
GROWTH AND DEVELOPMENT 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 29 - 
March 31, 2003, Publish Date: August 9, 2006 
Bone age 
(alteration in bone age) 
Bone age 
— 
+2 SD (standard 
deviation) from normal 
— 
— 
— 
Bone growth: 
femoral head; slipped 
capital femoral epiphysis 
Femoral head growth 
Mild valgus/varus 
deformity 
Moderate valgus/varus 
deformity, symptomatic, 
interfering with function 
but not interfering with 
ADL 
Mild slipped capital 
femoral epiphysis; 
operative intervention 
(e.g., fixation) indicated; 
interfering with ADL 
Disabling; severe slipped 
capital femoral epiphysis 
>60%; avascular necrosis 
— 
Bone growth: 
limb length discrepancy 
Limb length  
Mild length discrepancy 
<2 cm 
Moderate length 
discrepancy 2 – 5 cm; 
shoe lift indicated 
Severe length 
discrepancy >5 cm; 
operative intervention 
indicated; interfering with 
ADL 
Disabling; epiphysiodesis 
— 
Bone growth: 
spine kyphosis/lordosis 
Kyphosis/lordosis 
Mild radiographic 
changes  
Moderate accentuation; 
interfering with function 
but not interfering with 
ADL 
Severe accentuation; 
operative intervention 
indicated; interfering with 
ADL 
Disabling (e.g., cannot lift 
head) 
— 
Growth velocity 
(reduction in growth 
velocity) 
Reduction in growth 
velocity 
10 – 29% reduction in 
growth from the baseline 
growth curve 
30 – 49% reduction in 
growth from the baseline 
growth curve 
≥50% reduction in growth 
from the baseline growth 
curve  
— 
— 
Puberty (delayed) 
Delayed puberty 
— 
No breast development 
by age 13 yrs for females; 
no Tanner Stage 2 
development by age 14.5 
yrs for males 
No sexual development 
by age 14 yrs for girls, 
age 16 yrs for boys; 
hormone replacement 
indicated 
— 
— 
REMARK: Do not use testicular size for Tanner Stage in male cancer survivors. 
Puberty (precocious)  
Precocious puberty 
— 
Physical signs of puberty 
<7 years for females,  
<9 years for males 
— 
— 
— 
Short stature 
Short stature 
Beyond two standard 
deviations of age and 
gender mean height 
Altered ADL 
— 
— 
— 
REMARK: Short stature is secondary to growth hormone deficiency. 
ALSO CONSIDER: Neuroendocrine: growth hormone secretion abnormality. 
Growth and Development 
– Other (Specify, __) 
Growth and Development 
– Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
HEMORRHAGE/BLEEDING 
Page 1 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 30 - 
March 31, 2003, Publish Date: August 9, 2006 
Hematoma  
Hematoma 
Minimal symptoms, 
invasive intervention not 
indicated  
Minimally invasive 
evacuation or aspiration 
indicated 
Transfusion, 
interventional radiology, 
or operative intervention 
indicated 
Life-threatening 
consequences; major 
urgent intervention 
indicated 
Death 
REMARK: Hematoma refers to extravasation at wound or operative site or secondary to other intervention. Transfusion implies pRBC.  
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Hemorrhage/bleeding 
associated with surgery, 
intra-operative or 
postoperative 
Hemorrhage with surgery 
— 
— 
Requiring transfusion of  
2 units non-autologous 
(10 cc/kg for pediatrics) 
pRBCs beyond protocol 
specification; 
postoperative 
interventional radiology, 
endoscopic, or operative 
intervention indicated 
Life-threatening 
consequences  
Death 
REMARK: Postoperative period is defined as ≤72 hours after surgery. Verify protocol-specific acceptable guidelines regarding pRBC transfusion. 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Hemorrhage, CNS 
CNS hemorrhage 
Asymptomatic, 
radiographic findings only 
Medical intervention 
indicated  
Ventriculostomy, ICP 
monitoring, 
intraventricular 
thrombolysis, or operative 
intervention indicated 
Life-threatening 
consequences; 
neurologic deficit or 
disability 
Death 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 

 
HEMORRHAGE/BLEEDING 
Page 2 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 31 - 
March 31, 2003, Publish Date: August 9, 2006 
Hemorrhage, GI  
– Select: 
– Abdomen NOS 
– Anus 
– Biliary tree  
– Cecum/appendix  
– Colon 
– Duodenum 
– Esophagus 
– Ileum 
– Jejunum 
– Liver 
– Lower GI NOS 
– Oral cavity 
– Pancreas 
– Peritoneal cavity 
– Rectum 
– Stoma 
– Stomach 
– Upper GI NOS 
– Varices (esophageal) 
– Varices (rectal) 
Hemorrhage, GI – Select 
Mild, intervention (other 
than iron supplements) 
not indicated 
Symptomatic and medical 
intervention or minor 
cauterization indicated 
Transfusion, 
interventional radiology, 
endoscopic, or operative 
intervention indicated; 
radiation therapy (i.e., 
hemostasis of bleeding 
site) 
Life-threatening 
consequences; major 
urgent intervention 
indicated  
Death 
REMARK: Transfusion implies pRBC. 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 

 
HEMORRHAGE/BLEEDING 
Page 3 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 32 - 
March 31, 2003, Publish Date: August 9, 2006 
Hemorrhage, GU  
– Select:  
– Bladder 
– Fallopian tube 
– Kidney 
– Ovary 
– Prostate  
– Retroperitoneum  
– Spermatic cord 
– Stoma 
– Testes 
– Ureter 
– Urethra 
– Urinary NOS 
– Uterus 
– Vagina 
– Vas deferens 
Hemorrhage, GU – Select 
Minimal or microscopic 
bleeding; intervention not 
indicated 
Gross bleeding, medical 
intervention, or urinary 
tract irrigation indicated 
Transfusion, 
interventional radiology, 
endoscopic, or operative 
intervention indicated; 
radiation therapy (i.e., 
hemostasis of bleeding 
site) 
Life-threatening 
consequences; major 
urgent intervention 
indicated 
Death 
REMARK: Transfusion implies pRBC. 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Hemorrhage, pulmonary/ 
upper respiratory  
– Select: 
Hemorrhage pulmonary  
– Select 
– Bronchopulmonary NOS 
– Bronchus  
– Larynx  
– Lung  
– Mediastinum 
– Nose 
– Pharynx 
– Pleura 
– Respiratory tract NOS 
– Stoma 
– Trachea 
Mild, intervention not 
indicated 
Symptomatic and 
medical intervention 
indicated 
Transfusion, 
interventional radiology, 
endoscopic, or operative 
intervention indicated; 
radiation therapy (i.e., 
hemostasis of bleeding 
site) 
Life-threatening 
consequences; major 
urgent intervention 
indicated 
Death 
REMARK: Transfusion implies pRBC.  
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Petechiae/purpura 
(hemorrhage/bleeding 
into skin or mucosa) 
Petechiae 
Few petechiae 
Moderate petechiae; 
purpura 
Generalized petechiae or 
purpura 
— 
— 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 

 
HEMORRHAGE/BLEEDING 
Page 4 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 33 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Vitreous hemorrhage is graded in the OCULAR/VISUAL CATEGORY. 
Hemorrhage/Bleeding – 
Other (Specify, __) 
Hemorrhage – Other 
(Specify) 
Mild without transfusion 
— 
Transfusion indicated 
Catastrophic bleeding, 
requiring major non-
elective intervention 
Death 

 
HEPATOBILIARY/PANCREAS 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 34 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Biliary tree damage is graded as Fistula, GI – Select; Leak (including anastomotic), GI – Select; Necrosis, GI – Select; Obstruction, GI – Select; Perforation, GI – 
Select; Stricture/stenosis (including anastomotic), GI – Select in the GASTROINTESTINAL CATEGORY. 
Cholecystitis 
Cholecystitis 
Asymptomatic, 
radiographic findings only 
Symptomatic, medical 
intervention indicated 
Interventional radiology, 
endoscopic, or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
sepsis or perforation)  
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection 
with unknown ANC – Select.  
Liver dysfunction/failure 
(clinical)  
Liver dysfunction  
— 
Jaundice  
Asterixis 
Encephalopathy or coma 
Death 
REMARK: Jaundice is not an AE, but occurs when the liver is not working properly or when a bile duct is blocked. It is graded as a result of liver dysfunction/failure or elevated bilirubin. 
ALSO CONSIDER: Bilirubin (hyperbilirubinemia). 
Pancreas, exocrine 
enzyme deficiency 
Pancreas, exocrine 
enzyme deficiency 
— 
Increase in stool 
frequency, bulk, or odor; 
steatorrhea 
Sequelae of absorption 
deficiency (e.g., weight 
loss)  
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Diarrhea. 
Pancreatitis  
Pancreatitis 
Asymptomatic, enzyme 
elevation and/or 
radiographic findings  
Symptomatic, medical 
intervention indicated 
Interventional radiology or 
operative intervention 
indicated 
Life-threatening 
consequences 
(e.g., circulatory failure, 
hemorrhage, sepsis) 
Death 
ALSO CONSIDER: Amylase. 
NAVIGATION NOTE: Stricture (biliary tree, hepatic or pancreatic) is graded as Stricture/stenosis (including anastomotic), GI – Select in the GASTROINTESTINAL CATEGORY. 
Hepatobiliary/Pancreas – 
Other (Specify, __) 
Hepatobiliary – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
INFECTION 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 35 - 
March 31, 2003, Publish Date: August 9, 2006 
Colitis, infectious 
(e.g., Clostridium difficile) 
Colitis, infectious  
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain with 
mucus and/or blood in 
stool 
IV antibiotics or TPN 
indicated  
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis or 
toxic megacolon); 
operative resection or 
diversion indicated 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select; Typhlitis (cecal inflammation).  
Febrile neutropenia 
(fever of unknown origin 
without clinically or 
microbiologically 
documented infection) 
(ANC <1.0 x 109/L, fever 
≥38.5°C) 
Febrile neutropenia 
— 
— 
Present 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
ALSO CONSIDER: Neutrophils/granulocytes (ANC/AGC). 
Infection  
(documented clinically or 
microbiologically) with 
Grade 3 or 4 neutrophils  
(ANC <1.0 x 109/L) 
– Select  
‘Select’ AEs appear at the 
end of the CATEGORY. 
Infection (documented 
clinically) with Grade 3 or 
4 ANC – Select 
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
REMARK: Fever with Grade 3 or 4 neutrophils in the absence of documented infection is graded as Febrile neutropenia (fever of unknown origin without clinically or microbiologically 
documented infection). 
ALSO CONSIDER: Neutrophils/granulocytes (ANC/AGC). 
Infection with normal 
ANC or Grade 1 or 2 
neutrophils  
– Select  
‘Select’ AEs appear at the 
end of the CATEGORY. 
Infection with normal 
ANC – Select 
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 

 
INFECTION 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 36 - 
March 31, 2003, Publish Date: August 9, 2006 
Infection with unknown 
ANC 
– Select  
‘Select’ AEs appear at the 
end of the CATEGORY. 
Infection with unknown 
ANC – Select 
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
REMARK: Infection with unknown ANC – Select is to be used in the rare case when ANC is unknown. 
Opportunistic infection 
associated with ≥Grade 2 
Lymphopenia 
Opportunistic infection  
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
ALSO CONSIDER: Lymphopenia. 
Viral hepatitis 
Viral hepatitis 
Present; transaminases 
and liver function normal 
Transaminases 
abnormal, liver function 
normal  
Symptomatic liver 
dysfunction; fibrosis by 
biopsy; compensated 
cirrhosis 
Decompensated liver 
function (e.g., ascites, 
coagulopathy, 
encephalopathy, coma) 
Death 
REMARK: Non-viral hepatitis is graded as Infection – Select. 
ALSO CONSIDER: Albumin, serum-low (hypoalbuminemia); ALT, SGPT (serum glutamic pyruvic transaminase); AST, SGOT (serum glutamic oxaloacetic transaminase); Bilirubin 
(hyperbilirubinemia); Encephalopathy. 
Infection – Other 
(Specify, __) 
Infection – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
INFECTION – SELECT 
Page 3 of 3 
CTCAE v3.0  
- 37 - 
March 31, 2003, Publish Date: August 9, 2006 
AUDITORY/EAR 
– External ear (otitis externa) 
– Middle ear (otitis media) 
CARDIOVASCULAR 
– Artery 
– Heart (endocarditis) 
– Spleen 
– Vein 
DERMATOLOGY/SKIN  
– Lip/perioral 
– Peristomal 
– Skin (cellulitis) 
– Ungual (nails) 
GASTROINTESTINAL  
– Abdomen NOS 
– Anal/perianal 
– Appendix 
– Cecum 
– Colon 
– Dental-tooth 
– Duodenum 
– Esophagus 
– Ileum 
– Jejunum 
– Oral cavity-gums (gingivitis) 
– Peritoneal cavity 
– Rectum 
– Salivary gland 
– Small bowel NOS 
– Stomach 
GENERAL 
– Blood 
– Catheter-related 
– Foreign body (e.g., graft, implant,  
prosthesis, stent) 
– Wound  
HEPATOBILIARY/PANCREAS 
– Biliary tree 
– Gallbladder (cholecystitis) 
– Liver 
– Pancreas 
LYMPHATIC 
– Lymphatic 
MUSCULOSKELETAL 
– Bone (osteomyelitis) 
– Joint 
– Muscle (infection myositis) 
– Soft tissue NOS 
NEUROLOGY 
– Brain (encephalitis, infectious) 
– Brain + Spinal cord (encephalomyelitis) 
– Meninges (meningitis) 
– Nerve-cranial 
– Nerve-peripheral 
– Spinal cord (myelitis) 
OCULAR 
– Conjunctiva 
– Cornea 
– Eye NOS 
– Lens 
PULMONARY/UPPER RESPIRATORY 
– Bronchus 
– Larynx 
– Lung (pneumonia) 
– Mediastinum NOS 
– Mucosa 
– Neck NOS 
– Nose 
– Paranasal 
– Pharynx 
– Pleura (empyema) 
– Sinus 
– Trachea 
– Upper aerodigestive NOS 
– Upper airway NOS  
RENAL/GENITOURINARY  
– Bladder (urinary) 
– Kidney 
– Prostate 
– Ureter 
– Urethra 
– Urinary tract NOS 
SEXUAL/REPRODUCTIVE FUNCTION 
– Cervix 
– Fallopian tube 
– Pelvis NOS 
– Penis 
– Scrotum 
– Uterus 
– Vagina 
– Vulva 
 

 
LYMPHATICS 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 38 - 
March 31, 2003, Publish Date: August 9, 2006 
Chyle or lymph leakage  
Chyle or lymph leakage 
Asymptomatic, clinical or 
radiographic findings 
Symptomatic, medical 
intervention indicated  
Interventional radiology 
or operative intervention 
indicated 
Life-threatening 
complications 
Death 
ALSO CONSIDER: Chylothorax. 
Dermal change 
lymphedema, 
phlebolymphedema  
Dermal change 
Trace thickening or faint 
discoloration 
Marked discoloration; 
leathery skin texture; 
papillary formation 
— 
— 
— 
REMARK: Dermal change lymphedema, phlebolymphedema refers to changes due to venous stasis. 
ALSO CONSIDER: Ulceration.  
Edema: 
head and neck 
Edema: head and neck 
Localized to dependent 
areas, no disability or 
functional impairment 
Localized facial or neck 
edema with functional 
impairment 
Generalized facial or 
neck edema with 
functional impairment 
(e.g., difficulty in turning 
neck or opening mouth 
compared to baseline) 
Severe with ulceration or 
cerebral edema; 
tracheotomy or feeding 
tube indicated 
Death 
Edema: 
limb 
Edema: limb 
5 – 10% inter-limb 
discrepancy in volume or 
circumference at point of 
greatest visible 
difference; swelling or 
obscuration of anatomic 
architecture on close 
inspection; pitting edema 
>10 – 30% inter-limb 
discrepancy in volume or 
circumference at point of 
greatest visible 
difference; readily 
apparent obscuration of 
anatomic architecture; 
obliteration of skin folds; 
readily apparent 
deviation from normal 
anatomic contour  
>30% inter-limb 
discrepancy in volume; 
lymphorrhea; gross 
deviation from normal 
anatomic contour; 
interfering with ADL 
Progression to 
malignancy (i.e., 
lymphangiosarcoma); 
amputation indicated; 
disabling 
Death 
Edema: 
trunk/genital 
Edema: trunk/genital 
Swelling or obscuration 
of anatomic architecture 
on close inspection; 
pitting edema 
Readily apparent 
obscuration of anatomic 
architecture; obliteration 
of skin folds; readily 
apparent deviation from 
normal anatomic contour 
Lymphorrhea; interfering 
with ADL; gross deviation 
from normal anatomic 
contour 
Progression to 
malignancy (i.e., 
lymphangiosarcoma); 
disabling  
Death 
Edema: 
viscera 
Edema: viscera 
Asymptomatic; clinical or 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and unable 
to aliment adequately 
orally; interventional 
radiology or operative 
intervention indicated  
Life-threatening 
consequences 
Death 

 
LYMPHATICS 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 39 - 
March 31, 2003, Publish Date: August 9, 2006 
Lymphedema-related 
fibrosis 
Lymphedema-related 
fibrosis 
Minimal to moderate 
redundant soft tissue, 
unresponsive to elevation 
or compression, with 
moderately firm texture or 
spongy feel 
Marked increase in 
density and firmness, 
with or without tethering 
Very marked density and 
firmness with tethering 
affecting ≥40% of the 
edematous area 
— 
— 
Lymphocele 
Lymphocele 
Asymptomatic, clinical or 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and 
interventional radiology 
or operative intervention 
indicated 
— 
— 
Phlebolymphatic cording  
Phlebolymphatic cording 
Asymptomatic, clinical 
findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and leading 
to contracture or reduced 
range of motion 
— 
— 
Lymphatics – Other  
(Specify, __) 
Lymphatics – Other  
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling 
Death 

 
METABOLIC/LABORATORY 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 40 - 
March 31, 2003, Publish Date: August 9, 2006 
Acidosis  
(metabolic or respiratory) 
Acidosis  
pH <normal, but ≥7.3 
— 
pH <7.3 
pH <7.3 with life-
threatening 
consequences 
Death 
Albumin, serum-low 
(hypoalbuminemia)  
Hypoalbuminemia 
<LLN – 3 g/dL  
<LLN – 30 g/L 
<3 – 2 g/dL 
<30 – 20 g/L  
<2 g/dL  
<20 g/L 
— 
Death 
Alkaline phosphatase 
Alkaline phosphatase 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Alkalosis  
(metabolic or respiratory) 
Alkalosis 
pH >normal, but ≤7.5 
— 
pH >7.5 
pH >7.5 with life-
threatening 
consequences 
Death 
ALT, SGPT  
(serum glutamic pyruvic 
transaminase) 
ALT 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Amylase 
Amylase 
>ULN – 1.5 x ULN 
>1.5 – 2.0 x ULN 
>2.0 – 5.0 x ULN 
>5.0 x ULN 
— 
AST, SGOT 
(serum glutamic 
oxaloacetic 
transaminase) 
AST 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Bicarbonate, serum-low  
Bicarbonate, serum-low 
<LLN – 16 mmol/L 
<16 – 11 mmol/L 
<11 – 8 mmol/L 
<8 mmol/L 
Death 
Bilirubin 
(hyperbilirubinemia) 
Bilirubin 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x ULN 
>3.0 – 10.0 x ULN 
>10.0 x ULN 
— 
REMARK: Jaundice is not an AE, but may be a manifestation of liver dysfunction/failure or elevated bilirubin. If jaundice is associated with elevated bilirubin, grade bilirubin. 
Calcium, serum-low 
(hypocalcemia) 
Hypocalcemia 
<LLN – 8.0 mg/dL 
<LLN – 2.0 mmol/L 
Ionized calcium: 
<LLN – 1.0 mmol/L 
<8.0 – 7.0 mg/dL 
<2.0 – 1.75 mmol/L 
Ionized calcium: 
<1.0 – 0.9 mmol/L 
<7.0 – 6.0 mg/dL 
<1.75 – 1.5 mmol/L 
Ionized calcium: 
<0.9 – 0.8 mmol/L 
<6.0 mg/dL 
<1.5 mmol/L 
Ionized calcium: 
<0.8 mmol/L 
Death 
REMARK: Calcium can be falsely low if hypoalbuminemia is present. Serum albumin is <4.0 g/dL, hypocalcemia is reported after the following corrective calculation has been 
performed: Corrected Calcium (mg/dL) = Total Calcium (mg/dL) – 0.8 [Albumin (g/dL) – 4] 4. Alternatively, direct measurement of ionized calcium is the definitive method to diagnose 
metabolically relevant alterations in serum calcium. 
                                            
4Crit Rev Clin Lab Sci 1984;21(1):51-97 

 
METABOLIC/LABORATORY 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 41 - 
March 31, 2003, Publish Date: August 9, 2006 
Calcium, serum-high 
(hypercalcemia) 
Hypercalcemia 
>ULN – 11.5 mg/dL 
>ULN – 2.9 mmol/L 
Ionized calcium: 
>ULN – 1.5 mmol/L 
>11.5 – 12.5 mg/dL 
>2.9 – 3.1 mmol/L 
Ionized calcium: 
>1.5 – 1.6 mmol/L 
>12.5 – 13.5 mg/dL 
>3.1 – 3.4 mmol/L 
Ionized calcium: 
>1.6 – 1.8 mmol/L 
>13.5 mg/dL 
>3.4 mmol/L 
Ionized calcium: 
>1.8 mmol/L 
Death 
Cholesterol, serum-high 
(hypercholesteremia) 
Cholesterol 
>ULN – 300 mg/dL 
>ULN – 7.75 mmol/L 
>300 – 400 mg/dL 
>7.75 – 10.34 mmol/L 
>400 – 500 mg/dL 
>10.34 – 12.92 mmol/L 
>500 mg/dL 
>12.92 mmol/L 
Death 
CPK (creatine 
phosphokinase) 
CPK 
>ULN – 2.5 x ULN 
>2.5 x ULN – 5 x ULN 
>5 x ULN – 10 x ULN 
>10 x ULN 
Death 
Creatinine 
Creatinine 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x ULN 
>3.0 – 6.0 x ULN 
>6.0 x ULN 
Death 
REMARK: Adjust to age-appropriate levels for pediatric patients.  
ALSO CONSIDER: Glomerular filtration rate. 
GGT (γ-Glutamyl 
transpeptidase) 
GGT 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Glomerular filtration rate  
GFR 
<75 – 50% LLN 
<50 – 25% LLN 
<25% LLN, chronic 
dialysis not indicated 
Chronic dialysis or renal 
transplant indicated 
Death 
ALSO CONSIDER: Creatinine. 
Glucose, serum-high 
(hyperglycemia)  
Hyperglycemia 
>ULN – 160 mg/dL 
>ULN – 8.9 mmol/L 
>160 – 250 mg/dL 
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL 
>13.9 – 27.8 mmol/L 
>500 mg/dL 
>27.8 mmol/L or acidosis 
Death 
REMARK: Hyperglycemia, in general, is defined as fasting unless otherwise specified in protocol. 
Glucose, serum-low 
(hypoglycemia) 
Hypoglycemia 
<LLN – 55 mg/dL 
<LLN – 3.0 mmol/L 
<55 – 40 mg/dL 
<3.0 – 2.2 mmol/L 
<40 – 30 mg/dL 
<2.2 – 1.7 mmol/L 
<30 mg/dL 
<1.7 mmol/L 
Death 
Hemoglobinuria 
Hemoglobinuria 
Present 
— 
— 
— 
Death 
Lipase 
Lipase 
>ULN – 1.5 x ULN 
>1.5 – 2.0 x ULN 
>2.0 – 5.0 x ULN 
>5.0 x ULN 
— 
Magnesium, serum-high 
(hypermagnesemia) 
Hypermagnesemia 
>ULN – 3.0 mg/dL 
>ULN – 1.23 mmol/L 
— 
>3.0 – 8.0 mg/dL 
>1.23 – 3.30 mmol/L 
>8.0 mg/dL 
>3.30 mmol/L 
Death 
Magnesium, serum-low 
(hypomagnesemia)  
Hypomagnesemia 
<LLN – 1.2 mg/dL 
<LLN – 0.5 mmol/L 
<1.2 – 0.9 mg/dL 
<0.5 – 0.4 mmol/L 
<0.9 – 0.7 mg/dL 
<0.4 – 0.3 mmol/L 
<0.7 mg/dL 
<0.3 mmol/L 
Death 
Phosphate, serum-low 
(hypophosphatemia)  
Hypophosphatemia 
<LLN – 2.5 mg/dL 
<LLN – 0.8 mmol/L 
<2.5 – 2.0 mg/dL  
<0.8 – 0.6 mmol/L 
<2.0 – 1.0 mg/dL 
<0.6 – 0.3 mmol/L 
<1.0 mg/dL 
<0.3 mmol/L 
Death 
Potassium, serum-high 
(hyperkalemia) 
Hyperkalemia 
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L 
>6.0 – 7.0 mmol/L 
>7.0 mmol/L 
Death 

 
METABOLIC/LABORATORY 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 42 - 
March 31, 2003, Publish Date: August 9, 2006 
Potassium, serum-low 
(hypokalemia)  
Hypokalemia 
<LLN – 3.0 mmol/L 
— 
<3.0 – 2.5 mmol/L 
<2.5 mmol/L 
Death 
Proteinuria 
Proteinuria 
1+ or 
0.15 – 1.0 g/24 hrs 
2+ to 3+ or 
>1.0 – 3.5 g/24 hrs  
4+ or 
>3.5 g/24 hrs 
Nephrotic syndrome 
Death 
Sodium, serum-high 
(hypernatremia) 
Hypernatremia 
>ULN – 150 mmol/L 
>150 – 155 mmol/L 
>155 – 160 mmol/L 
>160 mmol/L 
Death 
Sodium, serum-low 
(hyponatremia) 
Hyponatremia 
<LLN – 130 mmol/L 
— 
<130 – 120 mmol/L 
<120 mmol/L 
Death 
Triglyceride, serum-high 
(hypertriglyceridemia) 
Hypertriglyceridemia 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 10 x ULN 
>10 x ULN 
Death 
Uric acid, serum-high 
(hyperuricemia) 
Hyperuricemia 
>ULN – 10 mg/dL 
≤0.59 mmol/L without 
physiologic 
consequences 
— 
>ULN – 10 mg/dL 
≤0.59 mmol/L with 
physiologic 
consequences 
>10 mg/dL 
>0.59 mmol/L 
Death 
ALSO CONSIDER: Creatinine; Potassium, serum-high (hyperkalemia); Renal failure; Tumor lysis syndrome. 
Metabolic/Laboratory – 
Other (Specify, __) 
Metabolic/Lab – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
MUSCULOSKELETAL/SOFT TISSUE 
Page 1 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 43 - 
March 31, 2003, Publish Date: August 9, 2006 
Arthritis (non-septic) 
Arthritis 
Mild pain with 
inflammation, erythema, 
or joint swelling, but not 
interfering with function 
Moderate pain with 
inflammation, erythema, 
or joint swelling 
interfering with function, 
but not interfering with 
ADL 
Severe pain with 
inflammation, erythema, 
or joint swelling and 
interfering with ADL 
Disabling 
Death 
REMARK: Report only when the diagnosis of arthritis (e.g., inflammation of a joint or a state characterized by inflammation of joints) is made. Arthralgia (sign or symptom of pain in a 
joint, especially non-inflammatory in character) is graded as Pain – Select in the PAIN CATEGORY.  
Bone: 
spine-scoliosis 
Scoliosis  
≤20 degrees; clinically 
undetectable 
>20 – 45 degrees; visible 
by forward flexion; 
interfering with function 
but not interfering with 
ADL 
>45 degrees; scapular 
prominence in forward 
flexion; operative 
intervention indicated; 
interfering with ADL 
Disabling (e.g., interfering 
with cardiopulmonary 
function) 
Death 
Cervical spine-range of 
motion 
Cervical spine ROM 
Mild restriction of rotation 
or flexion between  
60 – 70 degrees 
Rotation <60 degrees to 
right or left; <60 degrees 
of flexion 
Ankylosed/fused over 
multiple segments with 
no C-spine rotation 
— 
— 
REMARK: 60 – 65 degrees of rotation is required for reversing a car; 60 – 65 degrees of flexion is required to tie shoes. 
Exostosis 
Exostosis 
Asymptomatic 
Involving multiple sites; 
pain or interfering with 
function  
Excision indicated 
Progression to 
malignancy (i.e., 
chondrosarcoma) 
Death 
Extremity-lower 
(gait/walking) 
Gait/walking 
Limp evident only to 
trained observer and able 
to walk ≥1 kilometer; 
cane indicated for 
walking 
Noticeable limp, or 
limitation of limb function, 
but able to walk ≥0.1 
kilometer (1 city block); 
quad cane indicated for 
walking 
Severe limp with stride 
modified to maintain 
balance (widened base of 
support, marked 
reduction in step length); 
ambulation limited to 
walker; crutches 
indicated 
Unable to walk 
— 
ALSO CONSIDER: Ataxia (incoordination); Muscle weakness, generalized or specific area (not due to neuropathy) – Select.  
Extremity-upper 
(function)  
Extremity-upper 
(function) 
Able to perform most 
household or work 
activities with affected 
limb 
Able to perform most 
household or work 
activities with 
compensation from 
unaffected limb 
Interfering with ADL  
Disabling; no function of 
affected limb 
— 
Fibrosis-cosmesis 
Fibrosis-cosmesis 
Visible only on close 
examination 
Readily apparent but not 
disfiguring 
Significant disfigurement; 
operative intervention 
indicated if patient 
chooses 
— 
— 

 
MUSCULOSKELETAL/SOFT TISSUE 
Page 2 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 44 - 
March 31, 2003, Publish Date: August 9, 2006 
Fibrosis-deep connective 
tissue 
Fibrosis-deep connective 
tissue  
Increased density, 
“spongy” feel 
Increased density with 
firmness or tethering 
Increased density with 
fixation of tissue; 
operative intervention 
indicated; interfering with 
ADL 
Life-threatening; 
disabling; loss of limb; 
interfering with vital organ 
function 
Death 
ALSO CONSIDER: Induration/fibrosis (skin and subcutaneous tissue); Muscle weakness, generalized or specific area (not due to neuropathy) – Select; Neuropathy: motor; Neuropathy: 
sensory. 
Fracture 
Fracture 
Asymptomatic, 
radiographic findings only 
(e.g., asymptomatic rib 
fracture on plain x-ray, 
pelvic insufficiency 
fracture on MRI, etc.) 
Symptomatic but non-
displaced; immobilization 
indicated 
Symptomatic and 
displaced or open wound 
with bone exposure; 
operative intervention 
indicated 
Disabling; amputation 
indicated 
Death 
Joint-effusion 
Joint-effusion 
Asymptomatic, clinical or 
radiographic findings only 
Symptomatic; interfering 
with function but not 
interfering with ADL 
Symptomatic and 
interfering with ADL 
Disabling 
Death 
ALSO CONSIDER: Arthritis (non-septic). 
Joint-function5 
Joint-function 
Stiffness interfering with 
athletic activity; ≤25% 
loss of range of motion 
(ROM) 
Stiffness interfering with 
function but not 
interfering with ADL;  
>25 – 50% decrease in 
ROM 
Stiffness interfering with 
ADL; >50 – 75% 
decrease in ROM  
Fixed or non-functional 
joint (arthrodesis); 
>75% decrease in ROM 
— 
ALSO CONSIDER: Arthritis (non-septic). 
Local complication –
device/prosthesis-related 
Device/prosthesis 
Asymptomatic  
Symptomatic, but not 
interfering with ADL; local 
wound care; medical 
intervention indicated 
Symptomatic, interfering 
with ADL; operative 
intervention indicated 
(e.g., hardware/device 
replacement or removal, 
reconstruction)  
Life-threatening; 
disabling; loss of limb or 
organ 
Death 
Lumbar spine-range of 
motion 
Lumbar spine ROM 
Stiffness and difficulty 
bending to the floor to 
pick up a very light object 
but able to do activity 
Some lumbar spine 
flexion but requires a 
reaching aid to pick up a 
very light object from the 
floor 
Ankylosed/fused over 
multiple segments with 
no L-spine flexion (i.e., 
unable to reach to floor to 
pick up a very light 
— 
— 
                                            
5 Adapted from the International SFTR Method of Measuring and Recording Joint Motion, International Standard Orthopedic Measurements (ISOM), Jon J. Gerhardt and Otto A. 
Russee, Bern, Switzerland, Han Huber 9 Publisher), 1975. 

 
MUSCULOSKELETAL/SOFT TISSUE 
Page 3 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 45 - 
March 31, 2003, Publish Date: August 9, 2006 
object) 
Muscle weakness, 
generalized or specific 
area (not due to 
neuropathy)  
– Select: 
Muscle weakness  
– Select  
– Extraocular 
– Extremity-lower  
– Extremity-upper 
– Facial 
– Left-sided 
– Ocular 
– Pelvic 
– Right-sided 
– Trunk 
– Whole body/generalized  
Asymptomatic, weakness 
on physical exam 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Life-threatening; disabling 
Death 
ALSO CONSIDER: Fatigue (asthenia, lethargy, malaise). 
Muscular/skeletal 
hypoplasia 
Muscular/skeletal 
hypoplasia 
Cosmetically and 
functionally insignificant 
hypoplasia  
Deformity, hypoplasia, or 
asymmetry able to be 
remediated by prosthesis 
(e.g., shoe insert) or 
covered by clothing  
Functionally significant 
deformity, hypoplasia, or 
asymmetry, unable to be 
remediated by prosthesis 
or covered by clothing  
Disabling 
— 
Myositis 
(inflammation/damage of 
muscle) 
Myositis 
Mild pain, not interfering 
with function 
Pain interfering with 
function, but not 
interfering with ADL 
Pain interfering with ADL 
Disabling 
Death 
REMARK: Myositis implies muscle damage (i.e., elevated CPK). 
ALSO CONSIDER: CPK (creatine phosphokinase); Pain – Select. 
Osteonecrosis  
(avascular necrosis) 
Osteonecrosis 
Asymptomatic, 
radiographic findings only 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL; minimal bone 
removal indicated (i.e., 
minor sequestrectomy)  
Symptomatic and 
interfering with ADL; 
operative intervention or 
hyperbaric oxygen 
indicated 
Disabling  
Death 

 
MUSCULOSKELETAL/SOFT TISSUE 
Page 4 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 46 - 
March 31, 2003, Publish Date: August 9, 2006 
Osteoporosis6 
Osteoporosis 
Radiographic evidence of 
osteoporosis or Bone 
Mineral Density (BMD) 
t-score –1 to –2.5 
(osteopenia) and no loss 
of height or therapy 
indicated 
BMD t-score < –2.5; loss 
of height <2 cm; anti-
osteoporotic therapy 
indicated 
Fractures; loss of height 
≥2 cm 
Disabling 
Death 
Seroma 
Seroma 
Asymptomatic 
Symptomatic; medical 
intervention or simple 
aspiration indicated 
Symptomatic, 
interventional radiology 
or operative intervention 
indicated 
— 
— 
Soft tissue necrosis 
– Select: 
– Abdomen 
– Extremity-lower 
– Extremity-upper  
– Head 
– Neck 
– Pelvic 
– Thorax 
Soft tissue necrosis 
– Select 
— 
Local wound care; 
medical intervention 
indicated 
Operative debridement or 
other invasive 
intervention indicated 
(e.g., hyperbaric oxygen)  
Life-threatening 
consequences; major 
invasive intervention 
indicated (e.g., tissue 
reconstruction, flap, or 
grafting) 
Death 
Trismus (difficulty, 
restriction or pain when 
opening mouth) 
Trismus 
Decreased range of 
motion without impaired 
eating  
Decreased range of 
motion requiring small 
bites, soft foods or 
purees 
Decreased range of 
motion with inability to 
adequately aliment or 
hydrate orally 
— 
— 
NAVIGATION NOTE: Wound-infectious is graded as Infection – Select in the INFECTION CATEGORY. 
NAVIGATION NOTE: Wound non-infectious is graded as Wound complication, non-infectious in the DERMATOLOGY/SKIN CATEGORY.  
Musculoskeletal/Soft 
Tissue – Other 
(Specify, __) 
Musculoskeletal – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
                                            
6 "Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis," Report of a WHO Study Group Technical Report Series, No. 843, 1994, v + 129 
pages [C*, E, F, R, S], ISBN 92 4 120843 0, Sw.fr. 22.-/US $19.80; in developing countries: Sw.fr. 15.40, Order no. 1100843 

 
NEUROLOGY 
Page 1 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 47 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: ADD (Attention Deficit Disorder) is graded as Cognitive disturbance. 
NAVIGATION NOTE: Aphasia, receptive and/or expressive, is graded as Speech impairment (e.g., dysphasia or aphasia). 
Apnea 
Apnea 
— 
— 
Present 
Intubation indicated  
Death 
Arachnoiditis/ 
meningismus/radiculitis 
Arachnoiditis 
Symptomatic, not 
interfering with function; 
medical intervention 
indicated 
Symptomatic (e.g., 
photophobia, nausea) 
interfering with function 
but not interfering with 
ADL  
Symptomatic, interfering 
with ADL 
Life-threatening; disabling 
(e.g., paraplegia) 
Death 
ALSO CONSIDER: Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 109/L); Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select; Pain – Select; Vomiting. 
Ataxia (incoordination) 
Ataxia 
Asymptomatic  
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL; mechanical 
assistance indicated  
Disabling 
Death 
REMARK: Ataxia (incoordination) refers to the consequence of medical or operative intervention. 
Brachial plexopathy 
Brachial plexopathy 
Asymptomatic 
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
Disabling 
Death 
CNS cerebrovascular 
ischemia 
CNS ischemia 
— 
Asymptomatic, 
radiographic findings only 
Transient ischemic event 
or attack (TIA) ≤24 hrs 
duration 
Cerebral vascular 
accident (CVA, stroke), 
neurologic deficit 
>24 hrs  
Death 
NAVIGATION NOTE: CNS hemorrhage/bleeding is graded as Hemorrhage, CNS in the HEMORRHAGE/BLEEDING CATEGORY.  
CNS necrosis/cystic 
progression 
CNS necrosis 
Asymptomatic, 
radiographic findings only 
Symptomatic, not 
interfering with ADL; 
medical intervention 
indicated 
Symptomatic and 
interfering with ADL; 
hyperbaric oxygen 
indicated 
Life-threatening; 
disabling; operative 
intervention indicated to 
prevent or treat CNS 
necrosis/cystic 
progression 
Death 
Cognitive disturbance 
Cognitive disturbance 
Mild cognitive disability; 
not interfering with 
work/school/life 
performance; specialized 
educational 
services/devices not 
indicated 
Moderate cognitive 
disability; interfering with 
work/school/life 
performance but capable 
of independent living; 
specialized resources on 
part-time basis indicated 
Severe cognitive 
disability; significant 
impairment of 
work/school/life 
performance 
Unable to perform ADL; 
full-time specialized 
resources or 
institutionalization 
indicated 
Death 
REMARK: Cognitive disturbance may be used for Attention Deficit Disorder (ADD). 

 
NEUROLOGY 
Page 2 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 48 - 
March 31, 2003, Publish Date: August 9, 2006 
Confusion 
Confusion 
Transient confusion, 
disorientation, or attention 
deficit 
Confusion, disorientation, 
or attention deficit 
interfering with function, 
but not interfering with 
ADL 
Confusion or delirium 
interfering with ADL 
Harmful to others or self; 
hospitalization indicated 
Death 
REMARK: Attention Deficit Disorder (ADD) is graded as Cognitive disturbance. 
NAVIGATION NOTE: Cranial neuropathy is graded as Neuropathy-cranial – Select. 
Dizziness  
Dizziness 
With head movements or 
nystagmus only; not 
interfering with function 
Interfering with function, 
but not interfering with 
ADL 
Interfering with ADL 
Disabling 
— 
REMARK: Dizziness includes disequilibrium, lightheadedness, and vertigo. 
ALSO CONSIDER: Neuropathy: cranial – Select; Syncope (fainting). 
NAVIGATION NOTE: Dysphasia, receptive and/or expressive, is graded as Speech impairment (e.g., dysphasia or aphasia). 
Encephalopathy 
Encephalopathy 
— 
Mild signs or symptoms; 
not interfering with ADL 
Signs or symptoms 
interfering with ADL; 
hospitalization indicated 
Life-threatening; disabling 
Death 
ALSO CONSIDER: Cognitive disturbance; Confusion; Dizziness; Memory impairment; Mental status; Mood alteration – Select; Psychosis (hallucinations/delusions); 
Somnolence/depressed level of consciousness. 
Extrapyramidal/ 
involuntary movement/ 
restlessness 
Involuntary movement 
Mild involuntary 
movements not 
interfering with function 
Moderate involuntary 
movements interfering 
with function, but not 
interfering with ADL 
Severe involuntary 
movements or torticollis 
interfering with ADL 
Disabling 
 
Death 
NAVIGATION NOTE: Headache/neuropathic pain (e.g., jaw pain, neurologic pain, phantom limb pain, post-infectious neuralgia, or painful neuropathies) is graded as Pain – Select in the 
PAIN CATEGORY. 
Hydrocephalus 
Hydrocephalus 
Asymptomatic, 
radiographic findings only 
Mild to moderate 
symptoms not interfering 
with ADL 
Severe symptoms or 
neurological deficit 
interfering with ADL 
Disabling  
Death 
Irritability (children <3 
years of age) 
Irritability 
Mild; easily consolable 
Moderate; requiring 
increased attention 
Severe; inconsolable 
— 
— 
Laryngeal nerve 
dysfunction  
Laryngeal nerve 
Asymptomatic, weakness 
on clinical 
examination/testing only 
Symptomatic, but not 
interfering with ADL; 
intervention not indicated 
Symptomatic, interfering 
with ADL; intervention 
indicated (e.g., 
thyroplasty, vocal cord 
injection) 
Life-threatening; 
tracheostomy indicated 
 
Death 

 
NEUROLOGY 
Page 3 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 49 - 
March 31, 2003, Publish Date: August 9, 2006 
Leak, cerebrospinal fluid 
(CSF) 
CSF leak 
Transient headache; 
postural care indicated 
Symptomatic, not 
interfering with ADL; 
blood patch indicated 
Symptomatic, interfering 
with ADL; operative 
intervention indicated 
Life-threatening; disabling 
Death 
REMARK: Leak, cerebrospinal fluid (CSF) may be used for CSF leak associated with operation and persisting >72 hours. 
Leukoencephalopathy 
(radiographic findings) 
Leukoencephalopathy  
Mild increase in 
subarachnoid space 
(SAS); mild 
ventriculomegaly; small 
(+/- multiple) focal T2 
hyperintensities, involving 
periventricular white 
matter or <1/3 of 
susceptible areas of 
cerebrum 
Moderate increase in 
SAS; moderate 
ventriculomegaly; focal 
T2 hyperintensities 
extending into centrum 
ovale or involving 1/3 to 
2/3 of susceptible areas 
of cerebrum 
Severe increase in SAS; 
severe ventriculomegaly; 
near total white matter T2 
hyperintensities or diffuse 
low attenuation (CT) 
— 
— 
REMARK: Leukoencephalopathy is a diffuse white matter process, specifically NOT associated with necrosis. Leukoencephalopathy (radiographic findings) does not include lacunas, 
which are areas that become void of neural tissue.  
Memory impairment 
Memory impairment 
Memory impairment not 
interfering with function 
Memory impairment 
interfering with function, 
but not interfering with 
ADL 
Memory impairment 
interfering with ADL 
Amnesia 
— 
Mental status7 
Mental status 
— 
1 – 3 point below age  
and educational norm in 
Folstein Mini-Mental 
Status Exam (MMSE) 
>3 point below age and 
educational norm in 
Folstein MMSE  
— 
— 
Mood alteration  
– Select: 
– Agitation 
– Anxiety 
– Depression 
– Euphoria 
Mood alteration – Select 
Mild mood alteration not 
interfering with function 
Moderate mood alteration 
interfering with function, 
but not interfering with 
ADL; medication 
indicated 
Severe mood alteration 
interfering with ADL 
Suicidal ideation; danger 
to self or others 
Death 
Myelitis 
Myelitis 
Asymptomatic, mild signs 
(e.g., Babinski’s or 
Lhermitte’s sign) 
Weakness or sensory 
loss not interfering with 
ADL 
Weakness or sensory 
loss interfering with ADL 
Disabling 
Death 
                                            
7 Folstein MF, Folstein, SE and McHugh PR (1975) "Mini-Mental State: A Practical Method for Grading the State of Patients for the Clinician," Journal of Psychiatric Research, 12: 
189-198 

 
NEUROLOGY 
Page 4 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 50 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Neuropathic pain is graded as Pain – Select in the PAIN CATEGORY.  
Neuropathy: 
cranial  
– Select: 
Neuropathy: cranial  
– Select 
Asymptomatic, detected 
on exam/testing only 
– CN I  
Smell 
– CN II  Vision 
– CN III  Pupil, upper eyelid, extra ocular movements 
– CN IV  Downward, inward movement of eye 
– CN V  Motor-jaw muscles; Sensory-facial 
– CN VI  Lateral deviation of eye 
– CN VII Motor-face; Sensory-taste 
– CN VIII Hearing and balance 
– CN IX Motor-pharynx; Sensory-ear, pharynx, tongue 
– CN X 
Motor-palate; pharynx, larynx 
– CN XI Motor-sternomastoid and trapezius 
– CN XII Motor-tongue 
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
Life-threatening; disabling 
Death 
Neuropathy: 
motor  
Neuropathy-motor 
Asymptomatic, weakness 
on exam/testing only 
Symptomatic weakness 
interfering with function, 
but not interfering with 
ADL 
Weakness interfering with 
ADL; bracing or 
assistance to walk (e.g., 
cane or walker) indicated 
Life-threatening; disabling 
(e.g., paralysis)  
Death 
REMARK: Cranial nerve motor neuropathy is graded as Neuropathy: cranial – Select. 
ALSO CONSIDER: Laryngeal nerve dysfunction; Phrenic nerve dysfunction.  
Neuropathy: 
sensory 
Neuropathy-sensory 
Asymptomatic; loss of 
deep tendon reflexes or 
paresthesia (including 
tingling) but not 
interfering with function 
Sensory alteration or 
paresthesia (including 
tingling), interfering with 
function, but not 
interfering with ADL 
Sensory alteration or 
paresthesia interfering 
with ADL  
Disabling  
Death 
REMARK: Cranial nerve sensory neuropathy is graded as Neuropathy: cranial – Select. 
Personality/behavioral 
Personality 
Change, but not 
adversely affecting 
patient or family 
Change, adversely 
affecting patient or family  
Mental health intervention 
indicated 
Change harmful to others 
or self; hospitalization 
indicated 
Death 
Phrenic nerve dysfunction  Phrenic nerve 
Asymptomatic weakness 
on exam/testing only 
Symptomatic but not 
interfering with ADL; 
intervention not indicated 
Significant dysfunction; 
intervention indicated 
(e.g., diaphragmatic 
plication) 
Life-threatening 
respiratory compromise; 
mechanical ventilation 
indicated 
Death 
Psychosis (hallucinations/ 
delusions) 
Psychosis 
— 
Transient episode 
Interfering with ADL; 
medication, supervision 
Harmful to others or self; 
life-threatening 
Death 

 
NEUROLOGY 
Page 5 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 51 - 
March 31, 2003, Publish Date: August 9, 2006 
or restraints indicated  
consequences 
Pyramidal tract 
dysfunction (e.g., ↑ tone, 
hyperreflexia, positive 
Babinski, ↓ fine motor 
coordination) 
Pyramidal tract 
dysfunction 
Asymptomatic, 
abnormality on exam or 
testing only  
Symptomatic; interfering 
with function but not 
interfering with ADL 
Interfering with ADL 
Disabling; paralysis 
Death 
Seizure 
Seizure 
— 
One brief generalized 
seizure; seizure(s) well 
controlled by 
anticonvulsants or 
infrequent focal motor 
seizures not interfering 
with ADL 
Seizures in which 
consciousness is altered; 
poorly controlled seizure 
disorder, with 
breakthrough generalized 
seizures despite medical 
intervention 
Seizures of any kind 
which are prolonged, 
repetitive, or difficult to 
control (e.g., status 
epilepticus, intractable 
epilepsy) 
Death 
Somnolence/depressed 
level of consciousness 
Somnolence 
— 
Somnolence or sedation 
interfering with function, 
but not interfering with 
ADL 
Obtundation or stupor; 
difficult to arouse; 
interfering with ADL 
Coma 
Death 
Speech impairment  
(e.g., dysphasia or 
aphasia)  
Speech impairment 
— 
Awareness of receptive 
or expressive dysphasia, 
not impairing ability to 
communicate 
Receptive or expressive 
dysphasia, impairing 
ability to communicate 
Inability to communicate 
— 
REMARK: Speech impairment refers to a primary CNS process, not neuropathy or end organ dysfunction. 
ALSO CONSIDER: Laryngeal nerve dysfunction; Voice changes/dysarthria (e.g., hoarseness, loss, or alteration in voice, laryngitis). 
Syncope (fainting) 
Syncope (fainting) 
— 
— 
Present 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: CNS cerebrovascular ischemia; Conduction abnormality/atrioventricular heart block – Select; Dizziness; Supraventricular and nodal arrhythmia – Select; Vasovagal 
episode; Ventricular arrhythmia – Select. 
NAVIGATION NOTE: Taste alteration (CN VII, IX) is graded as Taste alteration (dysgeusia) in the GASTROINTESTINAL CATEGORY. 
Tremor 
Tremor 
Mild and brief or 
intermittent but not 
interfering with function 
Moderate tremor 
interfering with function, 
but not interfering with 
ADL 
Severe tremor interfering 
with ADL 
Disabling 
— 
Neurology – Other 
(Specify, __) 
Neurology – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
OCULAR/VISUAL 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 52 - 
March 31, 2003, Publish Date: August 9, 2006 
Cataract 
Cataract 
Asymptomatic, detected 
on exam only  
Symptomatic, with 
moderate decrease in 
visual acuity  
(20/40 or better); 
decreased visual function 
correctable with glasses  
Symptomatic with marked 
decrease in visual acuity 
(worse than 20/40); 
operative intervention 
indicated (e.g., cataract 
surgery) 
— 
— 
Dry eye syndrome  
Dry eye 
Mild, intervention not 
indicated 
Symptomatic, interfering 
with function but not 
interfering with ADL; 
medical intervention 
indicated  
Symptomatic or decrease 
in visual acuity interfering 
with ADL; operative 
intervention indicated 
— 
— 
Eyelid dysfunction  
Eyelid dysfunction 
Asymptomatic  
Symptomatic, interfering 
with function but not ADL; 
requiring topical agents or 
epilation 
Symptomatic; interfering 
with ADL; surgical 
intervention indicated 
— 
— 
REMARK: Eyelid dysfunction includes canalicular stenosis, ectropion, entropion, erythema, madarosis, symblepharon, telangiectasis, thickening, and trichiasis. 
ALSO CONSIDER: Neuropathy: cranial – Select. 
Glaucoma  
Glaucoma 
Elevated intraocular 
pressure (EIOP) with 
single topical agent for 
intervention; no visual 
field deficit 
EIOP causing early visual 
field deficit (i.e., nasal 
step or arcuate deficit); 
multiple topical or oral 
agents indicated 
EIOP causing marked 
visual field deficits (i.e., 
involving both superior 
and inferior visual fields); 
operative intervention 
indicated 
EIOP resulting in 
blindness (20/200 or 
worse); enucleation 
indicated 
— 
Keratitis (corneal 
inflammation/corneal 
ulceration) 
Keratitis 
Abnormal ophthalmologic 
changes only; 
intervention not indicated 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL; 
operative intervention 
indicated 
Perforation or blindness 
(20/200 or worse)  
— 
NAVIGATION NOTE: Ocular muscle weakness is graded as Muscle weakness, generalized or specific area (not due to neuropathy) – Select in the MUSCULOSKELETAL/SOFT TISSUE 
CATEGORY.  
Night blindness 
(nyctalopia) 
Nyctalopia 
Symptomatic, not 
interfering with function 
Symptomatic and 
interfering with function 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL  
Disabling 
— 

 
OCULAR/VISUAL 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 53 - 
March 31, 2003, Publish Date: August 9, 2006 
Nystagmus 
Nystagmus 
Asymptomatic 
Symptomatic and 
interfering with function 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
ALSO CONSIDER: Neuropathy: cranial – Select; Ophthalmoplegia/diplopia (double vision). 
Ocular surface disease  
Ocular surface disease  
Asymptomatic or 
minimally symptomatic 
but not interfering with 
function 
Symptomatic, interfering 
with function but not 
interfering with ADL; 
topical antibiotics or other 
topical intervention 
indicated 
Symptomatic, interfering 
with ADL; operative 
intervention indicated 
— 
— 
REMARK: Ocular surface disease includes conjunctivitis, keratoconjunctivitis sicca, chemosis, keratinization, and palpebral conjunctival epithelial metaplasia. 
Ophthalmoplegia/ 
diplopia (double vision) 
Diplopia 
Intermittently 
symptomatic, intervention 
not indicated 
Symptomatic and 
interfering with function 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL; 
surgical intervention 
indicated 
Disabling 
— 
ALSO CONSIDER: Neuropathy: cranial – Select. 
Optic disc edema 
Optic disc edema 
Asymptomatic 
Decreased visual acuity 
(20/40 or better); visual 
field defect present 
Decreased visual acuity 
(worse than 20/40); 
marked visual field defect 
but sparing the central 20 
degrees 
Blindness  
(20/200 or worse) 
— 
ALSO CONSIDER: Neuropathy: cranial – Select.  
Proptosis/enophthalmos 
Proptosis/enophthalmos 
Asymptomatic, 
intervention not indicated 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
— 
— 
Retinal detachment 
Retinal detachment 
Exudative; no central 
vision loss; intervention 
not indicated 
Exudative and visual 
acuity 20/40 or better but 
intervention not indicated 
Rhegmatogenous or 
exudative detachment; 
operative intervention 
indicated 
Blindness 
(20/200 or worse) 
— 
Retinopathy  
Retinopathy 
Asymptomatic  
Symptomatic with 
moderate decrease in 
visual acuity 
(20/40 or better) 
Symptomatic with marked 
decrease in visual acuity 
(worse than 20/40) 
Blindness 
(20/200 or worse) 
— 

 
OCULAR/VISUAL 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 54 - 
March 31, 2003, Publish Date: August 9, 2006 
Scleral necrosis/melt 
Scleral necrosis 
Asymptomatic or 
symptomatic but not 
interfering with function 
Symptomatic, interfering 
with function but not 
interfering with ADL; 
moderate decrease in 
visual acuity (20/40 or 
better); medical 
intervention indicated 
Symptomatic, interfering 
with ADL; marked 
decrease in visual acuity 
(worse than 20/40); 
operative intervention 
indicated 
Blindness (20/200 or 
worse); painful eye with 
enucleation indicated 
— 
Uveitis  
Uveitis 
Asymptomatic 
Anterior uveitis; medical 
intervention indicated 
Posterior or pan-uveitis; 
operative intervention 
indicated 
Blindness 
(20/200 or worse) 
— 
Vision-blurred vision 
Blurred vision 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
Vision-flashing 
lights/floaters 
Flashing lights 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
Vision-photophobia 
Photophobia 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
Vitreous hemorrhage 
Vitreous hemorrhage 
Asymptomatic, clinical 
findings only 
Symptomatic, interfering 
with function, but not 
interfering with ADL; 
intervention not indicated 
Symptomatic, interfering 
with ADL; vitrectomy 
indicated  
— 
— 
Watery eye (epiphora, 
tearing) 
Watery eye 
Symptomatic, intervention 
not indicated 
Symptomatic, interfering 
with function but not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
— 
— 
Ocular/Visual – Other  
(Specify, __) 
Ocular – Other  
(Specify) 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Blindness 
(20/200 or worse) 
Death 

 
PAIN 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 55 - 
March 31, 2003, Publish Date: August 9, 2006 
Pain  
– Select: 
‘Select’ AEs appear at the 
end of the CATEGORY. 
Pain – Select  
Mild pain not interfering 
with function 
Moderate pain; pain or 
analgesics interfering with 
function, but not 
interfering with ADL 
Severe pain; pain or 
analgesics severely 
interfering with ADL 
Disabling 
— 
Pain – Other 
(Specify, __) 
Pain – Other (Specify) 
Mild pain not interfering 
with function 
Moderate pain; pain or 
analgesics interfering with 
function, but not 
interfering with ADL 
Severe pain; pain or 
analgesics severely 
interfering with ADL 
Disabling 
— 
PAIN – SELECT 
AUDITORY/EAR 
– External ear 
– Middle ear 
CARDIOVASCULAR 
– Cardiac/heart  
– Pericardium 
DERMATOLOGY/SKIN 
– Face 
– Lip 
– Oral-gums 
– Scalp 
– Skin 
GASTROINTESTINAL 
– Abdomen NOS 
– Anus 
– Dental/teeth/peridontal 
– Esophagus 
– Oral cavity 
– Peritoneum 
– Rectum 
– Stomach 
GENERAL 
– Pain NOS 
– Tumor pain  
HEPATOBILIARY/PANCREAS 
– Gallbladder 
– Liver  
LYMPHATIC 
– Lymph node 
MUSCULOSKELETAL 
– Back 
– Bone 
– Buttock 
– Extremity-limb 
– Intestine 
– Joint 
– Muscle 
– Neck 
– Phantom (pain associated with missing limb) 
NEUROLOGY 
– Head/headache 
– Neuralgia/peripheral nerve 
OCULAR 
– Eye 
PULMONARY/UPPER RESPIRATORY 
– Chest wall 
– Chest/thorax NOS 
PULMONARY/UPPER RESPIRATORY (continued) 
– Larynx 
– Pleura 
– Sinus 
– Throat/pharynx/larynx 
RENAL/GENITOURINARY 
– Bladder 
– Kidney 
SEXUAL/REPRODUCTIVE FUNCTION 
– Breast 
– Ovulatory 
– Pelvis 
– Penis 
– Perineum 
– Prostate 
– Scrotum 
– Testicle 
– Urethra 
– Uterus 
– Vagina 
 
 

 
PULMONARY/UPPER RESPIRATORY 
Page 1 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 56 - 
March 31, 2003, Publish Date: August 9, 2006 
Adult Respiratory 
Distress Syndrome 
(ARDS) 
ARDS 
— 
— 
Present, intubation not 
indicated  
Present, intubation 
indicated 
Death 
ALSO CONSIDER: Dyspnea (shortness of breath); Hypoxia; Pneumonitis/pulmonary infiltrates. 
Aspiration 
Aspiration 
Asymptomatic (“silent 
aspiration”); endoscopy 
or radiographic (e.g., 
barium swallow) findings  
Symptomatic (e.g., 
altered eating habits, 
coughing or choking 
episodes consistent with 
aspiration); medical 
intervention indicated 
(e.g., antibiotics, suction 
or oxygen) 
Clinical or radiographic 
signs of pneumonia or 
pneumonitis; unable to 
aliment orally 
Life-threatening (e.g., 
aspiration pneumonia or 
pneumonitis)  
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils 
– Select; Infection with unknown ANC – Select; Laryngeal nerve dysfunction; Neuropathy: cranial – Select; Pneumonitis/pulmonary infiltrates. 
Atelectasis  
Atelectasis  
Asymptomatic  
Symptomatic (e.g., 
dyspnea, cough), medical 
intervention indicated 
(e.g., bronchoscopic 
suctioning, chest 
physiotherapy, 
suctioning)  
Operative (e.g., stent, 
laser) intervention 
indicated  
Life-threatening 
respiratory compromise 
Death 
ALSO CONSIDER: Adult Respiratory Distress Syndrome (ARDS); Cough; Dyspnea (shortness of breath); Hypoxia; Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select; Obstruction/stenosis of airway – 
Select; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes). 
Bronchospasm, 
wheezing  
Bronchospasm 
Asymptomatic  
Symptomatic not 
interfering with function 
Symptomatic interfering 
with function 
Life-threatening 
Death 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever); Dyspnea (shortness of breath).  
Carbon monoxide 
diffusion capacity (DLCO) 
DLCO 
90 – 75% of predicted 
value 
<75 – 50% of predicted 
value 
<50 – 25% of predicted 
value 
<25% of predicted value 
Death 
ALSO CONSIDER: Hypoxia; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes). 
Chylothorax  
Chylothorax 
Asymptomatic 
Symptomatic; 
thoracentesis or tube 
drainage indicated  
Operative intervention 
indicated 
Life-threatening (e.g., 
hemodynamic instability 
or ventilatory support 
indicated) 
Death 
Cough 
Cough 
Symptomatic, non-
narcotic medication only 
indicated  
Symptomatic and 
narcotic medication 
indicated  
Symptomatic and 
significantly interfering 
with sleep or ADL 
— 
— 

 
PULMONARY/UPPER RESPIRATORY 
Page 2 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 57 - 
March 31, 2003, Publish Date: August 9, 2006 
Dyspnea (shortness of 
breath)  
Dyspnea  
Dyspnea on exertion, but 
can walk 1 flight of stairs 
without stopping 
Dyspnea on exertion but 
unable to walk 1 flight of 
stairs or 1 city block 
(0.1km) without stopping 
Dyspnea with ADL 
Dyspnea at rest; 
intubation/ventilator 
indicated  
Death 
ALSO CONSIDER: Hypoxia; Neuropathy: motor; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes). 
Edema, larynx  
Edema, larynx 
Asymptomatic edema by 
exam only 
Symptomatic edema, no 
respiratory distress  
Stridor; respiratory 
distress; interfering with 
ADL 
Life-threatening airway 
compromise; 
tracheotomy, intubation, 
or laryngectomy indicated 
Death 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever). 
FEV1  
FEV1 
90 – 75% of predicted 
value 
<75 – 50% of predicted 
value 
<50 – 25% of predicted 
value 
<25% of predicted 
Death 
Fistula, pulmonary/upper 
respiratory  
– Select: 
– Bronchus 
– Larynx 
– Lung 
– Oral cavity 
– Pharynx  
– Pleura 
– Trachea 
Fistula, pulmonary  
– Select  
Asymptomatic, 
radiographic findings only 
Symptomatic, tube 
thoracostomy or medical 
management indicated; 
associated with altered 
respiratory function but 
not interfering with ADL 
Symptomatic and 
associated with altered 
respiratory function 
interfering with ADL; or 
endoscopic (e.g., stent) 
or primary closure by 
operative intervention 
indicated 
Life-threatening 
consequences; operative 
intervention with 
thoracoplasty, chronic 
open drainage or multiple 
thoracotomies indicated 
Death 
REMARK: A fistula is defined as an abnormal communication between two body cavities, potential spaces, and/or the skin. The site indicated for a fistula should be the site from which 
the abnormal process is believed to have arisen. For example, a tracheo-esophageal fistula arising in the context of a resected or irradiated esophageal cancer should be graded as 
Fistula, GI – esophagus in the GASTROINTESTINAL CATEGORY. 
NAVIGATION NOTE: Hemoptysis is graded as Hemorrhage, pulmonary/upper respiratory – Select in the HEMORRHAGE/BLEEDING CATEGORY.  
Hiccoughs (hiccups, 
singultus) 
Hiccoughs 
Symptomatic, 
intervention not indicated 
Symptomatic, 
intervention indicated  
Symptomatic, 
significantly interfering 
with sleep or ADL 
— 
— 
Hypoxia 
Hypoxia 
— 
Decreased O2 saturation 
with exercise (e.g., pulse 
oximeter <88%); 
intermittent supplemental 
oxygen  
Decreased O2 saturation 
at rest; continuous 
oxygen indicated 
Life-threatening; 
intubation or ventilation 
indicated  
Death 

 
PULMONARY/UPPER RESPIRATORY 
Page 3 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 58 - 
March 31, 2003, Publish Date: August 9, 2006 
Nasal cavity/paranasal 
sinus reactions 
Nasal/paranasal 
reactions 
Asymptomatic mucosal 
crusting, blood-tinged 
secretions 
Symptomatic stenosis or 
edema/narrowing 
interfering with airflow 
Stenosis with significant 
nasal obstruction; 
interfering with ADL 
Necrosis of soft tissue or 
bone 
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils 
– Select; Infection with unknown ANC – Select. 
Obstruction/stenosis of 
airway 
– Select: 
– Bronchus 
– Larynx 
– Pharynx 
– Trachea 
Airway obstruction  
– Select  
Asymptomatic obstruction 
or stenosis on exam, 
endoscopy, or radiograph 
Symptomatic (e.g., noisy 
airway breathing), but 
causing no respiratory 
distress; medical 
management indicated 
(e.g., steroids)  
Interfering with ADL; 
stridor or endoscopic 
intervention indicated 
(e.g., stent, laser)  
Life-threatening airway 
compromise; tracheotomy 
or intubation indicated 
Death 
Pleural effusion 
(non-malignant)  
Pleural effusion 
Asymptomatic 
Symptomatic, 
intervention such as 
diuretics or up to 2 
therapeutic 
thoracenteses indicated 
Symptomatic and 
supplemental oxygen,  
>2 therapeutic 
thoracenteses, tube 
drainage, or pleurodesis 
indicated 
Life-threatening (e.g., 
causing hemodynamic 
instability or ventilatory 
support indicated)  
Death 
ALSO CONSIDER: Atelectasis; Cough; Dyspnea (shortness of breath); Hypoxia; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes).  
NAVIGATION NOTE: Pleuritic pain is graded as Pain – Select in the PAIN CATEGORY. 
Pneumonitis/pulmonary 
infiltrates  
Pneumonitis 
Asymptomatic, 
radiographic findings only 
Symptomatic, not 
interfering with ADL  
Symptomatic, interfering 
with ADL; O2 indicated  
Life-threatening; 
ventilatory support 
indicated 
Death 
ALSO CONSIDER: Adult Respiratory Distress Syndrome (ARDS); Cough; Dyspnea (shortness of breath); Hypoxia; Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select; Pneumonitis/pulmonary infiltrates; 
Pulmonary fibrosis (radiographic changes). 
Pneumothorax  
Pneumothorax  
Asymptomatic, 
radiographic findings only 
Symptomatic; 
intervention indicated 
(e.g., hospitalization for 
observation, tube 
placement without 
sclerosis) 
Sclerosis and/or 
operative intervention 
indicated 
Life-threatening, causing 
hemodynamic instability 
(e.g., tension 
pneumothorax); 
ventilatory support 
indicated 
Death 
Prolonged chest tube 
drainage or air leak after 
pulmonary resection 
Chest tube drainage or 
leak 
— 
Sclerosis or additional 
tube thoracostomy 
indicated 
Operative intervention 
indicated (e.g., 
thoracotomy with stapling 
or sealant application) 
Life-threatening; 
debilitating; organ 
resection indicated 
Death 

 
PULMONARY/UPPER RESPIRATORY 
Page 4 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 59 - 
March 31, 2003, Publish Date: August 9, 2006 
Prolonged intubation 
after pulmonary resection 
(>24 hrs after surgery)  
Prolonged intubation 
— 
Extubated within  
24 – 72 hrs 
postoperatively 
Extubated >72 hrs 
postoperatively, but 
before tracheostomy 
indicated 
Tracheostomy indicated 
Death 
NAVIGATION NOTE: Pulmonary embolism is graded as Grade 4 either as Thrombosis/embolism (vascular access-related) or Thrombosis/thrombus/embolism in the VASCULAR 
CATEGORY.  
Pulmonary fibrosis 
(radiographic changes)  
Pulmonary fibrosis 
Minimal radiographic 
findings (or patchy or bi-
basilar changes) with 
estimated radiographic 
proportion of total lung 
volume that is fibrotic of 
<25% 
Patchy or bi-basilar 
changes with estimated 
radiographic proportion of 
total lung volume that is 
fibrotic of 25 – <50% 
Dense or widespread 
infiltrates/consolidation 
with estimated 
radiographic proportion of 
total lung volume that is 
fibrotic of 50 – <75% 
Estimated radiographic 
proportion of total lung 
volume that is fibrotic is 
≥75%; honeycombing 
Death 
REMARK: Fibrosis is usually a “late effect” seen >3 months after radiation or combined modality therapy (including surgery). It is thought to represent scar/fibrotic lung tissue. It may be 
difficult to distinguish from pneumonitis that is generally seen within 3 months of radiation or combined modality therapy.  
ALSO CONSIDER: Adult Respiratory Distress Syndrome (ARDS); Cough; Dyspnea (shortness of breath); Hypoxia; Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select. 
NAVIGATION NOTE: Recurrent laryngeal nerve dysfunction is graded as Laryngeal nerve dysfunction in the NEUROLOGY CATEGORY. 
Vital capacity  
Vital capacity 
90 – 75% of predicted 
value 
<75 – 50% of predicted 
value 
<50 – 25% of predicted 
value 
<25% of predicted value 
Death 
Voice changes/dysarthria 
(e.g., hoarseness, loss or 
alteration in voice, 
laryngitis)  
Voice changes  
Mild or intermittent 
hoarseness or voice 
change, but fully 
understandable 
Moderate or persistent 
voice changes, may 
require occasional 
repetition but 
understandable on 
telephone 
Severe voice changes 
including predominantly 
whispered speech; may 
require frequent repetition 
or face-to-face contact for 
understandability; 
requires voice aid (e.g., 
electrolarynx) for ≤50% of 
communication 
Disabling; 
non-understandable voice 
or aphonic; requires voice 
aid (e.g., electrolarynx) 
for >50% of 
communication or 
requires >50% written 
communication 
Death 
ALSO CONSIDER: Laryngeal nerve dysfunction; Speech impairment (e.g., dysphasia or aphasia). 
Pulmonary/Upper 
Respiratory – Other 
(Specify, __) 
Pulmonary – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling 
Death 

 
RENAL/GENITOURINARY 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 60 - 
March 31, 2003, Publish Date: August 9, 2006 
Bladder spasms 
Bladder spasms 
Symptomatic, intervention 
not indicated 
Symptomatic, 
antispasmodics indicated 
Narcotics indicated 
Major surgical 
intervention indicated 
(e.g., cystectomy) 
— 
Cystitis 
Cystitis 
Asymptomatic 
Frequency with dysuria; 
macroscopic hematuria 
Transfusion; IV pain 
medications; bladder 
irrigation indicated 
Catastrophic bleeding; 
major non-elective 
intervention indicated 
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils 
– Select; Infection with unknown ANC – Select; Pain – Select. 
Fistula, GU 
– Select:  
– Bladder 
– Genital tract-female 
– Kidney 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
Fistula, GU – Select  
Asymptomatic, 
radiographic findings only 
Symptomatic; 
noninvasive intervention 
indicated  
Symptomatic interfering 
with ADL; invasive 
intervention indicated  
Life-threatening 
consequences; operative 
intervention requiring 
partial or full organ 
resection; permanent 
urinary diversion  
Death 
REMARK: A fistula is defined as an abnormal communication between two body cavities, potential spaces, and/or the skin. The site indicated for a fistula should be the site from which 
the abnormal process is believed to have originated. 
Incontinence, urinary  
Incontinence, urinary 
Occasional (e.g., with 
coughing, sneezing, etc.), 
pads not indicated 
Spontaneous, pads 
indicated  
Interfering with ADL; 
intervention indicated 
(e.g., clamp, collagen 
injections) 
Operative intervention 
indicated (e.g., 
cystectomy or permanent 
urinary diversion) 
— 
Leak (including 
anastomotic), GU 
– Select: 
– Bladder 
– Fallopian tube  
– Kidney 
– Spermatic cord 
– Stoma 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Leak, GU – Select  
Asymptomatic, 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic, interfering 
with GU function; invasive 
or endoscopic 
intervention indicated 
Life-threatening 
Death 
REMARK: Leak (including anastomotic), GU – Select refers to clinical signs and symptoms or radiographic confirmation of anastomotic leak but without development of fistula. 

 
RENAL/GENITOURINARY 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 61 - 
March 31, 2003, Publish Date: August 9, 2006 
Obstruction, GU  
– Select: 
– Bladder 
– Fallopian tube 
– Prostate 
– Spermatic cord 
– Stoma 
– Testes 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Obstruction, GU – Select  
Asymptomatic, 
radiographic or 
endoscopic findings only 
Symptomatic but no 
hydronephrosis, sepsis or 
renal dysfunction; dilation 
or endoscopic repair or 
stent placement indicated 
Symptomatic and altered 
organ function (e.g., 
sepsis or hydronephrosis, 
or renal dysfunction); 
operative intervention 
indicated  
Life-threatening 
consequences; organ 
failure or operative 
intervention requiring 
complete organ resection 
indicated  
Death 
NAVIGATION NOTE: Operative injury is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY CATEGORY.  
Perforation, GU  
– Select: 
– Bladder 
– Fallopian tube 
– Kidney  
– Ovary 
– Prostate 
– Spermatic cord 
– Stoma 
– Testes 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Perforation, GU – Select 
Asymptomatic 
radiographic findings only 
Symptomatic, associated 
with altered renal/GU 
function 
Symptomatic, operative 
intervention indicated 
Life-threatening 
consequences or organ 
failure; operative 
intervention requiring 
organ resection indicated 
Death 
Prolapse of stoma, GU 
Prolapse stoma, GU 
Asymptomatic; special 
intervention, 
extraordinary care not 
indicated 
Extraordinary local care 
or maintenance; minor 
revision under local 
anesthesia indicated 
Dysfunctional stoma; 
operative intervention or 
major stomal revision 
indicated 
Life-threatening 
consequences 
Death 
REMARK: Other stoma complications may be graded as Fistula, GU – Select; Leak (including anastomotic), GU – Select; Obstruction, GU – Select; Perforation, GU – Select; 
Stricture/stenosis (including anastomotic), GU – Select. 
Renal failure  
Renal failure 
— 
— 
Chronic dialysis not 
indicated 
Chronic dialysis or renal 
transplant indicated 
Death 
ALSO CONSIDER: Glomerular filtration rate. 

 
RENAL/GENITOURINARY 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 62 - 
March 31, 2003, Publish Date: August 9, 2006 
Stricture/stenosis 
(including anastomotic), 
GU 
– Select: 
– Bladder 
– Fallopian tube 
– Prostate 
– Spermatic cord 
– Stoma 
– Testes 
– Ureter  
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Stricture, anastomotic, 
GU – Select  
Asymptomatic, 
radiographic or 
endoscopic findings only 
Symptomatic but no 
hydronephrosis, sepsis or 
renal dysfunction; dilation 
or endoscopic repair or 
stent placement indicated 
Symptomatic and altered 
organ function (e.g., 
sepsis or hydronephrosis, 
or renal dysfunction); 
operative intervention 
indicated  
Life-threatening 
consequences; organ 
failure or operative 
intervention requiring 
organ resection indicated  
Death 
ALSO CONSIDER: Obstruction, GU – Select. 
Urinary electrolyte 
wasting (e.g., Fanconi’s 
syndrome, renal tubular 
acidosis) 
Urinary electrolyte 
wasting 
Asymptomatic, 
intervention not indicated 
Mild, reversible and 
manageable with 
replacement 
Irreversible, requiring 
continued replacement  
— 
— 
ALSO CONSIDER: Acidosis (metabolic or respiratory); Bicarbonate, serum-low; Calcium, serum-low (hypocalcemia); Phosphate, serum-low (hypophosphatemia). 
Urinary 
frequency/urgency 
Urinary frequency 
Increase in frequency or 
nocturia up to 2 x normal; 
enuresis 
Increase >2 x normal but 
<hourly 
≥1 x/hr; urgency; catheter 
indicated 
— 
— 
Urinary retention 
(including neurogenic 
bladder)  
Urinary retention 
Hesitancy or dribbling, no 
significant residual urine; 
retention occurring during 
the immediate 
postoperative period 
Hesitancy requiring 
medication; or operative 
bladder atony requiring 
indwelling catheter 
beyond immediate 
postoperative period but 
for <6 weeks 
More than daily 
catheterization indicated; 
urological intervention 
indicated (e.g., TURP, 
suprapubic tube, 
urethrotomy) 
Life-threatening 
consequences; organ 
failure (e.g., bladder 
rupture); operative 
intervention requiring 
organ resection indicated 
Death 
REMARK: The etiology of retention (if known) is graded as Obstruction, GU – Select; Stricture/stenosis (including anastomotic), GU – Select. 
ALSO CONSIDER: Obstruction, GU – Select; Stricture/stenosis (including anastomotic), GU – Select. 
Urine color change  
Urine color change 
Present 
— 
— 
— 
— 
REMARK: Urine color refers to change that is not related to other dietary or physiologic cause (e.g., bilirubin, concentrated urine, and hematuria). 
Renal/Genitourinary – 
Other (Specify, __) 
Renal – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
SECONDARY MALIGNANCY 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 63 - 
March 31, 2003, Publish Date: August 9, 2006 
Secondary Malignancy – 
possibly related to cancer 
treatment (Specify, __)  
Secondary Malignancy 
(possibly related to 
cancer treatment) 
— 
— 
Non-life-threatening basal 
or squamous cell 
carcinoma of the skin 
Solid tumor, leukemia or 
lymphoma  
Death 
REMARK: Secondary malignancy excludes metastasis from initial primary. Any malignancy possibly related to cancer treatment (including AML/MDS) should be reported via the routine 
reporting mechanisms outlined in each protocol. Important: Secondary Malignancy is an exception to NCI Expedited Adverse Event Reporting Guidelines. Secondary Malignancy is 
“Grade 4, present” but NCI does not require AdEERS Expedited Reporting for any (related or unrelated to treatment) Secondary Malignancy. A diagnosis of AML/MDS following 
treatment with an NCI-sponsored investigational agent is to be reported using the form available from the CTEP Web site at http://ctep.cancer.gov. Cancers not suspected of being 
treatment-related are not to be reported here. 

 
SEXUAL/REPRODUCTIVE FUNCTION 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 64 - 
March 31, 2003, Publish Date: August 9, 2006 
Breast function/lactation 
Breast function 
Mammary abnormality, 
not functionally significant 
Mammary abnormality, 
functionally significant 
— 
— 
— 
Breast nipple/areolar 
deformity  
Nipple/areolar 
Limited areolar 
asymmetry with no 
change in nipple/areolar 
projection 
Asymmetry of nipple 
areolar complex with 
slight deviation in nipple 
projection 
Marked deviation of 
nipple projection  
— 
— 
Breast volume/hypoplasia 
Breast 
Minimal asymmetry; 
minimal hypoplasia 
Asymmetry exists, ≤1/3 of 
the breast volume; 
moderate hypoplasia  
Asymmetry exists, >1/3 of 
the breast volume; severe 
hypoplasia 
— 
— 
REMARK: Breast volume is referenced with both arms straight overhead. 
NAVIGATION NOTE: Dysmenorrhea is graded as Pain – Select in the PAIN CATEGORY.  
NAVIGATION NOTE: Dyspareunia is graded as Pain – Select in the PAIN CATEGORY.  
NAVIGATION NOTE: Dysuria (painful urination) is graded as Pain – Select in the PAIN CATEGORY.  
Erectile dysfunction 
Erectile dysfunction 
Decrease in erectile 
function 
(frequency/rigidity of 
erections) but erectile 
aids not indicated 
Decrease in erectile 
function 
(frequency/rigidity of 
erections), erectile aids 
indicated 
Decrease in erectile 
function 
(frequency/rigidity of 
erections) but erectile 
aids not helpful; penile 
prosthesis indicated 
— 
— 
Ejaculatory dysfunction 
Ejaculatory dysfunction 
Diminished ejaculation 
Anejaculation or 
retrograde ejaculation 
— 
— 
— 
NAVIGATION NOTE: Feminization of male is graded in the ENDOCRINE CATEGORY. 
Gynecomastia 
Gynecomastia 
— 
Asymptomatic breast 
enlargement 
Symptomatic breast 
enlargement; intervention 
indicated 
— 
— 
ALSO CONSIDER: Pain – Select.  
Infertility/sterility 
Infertility/sterility 
— 
Male: oligospermia/low 
sperm count 
Female: diminished 
fertility/ovulation 
Male: sterile/azoospermia 
Female: infertile/ 
anovulatory 
— 
— 
Irregular menses  
(change from baseline) 
Irregular menses 
1 – 3 months without 
menses 
>3 – 6 months without 
menses but continuing 
menstrual cycles 
Persistent amenorrhea 
for >6 months 
— 
— 

 
SEXUAL/REPRODUCTIVE FUNCTION 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 65 - 
March 31, 2003, Publish Date: August 9, 2006 
Libido 
Libido 
Decrease in interest but 
not affecting relationship; 
intervention not indicated 
Decrease in interest and 
adversely affecting 
relationship; intervention 
indicated 
— 
— 
— 
NAVIGATION NOTE: Masculinization of female is graded in the ENDOCRINE CATEGORY. 
Orgasmic dysfunction 
Orgasmic function 
Transient decrease 
Decrease in orgasmic 
response requiring 
intervention 
Complete inability of 
orgasmic response; not 
responding to intervention 
— 
— 
NAVIGATION NOTE: Pelvic pain is graded as Pain – Select in the PAIN CATEGORY. 
NAVIGATION NOTE: Ulcers of the labia or perineum are graded as Ulceration in DERMATOLOGY/SKIN CATEGORY. 
Vaginal discharge  
(non-infectious) 
Vaginal discharge 
Mild 
Moderate to heavy; pad 
use indicated 
— 
— 
— 
Vaginal dryness 
Vaginal dryness 
Mild 
Interfering with sexual 
function; dyspareunia; 
intervention indicated 
— 
— 
— 
ALSO CONSIDER: Pain – Select. 
Vaginal mucositis 
Vaginal mucositis 
Erythema of the mucosa; 
minimal symptoms 
Patchy ulcerations; 
moderate symptoms or 
dyspareunia 
Confluent ulcerations; 
bleeding with trauma; 
unable to tolerate vaginal 
exam, sexual intercourse 
or tampon placement  
Tissue necrosis; 
significant spontaneous 
bleeding; life-threatening 
consequences 
— 
Vaginal stenosis/length 
Vaginal stenosis 
Vaginal narrowing and/or 
shortening not interfering 
with function  
Vaginal narrowing and/or 
shortening interfering with 
function  
Complete obliteration; not 
surgically correctable 
— 
— 
Vaginitis (not due to 
infection) 
Vaginitis 
Mild, intervention not 
indicated 
Moderate, intervention 
indicated 
Severe, not relieved with 
treatment; ulceration, but 
operative intervention not 
indicated 
Ulceration and operative 
intervention indicated 
— 
Sexual/Reproductive 
Function – Other 
(Specify, __) 
Sexual – Other (Specify) 
Mild 
Moderate 
Severe 
Disabling 
Death 

 
SURGERY/INTRA-OPERATIVE INJURY 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 66 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Intra-operative hemorrhage is graded as Hemorrhage/bleeding associated with surgery, intra-operative or postoperative in the HEMORRHAGE/BLEEDING 
CATEGORY.  
Intra-operative injury  
– Select Organ or 
Structure 
‘Select’ AEs appear at the 
end of the CATEGORY. 
Intraop injury – Select  
Primary repair of injured 
organ/structure indicated  
Partial resection of 
injured organ/structure 
indicated 
Complete resection or 
reconstruction of injured 
organ/structure indicated 
Life threatening 
consequences; disabling 
— 
REMARK: The ‘Select’ AEs are defined as significant, unanticipated injuries that are recognized at the time of surgery. These AEs do not refer to additional surgical procedures that 
must be performed because of a change in the operative plan based on intra-operative findings. Any sequelae resulting from the intra-operative injury that result in an adverse 
outcome for the patient must also be recorded and graded under the relevant CTCAE Term. 
Intra-operative Injury – 
Other (Specify, __) 
Intraop Injury – Other 
(Specify) 
Primary repair of injured 
organ/structure indicated  
Partial resection of 
injured organ/structure 
indicated 
Complete resection or 
reconstruction of injured 
organ/structure indicated 
Life threatening 
consequences; disabling 
— 
REMARK: Intra-operative Injury – Other (Specify, __) is to be used only to report an organ/structure not included in the ‘Select’ AEs found at the end of the CATEGORY. Any sequelae 
resulting from the intra-operative injury that result in an adverse outcome for the patient must also be recorded and graded under the relevant CTCAE Term. 

 
SURGERY/INTRA-OPERATIVE INJURY – SELECT  
Page 2 of 2 
CTCAE v3.0  
- 67 - 
March 31, 2003, Publish Date: August 9, 2006 
AUDITORY/EAR 
– Inner ear  
– Middle ear  
– Outer ear NOS  
– Outer ear-Pinna  
CARDIOVASCULAR 
– Artery-aorta  
– Artery-carotid  
– Artery-cerebral  
– Artery-extremity (lower)  
– Artery-extremity (upper)  
– Artery-hepatic  
– Artery-major visceral artery  
– Artery-pulmonary  
– Artery NOS 
– Heart  
– Spleen 
– Vein-extremity (lower)  
– Vein-extremity (upper)  
– Vein-hepatic  
– Vein-inferior vena cava  
– Vein-jugular  
– Vein-major visceral vein  
– Vein-portal vein  
– Vein-pulmonary  
– Vein-superior vena cava  
– Vein NOS 
DERMATOLOGY/SKIN 
– Breast  
– Nails  
– Skin 
ENDOCRINE 
– Adrenal gland 
– Parathyroid 
– Pituitary  
ENDOCRINE (continued) 
– Thyroid 
HEAD AND NECK 
– Gingiva  
– Larynx  
– Lip/perioral area  
– Face NOS  
– Nasal cavity  
– Nasopharynx  
– Neck NOS 
– Nose  
– Oral cavity NOS  
– Parotid gland  
– Pharynx  
– Salivary duct  
– Salivary gland  
– Sinus  
– Teeth  
– Tongue  
– Upper aerodigestive NOS 
GASTROINTESTINAL 
– Abdomen NOS  
– Anal sphincter  
– Anus 
– Appendix  
– Cecum  
– Colon  
– Duodenum  
– Esophagus  
– Ileum  
– Jejunum  
– Oral  
– Peritoneal cavity  
– Rectum 
– Small bowel NOS 
GASTROINTESTINAL (continued) 
– Stoma (GI)  
– Stomach  
HEPATOBILIARY/ PANCREAS 
– Biliary tree-common bile  
duct  
– Biliary tree-common hepatic 
duct  
– Biliary tree-left hepatic duct  
– Biliary tree-right hepatic duct  
– Biliary tree NOS  
– Gallbladder  
– Liver 
– Pancreas 
– Pancreatic duct 
MUSCULOSKELETAL 
– Bone  
– Cartilage  
– Extremity-lower 
– Extremity-upper 
– Joint  
– Ligament  
– Muscle  
– Soft tissue NOS 
– Tendon 
NEUROLOGY  
– Brain  
– Meninges  
– Spinal cord 
NERVES: 
– Brachial plexus 
– CN I (olfactory) 
– CN II (optic) 
– CN III (oculomotor) 
– CN IV (trochlear)  
NEUROLOGY (continued) 
NERVES: 
– CN V (trigeminal) motor  
– CN V (trigeminal) sensory  
– CN VI (abducens)  
– CN VII (facial) motor-face  
– CN VII (facial) sensory-
taste  
– CN VIII (vestibulocochlear)  
– CN IX (glossopharyngeal) 
motor pharynx  
– CN IX (glossopharyngeal) 
sensory ear-pharynx-
tongue  
– CN X (vagus)  
– CN XI (spinal accessory)  
– CN XII (hypoglossal)  
– Cranial nerve or branch 
NOS  
– Lingual  
– Lung thoracic  
– Peripheral motor NOS 
– Peripheral sensory NOS 
– Recurrent laryngeal  
– Sacral plexus  
– Sciatic 
– Thoracodorsal 
OCULAR 
– Conjunctiva  
– Cornea  
– Eye NOS 
– Lens 
– Retina 
PULMONARY/UPPER 
RESPIRATORY 
– Bronchus  
– Lung  
– Mediastinum  
– Pleura  
– Thoracic duct  
– Trachea 
– Upper airway NOS 
RENAL/GENITOURINARY 
– Bladder  
– Cervix  
– Fallopian tube  
– Kidney  
– Ovary  
– Pelvis NOS  
– Penis  
– Prostate  
– Scrotum  
– Testis  
– Ureter  
– Urethra  
– Urinary conduit  
– Urinary tract NOS  
– Uterus  
– Vagina  
– Vulva 
 
 

 
SYNDROMES 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 68 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Acute vascular leak syndrome is graded in the VASCULAR CATEGORY. 
NAVIGATION NOTE: Adrenal insufficiency is graded in the ENDOCRINE CATEGORY. 
NAVIGATION NOTE: Adult Respiratory Distress Syndrome (ARDS) is graded in the PULMONARY/UPPER RESPIRATORY CATEGORY. 
Alcohol intolerance 
syndrome (antabuse-like 
syndrome) 
Alcohol intolerance 
syndrome 
— 
— 
Present 
— 
Death 
REMARK: An antabuse-like syndrome occurs with some new anti-androgens (e.g., nilutamide) when patient also consumes alcohol. 
NAVIGATION NOTE: Autoimmune reaction is graded as Autoimmune reaction/hypersensitivity (including drug fever) in the ALLERGY/IMMUNOLOGY CATEGORY. 
Cytokine release 
syndrome/acute infusion 
reaction 
Cytokine release 
syndrome 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDS, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption of 
infusion); recurrence of 
symptoms following initial 
improvement; 
hospitalization indicated 
for other clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates) 
Life-threatening; pressor 
or ventilatory support 
indicated 
Death 
REMARK: Cytokine release syndromes/acute infusion reactions are different from Allergic/hypersensitive reactions, although some of the manifestations are common to both AEs. An 
acute infusion reaction may occur with an agent that causes cytokine release (e.g., monoclonal antibodies or other biological agents). Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hrs of completion of infusion. Signs/symptoms may include: Allergic reaction/hypersensitivity (including drug 
fever); Arthralgia (joint pain); Bronchospasm; Cough; Dizziness; Dyspnea (shortness of breath); Fatigue (asthenia, lethargy, malaise); Headache; Hypertension; Hypotension; Myalgia 
(muscle pain); Nausea; Pruritis/itching; Rash/desquamation; Rigors/chills; Sweating (diaphoresis); Tachycardia; Tumor pain (onset or exacerbation of tumor pain due to treatment); 
Urticaria (hives, welts, wheals); Vomiting.  
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever); Bronchospasm, wheezing; Dyspnea (shortness of breath); Hypertension; Hypotension; Hypoxia; Prolonged 
QTc interval; Supraventricular and nodal arrhythmia – Select; Ventricular arrhythmia – Select.  
NAVIGATION NOTE: Disseminated intravascular coagulation (DIC) is graded in the COAGULATION CATEGORY. 
NAVIGATION NOTE: Fanconi’s syndrome is graded as Urinary electrolyte wasting (e.g., Fanconi’s syndrome, renal tubular acidosis) in the RENAL/GENITOURINARY CATEGORY. 
Flu-like syndrome 
Flu-like syndrome 
Symptoms present but 
not interfering with 
function 
Moderate or causing 
difficulty performing some 
ADL 
Severe symptoms 
interfering with ADL 
Disabling 
Death 
REMARK: Flu-like syndrome represents a constellation of symptoms which may include cough with catarrhal symptoms, fever, headache, malaise, myalgia, prostration, and is to be 
used when the symptoms occur in a cluster consistent with one single pathophysiological process. 
NAVIGATION NOTE: Renal tubular acidosis is graded as Urinary electrolyte wasting (e.g., Fanconi’s syndrome, renal tubular acidosis) in the RENAL/GENITOURINARY CATEGORY. 

 
SYNDROMES 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 69 - 
March 31, 2003, Publish Date: August 9, 2006 
“Retinoic acid syndrome”  
“Retinoic acid syndrome” 
Fluid retention; less than 
3 kg of weight gain; 
intervention with fluid 
restriction and/or diuretics 
indicated 
Mild to moderate signs/ 
symptoms; steroids 
indicated 
Severe signs/symptoms; 
hospitalization indicated 
Life-threatening; 
ventilatory support 
indicated 
Death 
REMARK: Patients with acute promyelocytic leukemia may experience a syndrome similar to “retinoic acid syndrome” in association with other agents such as arsenic trioxide. The 
syndrome is usually manifested by otherwise unexplained fever, weight gain, respiratory distress, pulmonary infiltrates and/or pleural effusion, with or without leukocytosis.  
ALSO CONSIDER: Acute vascular leak syndrome; Pleural effusion (non-malignant); Pneumonitis/pulmonary infiltrates. 
NAVIGATION NOTE: SIADH is graded as Neuroendocrine: ADH secretion abnormality (e.g., SIADH or low ADH) in the ENDOCRINE CATEGORY.  
NAVIGATION NOTE: Stevens-Johnson syndrome is graded as Rash: erythema multiforme (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis) in the DERMATOLOGY/SKIN 
CATEGORY. 
NAVIGATION NOTE: Thrombotic microangiopathy is graded as Thrombotic microangiopathy (e.g., thrombotic thrombocytopenic purpura [TTP] or hemolytic uremic syndrome [HUS]) in 
the COAGULATION CATEGORY. 
Tumor flare 
Tumor flare 
Mild pain not interfering 
with function 
Moderate pain; pain or 
analgesics interfering with 
function, but not 
interfering with ADL 
Severe pain; pain or 
analgesics interfering with 
function and interfering 
with ADL 
Disabling 
Death 
REMARK: Tumor flare is characterized by a constellation of signs and symptoms in direct relation to initiation of therapy (e.g., anti-estrogens/androgens or additional hormones). The 
symptoms/signs include tumor pain, inflammation of visible tumor, hypercalcemia, diffuse bone pain, and other electrolyte disturbances.  
ALSO CONSIDER: Calcium, serum-high (hypercalcemia). 
Tumor lysis syndrome 
Tumor lysis syndrome 
— 
— 
Present 
— 
Death 
ALSO CONSIDER: Creatinine; Potassium, serum-high (hyperkalemia). 
Syndromes – Other 
(Specify, __) 
Syndromes – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
VASCULAR 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 70 - 
March 31, 2003, Publish Date: August 9, 2006 
Acute vascular leak 
syndrome 
Acute vascular leak 
syndrome 
— 
Symptomatic, fluid 
support not indicated 
Respiratory compromise 
or fluids indicated 
Life-threatening; pressor 
support or ventilatory 
support indicated  
Death 
Peripheral arterial 
ischemia 
Peripheral arterial 
ischemia 
— 
Brief (<24 hrs) episode of 
ischemia managed non-
surgically and without 
permanent deficit 
Recurring or prolonged 
(≥24 hrs) and/or invasive 
intervention indicated 
Life-threatening, disabling 
and/or associated with 
end organ damage 
(e.g., limb loss) 
Death 
Phlebitis (including 
superficial thrombosis) 
Phlebitis 
— 
Present 
— 
— 
— 
ALSO CONSIDER: Injection site reaction/extravasation changes. 
Portal vein flow 
Portal flow 
— 
Decreased portal vein 
flow 
Reversal/retrograde 
portal vein flow 
— 
— 
Thrombosis/embolism 
(vascular access-related) 
Thrombosis/embolism 
(vascular access) 
— 
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
not indicated 
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
indicated 
Embolic event including 
pulmonary embolism or 
life-threatening thrombus 
Death 
Thrombosis/thrombus/ 
embolism 
Thrombosis/thrombus/ 
embolism 
— 
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
not indicated  
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
indicated  
Embolic event including 
pulmonary embolism or 
life-threatening thrombus 
Death 
Vessel injury-artery  
– Select:  
– Aorta 
– Carotid 
– Extremity-lower 
– Extremity-upper  
– Other NOS 
– Visceral 
Artery injury – Select 
Asymptomatic diagnostic 
finding; intervention not 
indicated 
Symptomatic (e.g., 
claudication); not 
interfering with ADL; 
repair or revision not 
indicated 
Symptomatic interfering 
with ADL; repair or 
revision indicated 
Life-threatening; 
disabling; evidence of 
end organ damage (e.g., 
stroke, MI, organ or limb 
loss) 
Death 
NAVIGATION NOTE: Vessel injury to an artery intra-operatively is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY 
CATEGORY. 

 
VASCULAR 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 71 - 
March 31, 2003, Publish Date: August 9, 2006 
Vessel injury-vein  
– Select: 
– Extremity-lower  
– Extremity-upper 
– IVC 
– Jugular 
– Other NOS 
– SVC 
– Viscera 
Vein injury – Select 
Asymptomatic diagnostic 
finding; intervention not 
indicated 
Symptomatic (e.g., 
claudication); not 
interfering with ADL; 
repair or revision not 
indicated  
Symptomatic interfering 
with ADL; repair or 
revision indicated 
Life-threatening; 
disabling; evidence of 
end organ damage  
Death 
NAVIGATION NOTE: Vessel injury to a vein intra-operatively is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY CATEGORY. 
Visceral arterial ischemia 
(non-myocardial) 
Visceral arterial ischemia 
— 
Brief (<24 hrs) episode of 
ischemia managed 
medically and without 
permanent deficit 
Prolonged (≥24 hrs) or 
recurring symptoms 
and/or invasive 
intervention indicated 
Life-threatening; 
disabling; evidence of 
end organ damage  
Death 
ALSO CONSIDER: CNS cerebrovascular ischemia.  
Vascular – Other  
(Specify, __) 
Vascular – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
 

Clinical Trial Protocol:  HGT-SAN-067
Study Title:
An Open-Label Extension of Study HGT-SAN-055 Evaluating 
Long-Term Safety and Clinical Outcomes of Intrathecal 
Administration of rhHNS in Patients with Sanfilippo Syndrome
Type A (MPS IIIA)
Study Number:
HGT-SAN-067
Study Phase:
I/II
Product Name:
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Device Names:
SOPH-A-PORT® Mini S, Implantable Access Port, Spinal, Mini 
Unattached, with Guidewire
and
PORT-A-CATH® II Low Profile™Intrathecal Implantable Access 
System (Smiths device)
EudraCT 
Number:
2010-021348-16
Indication:
Sanfilippo Syndrome A
Investigators:
Multicenter
Sponsor:
Shire Human Genetic Therapies, Inc. 
300 Shire Way
Lexington, MA  02421, United States
Medical Monitor:
MD,
Date
Original Protocol:
21 June 2010
Amendment 1:
27 January 2011
Amendment 2:
13 January 2012
Amendment 3:
28 August 2012
Amendment 4:
3 May 2013
Amendment 5:
17 January 2014
Confidentiality Statement
This document is the proprietary and confidential property of 
Shire Human Genetic Therapies, Inc.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
2
TABLE OF CONTENTS
TABLE OF CONTENTS...........................................................................................................2
SYNOPSIS.................................................................................................................................7
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..........................................14
1
INTRODUCTION ...........................................................................................................18
1.1
Disease Background...............................................................................................18
1.2
Nonclinical Overview............................................................................................20
1.2.1
Toxicology in Monkeys ...............................................................................20
1.2.2
Efficacy in Murine and Canine Models of MPS IIIA..................................21
1.3
HGT-SAN-067 Study Rationale............................................................................21
2
STUDY OBJECTIVES....................................................................................................23
2.1
Primary Objective..................................................................................................23
2.2
Secondary Objectives.............................................................................................23
2.3
Exploratory Objective............................................................................................23
3
STUDY ENDPOINTS.....................................................................................................24
3.1
Primary Endpoint...................................................................................................24
3.2
Secondary Endpoints .............................................................................................24
3.3
SOPH-A-PORT Mini S Assessments....................................................................24
4
INVESTIGATIONAL PLAN..........................................................................................25
4.1
Overall Study Design and Plan..............................................................................25
4.2
Rationale for Study Design and Control Group.....................................................27
4.3
Study Duration and Dates......................................................................................27
5
STUDY POPULATION SELECTION ...........................................................................28
5.1
Study Population....................................................................................................28
5.2
Inclusion Criteria ...................................................................................................28
5.3
Exclusion Criteria ..................................................................................................28
6
STUDY TREATMENT(S)..............................................................................................30
6.1
Description of Treatment(s)...................................................................................30
6.1.1
Study Drug...................................................................................................30
6.1.2
Intrathecal Drug Delivery Device................................................................30
6.1.3
Placebo or Control .......................................................................................30
6.2
Treatment Administered ........................................................................................30
6.3
Selection and Timing of Dose for Each Patient.....................................................31
6.3.1
Cerebral Spinal Fluid Sample Procedure.....................................................31
6.3.2
Intrathecal Administration of HGT-1410 ....................................................32
6.3.3
Administration of HGT-1410 via Lumbar Puncture....................................32
6.4
Method of Assigning Patients to Treatment Groups..............................................33
6.5
Blinding..................................................................................................................33

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
3
6.6
Concomitant Therapy.............................................................................................33
6.7
Restrictions ............................................................................................................33
6.7.1
Prior Therapy ...............................................................................................33
6.7.2
Fluid and Food Intake..................................................................................33
6.7.3
Patient Activity Restrictions ........................................................................34
6.8
Treatment Compliance...........................................................................................34
6.9
Packaging and Labeling.........................................................................................34
6.9.1
Drug Product................................................................................................34
6.9.2
SOPH-A-PORT Mini S Access Port............................................................34
6.10
Storage and Accountability....................................................................................34
6.10.1
Investigational Product ................................................................................34
6.10.2
Intrathecal Drug Delivery Device................................................................35
6.10.2.1
PORT-A-CATH IDDD......................................................................35
6.10.2.2
SOPH-A-PORT Mini S IDDD...........................................................35
6.11
Investigational Product Retention at Study Site ....................................................35
7
STUDY PROCEDURES .................................................................................................36
7.1
Informed Consent...................................................................................................36
7.2
Physical Examination.............................................................................................36
7.3
Height and Weight .................................................................................................36
7.4
Head Circumference ..............................................................................................36
7.5
Vital Signs..............................................................................................................37
7.6
Electrocardiography...............................................................................................37
7.6.1
Electrocardiograms ......................................................................................37
7.7
Clinical Laboratory Tests.......................................................................................37
7.7.1
Hematology..................................................................................................37
7.7.2
Serum Chemistry .........................................................................................38
7.7.3
Pregnancy Test.............................................................................................38
7.7.4
Urinalysis .....................................................................................................38
7.7.4.1
Standard Urinalysis............................................................................38
7.7.4.2
Urine Heparan Sulfate and Heparan Sulfate Derivatives...................38
7.7.5
Cerebrospinal Fluid Assessments ................................................................39
7.7.5.1
Cerebrospinal Fluid Cell Counts........................................................39
7.7.5.2
Cerebrospinal Fluid Heparan Sulfate Levels and Heparan Sulfate 
Derivatives .........................................................................................39
7.7.5.3
Anti-rhHNS Antibodies .....................................................................39
7.7.5.4
Cerebrospinal Fluid Biomarkers........................................................39
7.7.6
Sample Collection, Storage, and Shipping ..................................................39
7.8
Anesthesia..............................................................................................................39
7.9
Audiometry and Auditory Brainstem Response ....................................................40

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
4
7.10
Magnetic Resonance Imaging of the Head ............................................................40
7.11
Device Data............................................................................................................40
7.12
Surgical Re-implantation of the IDDD..................................................................40
7.12.1
Restrictions on the Number of Revision and/or re-implantation of the 
IDDD ...........................................................................................................41
7.13
Device Related Study Procedures..........................................................................41
7.13.1
IDDD Implantation or Revision Procedures................................................41
7.13.2
X-ray Verification of Intrathecal Drug Delivery Device Placement ...........41
7.13.3
CSF Sampling Procedure.............................................................................42
7.13.4
Device Removal...........................................................................................42
7.14
Cerebrospinal Fluid Opening Pressure Measurement............................................42
7.15
Dispensing Study Drug..........................................................................................42
7.16
Pharmacokinetic Assessments ...............................................................................43
7.17
Neurological Examination .....................................................................................43
7.18
Anti-rhHNS Antibody, Heparan Sulfate, and Heparan Sulfate Derivative 
Determination ........................................................................................................43
7.19
Neurocognitive and Developmental Assessments.................................................43
7.20
Sleep Questionnaire:  Children’s Sleep Habits Rating Scale.................................45
7.21
Age-Dependent, Health-Related Quality of Life in Children................................45
7.21.1
Quality of Life Indicator:  CHQ-50 .............................................................45
7.21.2
Quality of Life Indicator:  CHQ-87 .............................................................45
7.21.3
Quality of Life Indicator:  ITQOL...............................................................45
7.22
Concomitant Medications, Therapies and Medical/Surgical Procedures ..............45
7.23
Adverse Events ......................................................................................................46
7.23.1
Definitions of Adverse Events and Serious Adverse Events.......................46
7.23.1.1
Adverse Event....................................................................................46
7.23.1.2
Potential Adverse Events: Intrathecal recombinant human heparan 
N-sulfatase .........................................................................................47
7.23.1.3
IDDD-related Adverse Events ...........................................................47
7.23.1.4
Serious Adverse Event.......................................................................48
7.23.2
Device-Associated Definitions ....................................................................48
7.23.2.1
Device Revision (Partial and Full).....................................................48
7.23.2.2
Device Malfunction ...........................................................................49
7.23.2.3
Device Failure....................................................................................49
7.23.3
Classification of Adverse Events and Serious Adverse Events...................49
7.23.4
Relatedness of Adverse Events and Serious Adverse Events......................50
7.23.5
Procedures for Recording and Reporting Adverse Events ..........................50
7.23.5.1
Reporting Serious Adverse Events Related to Study Procedures......50
7.23.5.2
Eliciting Adverse Events....................................................................52
7.23.5.3
Protocol Deviations for Medical Emergency or Adverse Event........52

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
5
7.24
Abuse, Overdose and Medication Errors...............................................................53
7.25
Safety-related Study Stopping Rules .....................................................................53
7.26
Pregnancy...............................................................................................................53
7.27
Removal of Patients from the Trial or Study Drug................................................54
7.28
Other Study Procedures .........................................................................................55
7.29
Appropriateness of Measurements.........................................................................55
8
STUDY ACTIVITIES .....................................................................................................56
8.1
Screening Visit/Study Start Visit...........................................................................56
8.2
Treatment:  Drug Administration and Weekly Assessments.................................57
8.2.1
Week 1 .........................................................................................................57
8.2.1.1
Day 1 (Pre-treatment) Assessments Performed Prior to Each Dose..57
8.2.1.2
Day 2 (±2 days) Assessments and Administration of HGT-1410 .....58
8.3
End of Study/Early Termination Procedures:  Month 55 ......................................58
8.4
Safety Follow-up (by Telephone or Visit) Month 56 ............................................59
9
QUALITY CONTROL AND ASSURANCE .................................................................61
10
PLANNED STATISTICAL METHODS ........................................................................62
10.1
General Statistical Methodology............................................................................62
10.2
Determination of Sample Size ...............................................................................62
10.3
Analysis Populations..............................................................................................62
10.4
Demographics and Baseline Characteristics..........................................................62
10.5
Statistical Analysis of Pharmacokinetic Variables ................................................63
10.6
Efficacy, Safety, and Pharmacodynamic Evaluations ...........................................63
10.6.1
Primary Analyses.........................................................................................63
10.6.1.1
Safety Analysis ..................................................................................63
10.6.2
Other Observations Related to Safety..........................................................64
10.6.2.1
IDDD Performance ............................................................................64
10.6.3
Secondary Analysis......................................................................................65
10.6.3.1
Clinical Assessments .........................................................................65
10.6.3.2
Pharmacodynamic Analyses ..............................................................65
11
ADMINISTRATIVE CONSIDERATIONS....................................................................66
11.1
Investigators and Study Administrative Structure.................................................66
11.2
Institutional Review Board or Independent Ethics Committee Approval .............66
11.3
Ethical Conduct of the Study.................................................................................66
11.4
Patient Information and Consent ...........................................................................66
11.5
Patient Confidentiality...........................................................................................67
11.6
Study Monitoring...................................................................................................67
11.7
Case Report Forms and Study Records .................................................................68
11.7.1
Critical Documents ......................................................................................68
11.8
Device Failure Adjudication Process.....................................................................69

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410) 
Clinical Trial Protocol: HGT-SAN-067 Amendment 5 
17 January 2014 
11.9 
Protocol Violations/Deviations..............................................................................69 
11.10 Access to Source Documentation ..........................................................................69 
11.11 Data Generation and Analysis ...............................................................................69 
11.12 Premature Closure of the Study.............................................................................70 
11.12.1 Study Termination .......................................................................................70 
11.12.2 Site Termination...........................................................................................70 
11.13 Retention of Data...................................................................................................70 
11.14 Financial Disclosure...............................................................................................70 
11.15 Publication and Disclosure Policy .........................................................................70 
12 LIST OF REFERENCES.................................................................................................72 
 
LIST OF IN-TEXT TABLES 
Table 7-1 
Neurodevelopmental Assessments Tests....................................................44 
Table 7-2 
Sanfilippo-Specific Disability Assessment And Behavior Rating 
Scales..........................................................................................................44 
Table 7-3 
Adverse Event Severity..............................................................................49 
Table 7-4 
Adverse Event Relatedness ........................................................................50 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Events.....................................................................................74 
Appendix 2 
Neurodevelopmental and Behavioral Assessments....................................77 
Appendix 3 
Expected Adverse Device Effects ..............................................................81 
Appendix 4 
Protocol Amendment 5 Summary of Changes...........................................83 
Appendix 5 
Protocol Signature Page .............................................................................84 
Appendix 6 
The National Cancer Institute Common Terminology Criteria version 
3.0...............................................................................................................85 
 
Shire 
Confidential 
6 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
7
SYNOPSIS
Sponsor:
Shire Human Genetic Therapies, Inc. 
300 Shire Way
Lexington, MA  02421, United States
Name of Finished Product:
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Name of Active Ingredient:
rhHNS, HGT-1410
Name of Inactive Ingredient:
N/A
Names of Devices:  
SOPH-A-PORTMini S, Implantable Access Port, Spinal, Mini Unattached, with 
Guidewire (SOPH-A-PORT Mini S)
and
PORT-A-CATHII Low ProfileIntrathecal Implantable Access System 
(PORT-A-CATH)
Study Title:
An Open-Label Extension of Study HGT-SAN-055 Evaluating Long-Term Safety and 
Clinical Outcomes of Intrathecal Administration of rhHNS in Patients with Sanfilippo 
Syndrome Type A (MPS IIIA) 
Study Number:
HGT-SAN-067
Study Phase:  I/II
Device, Intended Use
The SOPH-A-PORT Mini S is a system intended for implantation by physicians. The 
SOPH-A-PORT Mini S, once implanted, allows healthcare personnel to administer 
HGT-1410 indicated for intrathecal delivery intermittently over a long period of time.
Prior to approval of Amendment 4 patients were implanted with a PORT-A-CATH 
(Smith’s device). After approval of Amendment 4 all PORT-A-CATH IDDDs requiring 
revision or replacement will be replaced with a SOPH-A-PORT at a time judged 
appropriate by the Investigator.
Study Objectives:
Primary Objective: 
The primary objective of this study is:

To collect long-term safety and tolerability data in patients with Sanfilippo Syndrome 
Type A (MPS IIIA) who received HGT-1410 via a surgically implanted intrathecal 
drug delivery device (IDDD) in study HGT-SAN-055 and elected to continue therapy 
in study HGT-SAN-067.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
8
Secondary Objectives:
The secondary objectives of this study are:

To collect as measures of drug efficacy, over an extended treatment period (as change 
from baseline), the following:  clinical, neurological, cognitive, behavioral, 
functional, and quality of life (QoL) assessments, together with potential imaging and 
biochemical biomarkers.
Study Endpoints: 
Primary Endpoints:
The primary endpoints of this study are related to the long-term safety of intrathecal 
HGT-1410 administration. The safety endpoints are:

adverse events (type and severity)

changes in clinical laboratory testing (serum chemistry including  liver function tests, 
hematology, and urinalysis)

electrocardiograms (ECG)

cerebrospinal fluid (CSF) chemistries (including cell counts and inflammatory 
markers)

anti-rhHNS antibodies (in CSF and serum).
Secondary Endpoints:
The secondary endpoints of this study are to collect over an extended treatment period (as 
change from baseline) clinical and potential surrogate biomarker efficacy data:

Standardized neurocognitive and behavioral assessments, Sanfilippo-specific 
behavioral rating scales, gross and fine motor assessments, functional adaptive rating 
scales, quality of life questionnaires, and Children’s Sleep Habits Rating Scale.

Concentration of inflammatory cytokines in serum and CSF.

Concentration of safety and potential surrogate efficacy biomarkers in CSF, urine, 
and serum.

Concentration of heparan sulfate and heparan sulfate derivatives in urine and/or CSF, 
and if possible, in serum and/or plasma.

Brain magnetic resonance imaging (MRI) and auditory brainstem response (ABR), 
Brainstem Auditory Evoked Potentials).
Study Design:
This study, HGT-SAN-067, is an open-label, long term, multicenter, extension of 
Study HGT-SAN-055.  The study is designed to evaluate the long-term safety, clinical 
activity, and biomarker outcomes of intrathecal (IT) administration of 3 dose levels 
(10 mg, 45 mg, and 90 mg once per month [Q4W]) of HGT-1410 via an IDDD in patients 
with MPS IIIA who successfully complete the Phase I/II study HGT-SAN-055 (including 
end of study [EOS] assessments) and elect to continue to receive HGT-1410 treatment.  
Initially, patients will continue in the same treatment group they were assigned to in the 
HGT-SAN-055 study. Following approval of protocol Amendment 4, patients in the 
10 mg group will have their dose increased to 45 mg per month.
For nomenclature of chronology purposes, the Baseline Visit for this extension study will 
be considered to be the first day the patient received his/her IT dose of HGT-1410 in 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
9
Study HGT-SAN-055.  The HGT-SAN-055 EOS assessment information will provide the 
screening/start of study information for patients who continue into the HGT-SAN-067 
extension study.  Note:  HGT-SAN-055 EOS data must be recorded in the context of the 
HGT-SAN-055 trial, and a copy of those data can be used for HGT-SAN-067 screening.  
Once eligibility is confirmed, informed consent must be obtained prior to performing any 
study-related procedures that are specific to HGT-SAN-067.  
Informed consent will be provided by the patient’s parent(s)/legally authorized 
representative(s) prior to the start of the extension study procedures.  Informed consent 
may be obtained anytime from week 20 in HGT-SAN-055.  This would allow a patient to 
have a nonfunctional IDDD replaced or revised prior to the first HGT-1410 dose in 
HGT-SAN-067.
Enrolled patients will check in to the study center 1 day before each of the scheduled 
HGT-1410 dosing days for safety assessments (designated Day 1). If no safety concerns 
exist, the patient will subsequently receive IT administration of HGT-1410 on Day 2 
(±2 days). However, if feasible and there are no safety concerns in the opinion of the 
investigator, the Day 1 and Day 2 assessments may be combined and performed on 
Day 2; if this is done the results will be recorded as Day 2. Patients will remain in the 
study center for at least 4 hours following dosing with HGT-1410 and will be discharged 
from the unit when deemed clinically stable by the Investigator.
All patients will have received a series of standardized neurodevelopment assessments in 
the HGT-SAN-055 study.  These assessments will have occurred at Baseline and either 
prior to or at the 6-month time point. Patients will continue in HGT-SAN-067 with 
whichever age specific assessment they began with in HGT-SAN-055. If, however, a 
patient’s capability improves and they become capable of completing assessments at a 
higher level, such additional assessments may be added. Any additional assessments 
would be performed after the original assessments (those previously used in study 
HGT-SAN-055) have been carried out. A MRI of the head and ABR testing will be 
performed at Months 12, 24, 36, and 54 (note that assessment time point nomenclature 
includes the 6 months in the HGT-SAN-055 study). Note: X-rays may be performed to 
investigate device malfunction, and to verify correct catheter and port placement 
following surgical implantation or revision. In addition, fluoroscopy should be employed 
intraoperatively to guide catheter placement. Thus, patients may undergo 3 X-ray 
examinations in association with each episode of IDDD malfunction and subsequent 
IDDD revision or replacement. Since the number of IDDD revisions/replacements is 
limited to 2 in any 6-month period (including the time in the HGT-SAN-055 study), the 
number of protocol-associated X-ray evaluations is limited to 6 exposures in any 6-month 
period (including time in the HGT-SAN-055). Patients will also have X-ray examinations 
of the device performed at the EOS visit if the patient is to continue to receive intrathecal 
HGT-1410 beyond the end of the study.
Patients will be evaluated for safety throughout the study.  Adverse events that occur in 
HGT-SAN-055 and that are ongoing at enrollment in HGT-SAN-067 will be captured in 
the case report forms (CRFs) for study HGT-SAN-067.  Specific safety stopping criteria 
will be applied and will be based on the types and severity of adverse events (AEs) 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
10
reported while on-study.  These data will be reviewed to inform the decision to 
discontinue a patient, a dose group, or the study as a whole. 
All patients will have an EOS visit 30 (±7) days following their last administration of 
HGT-1410 (ie, Month 55).  The EOS procedures will include standard clinical laboratory 
tests (serum chemistry, hematology, and urinalysis) in CSF and blood, protocol specific 
laboratory testing (eg, anti-rhHNS antibody testing), neurodevelopmental testing, ABR, 
child health questionnaires, MRI and an X-ray examination of the device.  
Use of concomitant medications, therapies, and procedures will be recorded and AEs will 
be monitored. 
All patients will be contacted by telephone or will have a visit for a Final Safety 
Follow-up, to be conducted at 30 (±7) days after the EOS visit (ie, Month 56) to collect 
updated information on AEs and concomitant medications, therapies, and procedures. 
It is anticipated that the IDDD will be used to obtain CSF samples and to deliver 
administrations of HGT-1410.  However, if a patient’s IDDD appears nonfunctional or if 
its use is precluded on a scheduled day of dosing, site personnel will refer to the 
operations manual (for PORT-A-CATH) or the IDDD Manual (for SOPH-A-PORT), 
which describes the investigation and management of IDDD-related issues.  This will 
include possible partial revision or complete replacement of the IDDD.  As noted above, 
a maximum of 2 partial revisions and/or complete replacements can occur in any 6 month 
period.  If revision or replacement of the IDDD cannot be scheduled in time to avoid a 
delay of the next scheduled dose of HGT-1410, or if the patient experiences more than 
2 IDDD malfunctions in a 6 month period (including participation in study 
HGT-SAN-055), HGT-1410 will be administered via lumbar puncture (LP).  Study drug 
may be administered via LP for a maximum of 5 successive monthly doses, after which, 
IDDD re-implantation or revision must occur. 
If there is no significant safety risk in the opinion of the Investigator, a non-functional 
IDDD may be left in situ for up to 3 months.
In light of the higher than expected complications experienced with the PORT-A-CATH 
IDDD, the SOPH-A-PORT Mini S device will be introduced for those patients requiring 
replacement or revision.  This new device has design features anticipated to reduce 
complications encountered with the PORT-A-CATH IDDD device.  Specific device 
assessments are included in the protocol to collect information with respect to 
information specific to SOPH-A-PORT Mini S device safety and function.  
Patients who discontinue or are withdrawn before receiving 3 monthly IT injections will 
not have to undergo the EOS evaluations but will have their IDDD removed.  
Patients will have the IDDD removed when they discontinue from the study, unless the 
patient is continuing to receive treatment through another mechanism (eg, extension 
study, expanded access, commercially available).

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
11
An overview of the study appears in the Schedule of Events.
Study Population: 
A maximum of 12 patients are planned for this study.  To be eligible for participation 
patients will have completed all study requirements in Study HGT-SAN-055, including 
the EOS visit, and will have elected to continue treatment with HGT-1410. 
Test Product; Dose; and Mode of Administration: Recombinant human heparan 
N-sulfatase (rhHNS, HGT-1410) will be administered via an IDDD according to the same 
dose to which the patient was assigned in HGT-SAN-055 (ie, 10 mg, 45 mg, or 90 mg 
monthly). Patients assigned to the 10 mg monthly dose will have their dose increased to 
45 mg once per month (Q4W) at the first administration of HGT-1410 following full 
approval of the protocol amendment.
Reference Therapy; Dose; and Mode of Administration: 
N/A
Diagnosis and Main Criteria for Inclusion
Inclusion Criteria:
Each patient must meet the following criteria to be enrolled in this study.
1. The patient must have completed Study HGT-SAN-055 and, in the opinion of the 
investigator, have no safety or medical issues that contraindicate participation. 
2. The patient, patient’s parent(s) or legally authorized representative(s) has voluntarily 
signed an Institutional Review Board/Independent Ethics Committee-approved 
informed consent (and assent, if applicable) form after all relevant aspects of the 
study have been explained and discussed with them.  Informed consent/assent must be 
obtained prior to any study specific procedures.
3. The patient received at least 5 of the 6 planned infusions of HGT-1410 in the 
HGT-SAN-055 study. 
4. The patient must be medically stable, in the opinion of the Investigator, to 
accommodate the protocol requirements, including travel, assessments, and IDDD 
surgery (if necessary for replacement purposes), without placing an undue burden on 
the patient/patient's family.
Exclusion Criteria: 
Patients will be excluded from the study if there is evidence of any of the following:
1. The patient has experienced an adverse reaction to study drug in Study 
HGT-SAN-055 that contraindicates further treatment withHGT-1410.
5. The patient has a known hypersensitivity to the active ingredient or any excipients in 
HGT-1410 drug product.
6. The patient has non-MPS IIIA related central nervous system (CNS) impairment or 
behavioral disturbances that would confound the scientific integrity or interpretation 
of study assessments, as determined by the Investigator.
7. The patient has MPS IIIA behavioral-related issues, as determined by the 
Investigator, which would preclude performance of study neurocognitive and 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
12
developmental testing procedures.
8. The patient is pregnant, breast feeding, or is a patient of childbearing potential who 
will not or cannot comply with the use of an acceptable method of birth control, such 
as condoms, barrier method, oral contraception, etc.
9. The patient has any known or suspected hypersensitivity to anesthesia or is thought to 
have an unacceptably high risk for anesthesia due to airway compromise or other 
conditions.
10. The patient has a history of a poorly controlled seizure disorder. 
11. The patient is currently receiving psychotropic or other medications, which in the 
Investigator’s opinion, would be likely to substantially confound test results and the 
dose and regimen of which cannot be kept constant throughout the study.
12. The patient cannot sustain absence from aspirin, non-steroidal medications, or 
medications that affect blood clotting within 1 week prior to a relevant study-related 
procedure (eg, device re-implantation if applicable), or has ingested such medications 
within 1 week before any procedures in which any change in clotting activity would 
be deleterious.
13. The patient has received treatment with any investigational drug (other than 
HGT-1410) intended as a treatment for MPS IIIA within the 30 days prior to, during 
the study, or is currently enrolled in another study that involves an investigational 
drug or device (screening through safety follow-up contact).
14. The patient has received a hematopoietic stem cell or bone marrow transplant.
For patients to be implanted with the SOPH-A-PORT Mini S IDDD the following 
conditions are contraindicated, as described in the Instructions for Use: 
1. The patient has had, or may have, an allergic reaction to the materials of construction 
of the SOPH-A-PORT Mini S device
1. The patient’s body size is too small to support the size of the SOPH-A-PORT Mini S 
Access Port, as judged by the Investigator 
1. The patient has a known or suspected local or general infection
1. The patient is at risk of abnormal bleeding due to a medical condition or therapy
1. The patient has one or more spinal abnormalities that could complicate safe 
implantation or fixation
1. The patient has a functioning CSF shunt device
1. The patient has shown an intolerance to an implanted device
Duration of Treatment: 
The study duration will be 4 years.
Pharmacokinetic Variables:
N/A.
Safety Assessments: 
Safety evaluations will include vital signs, physical examinations, AE assessments, 
electrocardiograms (ECG); serum chemistry, hematology, urine laboratory tests, and 
screening for antibodies to rhHNS (in CSF and serum).  

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
13
Statistical Methods: The statistical methodology supporting the trial will focus on 
descriptive rather than inferential approaches, given the early phase and objectives of the 
trial. Data will be plotted and the mean, standard deviation, median, minimum, and 
maximum for each variable will be tabulated by dose group to look for gross trends over 
time, which may be attributed to treatment. For continuous data, 95% confidence interval 
(CI) around the mean will also be estimated and presented.
The analysis population consists of all eligible patients from HGT-SAN-055 who have 
completed Study HGT-SAN-055 and agreed to participate in this extension study.  Safety 
analyses will be performed using the above mentioned population.  The data will be 
presented by dose group.
Date of Original Protocol: 21 June 2010
Date of Amendment 5: 17 January 2014

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
14
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ABR
auditory brainstem response
AE
adverse event
ALB
albumin
ALK-P
alkaline phosphatase
ALT
alanine aminotransferase (SGPT)
AST
aspartate aminotransferase (SGOT)
βhCG
human chorionic gonadotropin
BSID-III
Bayley Scales of Infant Development, Third Edition
BBB
blood brain barrier
BUN
blood urea nitrogen
Ca
calcium
CE
Conformité Européenne
CFR
Code of Federal Regulations
CHQ-50
Child Health Questionnaire™ Parent Form 50
CHQ-87
Child Health Questionnaire™ Child Form 87
CK
creatine kinase
Cl
chloride
CNS
central nervous system
CO2
carbon dioxide
CTCAE
Common Terminology Criteria for Adverse Events
CRO
contract research organization
CRIM
cross-reacting immunologic material 
CS
clinically significant
CSF
cerebrospinal fluid
ECG
electrocardiogram
eCRF
electronic case report form
EDC
Electronic Data Capture 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
15
Abbreviation
Definition
ERT
enzyme replacement therapy
EOS
end of study
EOW
every other week
EU
European Union
FDA
Food and Drug Administration
FPSS/TDS
Four-Point Scoring System/Total Disability Score
GAG
glycosaminoglycan
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
Hct
hematocrit
Hgb
hemoglobin
HS
heparan sulfate
ICH
International Conference on Harmonization 
IDDD
intrathecal drug delivery device
IEC
Independent Ethics Committee
IFU
instructions for use
IND
Investigational New Drug 
IRB
Institutional Review Board
IT
intrathecal
ITQOL
Infant Toddler Quality of Life Questionnaire™
IV
intravenous
K
potassium
KABC-II
Kaufman Assessment Battery for Children, Second Edition
LDH
lactic dehydrogenase
LP
lumbar puncture 
LSD
lysosomal storage disease
M6P
mannose-6-phosphate
MABC-2
Movement Assessment Battery for Children

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
16
Abbreviation
Definition
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MABC-2
Movement Assessment Battery for Children, Second Edition
MPS
Mucopolysaccharidosis 
MPS IIIA
Mucopolysaccharidosis IIIA or Sanfilippo syndrome Type A
MRI
magnetic resonance imaging
Na
sodium 
NCI
National Cancer Institute
NCS
not clinically significant
PE
pressure-equalization
QoL
quality of life
Q4W
once per month
RBC
red blood cell (count)
rhHNS
recombinant human heparan N-sulfatase
RNA
ribonucleic acid
SAE
serious adverse event
SAP
Statistical Analysis Plan
SBRS
The Sanfilippo Behavior Rating Scale
SGOT
serum glutamic oxaloacetic transaminase (AST)
SGPT
serum glutamic pyruvic transaminase (ALT)
Shire HGT
Shire Human Genetic Therapies, Inc.
TMF
Trial Master File
TX
treatment
UADE
unanticipated adverse device effect
US
United States
VABS-II
Vineland Adaptive Behavior Scales 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
17
Abbreviation
Definition
WBC
white blood cell (count)
WHO-DD
WHO Drug Dictionary 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
18
1
INTRODUCTION
The progressive and irreversible nature of lysosomal storage diseases (LSDs) present a challenge 
in the interpretation of clinical benefit derived from treatment in studies using enzyme 
replacement therapy (ERT).  Any short-term improvement and/or stabilization of clinically 
important manifestations of the disease may be viewed as clinically meaningful.  However, the 
demonstration of the different aspects of a long-term, clinically-meaningful improvement may be 
limited by the short duration of treatment in clinical studies.  Extended access to treatment 
through extension studies provides an opportunity for further evaluation of long-term safety and 
clinical outcomes for treated patients.  In this extension study, patients who completed study 
HGT-SAN-055, a phase I/II safety and dose-escalation trial, and elected to continue to receive 
recombinant human heparan N-sulfatase (rhHNS), will receive treatment through this extension 
protocol.  Initially, the patient’s treatment group and dosing regimen will be the same as that 
employed in study HGT-SAN-055. Following the analysis of data from HGT-SAN-055, patients 
in the lowest dose group will have their dose increased to 45 mg, as outlined in Section 1.3, 
below.
1.1
Disease Background
Sanfilippo syndrome, or Mucopolysaccharidosis (MPS) III, is LSD caused by loss in activity of 
1 of 4 enzymes necessary for degradation of the glycosaminoglycan (GAG) heparan sulfate (HS) 
in lysosomes.  Four different subtypes (A, B, C, and D) have been identified and are each due to 
a specific enzyme deficiency involved in the lysosomal catabolism of HS.  
Mucopolysaccharidosis IIIA or Sanfilippo syndrome Type A (MPS IIIA) results from deficiency 
of the enzyme heparan N-sulfatase (sulfamidase).  In the absence of this enzyme, intermediates 
of the HS degradation process accumulate in the lysosomes of neurons and glial cells, with lesser 
accumulation outside the brain.  
MPS III is the most prevalent of all mucopolysaccharidoses, with subtype A the most common of 
these.1  The birth prevalence of MPS IIIA has been estimated as 1.28 in 100,000 in Australia, 
1.16 in 100,000 in the Netherlands, and 0.88 in 100,000 in Germany.1-3 In summary, MPS IIIA 
is a rare genetic disorder with apparently widespread geographic distribution and an average 
global birth incidence of approximately 1 in 100,000.
In a recent detailed review of all MPS IIIA patients diagnosed in the Netherlands, it was reported 
that among 81 patients in whom information was available, first symptoms arose at a median of 
2.5 years (range 0.5 to 7 years).4  Owing to the rarity of the disease and the non-specific and 
often subtle nature of its initial manifestations, diagnosis is usually delayed until an average age 
of 4 to 4.5 years.4, 5 Patients present a wide spectrum and severity of clinical symptoms.  The 
central nervous system (CNS) is the most severely affected organ system in patients with MPS 
IIIA, evidenced by deficits in language development, motor skills, and intellectual development.5  
In addition, there are abnormal behaviors including, but not limited to, aggression and excess 
motor activity/hyperactivity that contribute to disturbances in sleep.5 - 7 In contrast with other 
MPS types, the viscera are mildly affected, with transient enlargement of liver and spleen during
childhood with no evidence of dysfunction.  There are also reports of unexplained, recurrent and 
severe diarrhea.8  Overall, individuals with MPS IIIA have a marked developmental delay and 
significantly reduced lifespan of 15 years of age on average.8  

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
19
A milder variant has recently been identified with slower progression and survival to later age in 
approximately 10% of German patients with MPS IIIA.9
No effective, disease-modifying therapies are currently approved as treatments for this rare, 
devastating and disabling disease.  
A long-range goal of Shire Human Genetic Therapies, Inc. (Shire HGT) is to develop a 
recombinant human sulfamidase ERT for patients with MPS IIIA.  A particular problem for 
LSDs that damage the brain such as MPS III is how to target ERT to the brain.10  In animal 
studies, ERT was administered into the cerebrospinal fluid (CSF) via an intrathecal (IT) route, 
because when administered intravenously (IV), it was shown to not cross the blood brain barrier 
(BBB) after the immediate postnatal period of life.11, 12  
As the CNS in patients with MPS IIIA is the most severely affected body system, the main focus 
of the HGT-1410 clinical development program has been the development of ERT specifically 
for delivery directly to the CNS.  Recombinant human heparan N-sulfatase has been developed 
specifically for delivery into the CSF via an intrathecal drug delivery device (IDDD) due to the 
acknowledged impermeability of the BBB to macromolecules. 
Heparan N-sulfatase is a highly purified recombinant form of the naturally occurring human 
lysosomal enzyme sulfamidase.  It is expressed from the well characterized continuous human 
HT-1080 cell line as a 482 amino acid peptide, following cleavage of the 20 amino acid 
N-terminal signal peptide.  The mature protein in solution is a homodimeric glycoprotein of 
approximately 122 kDa, which undergoes post-translational modifications by conversion of 
Cys50 to formylglycine, required for enzyme activity, and glycosylation at 4 of the 5 potential 
N-linked glycosylation sites.  The rhHNS glycans contain mannose-6-phosphate (M6P) residues 
which target the protein for cellular uptake and internalization in its lysosomal site of action via 
the membrane-bound M6P receptors.13, 14, - 16
The first precedent for intraspinal ERT was recently published and has been shown to be both 
safe and effective for spinal cord compression in MPS I.17   In this study, a patient with MPS I 
received 4 IT doses of enzyme (Laronidase [recombinant α-L-Idurunonidase]) at 1-month 
intervals.  Safety evaluations included CSF opening pressure, serum chemistry and CSF protein, 
glucose and cell count, in addition to clinical efficacy studies.  No changes in safety evaluations
were observed.
In another recent study, a patient with MPS VI and spinal cord compression received IT 
injections of enzyme (Galsulfase) monthly, for 4 months.  CSF analysis revealed no 
inflammatory reaction; no other side effects were noted.18
Several MPS I patients have been treated since 2005 with IT Laronidase in 2 ongoing clinical 
trials (clinicaltrials.gov identifiers NCT00215527 and NCT00786968) studying efficacy on 
spinal cord compression. No results of these trials have yet been published. However, in 
June 2009 a study further investigating the effectiveness of IT ERT as a treatment for another 
neurological symptom in MPS I, cognitive decline, was initiated (clinicaltrials.gov identifier 
NCT00852358). 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
20
This study is a 24-month, open label, prospective, randomized trial in 16 patients with 
MPS I, 6 years of age or older, who have documented evidence of cognitive decline. In this 
study, the clinical safety of the regimen will be assessed by adverse event (AE) monitoring, CSF 
laboratory assessments, and clinical evaluations.  This study is ongoing; no efficacy or safety 
data have yet been published as of October 2011.19 
In addition, there are 4 ongoing Shire HGT-sponsored studies that are evaluating IT 
administration of ERT:  A Phase I/II safety and dose escalation study of monthly idursulfase-IT 
injection for cognitively impaired patients with Hunter syndrome (Study HGT HIT-045; 
NCT00920647), the open-label extension to this study (HGT-HIT-046); a Phase I/II ascending 
dose and dose frequency study of monthly IT injection of HGT-1410 in patients with Sanfilippo 
Syndrome Type A (Study HGT-SAN-055; NCT01155778), and the open-label extension to this 
study (HGT-SAN-067; NCT 01299727).
In light of the higher than expected complications experienced with the PORT-A-CATH IDDD, 
the SOPH-A-PORT Mini S device will be introduced for those patients requiring replacement or 
revision.  This new device has design features anticipated to reduce complications encountered 
with the PORT-A-CATH IDDD device.  Specific device assessments are included in the protocol 
to collect information with respect to information specific to SOPH-A-PORT Mini S device 
safety and function.  
1.2
Nonclinical Overview
To circumvent the restriction of the BBB, HGT-1410 was administered into the CSF of rats and 
monkeys via an IT route.  The non-clinical data demonstrate that IT administration of HGT-1410 
leads to uptake by target CNS tissues with appropriate efficacy and distribution.  In addition, 
there were no findings noted in the toxicity studies, allowing for a 6.2-fold safety margin from 
the results in the juvenile cynomolgus monkey.  Intermittent bolus injection of HGT-1410 to the 
brain via the IT route of administration is hypothesized to be of benefit in stabilizing, improving, 
or preventing the CNS manifestations of disease. 
The doses tested in the non-clinical studies adequately support the efficacy of the planned doses 
(10, 45 or 90 mg/month, normalized to the brain weight of the human) in the ongoing Phase I/II 
study, HGT-SAN-055.  Specifically, in the San A mouse, the 100 μg dose corresponds to a 
2.2-fold increase (per kg brain weight) from the highest anticipated human dose (90 mg) (human 
brain = 1 kg).  The 20 μg dose given IT every other week (EOW) or monthly, for which efficacy 
was also observed, corresponds to a 40 mg (per kg brain weight) human dose.  In the Huntaway 
(Sanfilippo A) dogs, the 3 mgHGT-1410 given IT weekly (corresponding to a 33 mg/kg of brain 
weight in man), was not only well tolerated but resulted in significant effects on biomarkers of 
disease activity and improved histopathology. 
1.2.1
Toxicology in Monkeys
In the pivotal, 6-month IT toxicity study in juvenile cynomolgus monkeys, and the highest dose 
of HGT-1410 was 8.3 mg given EOW.  This translates into a 138 mg/kg brain-weight dose (ie, 
based on a 60 g juvenile monkey brain).  Since no HGT-1410-related adverse effects were noted, 
the nonclinical study provides for the proposed Phase I/II clinical trial a ~13.8 × safety margin 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
21
relative to the starting clinical dose (10 mg), and a 1.5× safety margin relative to the highest 
clinical dose (90 mg).    
1.2.2
Efficacy in Murine and Canine Models of MPS IIIA
Non-clinical proof of concept efficacy studies were conducted using mouse and dog models of 
MPS IIIA, both of which contain naturally-occurring mutations in the HNS gene.  
In the MPS IIIA mouse, direct injection into the CNS had a beneficial effect on clinical signs, 
impaired neurobehavioral, and the biochemical and histopathologic markers of disease activity.  
In Huntaway (Sanfilippo A) dogs, HGT-1410 (3 mg) given IT weekly had a significant effect on 
biomarkers of disease activity and improved histopathology.
Efficacy has been demonstrated at a range of doses in nonclinical mouse and canine models.  In 
MPS IIIA mice, a dose-dependent reduction in the level of a heparan sulfate-derived monosulfate 
disaccharide was observed within the brain (up to 62% reduction compared with vehicle-treated 
mice) and spinal cord (up to 71% reduction).  An ultrastructural examination revealed a 
reduction in lysosomal vesicle formation in various cell types and fewer (ubiquitin-positive) 
axonal spheroids in several brain regions after repeated injections (5 to 20 µg) of HGT-1410 into 
the CSF of MPS III mutant mice via the cisterna magna (ie, IT).  The biochemical changes were 
accompanied by improved behavior, particularly in mice treated more frequently.20
In the MPS IIIA mutant mouse model, intracisternal (ie, IT) injection of a single dose of 100 µg 
HGT-1410 resulted in a substantial (and sustained) reduction of biomarkers of disease activity 
(heparan sulfate-derived disaccharides, microgliosis and astrogliosis).21   Equally impressive was 
the improvement in neurobehavioral parameters (learning in the Morris water maze, 
normalization of aggression) in these mice post-dose.21  One-hundred µg HGT-1410 per mouse 
translates into 200 mg/kg brain weight (ie, based on a 0.5 g mutant mouse brain).  Efficacy at 
lower doses of HGT-1410 (eg, 20 µg, given IT, EOW or monthly) has been demonstrated.11  A 
20 µg injection translates into a 40 mg human dose (ie, 40 mg per kilogram of brain weight).  
Thus, this data further suggests that efficacy will be seen at the highest clinical dose (90 mg, per 
month) in the proposed Phase I/II study. 
In the tolerized Huntaway (San A) dogs, 3 mg HGT-1410 was initially given IT on a weekly 
basis, then EOW, and had a significant effect on biomarkers of disease activity.22  The 3 mg dose 
in the dog translates into a 33 mg (per kg brain weight) human dose (based on a 90 g Huntaway 
dog brain). 
1.3
HGT-SAN-067 Study Rationale
This extension study (Study HGT-SAN-067) will evaluate the effects of long-term HGT-1410 
administration on safety, clinical activity, and biomarker outcomes in patients who completed 
Study HGT-SAN-055 and elected to continue therapy with HGT-1410.
Patients who were enrolled in Study HGT-SAN-055 through Week 26 and completed the end of 
study (EOS) evaluations are eligible for enrollment in this open-label extension study. All 
patients enrolled in this study will initially receive HGT-1410 at the same dose and schedule as 
they received in Study HGT-SAN-055. Patients assigned to 10 mg monthly will have their dose 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
22
increased to 45 mg monthly once per month (Q4W) at the first administration of HGT-1410 
following full approval of protocol Amendment 4. Based on analyses performed at the 
completion of Study HGT-SAN-055 a decline in the primary pharmacodynamic parameter, CSF 
heparan sulfate, was observed. This response to therapy was exhibited at all dose levels, 
however, the greatest impact was at the 2 higher dose levels. An effect on CSF heparan sulfate 
demonstrated in vivo activity of HGT-1410 in the target anatomical compartment. This effect is 
thought to have central importance in mediating the potential therapeutic benefit of HGT-1410. 
As no apparent difference in safety profile was observed between the 3 dose groups, it was 
believed that the increase in the potential therapeutic benefit of the higher dose outweighed any 
potential increase in risks for this lowest dose group.  
Please refer to the current edition of the Investigator’s Brochure for further information 
concerning the safety and clinical development of HGT-1410 and PORT-A-CATH IDDD and 
SOPH-A-PORT Mini S device.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
23
2
STUDY OBJECTIVES
2.1
Primary Objective 
The primary objective of this study is:

To collect long-term safety and tolerability data in patients with Sanfilippo Syndrome 
Type A (MPS IIIA) who received HGT-1410 via a surgically implanted IDDD in study 
HGT-SAN-055 and elect to continue therapy in study HGT-SAN-067.
2.2
Secondary Objectives 
The secondary objectives of this study are:

To collect, as measures of drug efficacy, over an extended treatment period (as change from 
baseline), the following:  clinical, neurological, cognitive, behavioral, functional, and quality 
of life (QoL) assessments, together with potential imaging and biochemical biomarkers.
2.3
Exploratory Objective
An exploratory objective of this study is:


Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
24
3
STUDY ENDPOINTS
3.1
Primary Endpoint
The primary endpoints of this study are related to the long-term safety of intrathecal HGT-1410 
administration. The safety endpoints are:

adverse events (type and severity)

changes in clinical laboratory testing (serum chemistry including  liver function tests, 
hematology, and urinalysis)

electrocardiograms (ECG)

cerebrospinal fluid (CSF) chemistries (including cell counts and inflammatory markers)

anti-rhHNS antibodies (in CSF and serum).
3.2
Secondary Endpoints 
The secondary endpoints of this study are to collect over an extended treatment period (as the 
change from baseline [defined as the start of the HGT-SAN-055 study]) clinical and potential 
surrogate biomarker efficacy data: 

Measures of standardized neurocognitive and behavioral assessments, Sanfilippo-specific 
behavioral rating scales, gross and fine motor assessments, functional adaptive rating scales, 
QoL questionnaires, and Children’s Sleep Habits Rating Scale.

Concentration of inflammatory cytokines in serum and CSF.

Concentration of safety and potential surrogate efficacy biomarkers in CSF, urine, and 
serum.

Concentration of heparan sulfate and heparan sulfate derivatives in urine, plasma, and serum. 

Brain magnetic resonance imaging (MRI) and auditory brainstem response (ABR), (also 
known as Brainstem Auditory Evoked Potentials).
3.3
SOPH-A-PORT Mini S Assessments

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
25
4
INVESTIGATIONAL PLAN
4.1
Overall Study Design and Plan
Study HGT-SAN-067, is an open-label, long term, multicenter, extension of Study 
HGT-SAN-055.  This study is designed to evaluate the long-term safety, clinical activity, and 
biomarker outcomes of IT administration of 3 dose levels (10 mg, 45 mg, and 90 mg once per 
month [Q4W]) of HGT-1410 via an IDDD in patients with MPS IIIA who successfully 
completed HGT-SAN-055 (including the EOS assessments) and elect to continue to receive 
uninterrupted HGT-1410 treatment.  Patients will initially continue in the same treatment group 
they were assigned to in the HGT-SAN-055 study: 

Group 1:  HGT-1410 administered by IT injection 10 mg once per month (Q4W) 

Group 2:  HGT-1410 administered by IT injection 45 mg once per month (Q4W)

Group 3:  HGT-1410 administered by IT injection 90 mg once per month (Q4W) 
Patients assigned to Group 1 will initially receive 10 mg monthly but will have their dose 
increased to 45 mg monthly (Q4W) at the first administration of HGT-1410 following full 
approval of protocol Amendment 4.
In order to maintain a nomenclature system based on study chronology across the original 
HGT-SAN-055 study and this extension study, the Baseline Visit for this extension study will be 
considered to be the day the patient received their first IT dose of HGT-1410 in 
Study HGT-SAN-055.  The HGT-SAN-055 EOS assessment information will provide the 
screening/start of study information for patients who continue into the HGT-SAN-067 extension 
study.  Note: HGT-SAN-055 EOS data must be recorded in the context of the HGT-SAN-055 
trial, and a copy of those data can be used for HGT-SAN-067 screening.  Once eligibility is 
confirmed, informed consent (and assent, if applicable), provided by the patient’s 
parent(s)/legally authorized representative(s), must be obtained prior to performing any 
HGT-SAN-067 study-related procedures.  Informed consent may be obtained anytime from 
Week 20 in HGT-SAN-055.  This would allow a patient to have a nonfunctional IDDD replaced 
or revised prior to the first HGT-1410 dose in HGT-SAN-067.
Enrolled patients will check in to the study center 1 day before each of the scheduled HGT-1410 
dosing days for safety assessments (designated Day 1).  If no safety concerns exist, the patient 
will subsequently receive IT administration of HGT-1410 on Day 2 (±2 days).  However, if 
feasible and there are no safety concerns in the opinion of the investigator, the Day 1 and Day 2 
assessments may be combined and performed on Day 2; if this is done the results will be 
recorded as Day 2.  Patients will remain in the study center for at least 4 hours following dosing 
with HGT-1410 and will be discharged from the unit when deemed clinically stable by the 
Investigator.  
All patients will have received a series of standardized neurodevelopment assessments; in the 
HGT-SAN-055 study, these will have occurred at Baseline and either prior to or at the 6-month 
time point.  Patients will continue in HGT-SAN-067 with whichever age specific assessment 
they began with in HGT-SAN-055.  If, however, a patient’s capability improves and they 
become capable of completing assessments at a higher level, such additional assessments may be 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
26
added.  Any additional assessments are to be performed after the original assessments (those 
used in study HGT-SAN-055) have been carried out.  
A MRI of the head and ABR testing will be performed at Months 12, 24, 36, and 54 (note that 
assessment time point nomenclature includes the 6 months in the HGT-SAN-055 study). 
In the event of a device malfunction, X-rays may be performed to investigate, as well as to verify 
correct catheter and port placement following surgical IDDD implantation or revision.  In 
addition, fluoroscopy may be employed intra-operatively to guide catheter placement.  Patients 
may undergo 3 X-ray examinations in association with each episode of IDDD malfunction and 
subsequent IDDD revision or replacement.  The number of IDDD revisions/replacements is 
limited to 2 in any 6-month period (including the time in the HGT-SAN-055 study), and the 
number of protocol-associated X-ray evaluations is limited to 6 exposures in any 6-month period 
(including time in study HGT-SAN-055). If patients are to continue to receive HGT-1410 using 
the IDDD beyond the duration of this study, they will also have X-ray examinations of the 
device performed at the EOS visit, to document correct positioning.
Patients will be evaluated for safety throughout the study.  Adverse events that occur in 
HGT-SAN-055 and are ongoing at enrollment in HGT-SAN-067 will be captured as ongoing in 
the HGT-SAN-055 study and also be reported as a concurrent condition in the HGT-SAN-067 
eCRFs.  Specific safety stopping criteria will be applied and will be based on the types and 
severity of AEs reported while on-study.  These data will be reviewed to inform the decision to 
discontinue a patient, a dose group, or the study as a whole. 
All patients will have an EOS visit 30 (±7) days following their last administration of HGT-1410 
(ie, Month 55).  The EOS procedures will include standard clinical laboratory tests (serum 
chemistry, hematology, and urinalysis) in CSF and blood, protocol specific laboratory testing 
(eg, anti-rhHNS antibody testing), neurodevelopmental testing, ABR, child health 
questionnaires, MRI and X-ray examination of the device.  Use of concomitant medications, 
therapies, and procedures will be recorded and AEs will be monitored. 
All patients will be contacted by telephone or will have a visit for a Final Safety Follow-up, 
conducted at 30 (±7) days after the EOS visit (ie, Month 56) to collect updated information on 
AEs and concomitant medications, therapies, and procedures. 
It is anticipated that the IDDD will be used to obtain CSF samples and to administer HGT-1410. 
However, if a patient’s PORT-A-CATH IDDD appears nonfunctional or if its use is precluded 
on a scheduled day of dosing, site personnel will refer to the PORT-A-CATH Instructions for 
Use (IFU), which describes the investigation and management of IDDD-related issues with this 
device. This will include possible partial revision or complete replacement of the PORT-A-
CATH IDDD with a SOPH-A-PORT IDDD. For malfunctions involving the SOPH-A-PORT 
Mini S, site personnel will refer to the SOPH-A-PORT IFU.  For either IDDD, a maximum of 
2 partial revisions and/or complete replacements are permitted in any 6 month period (including 
participation in study HGT-SAN-055). If a revision or replacement of the IDDD cannot be 
scheduled in time to avoid a delay of the next scheduled dose of HGT-1410, or if the patient 
experiences more than 2 IDDD malfunctions in a 6 month period, HGT-1410 will be 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
27
administered via lumbar puncture (LP). Drug may be administered via LP for a maximum of 
5 successive monthly doses, after which, IDDD re-implantation or revision must occur. 
If there is no significant safety risk in the opinion of the Investigator, a non-functional IDDD 
may be left in situ for up to 3 months.
Patients who discontinue or are withdrawn before receiving 3 monthly IT injections will not have 
to undergo the EOS evaluations but will have their IDDD removed.  
If a patient discontinues, or withdraws from the study, or the study is stopped by the Sponsor, the 
IDDD will be removed as part of the EOS Procedures. 
An overview of the study appears in the Schedule of Events (Appendix 1).
4.2
Rationale for Study Design and Control Group
The original study, Study HGT-SAN-055, is an ongoing Phase I/II safety and ascending dose 
ranging study of IT administration of HGT-1410 via an IDDD, in patients 3 years of age and 
older with MPS IIIA and early cognitive impairment.  This extension study is proposed to 
continue evaluation of the effects of IT HGT-1410 administration on long-term safety and 
clinical outcomes for patients who completed Study HGT-SAN-055 and elected to continue 
treatment with HGT-1410 in the HGT-SAN-067 study. 
In order to traverse the blood-brain barrier, Shire HGT is evaluating HGT-1410 delivered 
directly to the CNS using an IDDD. The advantage of using an IDDD is that it obviates the need 
for multiple lumbar punctures for drug delivery. Drug products will be administered through this 
port or, if the IDDD is non functional, via lumbar puncture.
If patients in the study require revision and/or replacement of the PORT-A-CATH IDDD, it will 
be removed and replaced with the SOPH-A-PORT Mini S device at a time judged appropriate by 
the Investigator.
4.3
Study Duration and Dates
The study duration will be 4 years.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
28
5
STUDY POPULATION SELECTION
5.1
Study Population
Patients who have completed all study requirements in Study-HGT-SAN-055 and who elected to 
continue HGT-1410 treatment will be eligible to participate; a maximum of 12 patients are 
planned for this study. 
5.2
Inclusion Criteria
Each patient must meet the following criteria to be considered eligible for enrollment in this 
study.
1. The patient must have completed Study HGT-SAN-055 and, in the opinion of the 
investigator, have no safety or medical issues that contraindicate participation. 
2. The patient, patient’s parent(s) or legally authorized representative(s) has voluntarily signed 
an Institutional Review Board/Independent Ethics Committee-approved informed consent 
(and assent, if applicable) form after all relevant aspects of the study have been explained and 
discussed with them.  Informed consent/assent must be obtained prior to any study specific 
procedures.
3. The patient has received at least 5 of the 6 planned infusions of HGT-1410 in the 
HGT-SAN-055 study. 
4. The patient must be medically stable, in the opinion of the Investigator, to accommodate the 
protocol requirements, including travel, assessments, and IDDD surgery (if necessary for 
replacement purposes), without placing an undue burden on the patient/patient's family.
5.3
Exclusion Criteria
Patients will be excluded from the study if there is evidence of any of the following: 
1. The patient has experienced an adverse reaction to study drug in Study HGT-SAN-055 that 
contraindicates further treatment with HGT-1410.
2. The patient has a known hypersensitivity to the active ingredient or any excipients in 
HGT-1410 drug product.
3. The patient has significant non-MPS IIIA related central nervous system impairment or 
behavioral disturbances that would confound the scientific integrity or interpretation of study 
assessments, as determined by the Investigator.
4. The patient has MPS IIIA behavioral-related issues, as determined by the Investigator, which 
would preclude performance of study neurocognitive and developmental testing procedures.
5. The patient is pregnant, breast feeding, or is of childbearing potential who will not or cannot 
comply with the use of an acceptable method of birth control, such as condoms, barrier 
method, oral contraception, etc.
6. The patient has any known or suspected hypersensitivity to anesthesia or is thought to have 
an unacceptably high risk for anesthesia due to airway compromise or other conditions.
7. The patient has a history of a poorly controlled seizure disorder. 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
29
8. The patient is currently receiving psychotropic or other medications, which in the 
Investigator’s opinion, would be likely to substantially confound test results and the dose and 
regimen of which cannot be kept constant throughout the study.
9. The patient cannot sustain absence of aspirin, non-steroidal medications, or medications that 
affect blood clotting within 1 week prior to a relevant study-related procedure (eg, device 
re-implantation if applicable), or has ingested such medications within 1 week before any 
procedures in which any change in clotting activity would be deleterious.
10. The patient has received treatment with any investigational drug (other than HGT-1410) 
intended as a treatment for MPS IIIA within the 30 days prior to, during the study, or is 
currently enrolled in another study that involves an investigational drug or device (screening 
through safety follow-up contact).
11. The patient has received a hematopoietic stem cell or bone marrow transplant.
For patients to be implanted with the SOPH-A-PORT Mini S IDDD the following conditions are 
contraindicated, as described in the Instructions for Use: 
1. The patient has had, or may have, an allergic reaction to the materials of construction of the 
SOPH-A-PORT Mini S device
2. The patient’s body size is too small to support the size of the SOPH-A-PORT Mini S Access 
Port, as judged by the Investigator 
3. The patient has a known or suspected local or general infection
4. The patient is at risk of abnormal bleeding due to a medical condition or therapy
5. The patient has one or more spinal abnormalities that could complicate safe implantation or 
fixation
6. The patient has a functioning CSF shunt device
7. The patient has shown an intolerance to an implanted device

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
30
6
STUDY TREATMENT(S)
6.1
Description of Treatment(s)
6.1.1
Study Drug
Recombinant human heparan N-sulfatase (HGT-1410 drug product) formulation is a sterile 
solution for injection in single-use vials for IT administration.  It is formulated in an aqueous 
isotonic solution containing 15.0 mg/mL HGT-1410 in 145 mM sodium chloride, 0.02% (v/v) 
polysorbate 20, 5 mM sodium phosphate at pH 7.0.
6.1.2
Intrathecal Drug Delivery Device
The PORT-A-CATH will continue to be used for the administration of drug product for each 
patient until such time as an IDDD replacement may be required. Following implementation of 
protocol Amendment 4, any replacements will be performed using the SOPH-A-PORT Mini S.   
After IDDD replacement the drug product will be administered via the SOPH-A-PORT Mini S 
Implantable Access Port.  The SOPH-A-PORT Mini S device is intended for long-term, 
intermittent access to the IT space for the delivery of investigational drug.
The SOPH-A-PORT Mini S is comprised of the following 7 components:

One SOPH-A-PORT Mini S Access Port

One intrathecal port closed-tip catheter

One guidewire

Two suture wings

One 14-gauge Tuohy needle

One 22-gauge non-coring Huber needle

One Luer lock Connector.
Further details are provided in the Instructions for Use.
6.1.3
Placebo or Control
This study will not employ a placebo or control.  
6.2
Treatment Administered
HGT-1410 for IT administration will be provided by Shire HGT.  HGT-1410 will be 
administered by an IDDD.  Following the review and signing of informed consent (and assent, if 
applicable), eligible patients will initially receive the same dose of HGT-1410 they received in 
Study HGT-SAN-055:

Group 1:  HGT-1410 administered by IT injection 10 mg once per month (Q4W) 

Group 2:  HGT-1410 administered by IT injection 45 mg once per month (Q4W)

Group 3:  HGT-1410 administered by IT injection 90 mg once per month (Q4W)

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
31
Patients assigned to Group 1 will have their dose increased to 45 mg once per month (Q4W) at 
the first administration of HGT-1410 following full approval of protocol Amendment 4.
The study drug will be administered through an IDDD.
The initial implantation and revision and/or explantation of the PORT-A-CATH IDDD or 
SOPH-A-PORT Mini S will be performed by pediatric or general neurosurgeons or 
anesthesiologists who have experience in port and catheter implant procedures and
intrathecal-access procedures. Please refer to the relevant IFU for further details.
Drug administration will be performed in a clinical setting by appropriately trained and skilled 
healthcare providers (nurses or physicians) with knowledge of the patient’s drug regimen and 
experienced in accessing vascular or CNS ports or CNS infusion pumps. Patients and patients’ 
families will not be directly using the device to administer drugs and will have limited direct 
interaction with the device as there is minimal care required during the immediate postoperative 
period as the implant site heals, or at times of drug administration.
6.3
Selection and Timing of Dose for Each Patient
Patients will check into the study center 1 day prior to IT HGT-1410 dosing for safety 
assessments, designated Day 1, on each HGT-1410 treatment week, and if no safety concerns 
exist, will receive IT administration of HGT-1410 on Day 2 (±2 days).  However, if feasible and 
there are no safety concerns in the opinion of the Investigator, the Day 1 and Day 2 assessments 
and dosing may be combined and performed on Day 2; if this is done the results will be recorded 
as Day 2.  Patients will remain in the study center for at least 4 hours following dosing with 
HGT-1410 and will be discharged from the unit when deemed clinically stable by the 
Investigator.  
The IT injections are to be administered every 28 days (±7 days).  If a patient’s IDDD becomes 
nonfunctional, it may be revised (partial or complete) (a maximum of twice in a 6 month period) 
so that the patient can remain on study (see Section 7.12 for details).  In the event of a 
non-functional IDDD, HGT-1410 may be administered by LP, for up to 5 successive months (see 
Section 6.3.3). 
6.3.1
Cerebral Spinal Fluid Sample Procedure
CSF samples will be obtained prior to each injection for clinical laboratory evaluation and 
potential biomarker studies.  The IDDD will be used for CSF sampling and a topical anesthetic 
agent may be applied over the skin covering the IDDD reservoir prior to sampling. Site 
personnel should refer to the operations manual for instructions on the use of topical anesthesia 
prior to accessing the IDDD reservoir.
If use of the IDDD is precluded on a scheduled day of dosing, CSF samples may be obtained by 
LP, as described in the Study Operations Manual.  CSF opening pressure will be measured 
whenever a LP is performed, and at the time of IDDD revision (partial or replacement).  
Additional CSF samples may be taken during this time.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
32
6.3.2
Intrathecal Administration of HGT-1410
A visual examination of both the port and catheter track will be performed before each IT 
injection
HGT-1410 will be administered using an IDDD.  After appropriate pre-procedure assessments 
are completed, anesthesia cream will be applied to the skin over the port.  Patients may receive 
sedation as necessary to alleviate anxiety and/or to facilitate drug delivery.
Patients will receive HGT-1410 via slow push/injection through an appropriately sized syringe 
(see the Pharmacy Manual).  Replacement of fluid, including drug, to the CSF will be an 
approximate equal volume to that removed.  The patient’s vital signs will be continuously 
monitored.  The patient will also be monitored closely during study drug administration and 
through the next 4 hours for any adverse clinical reactions.  The patient will be encouraged to lie 
down comfortably for 1 to 3 hours post injection, although this may be difficult for the most 
hyperactive patients.
For the Soph-A-Port Mini S, a 22-gauge Huber non-coring needle is to be used for access to the 
implanted port; standard hypodermic needles would damage the septum and may cause leakage. 
If no needle-free connector is present, either a stopcock of the Huber needle infusion set’s clamp 
is to be used to prevent CSF backflow and to mitigate the risk of air entering the system. It is 
possible to use other brands of Huber non-coring needles, provided that their specifications are 
identical to that of the Huber needle supplied by Sophysa in the SOPH-A-PORT Mini S (22G).
The injection date, injection start/stop time, planned dose, injection volume, and flush volume 
will be recorded on the patient’s eCRF.  
In the event of IDDD malfunction, CSF collection and study drug administration may be 
performed via LP (see Section 6.3.3).  The investigation and management of a malfunctioning 
IDDD is detailed in the PORT-A-CATH or SOPH-A-PORT IFUs. Partial or complete 
replacement of the IDDD may be necessary (only permitted twice in a 6-month period, including 
the time a patient was in study HGT-SAN-055), and will require scheduling of the appropriate 
procedure.  The definitive diagnosis of the cause of IDDD failure may not be possible until the 
time of exploratory surgery.  Surgery will take place at the earliest convenience, so the patient 
may remain on, or as close as possible to their treatment schedule. 
6.3.3
Administration of HGT-1410 via Lumbar Puncture
In the event of a nonfunctional IDDD, HGT-1410 may be administered by LP, for up to 
5 successive months.  The performance of a LP is at the discretion of the Investigator.
If a LP is to be performed, the patient may require general anesthesia with appropriate airway 
management.  Once the patient is anesthetized, a LP will be performed and a CSF sample will be 
obtained.  Some cases may be managed with conscious sedation, if this is considered by the 
investigator to be adequate for the safe and expeditious performance of a LP.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
33
6.4
Method of Assigning Patients to Treatment Groups
This is an open-label, non-randomized study; all patients enrolled in this study will be treated 
with HGT-1410. Patients will initially receive the same dose of HGT-1410 they received in 
Study HGT-SAN-055.  Patients assigned to Group 1 (10 mg once per month [Q4W]) will have 
their dose increased to 45 mg once per month (Q4W) at the first administration of HGT-1410 
following full approval of protocol Amendment 4.
6.5
Blinding
Not applicable; as this trial is not blinded.
6.6
Concomitant Therapy
All non-protocol treatments and procedures that occur from the time of informed consent (and 
assent, if applicable) through the safety follow-up contact are regarded as concomitant and will 
be documented on the appropriate pages of the eCRF.  Concomitant therapy includes 
medications (including Genistein), therapies/interventions administered to patients, and 
medical/surgical procedures performed on the patients. 
Every effort should be made to keep the patient’s symptomatic Sanfilippo syndrome Type A
treatment constant throughout the study.  However, changes in medications are acceptable if 
necessary according to clinical judgment.  All changes will be recorded on the appropriate eCRF.  
Concomitant medication will be coded using World Health Organization Drug Dictionary 
(WHO-DD).
6.7
Restrictions
6.7.1
Prior Therapy
Prior therapy excluded for this study consists of the following:

Psychotropic or other medications, which in the Investigator’s opinion would be likely to 
substantially confound test results, and the dose and regimen of which cannot be kept 
constant throughout the study.

The patient cannot sustain absence from aspirin, non-steroidal medications, or medications 
that affect blood clotting within 1 week prior to a relevant study related procedure (eg, device 
implantation if applicable) or medications within 1 week before any procedures in which any 
change in clotting activity would be deleterious.

The patient has received any investigational drug or device intended as a treatment for 
MPS IIIA within the 30 days prior to the study other than HGT-1410 or is enrolled in another 
study that involves an investigational drug or device.

Hematopoietic stem cell or bone marrow transplant.
6.7.2
Fluid and Food Intake 
Food and fluid intake are not restricted over the course of the study, with the exception of 
hospital standard pre-anesthesia dietary restrictions.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
34
6.7.3
Patient Activity Restrictions
For patients implanted with the SOPH-A-PORT Mini S please refer to the SOPH-A-PORT Mini 
S IFU for details regarding patient activity restrictions for patients to be implanted with this 
device.
6.8
Treatment Compliance
HGT-1410 is administered under controlled conditions by the Investigator; therefore, full patient 
compliance with study treatment is anticipated in this study. 
6.9
Packaging and Labeling
6.9.1
Drug Product
Drug product will be supplied in a 3 mL clear, colorless glass (Type 1) vial. Each vial holds an 
extractable volume of 1 mL of HGT-1410. The closure is a gray, 13 mm stopper composed of 
butyl rubber with a fluoro resin lamination. The overseal is an aluminium seal with a flip-off, 
plastic, tamper evident cap. 
See the Pharmacy Manual for additional details.
6.9.2
SOPH-A-PORT Mini S Access Port
The SOPH-A-PORT Mini S Access Port is available in one size, individually packaged, with 
other SOPH-A-PORT Mini S components in double peel-off, sterile, pyrogen-free packaging, 
sterilized with Ethylene Oxide.  Instructions for use are also included in the packaging. A 
guidewire is provided in separate double pouch, sterile, pyrogen-free packaging.
Labels are provided on the outer carton, and on both the SOPH-A-PORT Mini S box and 
guidewire/cannula package inside.
6.10
Storage and Accountability
6.10.1
Investigational Product
Drug product should be stored refrigerated (2 to 8°C); drug product may not be stored beyond 
the expiration date on the vial.
All HGT-1410 study drug delivered to an Investigator will be recorded and accounted for 
throughout the study.  All HGT-1410 study drug must be recorded on a patient-by-patient basis.  
The lot number of the IDDD and the date and time of administration of the study medication will 
be documented on the appropriate eCRF.
All unused study medication and other study materials are to be returned to the Sponsor or its 
designee or disposed of after Sponsor approval per site policy after study completion.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
35
6.10.2
Intrathecal Drug Delivery Device
6.10.2.1
PORT-A-CATH IDDD
Please refer to the operations manual for return instructions.
6.10.2.2
SOPH-A-PORT Mini S IDDD
The disposition of all SOPH-A-PORT Mini S intrathecal drug delivery devices delivered to a 
Principal Investigator must be recorded on a patient-by-patient basis by completing the 
Accountability Log.  The date and time of administration of the investigational product and use 
of the SOPH-A-PORT Mini S device must be documented on the patient’s appropriate eCRF.
The Principal Investigator, Clinical Research Coordinator, or designee (eg, Pharmacist) must 
ensure that all documentation regarding receipt, storage, dispensing, loss/damaged 
SOPH-A-PORT Mini S intrathecal drug delivery devices and return of used/unused intrathecal 
drug delivery devices) is complete, accurate, and ready for review at each monitoring visit and/or 
audit.  The sites must ensure that the SOPH-A-PORT Mini S devices are available for the 
monitor to inventory and prepare for return shipment to the Sponsor or designee, if required.
The SOPH-A-PORT Mini S and its components are sterile, single-use devices.
Please refer to the relevant IDDD Manual for device return instructions.
6.11
Investigational Product Retention at Study Site
All HGT-1410 study drug delivered to an Investigator will be recorded and accounted for 
throughout the study.  All HGT-1410 study drug must be recorded on a patient-by-patient basis.  
The lot number of the IDDD and the date and time of administration of the study medication will 
be documented on the appropriate eCRF.
All unused study medication and other study materials are to be returned to the Sponsor or its 
designee or disposed of after Sponsor approval per site policy after study completion.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
36
7
STUDY PROCEDURES
7.1
Informed Consent
Study procedures will be conducted only after written informed consent for the patient to 
participate in this study is provided by the parent(s) or the patient’s legally authorized 
representative(s) and assent from the patient (if applicable).  Detailed descriptions of patient 
evaluations required for this protocol are described in this section.  These evaluations will be 
performed during the indicated days and weeks of each study month (see Appendix 1 Schedule 
of Events).
All data collected are to be recorded on the appropriate eCRF.  Blood, urine and CSF volumes to 
be collected for each clinical laboratory measurement are described in detail in the Laboratory 
and/or Study Operations Manual.
7.2
Physical Examination
A physical examination of each patient will be performed as detailed in Appendix 1 Schedule of 
Events.
Note:  if the patient’s hearing cannot be assessed during the physical examination, the patient 
will have an Ears, Nose, and Throat Evaluation performed under anesthesia at the screening/start 
of study visit.  If it is determined that the patient requires pressure-equalization (PE) tubes, they 
may be implanted during that evaluation (see Section 7.9).  Note:  PE tubes may be re-implanted 
if they fall out during this study.
The physical examination findings will be recorded on the eCRF and will include a review of the 
patient’s general appearance as well as the following evaluations:
-
Head and neck
-
Eyes, ears, nose, and throat
-
Chest and lungs
-
Cardiovascular
-
Abdomen
-
Skin
-
Lymphatic
-
Musculoskeletal
-
Neurological
-
Endocrine
-
Genitourinary
7.3
Height and Weight
Height or length (cm), and weight (kg) will be measured once and recorded on the eCRF.
7.4
Head Circumference
Head circumference (cm) will be measured and recorded on the eCRF.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
37
7.5
Vital Signs
Vital signs (blood pressure, heart rate, respiratory rate, and temperature measurements) will be 
measured and recorded on the eCRF.
7.6
Electrocardiography
7.6.1
Electrocardiograms
An ECG will be performed.  Each ECG will include an assessment of heart rate, sinus rhythm, 
atrial or ventricular hypertrophy, PR, QRS, QT, and QTc intervals.  The ECGs will be conducted 
in accordance with the clinical site’s standard practice(s), and will be read locally at the clinical 
site.  Identification of any clinically significant findings and/or conduction abnormalities will be 
recorded on the eCRF. 
7.7
Clinical Laboratory Tests
Blood, urine, and CSF samples will be collected as described below for clinical laboratory 
testing.  Procedures for collection and handling of samples are included in the Laboratory and/or 
Study Operations Manual. 
Patients will be in a seated or supine position during blood collection.  Clinical laboratory tests 
will include hematology, serum chemistry, and urinalysis.
Laboratory Parameters 
Clinical laboratory tests will be performed at a central laboratory.  Clinical laboratory tests will 
include the following:
7.7.1
Hematology

Hematocrit (Hct)

Hemoglobin (Hgb)

Mean corpuscular hemoglobin (MCH)

Mean corpuscular hemoglobin 
concentration (MCHC)

Mean corpuscular volume (MCV)

Platelet count

Red blood cell (RBC) count 

White blood cell (WBC) count with 
differential 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
38
7.7.2
Serum Chemistry

Albumin (ALB)

Alkaline phosphatase (ALK-P)

Alanine aminotransferase (ALT; SGPT)

Aspartate aminotransferase (AST; 
SGOT)

Blood urea nitrogen (BUN)

Calcium (Ca)

Carbon dioxide (CO2)

Chloride (Cl)

Creatinine

Creatine kinase (CK) and subtypes

Gamma-glutamyl transferase (GGT)

Globulin

Glucose

Lactate dehydrogenase (LDH)

Phosphorus

Potassium (K)

Sodium (Na)

Total bilirubin

Direct bilirubin

Total cholesterol

Total protein

Triglycerides

Uric acid

Human Chorionic Gonadotropin
(βhCG) Pregnancy Test
In addition a leukocyte pellet will be prepared, stored frozen, and will be used for additional 
disease-related laboratory studies, including possible assessment of cross-reactive immunologic 
material (CRIM).
7.7.3
Pregnancy Test
A pregnancy test will be performed on Day 1 of each dosing week.  Pregnancy testing will be 
performed using either a serum or urine sample (at the discretion of the site), and only on 
females who have reached menarche.  All pregnancy testing and the reporting of results will be 
performed locally by the clinical site staff.  Study drug must not be administered in the event of a 
positive or inconclusive pregnancy result. 
7.7.4
Urinalysis 
Patient catheterization may be required for obtaining urine samples (if deemed necessary by the 
Investigator).  
7.7.4.1
Standard Urinalysis
The following urinalysis parameters will be performed at a central laboratory:  pH, macroscopic 
and microscopic evaluations.
7.7.4.2
Urine Heparan Sulfate and Heparan Sulfate Derivatives
A urine sample will be collected for the determination of heparan sulfate and heparan sulfate 
derivatives and the analysis will be performed at Shire HGT or designated laboratories.  A urine 
sample from each visit will be reserved for possible exploratory biomarker studies that may
provide new indicators or markers of MPS IIIA disease severity or progression.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
39
7.7.5
Cerebrospinal Fluid Assessments
Cerebrospinal fluid sample collection, processing, and shipping instructions will be provided in 
the Laboratory and/or Study Operations Manual. A CSF sample will be reserved for possible 
exploratory biomarker studies for MPS IIIA disease.
Each CSF sample collected will be assessed for appearance and will be analyzed using the assays 
listed in Sections 7.7.5.1, 7.7.5.2, and 7.7.5.4.  In addition, as more is learned about Sanfilippo 
CNS pathology and etiology, future exploratory assays of CSF metabolites, protein or 
ribonucleic acid RNA may become used as they become available in the future.
7.7.5.1
Cerebrospinal Fluid Cell Counts
An aliquot of each CSF sample collected will be evaluated for CSF standard chemistries, 
glucose, protein, and cell counts.  These assessments will be performed at the local laboratory.
7.7.5.2
Cerebrospinal Fluid Heparan Sulfate Levels and Heparan Sulfate Derivatives
An aliquot of each CSF sample collected will be quick frozen as per the Laboratory and/or Study 
Operations Manual for subsequent determination of CSF heparan sulfate and heparan sulfate 
derivatives at Shire HGT laboratories.
7.7.5.3
Anti-rhHNS Antibodies
An aliquot of each CSF sample collected will be quick frozen as per the Laboratory and/or Study 
Operations Manual for subsequent determination of anti-rhHNS antibodies at Shire HGT or 
Shire HGT designated laboratories.
7.7.5.4
Cerebrospinal Fluid Biomarkers 
An aliquot of each CSF sample collected will be quick frozen as per the Laboratory and/or Study 
Operations Manual for subsequent determination of MPS exploratory biomarkers at Shire HGT 
laboratories.
7.7.6
Sample Collection, Storage, and Shipping
Sample collection, processing, and shipping instructions will be provided in the Laboratory 
and/or Study Operations Manual to be provided by Shire HGT.
CSF, urine, and serum samples may be reserved for potential, future, biomarker studies.  
Samples will be stored securely to ensure patient confidentiality.  
7.8
Anesthesia
Administration of anesthesia/sedation will be given prior to obtaining CSF (when the use of the 
IDDD is precluded), prior to performing a MRI of the head, the ABR, the CSF opening pressure, 
and the partial revision or replacement of the IDDD (if applicable).  

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
40
See Appendix 1 for the Schedule of Events. When logistically feasible, the MRI, ABR, and 
surgical implantation of the IDDD may be performed together to reduce exposure to 
general anesthesia.
Note:  The neurologic exam and the neurocognitive and developmental assessments must be 
performed prior to the administration of anesthesia.
7.9
Audiometry and Auditory Brainstem Response
The rare attenuated patients with MPS IIIA with high levels of cognitive functioning will have 
hearing tests via clinical audiometry measurement performed using age-appropriate testing 
methods based on the child’s developmental age at the time of the testing.  It is anticipated that 
most of the cognitively-impaired and/or behaviorally-deteriorated patients with Sanfilippo A will 
be unable to cooperate with a (conscious) hearing evaluation.  In these instances, the Investigator 
will utilize his best clinical judgment to estimate the extent of hearing loss (if any) during the 
physical examination.  In this situation, a specific evaluation of hearing loss will occur during an 
examination of waveforms in the ABR (see below).  If the patient has a history of multiple 
instances of otitis media or evidence of clinically-significant otitis media on physical 
examination, which the Investigator believes causes significant conductive hearing loss and 
impairment of daily living, the Investigator will discuss and offer the parent or legally authorized 
representative(s) placement of PE tubes as part of the scheduled anesthesia.  A patient’s PE tubes 
may be replaced if they fall out during the course of this study.
The ABR will be conducted under anesthesia.  The ABR findings will be considered within 
normal limits if, after applying appropriate correction factors, the waveforms reveal normal 
morphology. 
7.10
Magnetic Resonance Imaging of the Head
The regional brain volume will be assessed through a MRI, of the head.  The patient will be 
under general anesthesia for this assessment.  All MRIs will be centrally read by the University 
of Minnesota Medical Center.  Refer to the Study Operations Manual for specific procedures and 
precautions.
7.11
Device Data
7.12
Surgical Re-implantation of the IDDD
If a patient’s IDDD becomes nonfunctional or infected, it will be replaced or revised so that the 
patient can remain on study. After full approval of protocol Amendment 4, all IDDD 
replacements will be made with the SOPH-A-PORT IDDD. If the IDDD device is a 
PORT-A-CATH IDDD, it will be replaced by a SOPH-A PORT IDDD. Management details for 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
41
the PORT-A- CATH IDDD or for the SOPH-A PORT IDDD are provided in the respective 
device's IFU. Procedures for implantation are detailed in the relevant device’s Instructions for 
Use Manual and in the training materials provided by Shire HGT. The patient will be under 
general anesthesia for this procedure. The CSF opening pressure will be recorded when the 
intrathecal space is first entered at the time of the IDDD re-implantation. Standard hospital 
procedure for surgery will be followed and will include an X-ray to confirm that the device has 
been (1) surgically implanted correctly, and (2) positioned so that the intrathecal catheter tip is at 
the mid-thoracic level (a check list is provided in the Study Operations Manual). 
A post-operative check of the IDDD and incision will be performed on Day 4 following surgery.  
X-rays may be performed to check placement of the device, as needed, throughout the study (see 
Section 7.12.1 for limits on the number of x-rays and IDDD revisions and or replacement).
7.12.1
Restrictions on the Number of Revision and/or re-implantation of the IDDD
A non-functional IDDD can be replaced or revised twice in a 6-month period, including the time 
a patient was in study HGT-SAN-055.  Similarly, 6 X-rays may be taken in a 6-month period 
(including the time in HGT-SAN-055).
7.13
Device Related Study Procedures
7.13.1
IDDD Implantation or Revision Procedures
The IDDD will be surgically implanted or revised at the clinical site. Procedures for implantation 
and revision are detailed in the device’s IFU. Standard hospital procedures for surgery will be 
followed; the patient will be under general anesthesia for this procedure.
An additional medical device, the catheter passer, is necessary for the implantation procedure, 
for patients receiving the SOPH-A-PORT Mini S.  The catheter passer is a sterile, single use 
device that will be used in the subcutaneous placement of the catheter.  The Phoenix Neuro 
Disposable Catheter Passer, manufactured by Sophysa is CE marked in the European Union and 
cleared under K853370 in the United States (US). 
Details of the implantation/revision and malfunctions/failure for the SOPH-A-PORT will be 
documented on the patient’s eCRF.
7.13.2
X-ray Verification of Intrathecal Drug Delivery Device Placement 
A postoperative x-ray check of the IDDD will be performed following surgery to verify proper 
installation and confirmation of IDDD placement at the mid-thoracic level. The x-rays may be 
performed to check placement of the device, as needed, throughout the study. If the patient is to 
receive intrathecal HGT-1410 beyond the end of the study, an X-ray will be performed at the end 
of the study to verify that the IDDD is in the correct position. At a minimum, the date of the 
x-ray verifying correct IDDD placement will be documented on the patient’s eCRF. If the device 
requires revision or replacement during the study, additional x-rays will be taken to document 
proper positioning of the device. If an IDDD malfunctions, an X-ray may be performed to assess 
the potential cause of malfunction

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
42
7.13.3
CSF Sampling Procedure
Cerebrospinal fluid will be sampled via the device. If this is not possible, and if CSF sampling is 
necessary, either for adherence to the protocol, or to investigate clinical concerns, an LP may be 
performed to sample CSF, either with or without administration of drug afterwards.
7.13.4
Device Removal
If at the time of a scheduled dosing it is not possible to administer a full medication dosage as 
per the standard administration steps detailed in the device’s IFU due to a device-related issue, 
the IDDD will be declared a device malfunction. If the device malfunction is irreversible and 
cannot be corrected without a device surgical intervention, the IDDD will be declared a device
failure, starting from the date of the initial malfunction. 
The IDDD will then be surgically removed or revised and a new device and/or device 
components will be re-implanted at the earliest possible opportunity, preferably at the same time. 
Patients who have a PORT-A-CATH IDDD device failure will have this device replaced by a 
SOPH-A-PORT Mini S.
Details of the device removal will be recorded in the patient’s eCRF. Refer to the relevant IFU 
for further details.
If the IT space is not accessible via the IDDD, study drug may be administered by LP up to 
5 times.
Patients will have the IDDD removed when they discontinue from the study, unless the patient is 
continuing to receive treatment through another mechanism (eg, extension study, expanded 
access, commercially available).
7.14
Cerebrospinal Fluid Opening Pressure Measurement
A CSF opening pressure measurement (cm of H2O) will be conducted as per standard hospital 
practice.  The measurement will be obtained whenever a LP is performed and an IDDD revision 
or replacement is done.
7.15
Dispensing Study Drug
A visual examination of both the port and catheter track will be performed before each IT 
injection.
HGT-1410 will be administered IT by means of an IDDD (or via LP if necessary) to patients on 
Day 2 (±2 days) of Week 1 of each treatment month. 
The patient may be sedated for this procedure.  HGT-1410 will be administered through an 
appropriately sized syringe (see the Pharmacy Manual).  If the IT space is not accessible via the 
IDDD, HGT-1410 may be administered via LP.  See Section 6.3.3 for details.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
43
For the Soph-A-Port Mini S, a 22-gauge Huber non-coring needle is to be used for access to the 
implanted port; standard hypodermic needles would damage the septum and may cause leakage. 
If no needle-free connector is present, either a stopcock or the Huber needle infusion set’s clamp 
is to be used to prevent CSF backflow and to mitigate the risk of air entering the system. It is 
possible to use other brands of Huber non-coring needles, provided that their specifications are 
identical to that of the Huber needle supplied by Sophysa in the SOPH-A-PORT Mini S (22G).
7.16
Pharmacokinetic Assessments
Pharmacokinetic assessments are not included in this study.
7.17
Neurological Examination
A neurological examination to monitor CNS changes in a patient’s neurological status will be 
conducted during this study.  See Appendix 2 for a complete list of the neurological 
examinations.
The neurological exam should not occur sooner than 4 hours after study drug administration or 
before the patient has fully recovered from any anesthesia administered for the dosing, 
whichever occurs later.
7.18
Anti-rhHNS Antibody, Heparan Sulfate, and Heparan Sulfate Derivative 
Determination
Blood samples will be collected and evaluated at Shire HGT laboratories for the determination of 
anti-rhHNS antibodies, and plasma and serum heparan sulfate and heparan sulfate derivatives.  
Samples will be reserved in accordance with local regulations for potential future MPS IIIA 
research that may determine biomarkers of disease severity and progression. 
Two blood samples will be collected from each patient at each designated time point.  One 
sample will be collected in tubes intended for serum specimens, while the second sample will be 
collected in tubes intended for plasma specimens.  Blood sample collection, processing, and 
shipping instructions will be provided in the Laboratory and/or Study Operations Manual.
7.19
Neurocognitive and Developmental Assessments
Patients will undergo neurocognitive and neurobehavioral development testing.  The assessments 
are estimated to last between 2 and 4 hours and must be conducted prior to sedation or 
anesthesia. 
A full neurodevelopmental assessment, including global development, cognition, adaptive 
behavior, receptive and expressive language, and gross motor function, will be evaluated using 
standardized developmental and behavioral tests to provide a surrogate and quantifiable measure 
of global CNS neurodevelopmental/neurobehavioral function. 
All patients will have received a series of standardized neurodevelopment assessments; in the 
HGT-SAN-055 study, patients in HGT-SAN-067 will continue with the age specific assessment 
they began with in HGT-SAN-055.  If, however, a patient’s capability improves and they 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
44
become capable of completing assessments at a higher level, any such additional assessments 
may be added.  Any additional assessments would be performed after the original assessments 
have been carried out.  
For this study, outcome measures will be computed for each patient enrolled.  The psychometric 
instruments and Sanfilippo-specific assessments are summarized below in Table 7-1 and 
Table 7-2, respectively.  See Appendix 2 for details on these assessments.
Table 7-1
Neurodevelopmental Assessments Tests 
Developmental or Cognitive
Domain(s)
Patient Age:  Representative Cognitive Test or 
Scale
COGNITIVE DEVELOPMENT ASSESSMENT
Summary score and sub-domains:
- Cognitive
- Motor
- Social/emotional
0 to 42 months:  Bayley Scales of Infant Development-III 
Bayley Scales of Infant Development, Third Edition 
(BSID-III)23
- Cognitive 
- Processing skills
3 to 18 years:  Kaufman Assessment Battery for Children, 
Second Edition (KABC-II)24  
GROSS AND FINE MOTOR SKILLS ASSESSMENT AND VOLUNTARY MOVEMENT
Motor
3.0 to 16:11 years:  Movement Assessment Battery for 
Children II (MABC-2)25
- Cognitive
- Motor
0 to 5 ½ years:  Bayley Scales of Infant Development III 
(BSID-III)23
ADAPTIVE BEHAVIOR
Communication
Daily Living
Socialization
Motor Skills
0 to 90 years:  Vineland Adaptive Behavior Scales (VABS-II)  
Second Edition26
Table 7-2
Sanfilippo-Specific Disability Assessment And Behavior Rating Scales
DEVELOPMENTAL OR COGNITIVE 
DOMAIN(S)
SANFILIPPO SPECIFIC ASSESSMENTS
Parent-scored behavioral inventory
- communication:  understanding
- communication:  expression
- tantrums
- specific behaviors inventory
- mood & emotions inventory
Sanfilippo Behavior Rating Scale (SBRS)
MPS-specific disability score 
- cognitive functioning
- expressive language
- motor score
Four-Point Scoring System/Total Disability Score 
(FPSS/TDS)5

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
45
7.20
Sleep Questionnaire:  Children’s Sleep Habits Rating Scale 
A sleep questionnaire, Children’s Sleep Habits Rating Scale, will be administered to the patient's 
parent(s)/legally authorized representative(s).
7.21
Age-Dependent, Health-Related Quality of Life in Children
The Quality of Life questionnaires will be administered as outlined in Sections 7.21.1, 7.21.2, 
and 7.21.3.
7.21.1
Quality of Life Indicator:  CHQ-50
The Child Health Questionnaire™ Parent Form 50 Questions (CHQ-50) will be administered 
during the study.  The questionnaire is a generic quality of life instrument, measuring 14 unique 
physical and psychosocial concepts, which was developed for children from 5 to 18 years of age.
7.21.2
Quality of Life Indicator:  CHQ-87
The Child Health Questionnaire™ Child Form 87 (CHQ-87) will be administered during the 
study.  The CHQ-87 is a child and adolescent self-report, developed for ages 10 and older, which 
assesses the child’s self-perceived physical and psychosocial well-being.
7.21.3
Quality of Life Indicator:  ITQOL
The Infant Toddler Quality of Life Questionnaire™ (ITQOL) will be administered during the 
study.  The ITQOL was developed for children at least 2 months of age up to 5 years and 
assesses the physical, mental, and social well being of the child and assesses the quality of the 
parent/legally authorized representative(s) life.  
7.22
Concomitant Medications, Therapies and Medical/Surgical Procedures
All non-protocol treatments that occur from the time of informed consent (and assent, if 
applicable) through the safety follow-up contact are regarded as concomitant and will be 
documented on the appropriate pages of the eCRF. Concomitant therapy includes medication 
(including Genistein), therapies/interventions administered to patients, and medical/surgical 
procedures performed on the patients.
Every effort should be made to keep symptomatic Sanfilippo syndrome Type A treatment 
constant throughout the study.  However, changes in medications are acceptable if necessary 
according to clinical judgment.  All changes will be recorded on the appropriate eCRF.  
Concomitant medication will be coded using WHO-DD.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
46
7.23
Adverse Events
7.23.1
Definitions of Adverse Events and Serious Adverse Events
7.23.1.1
Adverse Event
An AE is any noxious, pathologic, or unintended change in anatomical, physiologic, or 
metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in 
any phase of a clinical study, whether or not considered study drug-related.  This includes an 
exacerbation of a pre-existing condition.  Once the informed consent is signed and dated, any 
adverse event prior to the start of study drug must be reported. 
AEs include:

Worsening (change in nature, severity, or frequency) of conditions present at the onset of the 
study

Intercurrent illnesses

Drug interactions

Events related to or possibly related to concomitant medications

Abnormal laboratory values (this includes significant shifts from baseline  within the range 
of normal that the Investigator considers to be clinically important)

Clinically significant abnormalities in physical examination, vital signs, and weight
Throughout the study, the Investigator must record all AEs on the AE eCRF, regardless of the 
severity or relationship to study drug.  The Investigator should treat patients with AEs 
appropriately and observe them at suitable intervals until the events stabilize or resolve.  AEs 
may be discovered through observation or examination of the patient, questioning of the patient, 
complaint by the patient, or by abnormal clinical laboratory values.
In addition, AEs may also include laboratory values that become significantly out of range.  In 
the event of an out-of-range value, the laboratory test should be repeated until it returns to 
normal or can be explained and the patient’s safety is not at risk.  
All AEs should be recorded with causality assessment.
The information presented below is intended to provide issues to consider for AEs associated 
with intrathecal injections of HGT-1410.  In general, these AEs can be classified as follows: 

Adverse events due to systemic exposure to HGT-1410 caused by the drug diffusion from the 
CSF to the peripheral circulation; 

Adverse events related to the direct delivery of HGT-1410 to the intrathecal CSF space and 
meninges, and subsequent diffusion into brain parenchyma, via an intrathecal route 

IDDD–related AEs  
Note:  the classification of potential AEs and the examples presented below are based on purely 
theoretical considerations and/or published literature as there is limited human experience with 
intrathecal HGT-1410 therapy to date.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
47
7.23.1.2
Potential Adverse Events:  Intrathecal recombinant human heparan 
N-sulfatase 
ADVERSE EVENTS RELATED TO THE DIRECT DELIVERY OF HGT-1410 TO THE CNS THROUGH 
INTRATHECAL ADMINISTRATION
Examples of AEs observed in other published clinical trials with intrathecally-administered 
peptides or proteins, include, but are not limited to the following:  headache, fever, feeling of 
warmth, sensory parathesias (including feelings of warmth, tingling, or pain) or autonomic 
symptoms such as dry mouth or gustatory abnormalities (including loss of smell and metallic 
taste).  Changes in mental cognitive status or level of consciousness that are not caused by 
pre-medication may either occur acutely or develop post-injection, over time
ADVERSE EVENTS DUE TO SYSTEMIC EXPOSURE TO HGT-1410
Although HGT-1410 is given intrathecally only, some proportion of the drug will diffuse from 
the CSF into the peripheral circulation.  The resulting systemic exposure may cause events that 
are typically seen in patients receiving ERT via an intravenous administration, known as 
infusion-related reactions.  An infusion-related reaction is defined as an adverse event that 
(1) begins either during or within 24 hours after the start of the infusion, and (2) is judged as 
possibly or probably related to study drug.  Other AEs that occur prior to the infusion, along with 
AEs associated with protocol-defined testing and assessments (laboratory testing and physical 
examinations) that were performed prior to the infusion will not be defined as infusion-related 
reactions.
7.23.1.3
IDDD-related Adverse Events 
IDDD ADVERSE EVENTS
Examples of AEs related to use of the IDDD include, but are not limited to, the following: device 
failure, device malfunction, incorrect connection of IDDD components, erosion of the 
portal/catheter through the skin, fibrin sheath formation around the catheter tip, hematoma, 
implant rejection, migration of the portal/catheter, occlusion of the portal/catheter, portal site or 
subcutaneous tract infection. The device may also need to be replaced or repaired as needed. A 
list of the more common IDDD AEs is included in Appendix 3.
If the patient is admitted to the hospital in association with an IDDD event (eg for subsequent 
revision or replacement) the surgery will be recorded as a SAE.
DEVICE SURGICAL PROCEDURE-RELATED ADVERSE EVENTS
Examples of AEs related to surgical procedures include, but are not limited to, the following: 
IDDD implant/explant, IDDD adjustment, full revision, partial revision, IDDD removal, and 
delayed re-implantation after previous IDDD removal.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
48
IT ADMINISTRATION PROCESS ADVERSE EVENTS 
In studies that include administration of investigational drug with an IDDD, potential AEs 
related to the IT Administration process include AEs that are caused by anesthesia during drug 
administration, drug administration issues (eg, extravasation during infusion or hematoma due to 
Huber needle), etc.
7.23.1.4
Serious Adverse Event
1. A serious AE (SAE) is any AE occurring at any dose of investigational drug or at any 
procedure that results in any of the following outcomes:

Death

Is life-threatening

Requires inpatient hospitalization

Requires prolongation of existing hospitalization

A persistent or significant disability or incapacity 

A congenital anomaly or birth defect
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization. Hospitalizations, which are the 
result of elective or previously scheduled surgery for pre-existing conditions, which have not 
worsened after initiation of treatment, should not be classified as SAEs. For example, an 
admission for a previously scheduled ventral hernia repair would not be classified as an SAE; 
however, complication(s) resulting from a hospitalization for an elective or previously scheduled 
surgery that meet(s) serious criteria must be reported as SAE(s). Furthermore, this does not 
apply to device failures resulting in scheduled surgical revisions, which should be reported as 
SAEs.”
2.  Unanticipated Adverse Device Effect (UADE) - Any serious adverse effect on health or
safety or any life-threatening problem or death caused by, or associated with, a device, if that 
effect, problem, or death was not previously identified in nature, severity, or degree of incidence 
in the investigational plan or application (including a supplementary plan or application), or any 
other unanticipated serious problem associated with a device that relates to the rights, safety, or 
welfare of patients. (21CFR812.3[s] or other regulatory requirements, as applicable).
7.23.2
Device-Associated Definitions
7.23.2.1
Device Revision (Partial and Full)
Partial device revision: surgical revision/replacement of one or more component(s) of the device; 
other component(s) of the original device remain implanted and are not affected (eg, port 
revision).

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
49
Full device revision: the device is removed (explanted) in its entirety and a completely new 
device is implanted.
7.23.2.2
Device Malfunction
The device does not perform as intended, based on the description in the device’s IFU, but does 
not require either a partial or full device revision.
7.23.2.3
Device Failure
The device irreversibly fails to perform as intended and requires either a partial or full device 
revision or removal.
7.23.3
Classification of Adverse Events and Serious Adverse Events
The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
version 3.0 grading scale should be referenced when assessing the severity of an AE (see 
Appendix 6).  If an AE is not described in the NCI CTC, the severity should be recorded based 
on the scale provided in Table 7-3. The severity of all AEs/SAEs should be recorded on the 
appropriate eCRF page. Adverse events are graded as Grade 1, 2, 3, 4, or 5 corresponding, 
respectively, to a severity of mild, moderate, severe, life-threatening, or death. 
Table 7-3
Adverse Event Severity
Severity
Definition
Grade 1 (Mild)
No limitation of usual activities.
Grade 2 (Moderate)
Some limitation of usual activities.
Grade 3 (Severe)
Inability to carry out usual activities.
Grade 4 (Life-threatening)
Immediate risk of death.
Grade 5 (Death related to an AE)
Death

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
50
7.23.4
Relatedness of Adverse Events and Serious Adverse Events
Relationship of an AE or SAE to investigational product, device, device surgical procedure, or 
IT administration process is to be determined by the Investigator based on the definitions in 
Table 7-4:
Table 7-4
Adverse Event Relatedness
Relationship to Product(s)
Definition
Not Related
Unrelated to study drug, device, device surgical procedure, or IT 
administration process..
Possibly Related
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of study drug, device, device surgical 
procedure, or IT administration process but which could also be 
explained by concurrent disease or other drugs or chemicals.
Probably Related
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of study drug, device, device surgical 
procedure, or IT administration process unlikely to be attributable to 
concurrent disease or other drugs and chemicals and which follows a 
clinically reasonable response on de-challenge.  The association of the 
clinical event or laboratory abnormality must also have some biologic 
plausibility, at least on theoretical grounds.
Definitely Related
The event follows a reasonable temporal sequence from administration 
of the medication,  device, device surgical procedure, or IT 
administration process follows a known or suspected response pattern 
to the medication, is confirmed by improvement upon stopping the 
medication (dechallenge) and reappears upon repeated exposure 
(rechallenge).  
Note that this is not to be construed as requiring re-exposure of the 
patient to study drug; however, the determination of definitely related 
can only be used when recurrence of event is observed.
7.23.5
Procedures for Recording and Reporting Adverse Events
7.23.5.1
Reporting Serious Adverse Events Related to Study Procedures
Any SAE regardless of relationship to investigational product, device, device surgical procedure, 
or IT administration process that occurs in a patient after informed consent (and assent if 
applicable) should be recorded by the clinical site on an SAE form that is to be transmitted to the 
Shire HGT Medical Monitor and to the Shire Pharmacovigilance and Risk Management 
Department at the contact number provided below.  The SAE must be completely described on 
the patient’s eCRF, including the judgment of the Investigator as to the relationship of the SAE 
to the study procedure.  The Investigator will promptly supply all information identified and 
requested by the Sponsor (and/or contract research organization [CRO]) regarding the SAE as to 
the relationship of the SAE to study drug, device, or procedure. 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
51
The SAE form must be completed and FAXED or scanned and EMAILED (PDF sent by e-mail) 
within 24 hours of the Investigator’s learning of the event to: 
Any follow-up information must also be completed on an SAE form and faxed or scanned to the 
same numbers or e-mail address listed above.
In the event of a severe and unexpected, fatal, or life-threatening SAE, the clinical site must 
contact the Shire HGT Medical Monitor by telephone; this is in addition to completing and 
transmitting the SAE form as stated above.  The following provides contact information for the 
Shire HGT Medical Monitor.
If an SAE is assessed as severe and unexpected, or life-threatening, contact:
MD 
Shire Human Genetic Therapies, Inc.
300 Shire Way
Lexington, MA  02421,  United States
Telephone: 
Fax:  
(United States)
Mobile: 
(24-hour access)
Shire Pharmacovigilance and Risk Management Department:
International FAX: 
United Kingdom OR 
United States FAX: 
Email: 
AND
Shire HGT Medical Monitor:
FAX: 
(United States)
The Investigator may also call the Medical Monitor directly (optional):
Shire HGT Medical Monitor: 
 MD
Shire HGT
Work: 
Cell:
(24 hour access)
Email:
AND
Clinical Project Manager CC’d: 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
52
The Investigator must promptly report all required information to the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC).  It is the responsibility of the Sponsor to ensure that 
each Investigator receives a copy of any CIOMS I/MedWatch report that has been submitted to 
the appropriate regulatory agencies notifying them of an unexpected related SAE.  The 
Investigator or Sponsor must ensure that the IRB/IEC receives a copy of the report and that a 
copy is also filed within their study files.  In addition, the Sponsor will also notify the 
Investigators and IRBs/IECs of all deaths that occur during the study, irrespective of relationship 
to study medication
7.23.5.2
Eliciting Adverse Events
Patients should be asked non-leading questions (eg, “How do you feel?”) and further questions 
should be posed if there is indication of an AE.  The questioning should be conducted with due 
regard for objectivity and, in particular, the questioner should gather information regarding AEs 
from questioning the patient, the patient’s parent/guardian, spontaneous report by the patient or 
parent/guardian, laboratory reports, and any health care provider’s observations.
The onset date, resolution date, treatment administered, and outcome of each AE must be 
recorded on the appropriate eCRF. The relationship of each AE to study medication must be 
recorded. In addition AEs may be considered to be related to the IDDD, the IDDD surgical 
procedure, or the IT administration process. Since the AE may be deemed to be related to more 
than one of these factors, as many of these IDDD-related options as apply should be indicated on 
the eCRF.
7.23.5.3
Protocol Deviations for Medical Emergency or Adverse Event
During and following a patient’s participation in the study, the Investigator should ensure that 
adequate medical care is provided to a patient for any AEs, including clinically significant 
laboratory test results.  
The Investigator should inform the patient, the patient’s parent(s), or the patient’s legally 
authorized representative when medical care is needed for intercurrent illness(es) of which the 
Investigator becomes aware.  In an emergency situation, the Investigator should contact the Shire 
HGT Medical Monitor (see Section 7.23.5.1).
Only when an emergency occurs that requires an immediate deviation from the protocol for the 
safety of a patient, will there be such a deviation and this will be only for that patient.  
The Investigator or other physician in attendance in such an emergency must contact the Shire 
HGT Medical Monitor as soon as possible.  
The Investigator, along with the Shire HGT Medical Monitor, will make a decision as to whether 
or not the patient should continue in the study prior to the next scheduled dose.  The departure 
from the protocol and the grounds for it should be stated in the eCRF.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
53
7.24
Abuse, Overdose and Medication Errors
Abuse, misuse, overdose or medication error must be reported to the Sponsor according to the 
SAE reporting procedure whether or not they result in an AE/SAE as described in Section 7.23.

Abuse – Persistent or sporadic intentional intake of investigational medicinal product at a 
dose higher than prescribed per protocol (but below the dose defined for overdose) or when 
used for non-medical purpose (eg, altering one’s state of consciousness)

Misuse – Intentional or unintentional use of investigational medicinal product other than as 
directed or indicated at any dose, which is at or below the dose defined for overdose (Note: 
This includes a situation where the test article is not used as directed at the dose prescribed 
by the protocol)

Overdose – Overdosage with adverse clinical consequences is not anticipated with the use of 
HGT-1410. Additionally, HGT-1410 will be given in a clinical setting by a health care 
provider. 

Medication Error – A mistake made in prescribing, dispensing, administration and/or use of 
the investigational medicinal product.
7.25
Safety-related Study Stopping Rules
If any patient experiences a life-threatening (Grade 4) adverse event or death which is considered 
by the sponsor to be possibly, probably, or definitely related to study drug or the IDDD, or if 
2 or more patients experience a Grade 3 adverse event during the trial that is considered by the 
sponsor to be possibly, probably, or definitely related to the study drug or the IDDD, then the 
site will be instructed to halt further HGT-1410 administration to all patients and the safety data 
reviewed. Following a review of safety data, the study will be either:

Resumed unchanged

Resumed with modifications to the protocol or

Terminated
Patient safety will be monitored on a continuous basis during this study until the last patient 
completes his or her last scheduled study visit/assessment.  
7.26
Pregnancy
Pregnancy and breast feeding are exclusion criteria.  Only female patients who have 
reached menarche will be tested for pregnancy in HGT-SAN-067.  If applicable, this will occur 
at study start and before each dose of HGT-1410 throughout the study.  Pregnancy testing will be 
performed on a blood or urine sample.  Patients with a positive or inconclusive result will not be 
eligible for this study.
At study start, a pregnancy test will be performed if more than 30 days have passed since the 
initial screening sample.  Throughout the study pregnancy testing will occur prior to each dose of 
HGT-1410.  The clinical site’s local laboratory will analyze and report all pregnancy testing 
results.  If a pregnancy test is positive the patient will be discontinued from the study, and the 
Investigator must contact the Shire HGT Medical Monitor. 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
54
Pregnancy is not to be reported as an AE; the Pregnancy Reporting Form, found in the Study 
Operations Manual along with instructions for completion, should be used to report the 
pregnancy.  The pregnancy will be followed up through delivery or final outcome.
7.27
Removal of Patients from the Trial or Study Drug
The patient's parent or legally authorized representative acting on behalf of the patient is free to 
withdraw consent and discontinue participation in the study at any time without prejudice to 
further treatment.  Since this is an extension trial, there will be no replacement of patients who 
discontinue the study for any reason.
A patient’s participation in the study may be discontinued at any time at the discretion of the 
Investigator, Sponsor, or Medical Monitor.  The following may be justifiable reasons for the 
Investigator, Sponsor, or Medical Monitor to remove a patient from the study:

Adverse Event:  If a patient experiences an AE which, in the judgment of the investigator, the 
sponsor, or the medical monitor, presents an unacceptable consequence or risk to the patient.

Adverse Laboratory Experience:  If a patient has an adverse laboratory experience which, in 
the judgment of the investigator, the Sponsor, or the medical monitor, presents an 
unacceptable consequence or risk to the patient, the patient may be withdrawn from the 
study.

Comorbidity:  If a patient develops comorbidity during the course of the study that is 
independent of the study indication, and treatment is required that is not consistent with 
protocol requirements. 

Intercurrent Illness:  If a patient develops an illness during the course of the study that is not 
associated with the condition under study, and which requires treatment that is not consistent 
with protocol requirements.

Refusal of Treatment:  If the patient, the patient’s parent(s) or legally authorized 
representative(s) discontinues participation in the study, or the patient is discontinued by the 
Investigator, reasonable efforts will be made to follow the patient through the end of study 
assessments.  The reason for refusal will be documented on the eCRF.  

Withdrawal of Informed Consent:  A patient’s parent or legally authorized representative 
may withdraw his informed consent to participate in the study at any time.

Cerebrospinal fluid leukocyte count >100 cells per cubic millimeter for 2 consecutive 
months.

New onset seizure.

Anaphylactic reaction beyond reasonable management as described in the Investigator’s 
Brochure.

Clinically problematic intubations or extubations, which may preclude safe airway 
management and anesthesia.

Development of refractory spinal fluid leakage. 

Clinically significant prolonged (eg, greater than 24 to 48 hours) worsening in mental status, 
including development of new focal or non-focal neurological symptoms, or recurrence of a 
previously stable prior medical problem judged due to study drug or participation that is 
exclusive of effects from anesthesia.

Non-compliance, including failure to appear at 1 or more study visits.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
55

The patient was erroneously included in the study.

The patient develops an exclusion criterion.

The study is terminated by the Sponsor.

The patient becomes pregnant during the trial.
If a patient discontinues the study the Patient Completion/Discontinuation eCRF describing the 
reason for discontinuation must be completed.  Any AE’s experienced up to the point of 
discontinuation must be documented on the AE eCRF.  
If AEs are present when the patient withdraws from the study, the patient will be re-evaluated 
within 30 days of withdrawal.  All ongoing SAEs at the time of withdrawal will be followed until 
resolution.
At the time of discontinuation or withdrawal, patients will be asked to participate in all safety 
and efficacy evaluations required for the end of study visit and for the safety follow-up visit.  
Participation in these EOS procedures will be strongly encouraged, but is voluntary for those 
patients electing to discontinue from the study.  The patient will be scheduled for the removal of 
the IDDD. 
7.28
Other Study Procedures
This section is not applicable.
7.29
Appropriateness of Measurements
The neurocognitive and developmental assessments are intended to gauge which domains can be 
accurately measured, with which specific tools, despite the considerable behavioral and cognitive 
challenges in Sanfilippo syndrome.  The evaluation of these domains and the analysis of CSF, 
serum, and urine biomarkers may provide the pivotal data necessary to inform the clinical 
assessments and biomarkers used in possible future Sanfilippo syndrome ERT trials.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
56
8
STUDY ACTIVITIES
Patients who participated in Study HGT-SAN-055 through Week 26 and completed the EOS 
evaluations may be eligible for enrollment in this open-label extension study.  Informed consent 
(and assent, if applicable) must be obtained prior to performing any study related procedures that 
are specific to HGT-SAN-067.  Informed consent may be obtained anytime from Week 20 in 
HGT-SAN-055.  This would allow a patient to have a nonfunctional IDDD replaced or revised 
prior to the first HGT-1410 dose in HGT-SAN-067.
8.1
Screening Visit/Study Start Visit 
All Screening assessments for this study are to have been performed during the Week 26 EOS 
procedures in HGT-SAN-055 (ie, 30 [±7] days after the last HGT-1410 administration).  If less 
than 60 days have elapsed since completion of the EOS assessments for HGT-SAN-055, and the 
start of HGT-SAN-067, the assessments detailed in this Screening visit do not need to be 
repeated.  The Baseline visit for this study will be the first day the patient received their first 
dose of HGT-1410 in the HGT-SAN-055 Study.  
If more than 60 days have elapsed following the HGT-SAN-055 EOS procedures, patients will 
be evaluated for enrollment in HGT-SAN-067 on a case-by-case basis by the Investigator.  A 
decision about enrollment will be made following discussion with the Medical Monitor.  If the 
patient is enrolled, the following assessments are to be repeated within 30 days prior to the first 
scheduled intrathecal HGT-1410 dose:

Physical examination

Height and weight

Head circumference

ECG

Vital signs

Hematology 

Leukocyte pellet preparation to be used for additional disease-related laboratory studies, 
including possible assessment of cross-reactive immunologic material (if this is not collected 
at baseline, it can be collected at any subsequent pre-dosing time point)

Serum chemistry 

Pregnancy testing (for post menarche premenopausal females only)

Urinalysis 

Urine heparan sulfate and heparan sulfate derivatives

Plasma and serum heparan sulfate and heparan sulfate derivatives

Anti-rhHNS antibody testing

General anesthesia:  administration of anesthesia will be given prior to the following 
assessments:

ABR

MRI of the head

Neurological examination (performed prior to the administration of anesthesia)

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
57

Full Neurodevelopmental assessments, including Vineland Adaptive Behavior Scales, 
Second Edition (VABS-II; all assessments performed prior to the administration of 
anesthesia)

CSF sample collection (chemistry, cell count, heparan sulfate and heparan sulfate derivatives, 
and other MPS exploratory biomarkers) via the IDDD

Children’s Sleep Habits Rating Scale 

CHQ-50

CHQ-87

ITQOL

Concomitant medications, therapies, and procedures

AE assessments
8.2
Treatment:  Drug Administration and Weekly Assessments
Patients will receive HGT-1410 IDDD monthly (Q4W), on Day 2 (±2 days), Week 1.  
Patient assessments for safety, biochemical, and neurological baseline measures (Day 1, Week 1) 
will occur on the day before the first IT injection.  Note:  Day 1 assessments may be performed 
on the same day as the administration of study drug (Day 2).  This can occur if it is feasible for 
the patient to arrive at the study site early in the day, and if it is deemed clinically appropriate by 
the Investigator.  If the procedures on Day 1 and Day 2 are combined in this way, the 
assessments will be recorded as occurring on Day 2.
CSF samples will be obtained from these patients on Day 2, immediately prior to the first IT 
study drug injection.  
8.2.1
Week 1 
8.2.1.1
Day 1 (Pre-treatment) Assessments Performed Prior to Each Dose

Physical examination

Height and weight

Vital signs

Hematology

Serum chemistry

Urinalysis

Pregnancy testing (applicable females only)

Neurological examination (performed prior to the administration of anesthesia and the 
HGT-1410 IT injection)

Concomitant medications, therapies, and procedures

AE assessments

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
58
Note: If the HGT-SAN-055 EOS (or HGT-SAN-067 Screening) assessments were performed 
within 7 days of first intrathecal HGT-1410 treatment in this study, the pre-treatment 
assessments described in this section do not need to be completed prior to the first treatment in 
study HGT-SAN-067.
DAY 1 (PRE-TREATMENT) ADDITIONAL ASSESSMENTS PERFORMED AT MONTHS 12, 24, 36, AND 
54

Head circumference

Visual and hearing assessments 

Urine heparan sulfate and heparan sulfate derivatives 

Plasma and /or serum heparan sulfate and heparan sulfate derivatives 

Anti-rhHNS antibody testing

ABR

MRI of the head 

Full neurodevelopmental testing, including VABS-II (performed prior to the administration 
of anesthesia and the HGT-1410 IT injection)

Children’s Sleep Habits Rating Scale 

Child health questionnaire-50 

Child health questionnaire-87 

Infant toddler QoL Questionnaire 
8.2.1.2
Day 2 (±2 days) Assessments and Administration of HGT-1410
Patients may be discharged from the clinical site 4 hours after dosing, if deemed stable by the 
Investigator.

Physical examination

ECG (performed following IT study drug injection)

Vital signs

CSF sample collection (obtained prior to IT study drug injection)

HGT-1410 IT injection (Day 2 ±2 days)

Neurological examination 

Concomitant medications, therapies, and procedures

AE assessments
The neurological exam should not occur sooner than 4 hours after study drug administration or 
before the patient has fully recovered from any anesthesia administered for the dosing, 
whichever occurs later.
8.3
End of Study/Early Termination Procedures:  Month 55
Patients who complete the study or who discontinue prior to the end of the study, will have EOS 
assessments performed 30 (±7 days) after their last dose of HGT-1410.  

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
59
Patients who discontinue or are withdrawn prior to study completion will be asked to participate 
in the EOS procedures at the time of discontinuation.  Participation in these EOS procedures will 
be strongly encouraged, but is voluntary for those patients electing to discontinue from the study.  
Note:  Patients will have the IDDD removed when they discontinue from the study, unless the 
patient is continuing to receive treatment through another mechanism (eg, expanded access, 
commercially available).

Physical examination

Height and weight

Head circumference

Visual and hearing assessment

ECG

Vital signs

Hematology

Serum chemistries

Urinalysis

Urine heparan sulfate and heparan sulfate derivatives 

Plasma and serum heparan sulfate and heparan sulfate derivatives 

Anti-rhHNS antibody testing

ABR (unless performed at Month 54)

MRI of the head (unless performed at Month 54)

CSF sample collection (unless performed at Month 54)

Neurological examination

Full neurodevelopmental testing, including VABS-II 

Children’s Sleep Habits Rating Scale 

Child health questionnaire-50 

Child health questionnaire-87 

Infant toddler QoL Questionnaire 

Concomitant medications, therapies, and procedures

AE assessments

X-ray of device, if the patient is to continue to receive intrathecal HGT-1410 beyond the end 
of the study
All patients who discontinue the study early will have their IDDD removed.  
Patients who withdraw or discontinue after having received fewer than 3 IT injections will not 
need to complete the EOS visit.  
Patients who withdraw or discontinue from the study after having received 3 or more IT 
injections, will be asked to complete the EOS visit and undergo all the scheduled assessments.
8.4
Safety Follow-up (by Telephone or Visit) Month 56
Patients who complete the study or withdraw early will have a safety follow-up telephone call or 
visit 30 Days (±7 days) after the last study visit.  This will assess:

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
60

Concomitant medications, therapies, and procedures

AE assessments

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
61
9
QUALITY CONTROL AND ASSURANCE
Training will occur at an investigator meeting or at the site initiation visit or both, and instruction 
manuals (eg, laboratory manuals and pharmacy manuals) will be provided to aid consistency in 
data collection and reporting across sites.
Clinical sites will be monitored by Shire HGT or its designee to ensure the accuracy of data 
against source documents.  The required data will be captured in a validated clinical data 
management system that is compliant with the Food and Drug Administration (FDA) 21 Code of 
Federal Regulations (CFR) Part 11 Guidance.  The clinical trial database will include an audit 
trail to document any evidence of data processing or activity on each data field by each user.  
Users will be trained and given restricted access, based on their role in the study, through a 
password protected environment.  
Data entered in the system will be reviewed manually for validity and completeness against the 
source documents by a clinical monitor from Shire HGT or its designee.  If necessary, the study 
site will be contacted for corrections or clarifications; all missing data will be accounted for.
SAE information captured in the clinical trial database will be reconciled with the information 
captured in the Pharmacovigilance database.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
62
10
PLANNED STATISTICAL METHODS
10.1
General Statistical Methodology
This is an open-label extension of study HGT-SAN-055 to evaluate the long-term safety and 
clinical outcomes of intrathecal administration of HGT-1410 in patients with MPS IIIA.  The 
statistical methodology supporting the trial will focus on descriptive rather than inferential 
approaches, given the early phase and objectives of this trial. 
Data will be summarized by dose group (10 mg, 45 mg, and 90 mg) with respect to demographic 
and baseline characteristics, efficacy variables, and safety variables. Summary statistics for 
continuous variables will include the n, mean, standard deviation, median, minimum and 
maximum. Categorical variables will be summarized in a contingency table by the frequency and 
percentage of patients in each category. Data will be plotted to assess trends across time as 
appropriate.
No a priori hypotheses will be tested.  Exploratory hypotheses may emerge from the data 
analysis, in which case, appropriate testing methods will be applied and specified in the 
statistical analysis plan.
There are no formal hypotheses associated with the evaluation of the safety and performance of 
the IDDD device (SOPH-A-PORT Mini S). All analyses of device safety and performance will 
be descriptive and no statistical testing will be performed. Device related analyses will be based 
on patients for whom the device implant procedure was performed and are described in the 
sections below.
10.2
Determination of Sample Size
Since this is an extension study, sample size is determined by the number of patients who 
completed HGT-SAN-055 (maximum of 12 patients) and elected to continue treatment with 
HGT-1410 in this study. Hence no statistical estimation of the sample size was performed.
10.3
Analysis Populations
The primary analysis population consists of all eligible patients from HGT-SAN-055 who have 
agreed to participate in the extension study. This population will be used to perform both safety 
and efficacy analyses. The collection of detailed data pertaining to the SOPH-A-PORT mini S 
will permit device-related analyses to be conducted in the subset of patients in the primary 
analysis population who had the SOPH-A-PORT Mini S implant procedure performed.
10.4
Demographics and Baseline Characteristics
Patient disposition for those enrolled will be presented in a summary table using number and 
percentage of patients enrolled, completed or discontinued/withdrew. The reasons for 
discontinuation/withdrawal will also be presented.
Demographic and baseline characteristics (eg, age, race, ethnicity, medical history, and surgical 
history) will be reported in summary tables.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
63
10.5
Statistical Analysis of Pharmacokinetic Variables
Not applicable.
10.6
Efficacy, Safety, and Pharmacodynamic Evaluations    
10.6.1
Primary Analyses
10.6.1.1
Safety Analysis
In general, safety assessments will be based on all assessments post-baseline.  The assessment of 
safety will be based primarily on the frequency of AEs, and on the frequency of clinically 
notable abnormal vital sign and laboratory values.  Changes from baseline will be calculated by 
subtracting the baseline value from the post-baseline value.
All enrolled patients who had an IDDD surgical procedure and/or received administration of 
HGT-1410 will be included in the safety analysis.  
Adverse events will be recorded throughout the study and at early termination.  Adverse events 
and medical conditions will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). 
Adverse events will be summarized by presenting, for each dose group, the number and 
percentage of patients having any AE, having an AE in system organ class, and having each 
individual AE. In addition, those events which resulted in death or were otherwise classified as 
serious will be presented in a separate listing. The incidence of treatment-emergent adverse 
events , defined as all AEs from the time of the surgery for IDDD implantation to the last follow 
up contact, ie, 30 days after the last HGT-1410 administration, (new or worsened from baseline) 
will be summarized by system organ class, severity, type of adverse event and relationship to 
trial medication/procedure. 
Treatment-emergent AEs deemed related to HGT-1410 administration will be summarized 
separately.
IDDD, and procedure-related AEs will be summarized within system organ class by preferred 
term. IDDD and procedure-related AEs will be tabulated by severity (mild, moderate, severe) 
and degree of relatedness.  Separate tabulations will be provided for adverse events related to the 
IDDD, device surgical procedure (including post-implant infections) and IT administration 
process.  These summaries will be presented by device and overall, as appropriate. 
Descriptive summaries of clinical laboratory evaluations (hematology, serum chemistry, 
urinalysis and CSF) results will be presented in summary tables by evaluation visit.  Changes 
from baseline will be summarized for each post-baseline visit.  Each laboratory result will be 
categorized as a patient having had (1) an Abnormal and Clinically Significant (CS) value at any 
time, (2) no CS values at any time but had at least one Abnormal and not CS (NCS) value, and 
(3) no CS or NCS values at any time; the number and percentage in each category will be 
presented.  For any patient who experiences a CS laboratory result at any time that was not CS at 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
64
baseline (or the most recent non-missing value prior to the start of the treatment), their entire 
profile for that particular laboratory parameter will be presented as a listing.
The observed values and changes from baseline for vital sign data will be summarized for each 
dose group. Shift tables may be presented, utilizing reference ranges.  Patients with notably 
abnormal values will be identified and listed separately along with their values.
The observed values and changes from baseline for ECG data will be summarized for each dose
group.  Patients with any clinically significant findings and/or conduction abnormalities will be 
listed separately along with their values. 
Anti-rhHNS antibody formation will be monitored throughout the study.  Results will be 
presented in summary tables by number and percentage of positive and negative specimens by 
evaluation visit, and number and percentage of positive and negative specimens overall.  The 
effect of antibodies on other safety parameters will be assessed by presenting summary tables by 
antibody status.  
For those patients who fail to complete the study, the reason for discontinuation will be listed by 
patient and dose group. 
Listings of all study safety data will be presented.
10.6.2
Other Observations Related to Safety
10.6.2.1
IDDD Performance
IDDD safety and performance will be summarized in detail for patients implanted with the 
SOPH-A-PORT Mini S. Difficulties associated with the implant procedure (e.g. excessive 
bleeding, CSF leakage, etc.) will be summarized.  A summary of abnormal findings from the 
IDDD radiological assessments will also be presented.  
The proportion of patients with at least one IDDD failure and/or malfunction, as well as the 
number of and reasons for IDDD failures/malfunctions and actions taken will be summarized.  
The rate of IDDD failures/malfunctions and 95% confidence interval will also be estimated.  The 
time from initial implant surgery to first IDDD failure and/or malfunction will be summarized.  
Patients without an IDDD failure/malfunction will be censored at their last study drug injection 
date.  A by-patient listing of the device failure/malfunction data will be displayed.
The proportion of patients for whom a successful first injection of study drug occurred will be 
reported among those for whom a first injection was attempted (i.e. those who had an apparently 
successful implantation and did not suffer a device removal or revision prior to first scheduled 
injection).  The proportion of patients who had no failed injection attempts during the study will 
also be summarized. The corresponding 95% confidence intervals of the proportion of interest 
will be estimated, where appropriate. Injections not given for patient reasons (e.g. patient 
uncooperative, competing medical issue, etc) will not be included in the determination of these 
success proportions.  The frequency and reasons for unsuccessful injection attempts will be 
reported.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
65
10.6.3
Secondary Analysis
10.6.3.1
Clinical Assessments
The change from baseline in neurocognitive assessment based scores will be examined by dose 
group.  Furthermore, the effect of HGT-1410 administration on QoL measures will be examined 
by presenting mean change from baseline by dose groups.  Other relevant assessments which 
might help in the understanding of clinical activity will also be analyzed.
10.6.3.2
Pharmacodynamic Analyses
To determine the effects of HGT-1410 administration on biomarkers, mean change from baseline 
will be assessed at selected time points.  The heparan sulfate reduction (in CSF and urine) will be 
examined using mean change and the corresponding 95% confidence interval.  The concentration 
of inflammatory cytokines in serum and CSF will also be examined.  Other exploratory 
biomarkers in CSF, serum, and urine may also be examined.
The effect of anti- rhHNS antibodies on the changes in CSF biomarkers may also be examined 
by presenting summary tables by antibody status.
The planned analyses and presentations will be defined in the Statistical Analysis Plan (SAP).

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
66
11
ADMINISTRATIVE CONSIDERATIONS
11.1
Investigators and Study Administrative Structure
Before initiation of the study, the Investigators must provide the Sponsor with a completed Form 
Food and Drug Administration (FDA) 1572 or Investigator Agreement.  Study medications may 
be administered only under the supervision of the Investigators listed on this form.  Curriculum 
vitae must be provided for the Investigators and sub-investigators listed on Form FDA 1572 or 
Investigator Agreement.
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, any amendments to the protocol, the study treatments, and their study related 
duties and functions.  The Investigator must maintain a list of sub-investigators and other 
appropriately qualified persons to whom he or she has delegated significant study related duties.
11.2
Institutional Review Board or Independent Ethics Committee Approval
Before initiation of the study, the Investigator must provide the Sponsor with a copy of the 
written IRB or IEC approval of the protocol and the informed consent form.  This approval must 
refer to the informed consent form and to the study title, study number, and version and date of 
issue of the study protocol, as given by the Sponsor on the cover page of the protocol.  
Status reports must be submitted to the IRB/IEC at least once per year.  The IRB/IEC must be 
notified of completion of the study.  Within 3 months of study completion or termination, a final 
report must be provided to the IRB/IEC.  A copy of these reports will be sent to the study clinical 
monitor.  The Investigators must maintain an accurate and complete record of all submissions 
made to the IRB/IEC, including a list of all reports and documents submitted.  AEs which are 
reported to the US FDA or other Regulatory agencies (Investigational New Drug [IND] Safety 
Reports) must be submitted promptly to the IRB/IEC.
11.3
Ethical Conduct of the Study
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor and Investigators abide by 
good clinical practice (GCP) as described in the 21 CFR Parts 50, 56, and 312 and the 
International Conference on Harmonization (ICH) GCP Guidelines. 
11.4
Patient Information and Consent
Before enrolling in the clinical study, the patient’s parent(s), or the patient’s legally authorized 
representative(s) must consent to participate after the nature, scope, and possible consequences 
of the clinical study have been explained in a form understandable to him or her.  An informed 
consent form that includes information about the study will be prepared and given to the 
patient’s parent(s), or the patient’s legally authorized representative(s).  This document will 
contain all FDA and ICH-required elements.  

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
67
The informed consent form must be in a language understandable to the patient’s parent(s), or 
the patient’s legally authorized representative(s) and must specify who informed the patient’s 
parent(s) or the patient’s legally authorized representative.
After reading the informed consent document, the patient, patient’s parent(s), or the patient’s 
legally authorized representative(s) must give consent in writing.  The patient’s consent must be 
confirmed at the time of consent by the personally dated signature of the patient, patient’s 
parent(s) or the patient’s legally authorized representative(s) and by the personally dated 
signature of the person conducting the informed consent discussions.  If the patient, patient’s 
parent(s), or the patient’s legally authorized representative(s) is unable to read, oral presentation 
and explanation of the written informed consent form and information to be supplied must take 
place in the presence of an impartial witness.  Consent (or assent) must be confirmed at the time 
of consent orally and by the personally dated signature of the patient, patient’s parent(s) or by the 
patient’s legally authorized representative(s).  The witness and the person conducting the 
informed consent discussions must also sign and personally date the informed consent document.  
It should also be recorded and dated in the source document that consent was given.
A copy of the signed and dated consent document(s) must be given to the patient’s parent(s), or 
the patient’s legally authorized representative(s).  The original signed and dated consent 
document will be retained by the Investigator.
The Investigator will not undertake any measures specifically required solely for the clinical 
study until valid consent has been obtained.
A model of the informed consent form to be used in this study will be provided to the sites 
separately from this protocol.  
Where applicable, signed assent(s) to participate in the study must be obtained.
11.5
Patient Confidentiality
Patient names will not be supplied to the Sponsor.  Only the patient number and patient initials 
will be recorded in the eCRF, and if the patient name appears on any other document, it must be 
obliterated before a copy of the document is supplied to the Sponsor.  Study findings stored on a 
computer will be stored in accordance with local data protection laws.  The patients will be told 
that representatives of the Sponsor, a designated CRO, the IRB/IEC, or regulatory authorities 
may inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws.  The Investigator will maintain a personal patient 
identification list (patient numbers with the corresponding patient names) to enable records to be 
identified.
11.6
Study Monitoring
Monitoring procedures that comply with current GCP guidelines will be followed.  On-site 
review of the eCRFs for completeness and clarity, cross-checking with source documents, and 
clarification of administrative matters will be performed.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
68
The study will be monitored by the Sponsor or its designee.  On site monitoring will be 
performed by a representative of the Sponsor (Clinical Study Monitor) who will review the CRFs 
and source documents.  The site monitor will ensure that the investigation is conducted 
according to protocol design and regulatory requirements by frequent site visits and 
communications (letter, telephone, and facsimile).
11.7
Case Report Forms and Study Records
Case report forms are provided for each patient in electronic format.  Electronic Data Capture 
(EDC) will be used for this study.  The study data will be recorded from the source documents 
into the eCRF.  The electronic files will be considered as the CRFs. 
All forms must be filled out by authorized study personnel.  All corrections to the original eCRF 
entry must indicate the reason for change.  The Investigator is required to sign the eCRF after all 
data have been captured for each patient.  If corrections are made after review and signature by 
the Investigator, he or she must be made aware of the changes, and his or her awareness 
documented by re-signing the eCRF.   
11.7.1
Critical Documents
Before Shire HGT initiates the trial (ie, obtains informed consent [assent if applicable] from the 
first patient), it is the responsibility of the Investigator to ensure that the following documents are 
available to Shire HGT or their designee:

Curricula vitae of Investigator and sub-investigator(s) (current, dated and signed or supported 
by an official regulatory document)

Current medical license of Investigator and sub investigator(s)

Signed and dated agreement of the final protocol

Signed and dated agreement of any amendment(s), if applicable

Approval/favorable opinion from the IRB/IEC clearly identifying the documents reviewed:  
protocol, any amendments, Patient Information/Informed Consent Form (Assent form if 
applicable), and any other written information to be provided regarding patients recruitment 
procedures

Copy of IRB/IEC approved Patient Information/Informed Consent Form (Assent Form if 
applicable)/any other written information/advertisement

Any additional regulatory approvals, ie national regulatory approvals

List of IRB/IEC Committee members/constitution

Financial agreement(s)

Documentation from central or local laboratory as applicable
•
Reference ranges
•
Certification/QA scheme/other documentation
Regulatory approval and notification as required must also be available; these are the 
responsibility of Shire HGT.  All trial documents will be available in a Trial Master File (TMF)
at the Investigator/trial site and at Shire HGT.     

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
69
11.8
Device Failure Adjudication Process
The final cause for device failures will be adjudicated by a Shire team by examining the clinical 
database, safety database, and manufacturer investigation of returned devices.
11.9
Protocol Violations/Deviations
The Investigator will conduct the study in compliance with the protocol.  The protocol will not 
be initiated until the IRB/IEC and the appropriate regulatory authorities have given 
approval/favorable opinion.  Modifications to the protocol will not be made without agreement 
of the Sponsor.  Changes to the protocol will require written IRB/IEC approval/favorable opinion 
prior to implementation, except when the modification is needed to eliminate an immediate 
hazard(s) to patients.  The IRB/IEC may provide, if applicable regulatory authorities permit, 
expedited review and approval/favorable opinion for minor change(s) in ongoing studies that 
have the approval/favorable opinion of the IRB/IEC.  The Sponsor will submit all protocol 
modifications to the regulatory authorities in accordance with the governing regulations.  A 
record of patients screened, but not entered into the study, is also to be maintained.  There will be 
no protocol exemptions granted for this study.
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
patients, the Investigator will contact the Sponsor or its designee, if circumstances permit, to 
discuss the planned course of action.  Any departures from the protocol must be fully 
documented as a protocol deviation.  Protocol deviations will need to be reviewed by the medical 
monitor and may also be required to be submitted to the IRB/IEC.
Protocol modifications will only be initiated by the Sponsor and must be approved by the 
IRB/IEC and submitted to the FDA or other applicable international regulatory authority before 
initiation.
11.10 Access to Source Documentation
Regulatory authorities, the IEC/IRB, or the Sponsor may request access to all source documents, 
CRFs, and other study documentation for on-site audit or inspection.  Direct access to these 
documents must be guaranteed by the Investigator, who must provide support at all times for 
these activities.  Monitoring and auditing procedures that comply with current GCP guidelines 
will be followed.  On-site review of the CRFs for completeness and clarity, crosschecking with 
source documents, and clarification of administrative matters will be performed.
11.11 Data Generation and Analysis
The clinical database will be developed and maintained by a contract research organization or an 
electronic data capture technology provider as designated by Shire HGT.  Shire HGT or its 
designee will be responsible for performing study data management activities. 
Adverse events will be coded using MedDRA.  Concomitant medication will be coded using 
WHO-DD.  Centralized laboratories will be employed as described in the study manual to aid in 
consistent measurement of efficacy and safety parameters.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
70
11.12 Premature Closure of the Study
11.12.1
Study Termination
If the Sponsor or an Investigator discovers conditions arising during the study which indicate that 
the clinical investigation should be halted due to an unacceptable patient risk, the study may be 
terminated after appropriate consultation between Shire HGT and the Investigators.  In addition, 
a decision on the part of Shire HGT to suspend or discontinue development of the study material 
may be made at any time.
11.12.2
Site Termination
A specific site may be terminated separate from the general study for, but not limited to, the 
following conditions:

The discovery of an unexpected, significant, or unacceptable risk to the patients enrolled at 
the site.

Failure of the Investigator to enter patients at an acceptable rate.

Insufficient adherence by the Investigator to protocol requirements.
11.13 Retention of Data
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application and until there are no pending or contemplated marketing applications or 
at least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product.  The Sponsor will notify the Investigator if these documents must be 
retained for a longer period of time.  It is the responsibility of the Sponsor to inform the 
Investigator or institution as to when these documents no longer need to be retained. 
Biological samples may be reserved for potential, future, biomarker studies (see Section 7.7.6).  
11.14 Financial Disclosure
The Investigator should disclose any financial interests in the Sponsor as described in 21 CFR 
Part 54 prior to beginning this study.  The appropriate form will be provided to the Investigator 
by the Sponsor, which will be signed and dated by the Investigator, prior to the start of the study. 
11.15 Publication and Disclosure Policy
All information concerning the study material, such as patent applications, manufacturing 
processes, basic scientific data, and formulation information supplied by the Sponsor and not 
previously published are considered confidential and will remain the sole property of the 
Sponsor.  The Investigator agrees to use this information only in accomplishing this study and 
will not use it for other purposes.
It is understood by the Investigator that the information developed in the clinical study may be 
disclosed as required to the authorized regulatory authorities and governmental agencies.  

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
71
In order to allow for the use of the information derived from the clinical studies, it is understood
that there is an obligation to provide the Sponsor with complete test results and all data 
developed in the study in a timely manner.
The Investigator and any other clinical personnel associated with this study will not publish the 
results of the study, in whole or in part, at any time, unless they have consulted with Shire HGT, 
provided Shire HGT a copy of the draft document intended for publication, and obtained Shire 
HGT’s written consent for such publication.  All information obtained during the conduct of this 
study will be regarded as confidential.  Shire HGT will use the information for registration 
purposes and for the general development of the drug.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
72
12
LIST OF REFERENCES
1. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. 
JAMA : the journal of the American Medical Association 1999;281:249-54.
2. Poorthuis BJ, Wevers RA, Kleijer WJ, et al. The frequency of lysosomal storage diseases in 
The Netherlands. Human genetics 1999;105:151-6.
3. Baehner F, Schmiedeskamp C, Krummenauer F, et al. Cumulative incidence rates of the 
mucopolysaccharidoses in Germany. J Inherit Metab Dis 2005;28:1011-7.
4. Valstar MJ, Bruggenwirth HT, Olmer R, et al. Mucopolysaccharidosis type IIIB may 
predominantly present with an attenuated clinical phenotype. Journal of inherited metabolic 
disease 2010;33:759-67.
5. Meyer A, Kossow K, Gal A, et al. Scoring evaluation of the natural course of 
mucopolysaccharidosis type IIIA (Sanfilippo syndrome type A). Pediatrics 
2007;120:e1255-61.
6. Cleary MA, Wraith JE. Management of mucopolysaccharidosis type III. Arch Dis Child 
1993;69:403-6.
7. Fraser J, Wraith JE, Delatycki MB. Sleep disturbance in mucopolysaccharidosis type III 
(Sanfilippo syndrome): a survey of managing clinicians. Clin Genet 2002;62:418-21.
8. Neufeld E, Muenzer J. The Mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, 
Valle D, eds. The metabolic and molecular bases of inherited disease. 8th ed. New York: 
McGraw-Hill; 2001:4 v. (xivii, 6338, I-104 p.).
9. Meyer A, Kossow K, Gal A, et al. The mutation p.Ser298Pro in the sulphamidase gene 
(SGSH) is associated with a slowly progressive clinical phenotype in mucopolysaccharidosis 
type IIIA (Sanfilippo A syndrome). Hum Mutat 2008;29:770.
10. Vellodi A. Lysosomal storage disorders. Br J Haematol 2005;128:413-31.
11. Hemsley KM, Beard H, King BM, Hopwood JJ. Effect of high dose, repeated intra-CSF 
injection of sulphamidase on neuropathology in MPS IIIA mice. Genes Brain Behav 2008.
12. Urayama A, Grubb JH, Sly WS, Banks WA. Mannose 6-phosphate receptor-mediated 
transport of sulfamidase across the blood-brain barrier in the newborn mouse. Mol Ther 
2008;16:1261-6.
13. Bielicki J, Hopwood JJ, Melville EL, Anson DS. Recombinant human sulphamidase: 
expression, amplification, purification and characterization. Biochem J 1998;329 ( Pt 
1):145-50.
14. Di Natale P, Vanacore B, Daniele A, Esposito S. Heparan N-sulfatase: in vitro mutagenesis 
of potential N-glycosylation sites. Biochem Biophys Res Commun 2001;280:1251-7.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
73
15. Daniele A, Di Natale P. Heparan N-sulfatase: cysteine 70 plays a role in the enzyme catalysis 
and processing. FEBS Lett 2001;505:445-8.
16. Perkins KJ, Byers S, Yogalingam G, Weber B, Hopwood JJ. Expression and characterization 
of wild type and mutant recombinant human sulfamidase. Implications for Sanfilippo 
(Mucopolysaccharidosis IIIA) syndrome. J Biol Chem 1999;274:37193-9.
17. Munoz-Rojas MV, Vieira T, Costa R, et al. Intrathecal enzyme replacement therapy in a 
patient with mucopolysaccharidosis type I and symptomatic spinal cord compression. Am J 
Med Genet A 2008;146A:2538-44.
18. Muñoz-Rojas M, Dain D, Horovitz G, et al. Intrathecal administration of recombinant human 
N-acetylgalactosamine 4-sulfatase to a MPS VI patient with pachymeningitis cervicalis. 
Molecular Genetics and Metabolism 2010;99:346-50.
19. Chen A, Dickson P, Shapiro E, Lyons B, Kan S, Guillaume D. A study of intrathecal enzyme 
replacement for cognitivedecline in mucopolysaccharidosis. Mol Genet Metab 
2010;99:S13-S4.
20. Hemsley K, King B, Hopwood J. Injection of recombinant human sulfamidase into the CSF 
via the cerebellomedullary cistern in MPS IIIA mice. Mol Genet Metab 2007;90:313-28.
21. Hemsley KM, Luck AJ, Crawley AC, et al. Examination of intravenous and intra-CSF 
protein delivery for treatment of neurological disease. Eur J Neurosci 2009;29:1197-214.
22. Hemsley KM, Norman EJ, Crawley AC, et al. Effect of cisternal sulfamidase delivery in 
MPS IIIA Huntaway dogs-A proof of principle study. Mol Genet Metab 2009.
23. Bayley N. Bayley Scales of Infant and Toddler Development: Third Edition. San Antonio, 
TX The Psychological Corporation; 2005.
24. Kaufman S, Kaufman N. Kaufman Assessment Battery for Children (KABC-II). 2nd ed.
25. Henderson S, Sugden D, Barnett A. Movement Assessment Battery for Children (second 
ed.). London: Harcourt Assessment; 2007.
26. Sparrow S, Balla D, Cicchetti D. Vineland Adaptive Behavior Scales (Second Edition). 4201 
Woodland Road Circle Pines, MN 55014-1796: American Guidance Service, Inc; 2005.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
74
Appendix 1
Schedule of Events 
Table A1-1
HGT-SAN-067 Study Assessments for Patients Who Have Received 6 Months of HGT-1410 Treatment in Study 
HGT-SAN-055
Dosed every 28 (±7) days 
(ie, Q4W)
Assessment
Screening/or HGT-SAN-055 
EOS Visitk
(Month 6 from the start of 
HGT-SAN-055)
Pre-Tx
Day 1a
IT dosing
Day 2 (±2)
Months 12, 24, 36, 
and 54 
(from the start of 
HGT-SAN-055)
EOSf Month 55
(from the start of 
HGT-SAN-055)
Month 56
Safety 
Follow-upj
Informed Consent/Enrollment
●
Physical Examination
●
●
●
●
Height and Weight
●
●
●
Head Circumference
●
●
●
Visual and Hearing Assessment
●
●
ECG
●
●b
●
Vital Signs
●
●
●
●
Hematology
●
●
●
Serum Chemistry
●
●
●
Pregnancy Testingn
●
●
Urinalysis
●
●
●
Leukocyte pellet preparationo
●
Urine Heparan Sulfate and Heparan 
Sulfate Derivatives 
●
●e
●
Plasma and serum Heparan Sulfate and 
Heparan Sulfate Derivatives
●
●e
●
Anti-rhHNS antibody testing (serum and 
CSF)l
●
●
●
Auditory Brainstem Response (ABR)
●
●
●p
MRI of the Head
●
●
●p
CSF Sample Collectionm
●
●c
●c, p
HGT-1410 dosing: every 28 (7) days d, g , 
●
Neurological Examinationh
●
●
●
●
Full Neurodevelopmental Testingi
●
●
●
Children’s Sleep Habits Rating Scale
●
●
●

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
75
Table A1-1
HGT-SAN-067 Study Assessments for Patients Who Have Received 6 Months of HGT-1410 Treatment in Study 
HGT-SAN-055
Dosed every 28 (±7) days 
(ie, Q4W)
Assessment
Screening/or HGT-SAN-055 
EOS Visitk
(Month 6 from the start of 
HGT-SAN-055)
Pre-Tx
Day 1a
IT dosing
Day 2 (±2)
Months 12, 24, 36, 
and 54 
(from the start of 
HGT-SAN-055)
EOSf Month 55
(from the start of 
HGT-SAN-055)
Month 56
Safety 
Follow-upj
Child Health Questionnaire-50
●
●
●
Child Health Questionnaire-87
●
●
●
Infant Toddler QOL Questionnaire
●
●
●
Concomitant Medications, Therapies, and 
Procedures
●
●
●
●
●
Adverse Event Monitoring
●
●
●
●
●
X-ray examination of device (if treatment 
is to continue beyond end of study)
●
Removal of IDDD
●q
●q
Abbreviations:
ABR = Auditory brainstem response; CSF = cerebrospinal fluid; EOS  = end of study ; ECG = electrocardiogram; IT = intrathecal; 
MRI = Magnetic resonance imaging; TX = treatment
Note: The timing of assessments is calculated from the start of HGT-SAN-055.  Therefore, for example, the end-of-study visit, as presented here at Month 54, 
corresponds to Month 48 in HGT-SAN-067, but represents a total of 54 months of study treatment (48 months in HGT-SAN-067 + 6 months in 
HGT-SAN-055).
a
Week 1 only, and only performed  if >7 days have elapsed since  HGT-SAN-055 EOS visit assessments.
b
ECG to be performed following administration of study drug.
c
CSF samples will be obtained according to the process with in the study operations manual).  An attempt will be made to obtain a CSF sample via the IDDD 
prior to each administration of HGT-1410 and at the End of Study visit.  If it is not possible to obtain a CSF using the IDDD, the IDDD may be replaced (up 
to twice in a 6 month period [including the time in the HGT-SAN-055 study]) or a LP may be performed (can occur up to 5 times in a 6 month period). 
d
Patients may be discharged as early as 4 hours post HGT-1410 infusion (ie, on Day 2) when deemed clinically stable by the Investigator. 
e
Specimens collected once a month, at Day 1 of the first treatment week.
f
All patients who complete the study will have end of study assessments performed 30 (±7 days) after their last dose of study drug.
g
If a patient’s IDDD becomes nonfunctional or infected; it will be replaced (up to 2 times in a 6 month period; including the time in Study HGT-SAN-055).  
h
The neurological exam should not occur sooner than 4 hours after administration of study drug or before the patient has fully recovered from any anesthesia 
administered for the dosing, whichever occurs later.
i
Full neurodevelopmental testing includes an assessment with the Vineland Adaptive Behavior Scales, Second Edition (VABS-II)
j
A safety follow up telephone call will be made 30 (±7 days) after End of Study Procedures.
k
Assessments will be required only if more than 60 days have elapsed following the HGT-SAN-055 procedures.  These assessments would be repeated 
within 30 days prior to the first scheduled HGT-1410 IT dose.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
76
Table A1-1
HGT-SAN-067 Study Assessments for Patients Who Have Received 6 Months of HGT-1410 Treatment in Study 
HGT-SAN-055
Dosed every 28 (±7) days 
(ie, Q4W)
Assessment
Screening/or HGT-SAN-055 
EOS Visitk
(Month 6 from the start of 
HGT-SAN-055)
Pre-Tx
Day 1a
IT dosing
Day 2 (±2)
Months 12, 24, 36, 
and 54 
(from the start of 
HGT-SAN-055)
EOSf Month 55
(from the start of 
HGT-SAN-055)
Month 56
Safety 
Follow-upj
l
Blood sample drawn before IT injection of HGT-1410.
m
CSF will be tested for standard chemistries, heparan sulfate and heparan sulfate derivatives, anti-rhHNS antibodies, and MPS exploratory biomarkers.
n
A pregnancy test will be carried out on pre-treatment Day 1 in females who are postmenarche to premenopause (childbearing).  The results must be negative 
before study drug can be administered.
o
A blood sample for leukocyte pellet preparation is to be taken at baseline, before dosing.  This pellet should be stored frozen, and will be used for additional 
disease-related laboratory studies, including possible assessment of cross-reactive immunologic material.  If this is not drawn at baseline, it can be drawn at 
any subsequent visit, but it must be taken before dosing.  This only needs to be taken once during the study.
P    These assessments are not to be performed at an EOS visit conducted at Month 55 if they were performed at the Month 54 visit
q   The IDDD will be removed at the Month 54 visit, or at the EOS visit if the patient discontinues the study prior to the Month 54 visit

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
77
Appendix 2
Neurodevelopmental and Behavioral Assessments 
Table A2-1 and Table A2-2 detail the specific psychometric instruments that will be used to 
provide measures of each of relevant neurobehavioral or developmental domain assessed.  The 
tables also summarize the rules used to select a test for a patient, the subtests included in each 
test, and the subscales generated by the test battery.
Table A2-1
Summary of Neurodevelopmental Outcome Measures
Domain
Age
Test
Summary score and 
subdomains:
- Cognitive
- Motor
- Social/Emotional
0 to 42 months
Bayley Scales of Infant Development, Third 
Edition (BSID-III)23
- Cognitive 
- Processing skills
3 to 18 years
Kaufman Assessment Battery for Children, 
Second Edition (KABC-II)24  
Motor
3.0 to 16:11 
years
Movement Assessment Battery for Children, 
Second Edition (MABC-2)25  
Communication
Daily Living
Socialization
Motor Skills
0 to 90 years
Vineland Adaptive Behavior Scales, Second 
Edition (VABS-II)26
Table A2-2
Summary of Sanfilippo-specific Assessments
Domain
Assessment
Parent-scored behavioral inventory
- communication:  understanding
- communication:  expression
- tantrums
- specific behaviors inventory
- mood & emotions inventory
Sanfilippo Behavior Rating Scale
MPS-specific four-point scoring 
system/total disability score
- cognition
- expressive language
- motor score
Four-Point Scoring System/Total Disability 
Score (FPSS/TDS)5
The term “neurodevelopmental” refers to the process by which the neurological system matures 
and changes over time.  Assessing these changes in a population of children whose neurological 
system is progressively more affected can be very challenging.  
Typically, neurodevelopmental progress is reflected by the child’s abilities to perform certain 
skills (sitting, walking, and talking).  

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
78
However, a child with a neurological disorder may be able to perform age appropriate skills, but 
with atypical patterns.  For example, the child may be able to walk, but his gait is not normal.  
Most assessments will therefore measure the skills, but are not designed to capture the 
abnormalities in pattern or quality of the skill.  
These qualitative differences will be evident to the skilled test administrator/clinician who is 
familiar with the disorder.  However, only longitudinal tracking and repeated measures will 
reveal the significance of these abnormalities in overall function to the less experienced clinician.   
The rate at which different skills develop or regress over time will give insight into the disease 
process.  The next step is to determine how the learned skills are used for daily functional 
activities so that as the children grow up they become independent from caregivers.  These 
functional skills can be tracked to reflect quality of life issues for both parents and children. 
Neurodevelopmental assessments described below will be scheduled for administration in the 
morning and estimated to last between 2 and 4 hours.
The list of assessments and algorithm is discussed in detail in the Study Operations Manual and 
includes:
Bayley Scales of Infant Development, Third Edition (BSID-III) 23
The Bayley Scales of Infant Development is a standard series of measurements used primarily to 
assess the motor (fine and gross), language (receptive and expressive), and cognitive 
development of infants and toddlers, ages 0 to 42 months.  This measure consists of a series of 
developmental play tasks and takes between 45 and 60 minutes to administer.  Raw scores of 
successfully completed items are converted to scale scores and to composite scores.  These 
scores are used to determine the child's performance compared with norms taken from typically 
developing children of their age (in months).  The assessment is often used in conjunction with 
the Social-Emotional Adaptive Behavior Questionnaire.  Completed by the parent or caregiver, 
this questionnaire establishes the range of adaptive behaviors that the child can currently achieve 
and enables comparison with age norms.
Kaufman Assessment Battery for Children, Second Edition (KABC-II) 24
Purpose:
The KABC-II measures a child’s cognitive ability and processing skills and was designed to 
minimize verbal instructions and responses.  In addition, the assessment contains little cultural 
content to provide a more accurate assessment of children from diverse backgrounds.  Thus 
language difficulties or cultural differences are minimized in the test battery’s results.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
79
Description:
Investigators may choose either the Cattell-Horn-Carroll or the Luria model for a patient’s 
assessment.  
The Cattell-Horn-Carroll model is used with children from a mainstream cultural and language 
background and the Luria model is used for children with significantly limited verbal ability.  
Subtests are administered on four or five ability scales and interpreted using the chosen model. 
Movement Assessment Battery for Children, Second Edition (MABC-2)25
Purpose:
The Movement Assessment Battery for Children, Second Edition identifies, describes and guides 
treatment of motor impairment in children from 3.0 to 16:11 years of age.
Description:
The MABC-2 checklist is administered individually over approximately 30 minutes.  It yields 
both normative and qualitative measures of movement competence, manual dexterity, ball skills, 
static and dynamic balance.
Vineland Adaptive Behavior Scales, Second Edition (VABS-II) 26
Purpose:
The test measures adaptive behaviors, including the ability to cope with environmental changes, 
to learn new everyday skills and to demonstrate independence.  It is an instrument that supports 
the diagnosis of intellectual and developmental disabilities.  It encompasses ages from birth to 
90 years. 
Description:
Adaptive behavior is a composite of various dimensions.  This test measures 5 domains:  
communication, daily living skills, socialization, motor skills, and maladaptive behavior 
(optional) and is administered in a semi-structured interview in through a questionnaire.  The 
scales of the VABS-II were organized within a 3-domain structure:  Communication, Daily 
Living, and Socialization.  This structure corresponds to the 3 broad domains of adaptive 
functioning by the American Association of Intellectual and Developmental Disabilities:  
Conceptual, Practical, and Social.  In addition, VABS-II offers a Motor Skills Domain and an 
optional Maladaptive Behavior Index.  The scores are interpreted by means of score equivalents 
for the raw scores in each domain, percentile ranks, age equivalents, adaptive levels, and 
maladaptive levels.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
80
Sanfilippo Behavior Rating Scale (SBRS)
The Sanfilippo Behavior Rating Scale (SBRS) is a newly-developed scale designed by Drs. Elsa 
Shapiro and Michael Potegal to measure a cluster of behaviors known to occur in Sanfilippo 
syndrome.  The SBRS is a parent-scored behavioral inventory measuring (1) comprehensive 
language skills, (2) expressive language skills, (3) tantrums, (4) mood and emotions, and 
(5) other behaviors not otherwise classified.
Four-Point Scoring System/Total Disability Score (FPSS/TDS) 5
The FPSS assesses motor function, expressive language, and cognitive function on a 0 to 3 point 
scale and can be used for individuals of all ages.  The total disability score is the average of the 
motor function, speech, and cognitive function scores.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
81
Appendix 3
Expected Adverse Device Effects
Procedure-Related Complications

Components handled improperly before, during, or after implantation 

Access port implanted incorrectly

Catheter positioned improperly

Injection through septum performed incorrectly

Injection of incorrect medication through access port

Injection outside the access port into pocket or subcutaneous tissue or extravasation

Pocket seroma, hematoma, erosion, or infection
Intrathecal Access Complications

Surgical complications such as hemorrhage or hematoma

Infection of the implant site or catheter track

Radiculitis or arachnoiditis

Intrathecal space infection resulting in meningitis or encephalitis

Bleeding 

Spinal cord damage or trauma to the spinal cord or nerve roots

Post-lumbar puncture, cerebrospinal fluid (CSF) leak, leading to headache, or  subcutaneous 
CSF collection

Epidural instead of intrathecal placement of catheter

Inflammatory mass resulting in neurological impairment, including paralysis

Pain on injection

Complications of anesthesia

Pseudomeningocele

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
82
System-Related Complications

Improperly positioned access port

Erosion of the skin because of the underlying access port or the catheter

Wound dehiscence

Access port migration, fracture, breakage or occlusion

Catheter damage, dislodgement, migration, disconnection, kinking or occlusion, fibrosis, or 
hygroma, resulting in tissue damage or a loss of or change in therapy, or other potentially 
serious adverse health consequences

Catheter breakage and migration of residual catheter fragments, potentially resulting in 
serious adverse health consequences and the need for surgical removal 

Local immunological or fibrous reaction to the presence of a foreign body (the device)

End of device service life or component failure, requiring surgical replacement

Component failure, resulting in loss of therapy

Access port inversion (“flipping”), rotation, or extrusion

Access port or catheter rejection 

Fibrin sheath formation around catheter tip

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
83
Appendix 4
Protocol Amendment 5 Summary of Changes
AMENDMENT SUMMARY AND RATIONALE
Clinical protocol HGT-SAN-067 has been amended to remove the requirement for patients to 
have a WBC greater than 100 cubic millimeters in CSF just prior to dosing. It is believed that 
sufficient experience with HGT-1410 now exists that it is safe to proceed with dosing without 
waiting for CSF clinical laboratory results. This also reduces the time that a needle is in the 
device port, thus reducing the risk of introducing infection. 
Previous Amendment:  Amendment 4; 3 May 2013
DETAILED SUMMARY OF CHANGES FOR THE AMENDMENT 
This is a section that has been updated to describe the changes from the previous protocol 
version.  Significant changes and additions to the protocol text are captured below.  Bold text 
indicates new text.  Strikethrough text indicates deleted text.
Change:  Remove the pre-dose CSF requirement of WBC >100 cc
Section impacted by this change: Section 8.2
CSF samples will be obtained from these patients on Day 2, immediately prior to the first 
IT study drug injection.  Note:  Patients will not receive study drug if the pre-dose CSF 
contains >100 WBC per cubic millimeter.
Other sections impacted by this change: None
Change:  Minor editorial clarification
Section impacted by this change: Section 6.3.1
CSF samples will be obtained prior to each injection for clinical laboratory safety
evaluation and potential biomarker studies.  
Other sections impacted by this change: None

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410) 
Clinical Trial Protocol: HGT-SAN-067 Amendment 5 
 17 January 2014 
Appendix 5 
Protocol Signature Page 
Study Title: 
An Open-Label Extension of Study HGT -SAN -05 5 Evaluating 
Long-Term Safety and Clinical Outcomes oflntrathecal 
Administration of rhHNS in Patients with Sanfilippo Syndrome 
Type A (MPS IliA) 
Study Number: 
HGT-SAN-067 Amendment 5 
Final Date: 
21 June 2010 
Amendment 1 Date: 
22 January 2011 
Amendment 2 Date: 
13 January 2012 
Amendment 3 Date: 
28 August 2012 
Amendment 4 Date: 
3 May 2013 
Amendment 5 Date: 
17 January 2014 
I have read the protocol described above. I agree to comply with all applicable regulations and 
to conduct the study as described in the protocol. 
Signatory: 
Investigator 
Signature 
Printed Name 
I have read and approve the protocol described above. 
Signatory: 
ShireHGT 
Medical 
Monitor 
Shire 
Si
atu;e 
, MD 
Printed N arne 
Confidential 
Date 
Date 
84

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 5
17 January 2014
Shire
Confidential
85
Appendix 6
The National Cancer Institute Common Terminology Criteria version 3.0

Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, Version 3.0, DCTD, NCI, NIH, DHHS 
 
March 31, 2003 (http://ctep.cancer.gov), Publish Date: August 9, 2006 
Common Terminology Criteria for Adverse Events v3.0 (CTCAE) 
Publish Date: August 9, 2006 
Quick Reference 
The NCI Common Terminology Criteria for Adverse Events 
v3.0 is a descriptive terminology which can be utilized for 
Adverse Event (AE) reporting. A grading (severity) scale is 
provided for each AE term. 
Components and Organization  
CATEGORY 
A CATEGORY is a broad classification of AEs based on 
anatomy and/or pathophysiology. Within each CATEGORY, 
AEs are listed accompanied by their descriptions of severity 
(Grade). 
Adverse Event Terms 
An AE is any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medical treatment or procedure 
that may or may not be considered related to the medical 
treatment or procedure. An AE is a term that is a unique 
representation of a specific event used for medical 
documentation and scientific analyses. Each AE term is 
mapped to a MedDRA term and code. AEs are listed 
alphabetically within CATEGORIES. 
Short AE Name 
The ‘SHORT NAME’ column is new and it is used to simplify 
documentation of AE names on Case Report Forms.   
Supra-ordinate Terms  
A supra-ordinate term is located within a CATEGORY and is a 
grouping term based on disease process, signs, symptoms, 
or diagnosis. A supra-ordinate term is followed by the word 
‘Select’ and is accompanied by specific AEs that are all 
related to the supra-ordinate term. Supra-ordinate terms 
provide clustering and consistent representation of Grade for 
related AEs. Supra-ordinate terms are not AEs, are not 
mapped to a MedDRA term and code, cannot be graded and 
cannot be used for reporting. 
REMARK 
A ‘REMARK’ is a clarification of an AE. 
ALSO CONSIDER 
An ‘ALSO CONSIDER’ indicates additional AEs that are to be 
graded if they are clinically significant. 
NAVIGATION NOTE 
A ‘NAVIGATION NOTE’ indicates the location of an AE term 
within the CTCAE document. It lists signs/symptoms 
alphabetically and the CTCAE term will appear in the same 
CATEGORY unless the ‘NAVIGATION NOTE’ states differently. 
Grades 
Grade refers to the severity of the AE. The CTCAE v3.0 
displays Grades 1 through 5 with unique clinical descriptions 
of severity for each AE based on this general guideline: 
Grade 1 
Mild AE  
Grade 2 
Moderate AE 
Grade 3 
Severe AE 
Grade 4 
Life-threatening or disabling AE 
Grade 5 
Death related to AE 
A Semi-colon indicates ‘or’ within the description of the grade. 
An ‘Em dash’ (—) indicates a grade not available. 
Not all Grades are appropriate for all AEs. Therefore, some 
AEs are listed with fewer than five options for Grade 
selection. 
Grade 5 
Grade 5 (Death) is not appropriate for some AEs and 
therefore is not an option. 
The DEATH CATEGORY is new. Only one Supra-ordinate 
term is listed in this CATEGORY: ‘Death not associated with 
CTCAE term – Select’ with 4 AE options: Death NOS; 
Disease progression NOS; Multi-organ failure; Sudden death. 
Important: 
• 
Grade 5 is the only appropriate Grade 
• 
This AE is to be used in the situation where 
a death  
1. cannot be reported using a CTCAE v3.0 
term associated with Grade 5, or 
2. cannot be reported within a CTCAE 
CATEGORY as ‘Other (Specify)’ 
 
 
 
 
 
Contents 
ALLERGY/IMMUNOLOGY ............................................1 
AUDITORY/EAR............................................................2 
BLOOD/BONE MARROW .............................................4 
CARDIAC ARRHYTHMIA..............................................5 
CARDIAC GENERAL ....................................................7 
COAGULATION ..........................................................10 
CONSTITUTIONAL SYMPTOMS................................11 
DEATH ........................................................................13 
DERMATOLOGY/SKIN ...............................................14 
ENDOCRINE...............................................................17 
GASTROINTESTINAL.................................................19 
GROWTH AND DEVELOPMENT................................29 
HEMORRHAGE/BLEEDING ....................................... 30 
HEPATOBILIARY/PANCREAS ................................... 34 
INFECTION................................................................. 35 
LYMPHATICS ............................................................. 38 
METABOLIC/LABORATORY ...................................... 40 
MUSCULOSKELETAL/SOFT TISSUE........................ 43 
NEUROLOGY ............................................................. 47 
OCULAR/VISUAL........................................................ 52 
PAIN............................................................................ 55 
PULMONARY/UPPER RESPIRATORY...................... 56 
RENAL/GENITOURINARY.......................................... 60 
SECONDARY MALIGNANCY..................................... 63 
SEXUAL/REPRODUCTIVE FUNCTION ..................... 64 
SURGERY/INTRA-OPERATIVE INJURY ................... 66 
SYNDROMES............................................................. 68 
VASCULAR................................................................. 70 
 

 
ALLERGY/IMMUNOLOGY 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 1 - 
March 31, 2003, Publish Date: August 9, 2006 
Allergic reaction/ 
hypersensitivity  
(including drug fever) 
Allergic reaction 
Transient flushing or 
rash; drug fever <38°C 
(<100.4°F) 
Rash; flushing; urticaria; 
dyspnea; drug fever 
≥38°C (≥100.4°F) 
Symptomatic 
bronchospasm, with or 
without urticaria; 
parenteral medication(s) 
indicated; allergy-related 
edema/angioedema; 
hypotension 
Anaphylaxis 
Death 
REMARK: Urticaria with manifestations of allergic or hypersensitivity reaction is graded as Allergic reaction/hypersensitivity (including drug fever). 
ALSO CONSIDER: Cytokine release syndrome/acute infusion reaction. 
Allergic rhinitis  
(including sneezing, 
nasal stuffiness, 
postnasal drip) 
Rhinitis 
Mild, intervention not 
indicated  
Moderate, intervention 
indicated 
— 
— 
— 
REMARK: Rhinitis associated with obstruction or stenosis is graded as Obstruction/stenosis of airway – Select in the PULMONARY/UPPER RESPIRATORY CATEGORY. 
Autoimmune reaction 
Autoimmune reaction 
Asymptomatic and 
serologic or other 
evidence of autoimmune 
reaction, with normal 
organ function and 
intervention not indicated 
Evidence of autoimmune 
reaction involving a non-
essential organ or 
function (e.g., 
hypothyroidism) 
Reversible autoimmune 
reaction involving function 
of a major organ or other 
adverse event (e.g., 
transient colitis or 
anemia)  
Autoimmune reaction with 
life-threatening 
consequences 
Death 
ALSO CONSIDER: Colitis; Hemoglobin; Hemolysis (e.g., immune hemolytic anemia, drug-related hemolysis); Thyroid function, low (hypothyroidism). 
Serum sickness 
Serum sickness 
— 
— 
Present 
— 
Death 
NAVIGATION NOTE: Splenic function is graded in the BLOOD/BONE MARROW CATEGORY. 
NAVIGATION NOTE: Urticaria as an isolated symptom is graded as Urticaria (hives, welts, wheals) in the DERMATOLOGY/SKIN CATEGORY. 
Vasculitis 
Vasculitis 
Mild, intervention not 
indicated 
Symptomatic, non-
steroidal medical 
intervention indicated 
Steroids indicated 
Ischemic changes; 
amputation indicated 
Death 
Allergy/Immunology – 
Other (Specify, __) 
Allergy – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
AUDITORY/EAR 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 2 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Earache (otalgia) is graded as Pain – Select in the PAIN CATEGORY. 
Hearing:  
patients with/without 
baseline audiogram and 
enrolled in a monitoring 
program1 
Hearing (monitoring 
program) 
Threshold shift or loss of 
15 – 25 dB relative to 
baseline, averaged at 2 
or more contiguous test 
frequencies in at least 
one ear; or subjective 
change in the absence of 
a Grade 1 threshold shift 
Threshold shift or loss of 
>25 – 90 dB, averaged at 
2 contiguous test 
frequencies in at least 
one ear 
Adult only: Threshold shift 
of >25 – 90 dB, averaged 
at 3 contiguous test 
frequencies in at least 
one ear  
Pediatric:  
Hearing loss sufficient to 
indicate therapeutic 
intervention, including 
hearing aids (e.g., ≥20 dB 
bilateral HL in the speech 
frequencies; ≥30 dB 
unilateral HL; and 
requiring additional 
speech-language related 
services) 
Adult only: Profound 
bilateral hearing loss 
(>90 dB) 
Pediatric:  
Audiologic indication for 
cochlear implant and 
requiring additional 
speech-language related 
services  
— 
REMARK: Pediatric recommendations are identical to those for adults, unless specified. For children and adolescents (≤18 years of age) without a baseline test, pre-exposure/pre-
treatment hearing should be considered to be <5 dB loss. 
Hearing: 
patients without baseline 
audiogram and not 
enrolled in a monitoring 
program1  
Hearing (without 
monitoring program) 
— 
Hearing loss not requiring 
hearing aid or 
intervention (i.e., not 
interfering with ADL) 
Hearing loss requiring 
hearing aid or 
intervention (i.e., 
interfering with ADL) 
Profound bilateral hearing 
loss (>90 dB) 
— 
REMARK: Pediatric recommendations are identical to those for adults, unless specified. For children and adolescents (≤18 years of age) without a baseline test, pre-exposure/pre-
treatment hearing should be considered to be <5 dB loss. 
Otitis, external ear 
(non-infectious) 
Otitis, external  
External otitis with 
erythema or dry 
desquamation  
External otitis with moist 
desquamation, edema, 
enhanced cerumen or 
discharge; tympanic 
membrane perforation; 
tympanostomy 
External otitis with 
mastoiditis; stenosis or 
osteomyelitis 
Necrosis of soft tissue or 
bone 
Death 
ALSO CONSIDER: Hearing: patients with/without baseline audiogram and enrolled in a monitoring program1; Hearing: patients without baseline audiogram and not enrolled in a 
monitoring program1.  
Otitis, middle ear  
(non-infectious) 
Otitis, middle 
Serous otitis  
Serous otitis, medical 
intervention indicated 
Otitis with discharge; 
mastoiditis  
Necrosis of the canal soft 
tissue or bone 
Death 

 
AUDITORY/EAR 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 3 - 
March 31, 2003, Publish Date: August 9, 2006 
Tinnitus 
Tinnitus 
— 
Tinnitus not interfering 
with ADL 
Tinnitus interfering with 
ADL 
Disabling 
— 
ALSO CONSIDER: Hearing: patients with/without baseline audiogram and enrolled in a monitoring program1; Hearing: patients without baseline audiogram and not enrolled in a 
monitoring program1. 
Auditory/Ear – Other 
(Specify, __) 
Auditory/Ear – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
 
 
 
 
 
 
                                            
1 Drug-induced ototoxicity should be distinguished from age-related threshold decrements or unrelated cochlear insult. When considering whether an adverse event has occurred, it is 
first necessary to classify the patient into one of two groups. (1) The patient is under standard treatment/enrolled in a clinical trial <2.5 years, and has a 15 dB or greater threshold 
shift averaged across two contiguous frequencies; or (2) The patient is under standard treatment/enrolled in a clinical trial >2.5 years, and the difference between the expected age-
related and the observed threshold shifts is 15 dB or greater averaged across two contiguous frequencies. Consult standard references for appropriate age- and gender-specific 
hearing norms, e.g., Morrell, et al. Age- and gender-specific reference ranges for hearing level and longitudinal changes in hearing level. Journal of the Acoustical Society of America 
100:1949-1967, 1996; or Shotland, et al. Recommendations for cancer prevention trials using potentially ototoxic test agents. Journal of Clinical Oncology 19:1658-1663, 2001.  
In the absence of a baseline prior to initial treatment, subsequent audiograms should be referenced to an appropriate database of normals. ANSI. (1996) 
American National Standard: Determination of occupational noise exposure and estimation of noise-induced hearing impairment, ANSI S 3.44-1996. (Standard S 3.44). New York: 
American National Standards Institute. The recommended ANSI S3.44 database is Annex B. 

 
BLOOD/BONE MARROW 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 4 - 
March 31, 2003, Publish Date: August 9, 2006 
Bone marrow cellularity 
Bone marrow cellularity 
Mildly hypocellular or  
≤25% reduction from 
normal cellularity for age 
Moderately hypocellular 
or >25 – ≤50% reduction 
from normal cellularity for 
age  
Severely hypocellular or 
>50 – ≤75% reduction 
cellularity from normal for 
age  
— 
Death 
CD4 count  
CD4 count 
<LLN – 500/mm3 
<LLN – 0.5 x 109 /L 
<500 – 200/mm3  
<0.5 – 0.2 x 109 /L 
<200 – 50/mm3  
<0.2 x 0.05 – 109 /L 
<50/mm3  
<0.05 x 109 /L 
Death 
Haptoglobin  
Haptoglobin 
<LLN  
— 
Absent 
— 
Death 
Hemoglobin  
Hemoglobin 
<LLN – 10.0 g/dL  
<LLN – 6.2 mmol/L  
<LLN – 100 g/L 
<10.0 – 8.0 g/dL 
<6.2 – 4.9 mmol/L  
<100 – 80g/L 
<8.0 – 6.5 g/dL 
<4.9 – 4.0 mmol/L 
<80 – 65 g/L 
<6.5 g/dL 
<4.0 mmol/L  
<65 g/L 
Death 
Hemolysis (e.g., immune 
hemolytic anemia, drug-
related hemolysis) 
Hemolysis 
Laboratory evidence of 
hemolysis only (e.g., 
direct antiglobulin test 
[DAT, Coombs’] 
schistocytes) 
Evidence of red cell 
destruction and ≥2 gm 
decrease in hemoglobin, 
no transfusion 
Transfusion or medical 
intervention (e.g., 
steroids) indicated 
Catastrophic 
consequences of 
hemolysis (e.g., renal 
failure, hypotension, 
bronchospasm, 
emergency splenectomy) 
Death 
ALSO CONSIDER: Haptoglobin; Hemoglobin. 
Iron overload 
Iron overload 
— 
Asymptomatic iron 
overload, intervention not 
indicated  
Iron overload, 
intervention indicated  
Organ impairment (e.g., 
endocrinopathy, 
cardiopathy) 
Death 
Leukocytes (total WBC) 
Leukocytes 
<LLN – 3000/mm3 
<LLN – 3.0 x 109 /L  
<3000 – 2000/mm3 
<3.0 – 2.0 x 109 /L 
<2000 – 1000/mm3 
<2.0 – 1.0 x 109 /L 
<1000/mm3  
<1.0 x 109 /L 
Death 
Lymphopenia  
Lymphopenia 
<LLN – 800/mm3 
<LLN x 0.8 – 109 /L 
<800 – 500/mm3 
<0.8 – 0.5 x 109 /L 
<500 – 200 mm3 
<0.5 – 0.2 x 109 /L 
<200/mm3 
<0.2 x 109 /L 
Death 
Myelodysplasia 
Myelodysplasia 
— 
— 
Abnormal marrow 
cytogenetics (marrow 
blasts ≤5%)  
RAEB or RAEB-T 
(marrow blasts >5%) 
Death 
Neutrophils/granulocytes 
(ANC/AGC) 
Neutrophils 
<LLN – 1500/mm3  
<LLN – 1.5 x 109 /L 
<1500 – 1000/mm3 
<1.5 – 1.0 x 109 /L  
<1000 – 500/mm3 
<1.0 – 0.5 x 109 /L 
<500/mm3 
<0.5 x 109 /L 
Death 
Platelets 
Platelets 
<LLN – 75,000/mm3 
<LLN – 75.0 x 109 /L 
<75,000 – 50,000/mm3 
<75.0 – 50.0 x 109 /L 
<50,000 – 25,000/mm3  
<50.0 – 25.0 x 109 /L 
<25,000/mm3  
<25.0 x 109 /L 
Death 
Splenic function 
Splenic function 
Incidental findings (e.g., 
Howell-Jolly bodies) 
Prophylactic antibiotics 
indicated 
—  
Life-threatening 
consequences 
Death 
Blood/Bone Marrow – 
Other (Specify, __) 
Blood – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
CARDIAC ARRHYTHMIA 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 5 - 
March 31, 2003, Publish Date: August 9, 2006 
Conduction abnormality/ 
atrioventricular heart 
block  
– Select:  
Conduction abnormality 
– Select 
Asymptomatic, 
intervention not indicated 
– Asystole 
– AV Block-First degree 
– AV Block-Second degree Mobitz Type I (Wenckebach)  
– AV Block-Second degree Mobitz Type II 
– AV Block-Third degree (Complete AV block) 
– Conduction abnormality NOS 
– Sick Sinus Syndrome  
– Stokes-Adams Syndrome 
– Wolff-Parkinson-White Syndrome 
Non-urgent medical 
intervention indicated 
Incompletely controlled 
medically or controlled  
with device (e.g., 
pacemaker) 
Life-threatening (e.g., 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
Death 
Palpitations 
Palpitations 
Present 
Present with associated 
symptoms (e.g., 
lightheadedness, 
shortness of breath) 
— 
— 
— 
REMARK: Grade palpitations only in the absence of a documented arrhythmia. 
Prolonged QTc interval 
Prolonged QTc 
QTc >0.45 – 0.47 second 
 QTc >0.47 – 0.50 
second; ≥0.06 second 
above baseline 
QTc >0.50 second 
QTc >0.50 second; life-
threatening signs or 
symptoms (e.g., 
arrhythmia, CHF, 
hypotension, shock 
syncope); Torsade de 
pointes 
Death 
Supraventricular and 
nodal arrhythmia  
– Select: 
Supraventricular 
arrhythmia – Select 
Asymptomatic, 
intervention not indicated 
Non-urgent medical 
intervention indicated 
– Atrial fibrillation 
– Atrial flutter  
– Atrial tachycardia/Paroxysmal Atrial Tachycardia 
– Nodal/Junctional 
– Sinus arrhythmia  
– Sinus bradycardia 
– Sinus tachycardia  
– Supraventricular arrhythmia NOS 
– Supraventricular extrasystoles (Premature Atrial Contractions; Premature Nodal/Junctional Contractions) 
– Supraventricular tachycardia 
Symptomatic and 
incompletely controlled 
medically, or controlled 
with device (e.g., 
pacemaker) 
Life-threatening (e.g., 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
Death 
NAVIGATION NOTE: Syncope is graded as Syncope (fainting) in the NEUROLOGY CATEGORY. 

 
CARDIAC ARRHYTHMIA 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 6 - 
March 31, 2003, Publish Date: August 9, 2006 
Vasovagal episode 
Vasovagal episode 
— 
Present without loss of 
consciousness 
Present with loss of 
consciousness 
Life-threatening 
consequences  
Death 
Ventricular arrhythmia 
– Select: 
Ventricular arrhythmia 
– Select 
– Bigeminy 
– Idioventricular rhythm 
– PVCs 
– Torsade de pointes 
– Trigeminy 
– Ventricular arrhythmia NOS 
– Ventricular fibrillation  
– Ventricular flutter 
– Ventricular tachycardia 
Asymptomatic, no 
intervention indicated 
Non-urgent medical 
intervention indicated 
Symptomatic and 
incompletely controlled 
medically or controlled 
with device (e.g., 
defibrillator) 
Life-threatening (e.g., 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
Death 
Cardiac Arrhythmia  
– Other (Specify, __) 
Cardiac Arrhythmia – 
Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling  
Death 

 
CARDIAC GENERAL 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 7 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Angina is graded as Cardiac ischemia/infarction in the CARDIAC GENERAL CATEGORY. 
Cardiac 
ischemia/infarction 
Cardiac 
ischemia/infarction 
Asymptomatic arterial 
narrowing without 
ischemia 
Asymptomatic and testing 
suggesting ischemia; 
stable angina  
Symptomatic and testing 
consistent with ischemia; 
unstable angina; 
intervention indicated 
Acute myocardial 
infarction 
Death 
Cardiac troponin I (cTnI) 
cTnI 
— 
— 
Levels consistent with 
unstable angina as 
defined by the 
manufacturer 
Levels consistent with 
myocardial infarction as 
defined by the 
manufacturer 
Death 
Cardiac troponin T (cTnT) 
cTnT 
0.03 – <0.05 ng/mL 
0.05 – <0.1 ng/mL 
0.1 – <0.2 ng/mL 
0.2 ng/mL 
Death 
Cardiopulmonary arrest, 
cause unknown 
(non-fatal) 
Cardiopulmonary arrest 
— 
— 
— 
Life-threatening  
— 
REMARK: Grade 4 (non-fatal) is the only appropriate grade. CTCAE provides three alternatives for reporting Death: 
1. A CTCAE term associated with Grade 5.  
2. A CTCAE 'Other (Specify, __)’ within any CATEGORY. 
3. Death not associated with CTCAE term – Select in the DEATH CATEGORY. 
NAVIGATION NOTE: Chest pain (non-cardiac and non-pleuritic) is graded as Pain – Select in the PAIN CATEGORY. 
NAVIGATION NOTE: CNS ischemia is graded as CNS cerebrovascular ischemia in the NEUROLOGY CATEGORY. 
Hypertension 
Hypertension 
Asymptomatic, transient 
(<24 hrs) increase by >20 
mmHg (diastolic) or to 
>150/100 if previously 
WNL; intervention not 
indicated  
Pediatric: 
Asymptomatic, transient 
(<24 hrs) BP increase 
>ULN; intervention not 
indicated 
Recurrent or persistent 
(≥24 hrs) or symptomatic 
increase by >20 mmHg 
(diastolic) or to >150/100 
if previously WNL; 
monotherapy may be 
indicated  
Pediatric: 
Recurrent or persistent 
(≥24 hrs) BP >ULN; 
monotherapy may be 
indicated 
Requiring more than one 
drug or more intensive 
therapy than previously 
Pediatric: 
Same as adult 
Life-threatening 
consequences (e.g., 
hypertensive crisis) 
Pediatric: 
Same as adult 
Death 
REMARK: Use age and gender-appropriate normal values >95th percentile ULN for pediatric patients. 

 
CARDIAC GENERAL 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 8 - 
March 31, 2003, Publish Date: August 9, 2006 
Hypotension 
Hypotension 
Changes, intervention not 
indicated 
Brief (<24 hrs) fluid 
replacement or other 
therapy; no physiologic 
consequences 
Sustained (≥24 hrs) 
therapy, resolves without 
persisting physiologic 
consequences 
Shock (e.g., acidemia; 
impairment of vital organ 
function)  
Death 
ALSO CONSIDER: Syncope (fainting). 
Left ventricular diastolic 
dysfunction 
Left ventricular diastolic 
dysfunction 
Asymptomatic diagnostic 
finding; intervention not 
indicated 
Asymptomatic, 
intervention indicated 
Symptomatic CHF 
responsive to intervention 
Refractory CHF, poorly 
controlled; intervention 
such as ventricular assist 
device or heart transplant 
indicated  
Death 
Left ventricular systolic 
dysfunction 
Left ventricular systolic 
dysfunction 
Asymptomatic, resting 
ejection fraction (EF)  
<60 – 50%; shortening 
fraction (SF) <30 – 24% 
Asymptomatic, resting  
EF <50 – 40%; 
SF <24 – 15% 
Symptomatic CHF 
responsive to 
intervention; 
EF <40 – 20% 
SF <15% 
Refractory CHF or poorly 
controlled; EF <20%; 
intervention such as 
ventricular assist device, 
ventricular reduction 
surgery, or heart 
transplant indicated 
Death 
NAVIGATION NOTE: Myocardial infarction is graded as Cardiac ischemia/infarction in the CARDIAC GENERAL CATEGORY. 
Myocarditis 
Myocarditis 
— 
— 
CHF responsive to 
intervention 
Severe or refractory CHF 
Death 
Pericardial effusion 
(non-malignant) 
Pericardial effusion 
Asymptomatic effusion  
—  
Effusion with physiologic 
consequences 
Life-threatening 
consequences (e.g., 
tamponade); emergency 
intervention indicated 
Death 
Pericarditis 
Pericarditis 
Asymptomatic, ECG or 
physical exam (rub) 
changes consistent with 
pericarditis 
Symptomatic pericarditis 
(e.g., chest pain) 
Pericarditis with 
physiologic 
consequences (e.g., 
pericardial constriction) 
Life-threatening 
consequences; 
emergency intervention 
indicated 
Death 
NAVIGATION NOTE: Pleuritic pain is graded as Pain – Select in the PAIN CATEGORY. 
Pulmonary hypertension 
Pulmonary hypertension 
Asymptomatic without 
therapy 
Asymptomatic, therapy 
indicated 
Symptomatic 
hypertension, responsive 
to therapy 
Symptomatic 
hypertension, poorly 
controlled 
Death 
Restrictive 
cardiomyopathy  
Restrictive 
cardiomyopathy  
Asymptomatic, therapy 
not indicated 
Asymptomatic, therapy 
indicated 
Symptomatic CHF 
responsive to intervention 
Refractory CHF, poorly 
controlled; intervention 
such as ventricular assist 
device, or heart 
transplant indicated  
Death 

 
CARDIAC GENERAL 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 9 - 
March 31, 2003, Publish Date: August 9, 2006 
Right ventricular 
dysfunction 
(cor pulmonale) 
Right ventricular 
dysfunction 
Asymptomatic without 
therapy 
Asymptomatic, therapy 
indicated 
Symptomatic cor 
pulmonale, responsive to 
intervention 
Symptomatic cor 
pulmonale poorly 
controlled; intervention 
such as ventricular assist 
device, or heart 
transplant indicated  
Death 
Valvular heart disease 
Valvular heart disease 
Asymptomatic valvular 
thickening with or without 
mild valvular regurgitation 
or stenosis; treatment 
other than endocarditis 
prophylaxis not indicated 
Asymptomatic; moderate 
regurgitation or stenosis 
by imaging 
Symptomatic; severe 
regurgitation or stenosis; 
symptoms controlled with 
medical therapy 
Life-threatening; 
disabling; intervention 
(e.g., valve replacement, 
valvuloplasty) indicated 
Death 
Cardiac General – Other 
(Specify, __) 
Cardiac General – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
COAGULATION 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 10 - 
March 31, 2003, Publish Date: August 9, 2006 
DIC (disseminated 
intravascular coagulation) 
DIC 
— 
Laboratory findings with 
no bleeding 
Laboratory findings and 
bleeding 
Laboratory findings, life-
threatening or disabling 
consequences (e.g., CNS 
hemorrhage, organ 
damage, or 
hemodynamically 
significant blood loss) 
Death 
REMARK: DIC (disseminated intravascular coagulation) must have increased fibrin split products or D-dimer.  
ALSO CONSIDER: Platelets. 
 
Fibrinogen  
Fibrinogen 
<1.0 – 0.75 x LLN 
or <25% decrease from 
baseline 
<0.75 – 0.5 x LLN 
or 25 – <50% decrease 
from baseline 
<0.5 – 0.25 x LLN 
or 50 – <75% decrease 
from baseline 
<0.25 x LLN  
or 75% decrease from 
baseline or absolute 
value <50 mg/dL  
Death 
REMARK: Use % decrease only when baseline is <LLN (local laboratory value). 
INR (International 
Normalized Ratio of 
prothrombin time) 
INR 
 
>1 – 1.5 x ULN 
>1.5 – 2 x ULN 
>2 x ULN 
— 
— 
ALSO CONSIDER: Hemorrhage, CNS; Hemorrhage, GI – Select; Hemorrhage, GU – Select; Hemorrhage, pulmonary/upper respiratory – Select. 
PTT (Partial 
Thromboplastin Time)  
PTT 
>1 – 1.5 x ULN 
>1.5 – 2 x ULN 
>2 x ULN 
— 
— 
ALSO CONSIDER: Hemorrhage, CNS; Hemorrhage, GI – Select; Hemorrhage, GU – Select; Hemorrhage, pulmonary/upper respiratory – Select. 
Thrombotic 
microangiopathy (e.g., 
thrombotic 
thrombocytopenic 
purpura [TTP] or 
hemolytic uremic 
syndrome [HUS]) 
Thrombotic 
microangiopathy 
Evidence of RBC 
destruction 
(schistocytosis) without 
clinical consequences 
— 
Laboratory findings 
present with clinical 
consequences (e.g., renal 
insufficiency, petechiae) 
Laboratory findings and 
life-threatening or 
disabling consequences, 
(e.g., CNS hemorrhage/ 
bleeding or thrombosis/ 
embolism or renal failure) 
Death 
REMARK: Must have microangiopathic changes on blood smear (e.g., schistocytes, helmet cells, red cell fragments). 
ALSO CONSIDER: Creatinine; Hemoglobin; Platelets. 
Coagulation – Other 
(Specify, __) 
Coagulation – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
CONSTITUTIONAL SYMPTOMS 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 11 - 
March 31, 2003, Publish Date: August 9, 2006 
Fatigue  
(asthenia, lethargy, 
malaise) 
Fatigue 
Mild fatigue over baseline 
Moderate or causing 
difficulty performing some 
ADL 
Severe fatigue interfering 
with ADL 
Disabling 
— 
Fever  
(in the absence of 
neutropenia, where 
neutropenia is defined as 
ANC <1.0 x 109/L) 
Fever 
38.0 – 39.0°C  
(100.4 – 102.2°F) 
>39.0 – 40.0°C 
(102.3 – 104.0°F)  
>40.0°C 
(>104.0°F) for ≤24 hrs  
>40.0°C 
(>104.0°F) for >24 hrs 
Death 
REMARK: The temperature measurements listed are oral or tympanic. 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever).  
NAVIGATION NOTE: Hot flashes are graded as Hot flashes/flushes in the ENDOCRINE CATEGORY. 
Hypothermia 
Hypothermia 
— 
35 – >32°C 
95 – >89.6°F 
32 – >28°C  
89.6 – >82.4° F 
≤28 °C  
82.4°F or life-threatening 
consequences (e.g., 
coma, hypotension, 
pulmonary edema, 
acidemia, ventricular 
fibrillation) 
Death 
Insomnia 
Insomnia 
Occasional difficulty 
sleeping, not interfering 
with function 
Difficulty sleeping, 
interfering with function 
but not interfering with 
ADL 
Frequent difficulty 
sleeping, interfering with 
ADL 
Disabling 
— 
REMARK: If pain or other symptoms interfere with sleep, do NOT grade as insomnia. Grade primary event(s) causing insomnia. 
Obesity2 
Obesity 
— 
BMI 25 – 29.9 kg/m2 
BMI 30 – 39.99 kg/m2 
BMI ≥40 kg/m2 
— 
REMARK: BMI = (weight [kg]) / (height [m])2 
Odor  
(patient odor) 
Patient odor 
Mild odor 
Pronounced odor 
— 
— 
— 
Rigors/chills 
Rigors/chills 
Mild 
Moderate, narcotics 
indicated 
Severe or prolonged, not 
responsive to narcotics 
— 
— 
                                            
2 NHLBI Obesity Task Force. "Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults," The Evidence Report, Obes Res 6:51S-
209S, 1998.  

 
CONSTITUTIONAL SYMPTOMS 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 12 - 
March 31, 2003, Publish Date: August 9, 2006 
Sweating  
(diaphoresis) 
Sweating  
Mild and occasional 
Frequent or drenching 
— 
— 
— 
ALSO CONSIDER: Hot flashes/flushes.  
Weight gain  
Weight gain 
5 – <10% of baseline 
10 – <20% of baseline 
≥20% of baseline 
— 
— 
REMARK: Edema, depending on etiology, is graded in the CARDIAC GENERAL or LYMPHATICS CATEGORIES. 
ALSO CONSIDER: Ascites (non-malignant); Pleural effusion (non-malignant). 
Weight loss 
Weight loss 
5 to <10% from baseline; 
intervention not indicated 
10 – <20% from baseline; 
nutritional support 
indicated 
≥20% from baseline; tube 
feeding or TPN indicated 
— 
— 
Constitutional Symptoms 
– Other (Specify, __) 
Constitutional Symptoms 
– Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
DEATH 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 13 - 
March 31, 2003, Publish Date: August 9, 2006 
Death not associated with 
CTCAE term  
– Select: 
Death not associated with 
CTCAE term – Select 
– Death NOS 
– Disease progression NOS 
– Multi-organ failure 
– Sudden death 
— 
— 
— 
— 
Death 
REMARK: Grade 5 is the only appropriate grade. 'Death not associated with CTCAE term – Select' is to be used where a death: 
1. Cannot be attributed to a CTCAE term associated with Grade 5. 
2. Cannot be reported within any CATEGORY using a CTCAE 'Other (Specify, __)’.  

 
DERMATOLOGY/SKIN 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 14 - 
March 31, 2003, Publish Date: August 9, 2006 
Atrophy, skin 
Atrophy, skin 
Detectable 
Marked 
— 
— 
— 
Atrophy, subcutaneous 
fat 
Atrophy, subcutaneous 
fat 
Detectable 
Marked 
— 
— 
— 
ALSO CONSIDER: Induration/fibrosis (skin and subcutaneous tissue). 
Bruising  
(in absence of Grade 3 or 
4 thrombocytopenia) 
Bruising  
Localized or in a 
dependent area 
Generalized 
— 
— 
— 
Burn 
Burn 
Minimal symptoms; 
intervention not indicated  
Medical intervention; 
minimal debridement 
indicated  
Moderate to major 
debridement or 
reconstruction indicated  
Life-threatening 
consequences 
Death 
REMARK: Burn refers to all burns including radiation, chemical, etc. 
Cheilitis 
Cheilitis 
Asymptomatic 
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
— 
— 
Dry skin 
Dry skin 
Asymptomatic 
Symptomatic, not 
interfering with ADL 
Interfering with ADL 
— 
— 
Flushing 
Flushing 
Asymptomatic 
Symptomatic 
— 
— 
— 
Hair loss/alopecia 
(scalp or body) 
Alopecia 
Thinning or patchy 
Complete 
— 
— 
— 
Hyperpigmentation 
Hyperpigmentation 
Slight or localized 
Marked or generalized 
— 
— 
— 
Hypopigmentation 
Hypopigmentation 
Slight or localized 
Marked or generalized 
— 
— 
— 
Induration/fibrosis 
(skin and subcutaneous 
tissue) 
Induration  
Increased density on 
palpation 
Moderate impairment of 
function not interfering 
with ADL; marked 
increase in density and 
firmness on palpation 
with or without minimal 
retraction 
Dysfunction interfering 
with ADL; very marked 
density, retraction or 
fixation 
— 
— 
ALSO CONSIDER: Fibrosis-cosmesis; Fibrosis-deep connective tissue.  
Injection site reaction/ 
extravasation changes 
Injection site reaction 
Pain; itching; erythema 
Pain or swelling, with 
inflammation or phlebitis 
Ulceration or necrosis 
that is severe; operative 
intervention indicated  
— 
— 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever); Ulceration. 

 
DERMATOLOGY/SKIN 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 15 - 
March 31, 2003, Publish Date: August 9, 2006 
Nail changes 
Nail changes 
Discoloration; ridging 
(koilonychias); pitting 
Partial or complete loss of 
nail(s); pain in nailbed(s) 
Interfering with ADL  
— 
— 
NAVIGATION NOTE: Petechiae is graded as Petechiae/purpura (hemorrhage/bleeding into skin or mucosa) in the HEMORRHAGE/BLEEDING CATEGORY. 
Photosensitivity 
Photosensitivity 
Painless erythema 
Painful erythema 
Erythema with 
desquamation 
Life-threatening; disabling 
Death 
Pruritus/itching 
Pruritus 
Mild or localized 
Intense or widespread 
Intense or widespread 
and interfering with ADL  
— 
— 
ALSO CONSIDER: Rash/desquamation. 
Rash/desquamation  
Rash 
Macular or papular 
eruption or erythema 
without associated 
symptoms 
Macular or papular 
eruption or erythema with 
pruritus or other 
associated symptoms; 
localized desquamation 
or other lesions covering 
<50% of body surface 
area (BSA) 
Severe, generalized 
erythroderma or macular, 
papular or vesicular 
eruption; desquamation 
covering ≥50% BSA 
Generalized exfoliative, 
ulcerative, or bullous 
dermatitis 
Death 
REMARK: Rash/desquamation may be used for GVHD. 
Rash:  
acne/acneiform 
Acne 
Intervention not indicated  
Intervention indicated 
Associated with pain, 
disfigurement, ulceration, 
or desquamation 
— 
Death 
Rash:  
dermatitis associated with 
radiation  
– Select: 
– Chemoradiation 
– Radiation 
Dermatitis – Select  
Faint erythema or dry 
desquamation 
Moderate to brisk 
erythema; patchy moist 
desquamation, mostly 
confined to skin folds and 
creases; moderate 
edema 
Moist desquamation other 
than skin folds and 
creases; bleeding 
induced by minor trauma 
or abrasion 
Skin necrosis or 
ulceration of full thickness 
dermis; spontaneous 
bleeding from involved 
site  
Death 
Rash:  
erythema multiforme 
(e.g., Stevens-Johnson 
syndrome, toxic 
epidermal necrolysis) 
Erythema multiforme 
— 
Scattered, but not 
generalized eruption 
Severe (e.g., generalized 
rash or painful stomatitis); 
IV fluids, tube feedings, 
or TPN indicated 
Life-threatening; disabling 
Death 
Rash:  
hand-foot skin reaction 
Hand-foot 
Minimal skin changes or 
dermatitis (e.g., 
erythema) without pain  
Skin changes (e.g., 
peeling, blisters, 
bleeding, edema) or pain, 
not interfering with 
function  
Ulcerative dermatitis or 
skin changes with pain 
interfering with function  
— 
— 

 
DERMATOLOGY/SKIN 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 16 - 
March 31, 2003, Publish Date: August 9, 2006 
Skin breakdown/ 
decubitus ulcer 
Decubitus  
— 
Local wound care; 
medical intervention 
indicated 
Operative debridement or 
other invasive 
intervention indicated 
(e.g., hyperbaric oxygen)  
Life-threatening 
consequences; major 
invasive intervention 
indicated (e.g., tissue 
reconstruction, flap, or 
grafting) 
Death 
REMARK: Skin breakdown/decubitus ulcer is to be used for loss of skin integrity or decubitus ulcer from pressure or as the result of operative or medical intervention. 
Striae 
Striae 
Mild 
Cosmetically significant 
— 
— 
— 
Telangiectasia 
Telangiectasia 
Few 
Moderate number 
Many and confluent 
— 
— 
Ulceration 
Ulceration 
— 
Superficial ulceration  
<2 cm size; local wound 
care; medical intervention 
indicated 
Ulceration ≥2 cm size; 
operative debridement, 
primary closure or other 
invasive intervention 
indicated (e.g., hyperbaric 
oxygen)  
Life-threatening 
consequences; major 
invasive intervention 
indicated (e.g., complete 
resection, tissue 
reconstruction, flap, or 
grafting) 
Death 
Urticaria  
(hives, welts, wheals) 
Urticaria 
Intervention not indicated 
Intervention indicated for 
<24 hrs 
Intervention indicated for 
≥24 hrs 
— 
— 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever). 
Wound complication, 
non-infectious  
Wound complication, 
non-infectious 
Incisional separation of  
≤25% of wound, no 
deeper than superficial 
fascia 
Incisional separation 
>25% of wound with local 
care; asymptomatic 
hernia 
Symptomatic hernia 
without evidence of 
strangulation; fascial 
disruption/dehiscence 
without evisceration; 
primary wound closure or 
revision by operative 
intervention indicated; 
hospitalization or 
hyperbaric oxygen 
indicated 
Symptomatic hernia with 
evidence of strangulation; 
fascial disruption with 
evisceration; major 
reconstruction flap, 
grafting, resection, or 
amputation indicated 
Death 
REMARK: Wound complication, non-infectious is to be used for separation of incision, hernia, dehiscence, evisceration, or second surgery for wound revision. 
Dermatology/Skin – Other 
(Specify, __) 
Dermatology – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
ENDOCRINE 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 17 - 
March 31, 2003, Publish Date: August 9, 2006 
Adrenal insufficiency 
Adrenal insufficiency 
Asymptomatic, 
intervention not indicated 
Symptomatic, intervention 
indicated 
Hospitalization  
Life-threatening; disabling 
Death 
REMARK: Adrenal insufficiency includes any of the following signs and symptoms: abdominal pain, anorexia, constipation, diarrhea, hypotension, pigmentation of mucous membranes, 
pigmentation of skin, salt craving, syncope (fainting), vitiligo, vomiting, weakness, weight loss. Adrenal insufficiency must be confirmed by laboratory studies (low cortisol frequently 
accompanied by low aldosterone). 
ALSO CONSIDER: Potassium, serum-high (hyperkalemia); Thyroid function, low (hypothyroidism). 
Cushingoid appearance 
(e.g., moon face, buffalo 
hump, centripetal obesity, 
cutaneous striae) 
Cushingoid  
— 
Present 
— 
— 
— 
ALSO CONSIDER: Glucose, serum-high (hyperglycemia); Potassium, serum-low (hypokalemia). 
Feminization of male 
Feminization of male 
— 
— 
Present 
— 
— 
NAVIGATION NOTE: Gynecomastia is graded in the SEXUAL/REPRODUCTIVE FUNCTION CATEGORY. 
Hot flashes/flushes3 
Hot flashes 
Mild  
Moderate  
Interfering with ADL 
— 
— 
Masculinization of female 
Masculinization of female 
— 
— 
Present 
— 
— 
Neuroendocrine: 
ACTH deficiency 
ACTH  
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL; hospitalization 
indicated 
Life-threatening 
consequences (e.g., 
severe hypotension) 
Death 
Neuroendocrine: 
ADH secretion 
abnormality (e.g., SIADH 
or low ADH) 
ADH 
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL 
Life-threatening 
consequences 
Death 
Neuroendocrine: 
gonadotropin secretion 
abnormality 
Gonadotropin 
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL; osteopenia; 
fracture; infertility 
— 
— 
Neuroendocrine:  
growth hormone 
secretion abnormality 
Growth hormone  
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
— 
— 
— 
Neuroendocrine:  
prolactin hormone 
secretion abnormality 
Prolactin  
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL; amenorrhea; 
galactorrhea 
— 
Death 
                                            
3 Sloan JA, Loprinzi CL, Novotny PJ, Barton DL, Lavasseur BI, Windschitl HJ, "Methodologic Lessons Learned from Hot Flash Studies," J Clin Oncol 2001 Dec 1;19(23):4280-90 

 
ENDOCRINE 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 18 - 
March 31, 2003, Publish Date: August 9, 2006 
Pancreatic endocrine:  
glucose intolerance 
Diabetes 
Asymptomatic, 
intervention not indicated 
Symptomatic; dietary 
modification or oral agent 
indicated 
Symptoms interfering with 
ADL; insulin indicated 
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar non-ketotic 
coma)  
Death 
Parathyroid function, low 
(hypoparathyroidism) 
Hypoparathyroidism 
Asymptomatic, 
intervention not indicated 
Symptomatic; intervention 
indicated 
— 
— 
— 
Thyroid function, high 
(hyperthyroidism, 
thyrotoxicosis) 
Hyperthyroidism  
Asymptomatic, 
intervention not indicated 
Symptomatic, not 
interfering with ADL; 
thyroid suppression 
therapy indicated 
Symptoms interfering with 
ADL; hospitalization 
indicated  
Life-threatening 
consequences (e.g., 
thyroid storm) 
Death 
Thyroid function, low 
(hypothyroidism) 
Hypothyroidism 
Asymptomatic, 
intervention not indicated 
Symptomatic, not 
interfering with ADL; 
thyroid replacement 
indicated 
Symptoms interfering with 
ADL; hospitalization 
indicated  
Life-threatening 
myxedema coma 
Death 
Endocrine – Other  
(Specify, __) 
Endocrine – Other  
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
GASTROINTESTINAL 
Page 1 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 19 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Abdominal pain or cramping is graded as Pain – Select in the PAIN CATEGORY. 
Anorexia 
Anorexia 
Loss of appetite without 
alteration in eating habits 
Oral intake altered 
without significant weight 
loss or malnutrition; oral 
nutritional supplements 
indicated 
Associated with 
significant weight loss or 
malnutrition (e.g., 
inadequate oral caloric 
and/or fluid intake); IV 
fluids, tube feedings or 
TPN indicated 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Weight loss. 
Ascites (non-malignant) 
Ascites 
Asymptomatic 
Symptomatic, medical 
intervention indicated 
Symptomatic, invasive 
procedure indicated 
Life-threatening 
consequences 
Death 
REMARK: Ascites (non-malignant) refers to documented non-malignant ascites or unknown etiology, but unlikely malignant, and includes chylous ascites. 
Colitis 
Colitis 
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain; mucus 
or blood in stool 
Abdominal pain, fever, 
change in bowel habits 
with ileus; peritoneal 
signs 
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis, toxic 
megacolon) 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select.  
Constipation 
Constipation 
Occasional or intermittent 
symptoms; occasional 
use of stool softeners, 
laxatives, dietary 
modification, or enema 
Persistent symptoms with 
regular use of laxatives 
or enemas indicated 
Symptoms interfering 
with ADL; obstipation 
with manual evacuation 
indicated  
Life-threatening 
consequences (e.g., 
obstruction, toxic 
megacolon) 
Death 
ALSO CONSIDER: Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation); Obstruction, GI – Select. 
Dehydration 
Dehydration 
Increased oral fluids 
indicated; dry mucous 
membranes; diminished 
skin turgor 
IV fluids indicated <24 
hrs 
IV fluids indicated ≥24 hrs 
Life-threatening 
consequences (e.g., 
hemodynamic collapse) 
Death 
ALSO CONSIDER: Diarrhea; Hypotension; Vomiting. 
Dental:  
dentures or prosthesis 
Dentures  
Minimal discomfort, no 
restriction in activities  
Discomfort preventing 
use in some activities 
(e.g., eating), but not 
others (e.g., speaking) 
Unable to use dentures 
or prosthesis at any time 
— 
— 

 
GASTROINTESTINAL 
Page 2 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 20 - 
March 31, 2003, Publish Date: August 9, 2006 
Dental:  
periodontal disease  
Periodontal  
Gingival recession or 
gingivitis; limited bleeding 
on probing; mild local 
bone loss 
Moderate gingival 
recession or gingivitis; 
multiple sites of bleeding 
on probing; moderate 
bone loss 
Spontaneous bleeding; 
severe bone loss with or 
without tooth loss; 
osteonecrosis of maxilla 
or mandible  
— 
— 
REMARK: Severe periodontal disease leading to osteonecrosis is graded as Osteonecrosis (avascular necrosis) in the MUSCULOSKELETAL CATEGORY. 
Dental: 
teeth  
Teeth 
Surface stains; dental 
caries; restorable, without 
extractions 
Less than full mouth 
extractions; tooth fracture 
or crown amputation or 
repair indicated 
Full mouth extractions 
indicated 
— 
— 
Dental:  
teeth development 
Teeth development 
Hypoplasia of tooth or 
enamel not interfering 
with function 
Functional impairment 
correctable with oral 
surgery 
Maldevelopment with 
functional impairment not 
surgically correctable 
— 
— 
Diarrhea 
Diarrhea 
Increase of <4 stools per 
day over baseline; mild 
increase in ostomy output 
compared to baseline 
Increase of 4 – 6 stools 
per day over baseline; IV 
fluids indicated <24hrs; 
moderate increase in 
ostomy output compared 
to baseline; not 
interfering with ADL 
Increase of ≥7 stools per 
day over baseline; 
incontinence; IV fluids 
≥24 hrs; hospitalization; 
severe increase in 
ostomy output compared 
to baseline; interfering 
with ADL 
Life-threatening 
consequences (e.g., 
hemodynamic collapse) 
Death 
REMARK: Diarrhea includes diarrhea of small bowel or colonic origin, and/or ostomy diarrhea. 
ALSO CONSIDER: Dehydration; Hypotension. 
Distension/bloating, 
abdominal 
Distension 
Asymptomatic  
Symptomatic, but not 
interfering with GI 
function 
Symptomatic, interfering 
with GI function 
— 
— 
ALSO CONSIDER: Ascites (non-malignant); Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation); Obstruction, GI – Select.  

 
GASTROINTESTINAL 
Page 3 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 21 - 
March 31, 2003, Publish Date: August 9, 2006 
Dry mouth/salivary gland 
(xerostomia) 
Dry mouth 
Symptomatic (dry or thick 
saliva) without significant 
dietary alteration; 
unstimulated saliva flow 
>0.2 ml/min 
Symptomatic and 
significant oral intake 
alteration (e.g., copious 
water, other lubricants, 
diet limited to purees 
and/or soft, moist foods); 
unstimulated saliva 
0.1 to 0.2 ml/min 
Symptoms leading to 
inability to adequately 
aliment orally; IV fluids, 
tube feedings, or TPN 
indicated; unstimulated 
saliva <0.1 ml/min 
— 
— 
REMARK: Dry mouth/salivary gland (xerostomia) includes descriptions of grade using both subjective and objective assessment parameters. Record this event consistently throughout 
a patient’s participation on study. If salivary flow measurements are used for initial assessment, subsequent assessments must use salivary flow. 
ALSO CONSIDER: Salivary gland changes/saliva.  
Dysphagia 
(difficulty swallowing) 
Dysphagia 
Symptomatic, able to eat 
regular diet  
Symptomatic and altered 
eating/swallowing (e.g., 
altered dietary habits, 
oral supplements); IV 
fluids indicated <24 hrs 
Symptomatic and 
severely altered 
eating/swallowing (e.g., 
inadequate oral caloric or 
fluid intake); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences (e.g., 
obstruction, perforation) 
 
Death 
REMARK: Dysphagia (difficulty swallowing) is to be used for swallowing difficulty from oral, pharyngeal, esophageal, or neurologic origin. Dysphagia requiring dilation is graded as 
Stricture/stenosis (including anastomotic), GI – Select. 
ALSO CONSIDER: Dehydration; Esophagitis. 
Enteritis  
(inflammation of the small 
bowel) 
Enteritis 
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain; mucus 
or blood in stool 
Abdominal pain, fever, 
change in bowel habits 
with ileus; peritoneal 
signs 
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis) 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select; Typhlitis (cecal inflammation).  
Esophagitis 
Esophagitis 
Asymptomatic pathologic, 
radiographic, or 
endoscopic findings only 
Symptomatic; altered 
eating/swallowing (e.g., 
altered dietary habits, 
oral supplements); IV 
fluids indicated <24 hrs 
Symptomatic and 
severely altered 
eating/swallowing (e.g., 
inadequate oral caloric or 
fluid intake); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences 
Death 
REMARK: Esophagitis includes reflux esophagitis.  
ALSO CONSIDER: Dysphagia (difficulty swallowing). 

 
GASTROINTESTINAL 
Page 4 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 22 - 
March 31, 2003, Publish Date: August 9, 2006 
Fistula, GI 
– Select: 
Fistula, GI – Select  
– Abdomen NOS 
– Anus 
– Biliary tree  
– Colon/cecum/appendix 
– Duodenum 
– Esophagus 
– Gallbladder  
– Ileum 
– Jejunum 
– Oral cavity 
– Pancreas 
– Pharynx 
– Rectum 
– Salivary gland  
– Small bowel NOS 
– Stomach 
Asymptomatic, 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, diarrhea, 
or GI fluid loss); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered GI 
function (e.g., altered 
dietary habits, diarrhea, 
or GI fluid loss); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences  
Death 
REMARK: A fistula is defined as an abnormal communication between two body cavities, potential spaces, and/or the skin. The site indicated for a fistula should be the site from which 
the abnormal process is believed to have originated. For example, a tracheo-esophageal fistula arising in the context of a resected or irradiated esophageal cancer is graded as 
Fistula, GI – esophagus. 
Flatulence 
Flatulence 
Mild 
Moderate 
— 
— 
— 
Gastritis (including bile 
reflux gastritis) 
Gastritis 
Asymptomatic 
radiographic or 
endoscopic findings only 
Symptomatic; altered 
gastric function (e.g., 
inadequate oral caloric or 
fluid intake); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered gastric 
function (e.g., inadequate 
oral caloric or fluid 
intake); IV fluids, tube 
feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., gastrectomy)  
Death 
ALSO CONSIDER: Hemorrhage, GI – Select; Ulcer, GI – Select. 
NAVIGATION NOTE: Head and neck soft tissue necrosis is graded as Soft tissue necrosis – Select in the MUSCULOSKELETAL/SOFT TISSUE CATEGORY. 
Heartburn/dyspepsia 
Heartburn 
Mild 
Moderate 
Severe 
— 
— 
Hemorrhoids 
Hemorrhoids 
Asymptomatic 
Symptomatic; banding or 
medical intervention 
indicated 
Interfering with ADL; 
interventional radiology, 
endoscopic, or operative 
intervention indicated 
Life-threatening 
consequences 
Death 

 
GASTROINTESTINAL 
Page 5 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 23 - 
March 31, 2003, Publish Date: August 9, 2006 
Ileus, GI (functional 
obstruction of bowel, i.e., 
neuroconstipation) 
Ileus 
Asymptomatic, 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered GI 
function; IV fluids, tube 
feeding, or TPN indicated 
≥24 hrs 
Life-threatening 
consequences 
Death 
REMARK: Ileus, GI is to be used for altered upper or lower GI function (e.g., delayed gastric or colonic emptying). 
ALSO CONSIDER: Constipation; Nausea; Obstruction, GI – Select; Vomiting. 
Incontinence, anal 
Incontinence, anal 
Occasional use of pads 
required 
Daily use of pads 
required 
Interfering with ADL; 
operative intervention 
indicated 
Permanent bowel 
diversion indicated 
Death 
REMARK: Incontinence, anal is to be used for loss of sphincter control as sequelae of operative or therapeutic intervention. 
Leak (including 
anastomotic), GI 
– Select: 
– Biliary tree 
– Esophagus 
– Large bowel 
– Leak NOS 
– Pancreas 
– Pharynx 
– Rectum 
– Small bowel  
– Stoma 
– Stomach 
Leak, GI – Select  
Asymptomatic 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and 
interfering with GI 
function; invasive or 
endoscopic intervention 
indicated  
Life-threatening 
consequences 
Death 
REMARK: Leak (including anasomotic), GI – Select is to be used for clinical signs/symptoms or radiographic confirmation of anastomotic or conduit leak (e.g., biliary, esophageal, 
intestinal, pancreatic, pharyngeal, rectal), but without development of fistula. 
Malabsorption  
Malabsorption 
— 
Altered diet; oral 
therapies indicated (e.g., 
enzymes, medications, 
dietary supplements)  
Inability to aliment 
adequately via GI tract 
(i.e., TPN indicated) 
Life-threatening 
consequences 
Death 

 
GASTROINTESTINAL 
Page 6 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 24 - 
March 31, 2003, Publish Date: August 9, 2006 
Mucositis/stomatitis 
(clinical exam)  
– Select: 
– Anus 
– Esophagus 
– Large bowel 
– Larynx 
– Oral cavity 
– Pharynx 
– Rectum 
– Small bowel 
– Stomach 
– Trachea 
Mucositis (clinical exam) 
– Select  
Erythema of the mucosa 
Patchy ulcerations or 
pseudomembranes  
Confluent ulcerations or 
pseudomembranes; 
bleeding with minor 
trauma 
Tissue necrosis; 
significant spontaneous 
bleeding; life-threatening 
consequences 
Death 
REMARK: Mucositis/stomatitis (functional/symptomatic) may be used for mucositis of the upper aero-digestive tract caused by radiation, agents, or GVHD.  
Mucositis/stomatitis 
(functional/symptomatic)  
– Select: 
– Anus 
– Esophagus 
– Large bowel 
– Larynx 
– Oral cavity 
– Pharynx 
– Rectum 
– Small bowel 
– Stomach 
– Trachea 
Mucositis (functional/ 
symptomatic) – Select  
Upper aerodigestive tract 
sites: Minimal symptoms, 
normal diet; minimal 
respiratory symptoms but 
not interfering with 
function 
Lower GI sites: 
Minimal discomfort, 
intervention not indicated 
Upper aerodigestive tract 
sites: Symptomatic but 
can eat and swallow 
modified diet; respiratory 
symptoms interfering with 
function but not 
interfering with ADL 
Lower GI sites:  
Symptomatic, medical 
intervention indicated but 
not interfering with ADL 
Upper aerodigestive tract 
sites: Symptomatic and 
unable to adequately 
aliment or hydrate orally; 
respiratory symptoms 
interfering with ADL 
Lower GI sites: 
Stool incontinence or 
other symptoms 
interfering with ADL 
Symptoms associated 
with life-threatening 
consequences  
Death 
Nausea 
Nausea 
Loss of appetite without 
alteration in eating habits 
Oral intake decreased 
without significant weight 
loss, dehydration or 
malnutrition; IV fluids 
indicated <24 hrs 
Inadequate oral caloric or 
fluid intake; IV fluids, tube 
feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Anorexia; Vomiting. 

 
GASTROINTESTINAL 
Page 7 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 25 - 
March 31, 2003, Publish Date: August 9, 2006 
Necrosis, GI 
– Select:  
Necrosis, GI – Select  
– Anus 
– Colon/cecum/appendix 
– Duodenum 
– Esophagus 
– Gallbladder 
– Hepatic 
– Ileum 
– Jejunum 
– Oral 
– Pancreas 
– Peritoneal cavity 
– Pharynx  
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
— 
— 
Inability to aliment 
adequately by GI tract 
(e.g., requiring enteral or 
parenteral nutrition); 
interventional radiology, 
endoscopic, or operative 
intervention indicated  
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., total colectomy)  
Death 
ALSO CONSIDER: Visceral arterial ischemia (non-myocardial). 
Obstruction, GI 
– Select: 
– Cecum 
– Colon 
– Duodenum 
– Esophagus 
– Gallbladder 
– Ileum 
– Jejunum 
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
Obstruction, GI – Select 
Asymptomatic 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, vomiting, 
diarrhea, or GI fluid loss); 
IV fluids indicated <24 
hrs 
Symptomatic and 
severely altered GI 
function (e.g., altered 
dietary habits, vomiting, 
diarrhea, or GI fluid loss); 
IV fluids, tube feedings, 
or TPN indicated ≥24 hrs; 
operative intervention 
indicated 
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., total colectomy)  
Death 
NAVIGATION NOTE: Operative injury is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY CATEGORY. 
NAVIGATION NOTE: Pelvic pain is graded as Pain – Select in the PAIN CATEGORY. 

 
GASTROINTESTINAL 
Page 8 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 26 - 
March 31, 2003, Publish Date: August 9, 2006 
Perforation, GI 
– Select: 
– Appendix 
– Biliary tree 
– Cecum 
– Colon 
– Duodenum 
– Esophagus 
– Gallbladder 
– Ileum 
– Jejunum 
– Rectum 
– Small bowel NOS 
– Stomach 
Perforation, GI – Select 
Asymptomatic 
radiographic findings only 
Medical intervention 
indicated; IV fluids 
indicated <24 hrs 
IV fluids, tube feedings, 
or TPN indicated ≥24 hrs; 
operative intervention 
indicated 
Life-threatening 
consequences 
Death 
Proctitis  
Proctitis 
Rectal discomfort, 
intervention not indicated 
Symptoms not interfering 
with ADL; medical 
intervention indicated  
Stool incontinence or 
other symptoms 
interfering with ADL; 
operative intervention 
indicated 
Life-threatening 
consequences (e.g., 
perforation) 
Death 
Prolapse of stoma, GI 
Prolapse of stoma, GI 
Asymptomatic  
Extraordinary local care 
or maintenance; minor 
revision indicated 
Dysfunctional stoma; 
major revision indicated  
Life-threatening 
consequences 
Death 
REMARK: Other stoma complications may be graded as Fistula, GI – Select; Leak (including anastomotic), GI – Select; Obstruction, GI – Select; Perforation, GI – Select; 
Stricture/stenosis (including anastomotic), GI – Select. 
NAVIGATION NOTE: Rectal or perirectal pain (proctalgia) is graded as Pain – Select in the PAIN CATEGORY.  
Salivary gland 
changes/saliva 
Salivary gland changes 
Slightly thickened saliva; 
slightly altered taste (e.g., 
metallic) 
Thick, ropy, sticky saliva; 
markedly altered taste; 
alteration in diet 
indicated; secretion-
induced symptoms not 
interfering with ADL 
Acute salivary gland 
necrosis; severe 
secretion-induced 
symptoms interfering with 
ADL  
Disabling 
— 
ALSO CONSIDER: Dry mouth/salivary gland (xerostomia); Mucositis/stomatitis (clinical exam) – Select; Mucositis/stomatitis (functional/symptomatic) – Select; Taste alteration 
(dysgeusia). 
NAVIGATION NOTE: Splenic function is graded in the BLOOD/BONE MARROW CATEGORY. 

 
GASTROINTESTINAL 
Page 9 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 27 - 
March 31, 2003, Publish Date: August 9, 2006 
Stricture/stenosis 
(including anastomotic), 
GI 
– Select:  
Stricture, GI – Select  
– Anus 
– Biliary tree 
– Cecum 
– Colon  
– Duodenum  
– Esophagus 
– Ileum 
– Jejunum 
– Pancreas/pancreatic duct 
– Pharynx 
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
Asymptomatic 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, vomiting, 
bleeding, diarrhea); IV 
fluids indicated <24 hrs 
Symptomatic and 
severely altered GI 
function (e.g., altered 
dietary habits, diarrhea, 
or GI fluid loss); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs; 
operative intervention 
indicated 
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., total colectomy)  
Death 
Taste alteration 
(dysgeusia) 
Taste alteration 
Altered taste but no 
change in diet 
Altered taste with change 
in diet (e.g., oral 
supplements); noxious or 
unpleasant taste; loss of 
taste 
— 
— 
— 
Typhlitis 
(cecal inflammation) 
Typhlitis 
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain; mucus 
or blood in stool 
Abdominal pain, fever, 
change in bowel habits 
with ileus; peritoneal 
signs 
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis); 
operative intervention 
indicated 
Death 
ALSO CONSIDER: Colitis; Hemorrhage, GI – Select ; Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation).  

 
GASTROINTESTINAL 
Page 10 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 28 - 
March 31, 2003, Publish Date: August 9, 2006 
Ulcer, GI 
– Select: 
– Anus 
– Cecum 
– Colon 
– Duodenum 
– Esophagus 
– Ileum 
– Jejunum 
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
Ulcer, GI – Select 
Asymptomatic, 
radiographic or 
endoscopic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, oral 
supplements); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered GI 
function (e.g., inadequate 
oral caloric or fluid 
intake); IV fluids, tube 
feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select. 
Vomiting 
Vomiting 
1 episode in 24 hrs 
2 – 5 episodes in 24 hrs; 
IV fluids indicated  
<24 hrs 
≥6 episodes in 24 hrs; IV 
fluids, or TPN indicated 
≥24 hrs 
Life-threatening 
consequences  
Death 
ALSO CONSIDER: Dehydration. 
Gastrointestinal – Other 
(Specify, __) 
GI – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling 
Death 

 
GROWTH AND DEVELOPMENT 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 29 - 
March 31, 2003, Publish Date: August 9, 2006 
Bone age 
(alteration in bone age) 
Bone age 
— 
+2 SD (standard 
deviation) from normal 
— 
— 
— 
Bone growth: 
femoral head; slipped 
capital femoral epiphysis 
Femoral head growth 
Mild valgus/varus 
deformity 
Moderate valgus/varus 
deformity, symptomatic, 
interfering with function 
but not interfering with 
ADL 
Mild slipped capital 
femoral epiphysis; 
operative intervention 
(e.g., fixation) indicated; 
interfering with ADL 
Disabling; severe slipped 
capital femoral epiphysis 
>60%; avascular necrosis 
— 
Bone growth: 
limb length discrepancy 
Limb length  
Mild length discrepancy 
<2 cm 
Moderate length 
discrepancy 2 – 5 cm; 
shoe lift indicated 
Severe length 
discrepancy >5 cm; 
operative intervention 
indicated; interfering with 
ADL 
Disabling; epiphysiodesis 
— 
Bone growth: 
spine kyphosis/lordosis 
Kyphosis/lordosis 
Mild radiographic 
changes  
Moderate accentuation; 
interfering with function 
but not interfering with 
ADL 
Severe accentuation; 
operative intervention 
indicated; interfering with 
ADL 
Disabling (e.g., cannot lift 
head) 
— 
Growth velocity 
(reduction in growth 
velocity) 
Reduction in growth 
velocity 
10 – 29% reduction in 
growth from the baseline 
growth curve 
30 – 49% reduction in 
growth from the baseline 
growth curve 
≥50% reduction in growth 
from the baseline growth 
curve  
— 
— 
Puberty (delayed) 
Delayed puberty 
— 
No breast development 
by age 13 yrs for females; 
no Tanner Stage 2 
development by age 14.5 
yrs for males 
No sexual development 
by age 14 yrs for girls, 
age 16 yrs for boys; 
hormone replacement 
indicated 
— 
— 
REMARK: Do not use testicular size for Tanner Stage in male cancer survivors. 
Puberty (precocious)  
Precocious puberty 
— 
Physical signs of puberty 
<7 years for females,  
<9 years for males 
— 
— 
— 
Short stature 
Short stature 
Beyond two standard 
deviations of age and 
gender mean height 
Altered ADL 
— 
— 
— 
REMARK: Short stature is secondary to growth hormone deficiency. 
ALSO CONSIDER: Neuroendocrine: growth hormone secretion abnormality. 
Growth and Development 
– Other (Specify, __) 
Growth and Development 
– Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
HEMORRHAGE/BLEEDING 
Page 1 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 30 - 
March 31, 2003, Publish Date: August 9, 2006 
Hematoma  
Hematoma 
Minimal symptoms, 
invasive intervention not 
indicated  
Minimally invasive 
evacuation or aspiration 
indicated 
Transfusion, 
interventional radiology, 
or operative intervention 
indicated 
Life-threatening 
consequences; major 
urgent intervention 
indicated 
Death 
REMARK: Hematoma refers to extravasation at wound or operative site or secondary to other intervention. Transfusion implies pRBC.  
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Hemorrhage/bleeding 
associated with surgery, 
intra-operative or 
postoperative 
Hemorrhage with surgery 
— 
— 
Requiring transfusion of  
2 units non-autologous 
(10 cc/kg for pediatrics) 
pRBCs beyond protocol 
specification; 
postoperative 
interventional radiology, 
endoscopic, or operative 
intervention indicated 
Life-threatening 
consequences  
Death 
REMARK: Postoperative period is defined as ≤72 hours after surgery. Verify protocol-specific acceptable guidelines regarding pRBC transfusion. 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Hemorrhage, CNS 
CNS hemorrhage 
Asymptomatic, 
radiographic findings only 
Medical intervention 
indicated  
Ventriculostomy, ICP 
monitoring, 
intraventricular 
thrombolysis, or operative 
intervention indicated 
Life-threatening 
consequences; 
neurologic deficit or 
disability 
Death 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 

 
HEMORRHAGE/BLEEDING 
Page 2 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 31 - 
March 31, 2003, Publish Date: August 9, 2006 
Hemorrhage, GI  
– Select: 
– Abdomen NOS 
– Anus 
– Biliary tree  
– Cecum/appendix  
– Colon 
– Duodenum 
– Esophagus 
– Ileum 
– Jejunum 
– Liver 
– Lower GI NOS 
– Oral cavity 
– Pancreas 
– Peritoneal cavity 
– Rectum 
– Stoma 
– Stomach 
– Upper GI NOS 
– Varices (esophageal) 
– Varices (rectal) 
Hemorrhage, GI – Select 
Mild, intervention (other 
than iron supplements) 
not indicated 
Symptomatic and medical 
intervention or minor 
cauterization indicated 
Transfusion, 
interventional radiology, 
endoscopic, or operative 
intervention indicated; 
radiation therapy (i.e., 
hemostasis of bleeding 
site) 
Life-threatening 
consequences; major 
urgent intervention 
indicated  
Death 
REMARK: Transfusion implies pRBC. 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 

 
HEMORRHAGE/BLEEDING 
Page 3 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 32 - 
March 31, 2003, Publish Date: August 9, 2006 
Hemorrhage, GU  
– Select:  
– Bladder 
– Fallopian tube 
– Kidney 
– Ovary 
– Prostate  
– Retroperitoneum  
– Spermatic cord 
– Stoma 
– Testes 
– Ureter 
– Urethra 
– Urinary NOS 
– Uterus 
– Vagina 
– Vas deferens 
Hemorrhage, GU – Select 
Minimal or microscopic 
bleeding; intervention not 
indicated 
Gross bleeding, medical 
intervention, or urinary 
tract irrigation indicated 
Transfusion, 
interventional radiology, 
endoscopic, or operative 
intervention indicated; 
radiation therapy (i.e., 
hemostasis of bleeding 
site) 
Life-threatening 
consequences; major 
urgent intervention 
indicated 
Death 
REMARK: Transfusion implies pRBC. 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Hemorrhage, pulmonary/ 
upper respiratory  
– Select: 
Hemorrhage pulmonary  
– Select 
– Bronchopulmonary NOS 
– Bronchus  
– Larynx  
– Lung  
– Mediastinum 
– Nose 
– Pharynx 
– Pleura 
– Respiratory tract NOS 
– Stoma 
– Trachea 
Mild, intervention not 
indicated 
Symptomatic and 
medical intervention 
indicated 
Transfusion, 
interventional radiology, 
endoscopic, or operative 
intervention indicated; 
radiation therapy (i.e., 
hemostasis of bleeding 
site) 
Life-threatening 
consequences; major 
urgent intervention 
indicated 
Death 
REMARK: Transfusion implies pRBC.  
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Petechiae/purpura 
(hemorrhage/bleeding 
into skin or mucosa) 
Petechiae 
Few petechiae 
Moderate petechiae; 
purpura 
Generalized petechiae or 
purpura 
— 
— 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 

 
HEMORRHAGE/BLEEDING 
Page 4 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 33 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Vitreous hemorrhage is graded in the OCULAR/VISUAL CATEGORY. 
Hemorrhage/Bleeding – 
Other (Specify, __) 
Hemorrhage – Other 
(Specify) 
Mild without transfusion 
— 
Transfusion indicated 
Catastrophic bleeding, 
requiring major non-
elective intervention 
Death 

 
HEPATOBILIARY/PANCREAS 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 34 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Biliary tree damage is graded as Fistula, GI – Select; Leak (including anastomotic), GI – Select; Necrosis, GI – Select; Obstruction, GI – Select; Perforation, GI – 
Select; Stricture/stenosis (including anastomotic), GI – Select in the GASTROINTESTINAL CATEGORY. 
Cholecystitis 
Cholecystitis 
Asymptomatic, 
radiographic findings only 
Symptomatic, medical 
intervention indicated 
Interventional radiology, 
endoscopic, or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
sepsis or perforation)  
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection 
with unknown ANC – Select.  
Liver dysfunction/failure 
(clinical)  
Liver dysfunction  
— 
Jaundice  
Asterixis 
Encephalopathy or coma 
Death 
REMARK: Jaundice is not an AE, but occurs when the liver is not working properly or when a bile duct is blocked. It is graded as a result of liver dysfunction/failure or elevated bilirubin. 
ALSO CONSIDER: Bilirubin (hyperbilirubinemia). 
Pancreas, exocrine 
enzyme deficiency 
Pancreas, exocrine 
enzyme deficiency 
— 
Increase in stool 
frequency, bulk, or odor; 
steatorrhea 
Sequelae of absorption 
deficiency (e.g., weight 
loss)  
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Diarrhea. 
Pancreatitis  
Pancreatitis 
Asymptomatic, enzyme 
elevation and/or 
radiographic findings  
Symptomatic, medical 
intervention indicated 
Interventional radiology or 
operative intervention 
indicated 
Life-threatening 
consequences 
(e.g., circulatory failure, 
hemorrhage, sepsis) 
Death 
ALSO CONSIDER: Amylase. 
NAVIGATION NOTE: Stricture (biliary tree, hepatic or pancreatic) is graded as Stricture/stenosis (including anastomotic), GI – Select in the GASTROINTESTINAL CATEGORY. 
Hepatobiliary/Pancreas – 
Other (Specify, __) 
Hepatobiliary – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
INFECTION 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 35 - 
March 31, 2003, Publish Date: August 9, 2006 
Colitis, infectious 
(e.g., Clostridium difficile) 
Colitis, infectious  
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain with 
mucus and/or blood in 
stool 
IV antibiotics or TPN 
indicated  
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis or 
toxic megacolon); 
operative resection or 
diversion indicated 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select; Typhlitis (cecal inflammation).  
Febrile neutropenia 
(fever of unknown origin 
without clinically or 
microbiologically 
documented infection) 
(ANC <1.0 x 109/L, fever 
≥38.5°C) 
Febrile neutropenia 
— 
— 
Present 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
ALSO CONSIDER: Neutrophils/granulocytes (ANC/AGC). 
Infection  
(documented clinically or 
microbiologically) with 
Grade 3 or 4 neutrophils  
(ANC <1.0 x 109/L) 
– Select  
‘Select’ AEs appear at the 
end of the CATEGORY. 
Infection (documented 
clinically) with Grade 3 or 
4 ANC – Select 
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
REMARK: Fever with Grade 3 or 4 neutrophils in the absence of documented infection is graded as Febrile neutropenia (fever of unknown origin without clinically or microbiologically 
documented infection). 
ALSO CONSIDER: Neutrophils/granulocytes (ANC/AGC). 
Infection with normal 
ANC or Grade 1 or 2 
neutrophils  
– Select  
‘Select’ AEs appear at the 
end of the CATEGORY. 
Infection with normal 
ANC – Select 
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 

 
INFECTION 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 36 - 
March 31, 2003, Publish Date: August 9, 2006 
Infection with unknown 
ANC 
– Select  
‘Select’ AEs appear at the 
end of the CATEGORY. 
Infection with unknown 
ANC – Select 
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
REMARK: Infection with unknown ANC – Select is to be used in the rare case when ANC is unknown. 
Opportunistic infection 
associated with ≥Grade 2 
Lymphopenia 
Opportunistic infection  
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
ALSO CONSIDER: Lymphopenia. 
Viral hepatitis 
Viral hepatitis 
Present; transaminases 
and liver function normal 
Transaminases 
abnormal, liver function 
normal  
Symptomatic liver 
dysfunction; fibrosis by 
biopsy; compensated 
cirrhosis 
Decompensated liver 
function (e.g., ascites, 
coagulopathy, 
encephalopathy, coma) 
Death 
REMARK: Non-viral hepatitis is graded as Infection – Select. 
ALSO CONSIDER: Albumin, serum-low (hypoalbuminemia); ALT, SGPT (serum glutamic pyruvic transaminase); AST, SGOT (serum glutamic oxaloacetic transaminase); Bilirubin 
(hyperbilirubinemia); Encephalopathy. 
Infection – Other 
(Specify, __) 
Infection – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
INFECTION – SELECT 
Page 3 of 3 
CTCAE v3.0  
- 37 - 
March 31, 2003, Publish Date: August 9, 2006 
AUDITORY/EAR 
– External ear (otitis externa) 
– Middle ear (otitis media) 
CARDIOVASCULAR 
– Artery 
– Heart (endocarditis) 
– Spleen 
– Vein 
DERMATOLOGY/SKIN  
– Lip/perioral 
– Peristomal 
– Skin (cellulitis) 
– Ungual (nails) 
GASTROINTESTINAL  
– Abdomen NOS 
– Anal/perianal 
– Appendix 
– Cecum 
– Colon 
– Dental-tooth 
– Duodenum 
– Esophagus 
– Ileum 
– Jejunum 
– Oral cavity-gums (gingivitis) 
– Peritoneal cavity 
– Rectum 
– Salivary gland 
– Small bowel NOS 
– Stomach 
GENERAL 
– Blood 
– Catheter-related 
– Foreign body (e.g., graft, implant,  
prosthesis, stent) 
– Wound  
HEPATOBILIARY/PANCREAS 
– Biliary tree 
– Gallbladder (cholecystitis) 
– Liver 
– Pancreas 
LYMPHATIC 
– Lymphatic 
MUSCULOSKELETAL 
– Bone (osteomyelitis) 
– Joint 
– Muscle (infection myositis) 
– Soft tissue NOS 
NEUROLOGY 
– Brain (encephalitis, infectious) 
– Brain + Spinal cord (encephalomyelitis) 
– Meninges (meningitis) 
– Nerve-cranial 
– Nerve-peripheral 
– Spinal cord (myelitis) 
OCULAR 
– Conjunctiva 
– Cornea 
– Eye NOS 
– Lens 
PULMONARY/UPPER RESPIRATORY 
– Bronchus 
– Larynx 
– Lung (pneumonia) 
– Mediastinum NOS 
– Mucosa 
– Neck NOS 
– Nose 
– Paranasal 
– Pharynx 
– Pleura (empyema) 
– Sinus 
– Trachea 
– Upper aerodigestive NOS 
– Upper airway NOS  
RENAL/GENITOURINARY  
– Bladder (urinary) 
– Kidney 
– Prostate 
– Ureter 
– Urethra 
– Urinary tract NOS 
SEXUAL/REPRODUCTIVE FUNCTION 
– Cervix 
– Fallopian tube 
– Pelvis NOS 
– Penis 
– Scrotum 
– Uterus 
– Vagina 
– Vulva 
 

 
LYMPHATICS 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 38 - 
March 31, 2003, Publish Date: August 9, 2006 
Chyle or lymph leakage  
Chyle or lymph leakage 
Asymptomatic, clinical or 
radiographic findings 
Symptomatic, medical 
intervention indicated  
Interventional radiology 
or operative intervention 
indicated 
Life-threatening 
complications 
Death 
ALSO CONSIDER: Chylothorax. 
Dermal change 
lymphedema, 
phlebolymphedema  
Dermal change 
Trace thickening or faint 
discoloration 
Marked discoloration; 
leathery skin texture; 
papillary formation 
— 
— 
— 
REMARK: Dermal change lymphedema, phlebolymphedema refers to changes due to venous stasis. 
ALSO CONSIDER: Ulceration.  
Edema: 
head and neck 
Edema: head and neck 
Localized to dependent 
areas, no disability or 
functional impairment 
Localized facial or neck 
edema with functional 
impairment 
Generalized facial or 
neck edema with 
functional impairment 
(e.g., difficulty in turning 
neck or opening mouth 
compared to baseline) 
Severe with ulceration or 
cerebral edema; 
tracheotomy or feeding 
tube indicated 
Death 
Edema: 
limb 
Edema: limb 
5 – 10% inter-limb 
discrepancy in volume or 
circumference at point of 
greatest visible 
difference; swelling or 
obscuration of anatomic 
architecture on close 
inspection; pitting edema 
>10 – 30% inter-limb 
discrepancy in volume or 
circumference at point of 
greatest visible 
difference; readily 
apparent obscuration of 
anatomic architecture; 
obliteration of skin folds; 
readily apparent 
deviation from normal 
anatomic contour  
>30% inter-limb 
discrepancy in volume; 
lymphorrhea; gross 
deviation from normal 
anatomic contour; 
interfering with ADL 
Progression to 
malignancy (i.e., 
lymphangiosarcoma); 
amputation indicated; 
disabling 
Death 
Edema: 
trunk/genital 
Edema: trunk/genital 
Swelling or obscuration 
of anatomic architecture 
on close inspection; 
pitting edema 
Readily apparent 
obscuration of anatomic 
architecture; obliteration 
of skin folds; readily 
apparent deviation from 
normal anatomic contour 
Lymphorrhea; interfering 
with ADL; gross deviation 
from normal anatomic 
contour 
Progression to 
malignancy (i.e., 
lymphangiosarcoma); 
disabling  
Death 
Edema: 
viscera 
Edema: viscera 
Asymptomatic; clinical or 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and unable 
to aliment adequately 
orally; interventional 
radiology or operative 
intervention indicated  
Life-threatening 
consequences 
Death 

 
LYMPHATICS 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 39 - 
March 31, 2003, Publish Date: August 9, 2006 
Lymphedema-related 
fibrosis 
Lymphedema-related 
fibrosis 
Minimal to moderate 
redundant soft tissue, 
unresponsive to elevation 
or compression, with 
moderately firm texture or 
spongy feel 
Marked increase in 
density and firmness, 
with or without tethering 
Very marked density and 
firmness with tethering 
affecting ≥40% of the 
edematous area 
— 
— 
Lymphocele 
Lymphocele 
Asymptomatic, clinical or 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and 
interventional radiology 
or operative intervention 
indicated 
— 
— 
Phlebolymphatic cording  
Phlebolymphatic cording 
Asymptomatic, clinical 
findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and leading 
to contracture or reduced 
range of motion 
— 
— 
Lymphatics – Other  
(Specify, __) 
Lymphatics – Other  
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling 
Death 

 
METABOLIC/LABORATORY 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 40 - 
March 31, 2003, Publish Date: August 9, 2006 
Acidosis  
(metabolic or respiratory) 
Acidosis  
pH <normal, but ≥7.3 
— 
pH <7.3 
pH <7.3 with life-
threatening 
consequences 
Death 
Albumin, serum-low 
(hypoalbuminemia)  
Hypoalbuminemia 
<LLN – 3 g/dL  
<LLN – 30 g/L 
<3 – 2 g/dL 
<30 – 20 g/L  
<2 g/dL  
<20 g/L 
— 
Death 
Alkaline phosphatase 
Alkaline phosphatase 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Alkalosis  
(metabolic or respiratory) 
Alkalosis 
pH >normal, but ≤7.5 
— 
pH >7.5 
pH >7.5 with life-
threatening 
consequences 
Death 
ALT, SGPT  
(serum glutamic pyruvic 
transaminase) 
ALT 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Amylase 
Amylase 
>ULN – 1.5 x ULN 
>1.5 – 2.0 x ULN 
>2.0 – 5.0 x ULN 
>5.0 x ULN 
— 
AST, SGOT 
(serum glutamic 
oxaloacetic 
transaminase) 
AST 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Bicarbonate, serum-low  
Bicarbonate, serum-low 
<LLN – 16 mmol/L 
<16 – 11 mmol/L 
<11 – 8 mmol/L 
<8 mmol/L 
Death 
Bilirubin 
(hyperbilirubinemia) 
Bilirubin 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x ULN 
>3.0 – 10.0 x ULN 
>10.0 x ULN 
— 
REMARK: Jaundice is not an AE, but may be a manifestation of liver dysfunction/failure or elevated bilirubin. If jaundice is associated with elevated bilirubin, grade bilirubin. 
Calcium, serum-low 
(hypocalcemia) 
Hypocalcemia 
<LLN – 8.0 mg/dL 
<LLN – 2.0 mmol/L 
Ionized calcium: 
<LLN – 1.0 mmol/L 
<8.0 – 7.0 mg/dL 
<2.0 – 1.75 mmol/L 
Ionized calcium: 
<1.0 – 0.9 mmol/L 
<7.0 – 6.0 mg/dL 
<1.75 – 1.5 mmol/L 
Ionized calcium: 
<0.9 – 0.8 mmol/L 
<6.0 mg/dL 
<1.5 mmol/L 
Ionized calcium: 
<0.8 mmol/L 
Death 
REMARK: Calcium can be falsely low if hypoalbuminemia is present. Serum albumin is <4.0 g/dL, hypocalcemia is reported after the following corrective calculation has been 
performed: Corrected Calcium (mg/dL) = Total Calcium (mg/dL) – 0.8 [Albumin (g/dL) – 4] 4. Alternatively, direct measurement of ionized calcium is the definitive method to diagnose 
metabolically relevant alterations in serum calcium. 
                                            
4Crit Rev Clin Lab Sci 1984;21(1):51-97 

 
METABOLIC/LABORATORY 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 41 - 
March 31, 2003, Publish Date: August 9, 2006 
Calcium, serum-high 
(hypercalcemia) 
Hypercalcemia 
>ULN – 11.5 mg/dL 
>ULN – 2.9 mmol/L 
Ionized calcium: 
>ULN – 1.5 mmol/L 
>11.5 – 12.5 mg/dL 
>2.9 – 3.1 mmol/L 
Ionized calcium: 
>1.5 – 1.6 mmol/L 
>12.5 – 13.5 mg/dL 
>3.1 – 3.4 mmol/L 
Ionized calcium: 
>1.6 – 1.8 mmol/L 
>13.5 mg/dL 
>3.4 mmol/L 
Ionized calcium: 
>1.8 mmol/L 
Death 
Cholesterol, serum-high 
(hypercholesteremia) 
Cholesterol 
>ULN – 300 mg/dL 
>ULN – 7.75 mmol/L 
>300 – 400 mg/dL 
>7.75 – 10.34 mmol/L 
>400 – 500 mg/dL 
>10.34 – 12.92 mmol/L 
>500 mg/dL 
>12.92 mmol/L 
Death 
CPK (creatine 
phosphokinase) 
CPK 
>ULN – 2.5 x ULN 
>2.5 x ULN – 5 x ULN 
>5 x ULN – 10 x ULN 
>10 x ULN 
Death 
Creatinine 
Creatinine 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x ULN 
>3.0 – 6.0 x ULN 
>6.0 x ULN 
Death 
REMARK: Adjust to age-appropriate levels for pediatric patients.  
ALSO CONSIDER: Glomerular filtration rate. 
GGT (γ-Glutamyl 
transpeptidase) 
GGT 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Glomerular filtration rate  
GFR 
<75 – 50% LLN 
<50 – 25% LLN 
<25% LLN, chronic 
dialysis not indicated 
Chronic dialysis or renal 
transplant indicated 
Death 
ALSO CONSIDER: Creatinine. 
Glucose, serum-high 
(hyperglycemia)  
Hyperglycemia 
>ULN – 160 mg/dL 
>ULN – 8.9 mmol/L 
>160 – 250 mg/dL 
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL 
>13.9 – 27.8 mmol/L 
>500 mg/dL 
>27.8 mmol/L or acidosis 
Death 
REMARK: Hyperglycemia, in general, is defined as fasting unless otherwise specified in protocol. 
Glucose, serum-low 
(hypoglycemia) 
Hypoglycemia 
<LLN – 55 mg/dL 
<LLN – 3.0 mmol/L 
<55 – 40 mg/dL 
<3.0 – 2.2 mmol/L 
<40 – 30 mg/dL 
<2.2 – 1.7 mmol/L 
<30 mg/dL 
<1.7 mmol/L 
Death 
Hemoglobinuria 
Hemoglobinuria 
Present 
— 
— 
— 
Death 
Lipase 
Lipase 
>ULN – 1.5 x ULN 
>1.5 – 2.0 x ULN 
>2.0 – 5.0 x ULN 
>5.0 x ULN 
— 
Magnesium, serum-high 
(hypermagnesemia) 
Hypermagnesemia 
>ULN – 3.0 mg/dL 
>ULN – 1.23 mmol/L 
— 
>3.0 – 8.0 mg/dL 
>1.23 – 3.30 mmol/L 
>8.0 mg/dL 
>3.30 mmol/L 
Death 
Magnesium, serum-low 
(hypomagnesemia)  
Hypomagnesemia 
<LLN – 1.2 mg/dL 
<LLN – 0.5 mmol/L 
<1.2 – 0.9 mg/dL 
<0.5 – 0.4 mmol/L 
<0.9 – 0.7 mg/dL 
<0.4 – 0.3 mmol/L 
<0.7 mg/dL 
<0.3 mmol/L 
Death 
Phosphate, serum-low 
(hypophosphatemia)  
Hypophosphatemia 
<LLN – 2.5 mg/dL 
<LLN – 0.8 mmol/L 
<2.5 – 2.0 mg/dL  
<0.8 – 0.6 mmol/L 
<2.0 – 1.0 mg/dL 
<0.6 – 0.3 mmol/L 
<1.0 mg/dL 
<0.3 mmol/L 
Death 
Potassium, serum-high 
(hyperkalemia) 
Hyperkalemia 
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L 
>6.0 – 7.0 mmol/L 
>7.0 mmol/L 
Death 

 
METABOLIC/LABORATORY 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 42 - 
March 31, 2003, Publish Date: August 9, 2006 
Potassium, serum-low 
(hypokalemia)  
Hypokalemia 
<LLN – 3.0 mmol/L 
— 
<3.0 – 2.5 mmol/L 
<2.5 mmol/L 
Death 
Proteinuria 
Proteinuria 
1+ or 
0.15 – 1.0 g/24 hrs 
2+ to 3+ or 
>1.0 – 3.5 g/24 hrs  
4+ or 
>3.5 g/24 hrs 
Nephrotic syndrome 
Death 
Sodium, serum-high 
(hypernatremia) 
Hypernatremia 
>ULN – 150 mmol/L 
>150 – 155 mmol/L 
>155 – 160 mmol/L 
>160 mmol/L 
Death 
Sodium, serum-low 
(hyponatremia) 
Hyponatremia 
<LLN – 130 mmol/L 
— 
<130 – 120 mmol/L 
<120 mmol/L 
Death 
Triglyceride, serum-high 
(hypertriglyceridemia) 
Hypertriglyceridemia 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 10 x ULN 
>10 x ULN 
Death 
Uric acid, serum-high 
(hyperuricemia) 
Hyperuricemia 
>ULN – 10 mg/dL 
≤0.59 mmol/L without 
physiologic 
consequences 
— 
>ULN – 10 mg/dL 
≤0.59 mmol/L with 
physiologic 
consequences 
>10 mg/dL 
>0.59 mmol/L 
Death 
ALSO CONSIDER: Creatinine; Potassium, serum-high (hyperkalemia); Renal failure; Tumor lysis syndrome. 
Metabolic/Laboratory – 
Other (Specify, __) 
Metabolic/Lab – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
MUSCULOSKELETAL/SOFT TISSUE 
Page 1 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 43 - 
March 31, 2003, Publish Date: August 9, 2006 
Arthritis (non-septic) 
Arthritis 
Mild pain with 
inflammation, erythema, 
or joint swelling, but not 
interfering with function 
Moderate pain with 
inflammation, erythema, 
or joint swelling 
interfering with function, 
but not interfering with 
ADL 
Severe pain with 
inflammation, erythema, 
or joint swelling and 
interfering with ADL 
Disabling 
Death 
REMARK: Report only when the diagnosis of arthritis (e.g., inflammation of a joint or a state characterized by inflammation of joints) is made. Arthralgia (sign or symptom of pain in a 
joint, especially non-inflammatory in character) is graded as Pain – Select in the PAIN CATEGORY.  
Bone: 
spine-scoliosis 
Scoliosis  
≤20 degrees; clinically 
undetectable 
>20 – 45 degrees; visible 
by forward flexion; 
interfering with function 
but not interfering with 
ADL 
>45 degrees; scapular 
prominence in forward 
flexion; operative 
intervention indicated; 
interfering with ADL 
Disabling (e.g., interfering 
with cardiopulmonary 
function) 
Death 
Cervical spine-range of 
motion 
Cervical spine ROM 
Mild restriction of rotation 
or flexion between  
60 – 70 degrees 
Rotation <60 degrees to 
right or left; <60 degrees 
of flexion 
Ankylosed/fused over 
multiple segments with 
no C-spine rotation 
— 
— 
REMARK: 60 – 65 degrees of rotation is required for reversing a car; 60 – 65 degrees of flexion is required to tie shoes. 
Exostosis 
Exostosis 
Asymptomatic 
Involving multiple sites; 
pain or interfering with 
function  
Excision indicated 
Progression to 
malignancy (i.e., 
chondrosarcoma) 
Death 
Extremity-lower 
(gait/walking) 
Gait/walking 
Limp evident only to 
trained observer and able 
to walk ≥1 kilometer; 
cane indicated for 
walking 
Noticeable limp, or 
limitation of limb function, 
but able to walk ≥0.1 
kilometer (1 city block); 
quad cane indicated for 
walking 
Severe limp with stride 
modified to maintain 
balance (widened base of 
support, marked 
reduction in step length); 
ambulation limited to 
walker; crutches 
indicated 
Unable to walk 
— 
ALSO CONSIDER: Ataxia (incoordination); Muscle weakness, generalized or specific area (not due to neuropathy) – Select.  
Extremity-upper 
(function)  
Extremity-upper 
(function) 
Able to perform most 
household or work 
activities with affected 
limb 
Able to perform most 
household or work 
activities with 
compensation from 
unaffected limb 
Interfering with ADL  
Disabling; no function of 
affected limb 
— 
Fibrosis-cosmesis 
Fibrosis-cosmesis 
Visible only on close 
examination 
Readily apparent but not 
disfiguring 
Significant disfigurement; 
operative intervention 
indicated if patient 
chooses 
— 
— 

 
MUSCULOSKELETAL/SOFT TISSUE 
Page 2 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 44 - 
March 31, 2003, Publish Date: August 9, 2006 
Fibrosis-deep connective 
tissue 
Fibrosis-deep connective 
tissue  
Increased density, 
“spongy” feel 
Increased density with 
firmness or tethering 
Increased density with 
fixation of tissue; 
operative intervention 
indicated; interfering with 
ADL 
Life-threatening; 
disabling; loss of limb; 
interfering with vital organ 
function 
Death 
ALSO CONSIDER: Induration/fibrosis (skin and subcutaneous tissue); Muscle weakness, generalized or specific area (not due to neuropathy) – Select; Neuropathy: motor; Neuropathy: 
sensory. 
Fracture 
Fracture 
Asymptomatic, 
radiographic findings only 
(e.g., asymptomatic rib 
fracture on plain x-ray, 
pelvic insufficiency 
fracture on MRI, etc.) 
Symptomatic but non-
displaced; immobilization 
indicated 
Symptomatic and 
displaced or open wound 
with bone exposure; 
operative intervention 
indicated 
Disabling; amputation 
indicated 
Death 
Joint-effusion 
Joint-effusion 
Asymptomatic, clinical or 
radiographic findings only 
Symptomatic; interfering 
with function but not 
interfering with ADL 
Symptomatic and 
interfering with ADL 
Disabling 
Death 
ALSO CONSIDER: Arthritis (non-septic). 
Joint-function5 
Joint-function 
Stiffness interfering with 
athletic activity; ≤25% 
loss of range of motion 
(ROM) 
Stiffness interfering with 
function but not 
interfering with ADL;  
>25 – 50% decrease in 
ROM 
Stiffness interfering with 
ADL; >50 – 75% 
decrease in ROM  
Fixed or non-functional 
joint (arthrodesis); 
>75% decrease in ROM 
— 
ALSO CONSIDER: Arthritis (non-septic). 
Local complication –
device/prosthesis-related 
Device/prosthesis 
Asymptomatic  
Symptomatic, but not 
interfering with ADL; local 
wound care; medical 
intervention indicated 
Symptomatic, interfering 
with ADL; operative 
intervention indicated 
(e.g., hardware/device 
replacement or removal, 
reconstruction)  
Life-threatening; 
disabling; loss of limb or 
organ 
Death 
Lumbar spine-range of 
motion 
Lumbar spine ROM 
Stiffness and difficulty 
bending to the floor to 
pick up a very light object 
but able to do activity 
Some lumbar spine 
flexion but requires a 
reaching aid to pick up a 
very light object from the 
floor 
Ankylosed/fused over 
multiple segments with 
no L-spine flexion (i.e., 
unable to reach to floor to 
pick up a very light 
— 
— 
                                            
5 Adapted from the International SFTR Method of Measuring and Recording Joint Motion, International Standard Orthopedic Measurements (ISOM), Jon J. Gerhardt and Otto A. 
Russee, Bern, Switzerland, Han Huber 9 Publisher), 1975. 

 
MUSCULOSKELETAL/SOFT TISSUE 
Page 3 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 45 - 
March 31, 2003, Publish Date: August 9, 2006 
object) 
Muscle weakness, 
generalized or specific 
area (not due to 
neuropathy)  
– Select: 
Muscle weakness  
– Select  
– Extraocular 
– Extremity-lower  
– Extremity-upper 
– Facial 
– Left-sided 
– Ocular 
– Pelvic 
– Right-sided 
– Trunk 
– Whole body/generalized  
Asymptomatic, weakness 
on physical exam 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Life-threatening; disabling 
Death 
ALSO CONSIDER: Fatigue (asthenia, lethargy, malaise). 
Muscular/skeletal 
hypoplasia 
Muscular/skeletal 
hypoplasia 
Cosmetically and 
functionally insignificant 
hypoplasia  
Deformity, hypoplasia, or 
asymmetry able to be 
remediated by prosthesis 
(e.g., shoe insert) or 
covered by clothing  
Functionally significant 
deformity, hypoplasia, or 
asymmetry, unable to be 
remediated by prosthesis 
or covered by clothing  
Disabling 
— 
Myositis 
(inflammation/damage of 
muscle) 
Myositis 
Mild pain, not interfering 
with function 
Pain interfering with 
function, but not 
interfering with ADL 
Pain interfering with ADL 
Disabling 
Death 
REMARK: Myositis implies muscle damage (i.e., elevated CPK). 
ALSO CONSIDER: CPK (creatine phosphokinase); Pain – Select. 
Osteonecrosis  
(avascular necrosis) 
Osteonecrosis 
Asymptomatic, 
radiographic findings only 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL; minimal bone 
removal indicated (i.e., 
minor sequestrectomy)  
Symptomatic and 
interfering with ADL; 
operative intervention or 
hyperbaric oxygen 
indicated 
Disabling  
Death 

 
MUSCULOSKELETAL/SOFT TISSUE 
Page 4 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 46 - 
March 31, 2003, Publish Date: August 9, 2006 
Osteoporosis6 
Osteoporosis 
Radiographic evidence of 
osteoporosis or Bone 
Mineral Density (BMD) 
t-score –1 to –2.5 
(osteopenia) and no loss 
of height or therapy 
indicated 
BMD t-score < –2.5; loss 
of height <2 cm; anti-
osteoporotic therapy 
indicated 
Fractures; loss of height 
≥2 cm 
Disabling 
Death 
Seroma 
Seroma 
Asymptomatic 
Symptomatic; medical 
intervention or simple 
aspiration indicated 
Symptomatic, 
interventional radiology 
or operative intervention 
indicated 
— 
— 
Soft tissue necrosis 
– Select: 
– Abdomen 
– Extremity-lower 
– Extremity-upper  
– Head 
– Neck 
– Pelvic 
– Thorax 
Soft tissue necrosis 
– Select 
— 
Local wound care; 
medical intervention 
indicated 
Operative debridement or 
other invasive 
intervention indicated 
(e.g., hyperbaric oxygen)  
Life-threatening 
consequences; major 
invasive intervention 
indicated (e.g., tissue 
reconstruction, flap, or 
grafting) 
Death 
Trismus (difficulty, 
restriction or pain when 
opening mouth) 
Trismus 
Decreased range of 
motion without impaired 
eating  
Decreased range of 
motion requiring small 
bites, soft foods or 
purees 
Decreased range of 
motion with inability to 
adequately aliment or 
hydrate orally 
— 
— 
NAVIGATION NOTE: Wound-infectious is graded as Infection – Select in the INFECTION CATEGORY. 
NAVIGATION NOTE: Wound non-infectious is graded as Wound complication, non-infectious in the DERMATOLOGY/SKIN CATEGORY.  
Musculoskeletal/Soft 
Tissue – Other 
(Specify, __) 
Musculoskeletal – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
                                            
6 "Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis," Report of a WHO Study Group Technical Report Series, No. 843, 1994, v + 129 
pages [C*, E, F, R, S], ISBN 92 4 120843 0, Sw.fr. 22.-/US $19.80; in developing countries: Sw.fr. 15.40, Order no. 1100843 

 
NEUROLOGY 
Page 1 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 47 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: ADD (Attention Deficit Disorder) is graded as Cognitive disturbance. 
NAVIGATION NOTE: Aphasia, receptive and/or expressive, is graded as Speech impairment (e.g., dysphasia or aphasia). 
Apnea 
Apnea 
— 
— 
Present 
Intubation indicated  
Death 
Arachnoiditis/ 
meningismus/radiculitis 
Arachnoiditis 
Symptomatic, not 
interfering with function; 
medical intervention 
indicated 
Symptomatic (e.g., 
photophobia, nausea) 
interfering with function 
but not interfering with 
ADL  
Symptomatic, interfering 
with ADL 
Life-threatening; disabling 
(e.g., paraplegia) 
Death 
ALSO CONSIDER: Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 109/L); Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select; Pain – Select; Vomiting. 
Ataxia (incoordination) 
Ataxia 
Asymptomatic  
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL; mechanical 
assistance indicated  
Disabling 
Death 
REMARK: Ataxia (incoordination) refers to the consequence of medical or operative intervention. 
Brachial plexopathy 
Brachial plexopathy 
Asymptomatic 
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
Disabling 
Death 
CNS cerebrovascular 
ischemia 
CNS ischemia 
— 
Asymptomatic, 
radiographic findings only 
Transient ischemic event 
or attack (TIA) ≤24 hrs 
duration 
Cerebral vascular 
accident (CVA, stroke), 
neurologic deficit 
>24 hrs  
Death 
NAVIGATION NOTE: CNS hemorrhage/bleeding is graded as Hemorrhage, CNS in the HEMORRHAGE/BLEEDING CATEGORY.  
CNS necrosis/cystic 
progression 
CNS necrosis 
Asymptomatic, 
radiographic findings only 
Symptomatic, not 
interfering with ADL; 
medical intervention 
indicated 
Symptomatic and 
interfering with ADL; 
hyperbaric oxygen 
indicated 
Life-threatening; 
disabling; operative 
intervention indicated to 
prevent or treat CNS 
necrosis/cystic 
progression 
Death 
Cognitive disturbance 
Cognitive disturbance 
Mild cognitive disability; 
not interfering with 
work/school/life 
performance; specialized 
educational 
services/devices not 
indicated 
Moderate cognitive 
disability; interfering with 
work/school/life 
performance but capable 
of independent living; 
specialized resources on 
part-time basis indicated 
Severe cognitive 
disability; significant 
impairment of 
work/school/life 
performance 
Unable to perform ADL; 
full-time specialized 
resources or 
institutionalization 
indicated 
Death 
REMARK: Cognitive disturbance may be used for Attention Deficit Disorder (ADD). 

 
NEUROLOGY 
Page 2 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 48 - 
March 31, 2003, Publish Date: August 9, 2006 
Confusion 
Confusion 
Transient confusion, 
disorientation, or attention 
deficit 
Confusion, disorientation, 
or attention deficit 
interfering with function, 
but not interfering with 
ADL 
Confusion or delirium 
interfering with ADL 
Harmful to others or self; 
hospitalization indicated 
Death 
REMARK: Attention Deficit Disorder (ADD) is graded as Cognitive disturbance. 
NAVIGATION NOTE: Cranial neuropathy is graded as Neuropathy-cranial – Select. 
Dizziness  
Dizziness 
With head movements or 
nystagmus only; not 
interfering with function 
Interfering with function, 
but not interfering with 
ADL 
Interfering with ADL 
Disabling 
— 
REMARK: Dizziness includes disequilibrium, lightheadedness, and vertigo. 
ALSO CONSIDER: Neuropathy: cranial – Select; Syncope (fainting). 
NAVIGATION NOTE: Dysphasia, receptive and/or expressive, is graded as Speech impairment (e.g., dysphasia or aphasia). 
Encephalopathy 
Encephalopathy 
— 
Mild signs or symptoms; 
not interfering with ADL 
Signs or symptoms 
interfering with ADL; 
hospitalization indicated 
Life-threatening; disabling 
Death 
ALSO CONSIDER: Cognitive disturbance; Confusion; Dizziness; Memory impairment; Mental status; Mood alteration – Select; Psychosis (hallucinations/delusions); 
Somnolence/depressed level of consciousness. 
Extrapyramidal/ 
involuntary movement/ 
restlessness 
Involuntary movement 
Mild involuntary 
movements not 
interfering with function 
Moderate involuntary 
movements interfering 
with function, but not 
interfering with ADL 
Severe involuntary 
movements or torticollis 
interfering with ADL 
Disabling 
 
Death 
NAVIGATION NOTE: Headache/neuropathic pain (e.g., jaw pain, neurologic pain, phantom limb pain, post-infectious neuralgia, or painful neuropathies) is graded as Pain – Select in the 
PAIN CATEGORY. 
Hydrocephalus 
Hydrocephalus 
Asymptomatic, 
radiographic findings only 
Mild to moderate 
symptoms not interfering 
with ADL 
Severe symptoms or 
neurological deficit 
interfering with ADL 
Disabling  
Death 
Irritability (children <3 
years of age) 
Irritability 
Mild; easily consolable 
Moderate; requiring 
increased attention 
Severe; inconsolable 
— 
— 
Laryngeal nerve 
dysfunction  
Laryngeal nerve 
Asymptomatic, weakness 
on clinical 
examination/testing only 
Symptomatic, but not 
interfering with ADL; 
intervention not indicated 
Symptomatic, interfering 
with ADL; intervention 
indicated (e.g., 
thyroplasty, vocal cord 
injection) 
Life-threatening; 
tracheostomy indicated 
 
Death 

 
NEUROLOGY 
Page 3 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 49 - 
March 31, 2003, Publish Date: August 9, 2006 
Leak, cerebrospinal fluid 
(CSF) 
CSF leak 
Transient headache; 
postural care indicated 
Symptomatic, not 
interfering with ADL; 
blood patch indicated 
Symptomatic, interfering 
with ADL; operative 
intervention indicated 
Life-threatening; disabling 
Death 
REMARK: Leak, cerebrospinal fluid (CSF) may be used for CSF leak associated with operation and persisting >72 hours. 
Leukoencephalopathy 
(radiographic findings) 
Leukoencephalopathy  
Mild increase in 
subarachnoid space 
(SAS); mild 
ventriculomegaly; small 
(+/- multiple) focal T2 
hyperintensities, involving 
periventricular white 
matter or <1/3 of 
susceptible areas of 
cerebrum 
Moderate increase in 
SAS; moderate 
ventriculomegaly; focal 
T2 hyperintensities 
extending into centrum 
ovale or involving 1/3 to 
2/3 of susceptible areas 
of cerebrum 
Severe increase in SAS; 
severe ventriculomegaly; 
near total white matter T2 
hyperintensities or diffuse 
low attenuation (CT) 
— 
— 
REMARK: Leukoencephalopathy is a diffuse white matter process, specifically NOT associated with necrosis. Leukoencephalopathy (radiographic findings) does not include lacunas, 
which are areas that become void of neural tissue.  
Memory impairment 
Memory impairment 
Memory impairment not 
interfering with function 
Memory impairment 
interfering with function, 
but not interfering with 
ADL 
Memory impairment 
interfering with ADL 
Amnesia 
— 
Mental status7 
Mental status 
— 
1 – 3 point below age  
and educational norm in 
Folstein Mini-Mental 
Status Exam (MMSE) 
>3 point below age and 
educational norm in 
Folstein MMSE  
— 
— 
Mood alteration  
– Select: 
– Agitation 
– Anxiety 
– Depression 
– Euphoria 
Mood alteration – Select 
Mild mood alteration not 
interfering with function 
Moderate mood alteration 
interfering with function, 
but not interfering with 
ADL; medication 
indicated 
Severe mood alteration 
interfering with ADL 
Suicidal ideation; danger 
to self or others 
Death 
Myelitis 
Myelitis 
Asymptomatic, mild signs 
(e.g., Babinski’s or 
Lhermitte’s sign) 
Weakness or sensory 
loss not interfering with 
ADL 
Weakness or sensory 
loss interfering with ADL 
Disabling 
Death 
                                            
7 Folstein MF, Folstein, SE and McHugh PR (1975) "Mini-Mental State: A Practical Method for Grading the State of Patients for the Clinician," Journal of Psychiatric Research, 12: 
189-198 

 
NEUROLOGY 
Page 4 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 50 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Neuropathic pain is graded as Pain – Select in the PAIN CATEGORY.  
Neuropathy: 
cranial  
– Select: 
Neuropathy: cranial  
– Select 
Asymptomatic, detected 
on exam/testing only 
– CN I  
Smell 
– CN II  Vision 
– CN III  Pupil, upper eyelid, extra ocular movements 
– CN IV  Downward, inward movement of eye 
– CN V  Motor-jaw muscles; Sensory-facial 
– CN VI  Lateral deviation of eye 
– CN VII Motor-face; Sensory-taste 
– CN VIII Hearing and balance 
– CN IX Motor-pharynx; Sensory-ear, pharynx, tongue 
– CN X 
Motor-palate; pharynx, larynx 
– CN XI Motor-sternomastoid and trapezius 
– CN XII Motor-tongue 
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
Life-threatening; disabling 
Death 
Neuropathy: 
motor  
Neuropathy-motor 
Asymptomatic, weakness 
on exam/testing only 
Symptomatic weakness 
interfering with function, 
but not interfering with 
ADL 
Weakness interfering with 
ADL; bracing or 
assistance to walk (e.g., 
cane or walker) indicated 
Life-threatening; disabling 
(e.g., paralysis)  
Death 
REMARK: Cranial nerve motor neuropathy is graded as Neuropathy: cranial – Select. 
ALSO CONSIDER: Laryngeal nerve dysfunction; Phrenic nerve dysfunction.  
Neuropathy: 
sensory 
Neuropathy-sensory 
Asymptomatic; loss of 
deep tendon reflexes or 
paresthesia (including 
tingling) but not 
interfering with function 
Sensory alteration or 
paresthesia (including 
tingling), interfering with 
function, but not 
interfering with ADL 
Sensory alteration or 
paresthesia interfering 
with ADL  
Disabling  
Death 
REMARK: Cranial nerve sensory neuropathy is graded as Neuropathy: cranial – Select. 
Personality/behavioral 
Personality 
Change, but not 
adversely affecting 
patient or family 
Change, adversely 
affecting patient or family  
Mental health intervention 
indicated 
Change harmful to others 
or self; hospitalization 
indicated 
Death 
Phrenic nerve dysfunction  Phrenic nerve 
Asymptomatic weakness 
on exam/testing only 
Symptomatic but not 
interfering with ADL; 
intervention not indicated 
Significant dysfunction; 
intervention indicated 
(e.g., diaphragmatic 
plication) 
Life-threatening 
respiratory compromise; 
mechanical ventilation 
indicated 
Death 
Psychosis (hallucinations/ 
delusions) 
Psychosis 
— 
Transient episode 
Interfering with ADL; 
medication, supervision 
Harmful to others or self; 
life-threatening 
Death 

 
NEUROLOGY 
Page 5 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 51 - 
March 31, 2003, Publish Date: August 9, 2006 
or restraints indicated  
consequences 
Pyramidal tract 
dysfunction (e.g., ↑ tone, 
hyperreflexia, positive 
Babinski, ↓ fine motor 
coordination) 
Pyramidal tract 
dysfunction 
Asymptomatic, 
abnormality on exam or 
testing only  
Symptomatic; interfering 
with function but not 
interfering with ADL 
Interfering with ADL 
Disabling; paralysis 
Death 
Seizure 
Seizure 
— 
One brief generalized 
seizure; seizure(s) well 
controlled by 
anticonvulsants or 
infrequent focal motor 
seizures not interfering 
with ADL 
Seizures in which 
consciousness is altered; 
poorly controlled seizure 
disorder, with 
breakthrough generalized 
seizures despite medical 
intervention 
Seizures of any kind 
which are prolonged, 
repetitive, or difficult to 
control (e.g., status 
epilepticus, intractable 
epilepsy) 
Death 
Somnolence/depressed 
level of consciousness 
Somnolence 
— 
Somnolence or sedation 
interfering with function, 
but not interfering with 
ADL 
Obtundation or stupor; 
difficult to arouse; 
interfering with ADL 
Coma 
Death 
Speech impairment  
(e.g., dysphasia or 
aphasia)  
Speech impairment 
— 
Awareness of receptive 
or expressive dysphasia, 
not impairing ability to 
communicate 
Receptive or expressive 
dysphasia, impairing 
ability to communicate 
Inability to communicate 
— 
REMARK: Speech impairment refers to a primary CNS process, not neuropathy or end organ dysfunction. 
ALSO CONSIDER: Laryngeal nerve dysfunction; Voice changes/dysarthria (e.g., hoarseness, loss, or alteration in voice, laryngitis). 
Syncope (fainting) 
Syncope (fainting) 
— 
— 
Present 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: CNS cerebrovascular ischemia; Conduction abnormality/atrioventricular heart block – Select; Dizziness; Supraventricular and nodal arrhythmia – Select; Vasovagal 
episode; Ventricular arrhythmia – Select. 
NAVIGATION NOTE: Taste alteration (CN VII, IX) is graded as Taste alteration (dysgeusia) in the GASTROINTESTINAL CATEGORY. 
Tremor 
Tremor 
Mild and brief or 
intermittent but not 
interfering with function 
Moderate tremor 
interfering with function, 
but not interfering with 
ADL 
Severe tremor interfering 
with ADL 
Disabling 
— 
Neurology – Other 
(Specify, __) 
Neurology – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
OCULAR/VISUAL 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 52 - 
March 31, 2003, Publish Date: August 9, 2006 
Cataract 
Cataract 
Asymptomatic, detected 
on exam only  
Symptomatic, with 
moderate decrease in 
visual acuity  
(20/40 or better); 
decreased visual function 
correctable with glasses  
Symptomatic with marked 
decrease in visual acuity 
(worse than 20/40); 
operative intervention 
indicated (e.g., cataract 
surgery) 
— 
— 
Dry eye syndrome  
Dry eye 
Mild, intervention not 
indicated 
Symptomatic, interfering 
with function but not 
interfering with ADL; 
medical intervention 
indicated  
Symptomatic or decrease 
in visual acuity interfering 
with ADL; operative 
intervention indicated 
— 
— 
Eyelid dysfunction  
Eyelid dysfunction 
Asymptomatic  
Symptomatic, interfering 
with function but not ADL; 
requiring topical agents or 
epilation 
Symptomatic; interfering 
with ADL; surgical 
intervention indicated 
— 
— 
REMARK: Eyelid dysfunction includes canalicular stenosis, ectropion, entropion, erythema, madarosis, symblepharon, telangiectasis, thickening, and trichiasis. 
ALSO CONSIDER: Neuropathy: cranial – Select. 
Glaucoma  
Glaucoma 
Elevated intraocular 
pressure (EIOP) with 
single topical agent for 
intervention; no visual 
field deficit 
EIOP causing early visual 
field deficit (i.e., nasal 
step or arcuate deficit); 
multiple topical or oral 
agents indicated 
EIOP causing marked 
visual field deficits (i.e., 
involving both superior 
and inferior visual fields); 
operative intervention 
indicated 
EIOP resulting in 
blindness (20/200 or 
worse); enucleation 
indicated 
— 
Keratitis (corneal 
inflammation/corneal 
ulceration) 
Keratitis 
Abnormal ophthalmologic 
changes only; 
intervention not indicated 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL; 
operative intervention 
indicated 
Perforation or blindness 
(20/200 or worse)  
— 
NAVIGATION NOTE: Ocular muscle weakness is graded as Muscle weakness, generalized or specific area (not due to neuropathy) – Select in the MUSCULOSKELETAL/SOFT TISSUE 
CATEGORY.  
Night blindness 
(nyctalopia) 
Nyctalopia 
Symptomatic, not 
interfering with function 
Symptomatic and 
interfering with function 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL  
Disabling 
— 

 
OCULAR/VISUAL 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 53 - 
March 31, 2003, Publish Date: August 9, 2006 
Nystagmus 
Nystagmus 
Asymptomatic 
Symptomatic and 
interfering with function 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
ALSO CONSIDER: Neuropathy: cranial – Select; Ophthalmoplegia/diplopia (double vision). 
Ocular surface disease  
Ocular surface disease  
Asymptomatic or 
minimally symptomatic 
but not interfering with 
function 
Symptomatic, interfering 
with function but not 
interfering with ADL; 
topical antibiotics or other 
topical intervention 
indicated 
Symptomatic, interfering 
with ADL; operative 
intervention indicated 
— 
— 
REMARK: Ocular surface disease includes conjunctivitis, keratoconjunctivitis sicca, chemosis, keratinization, and palpebral conjunctival epithelial metaplasia. 
Ophthalmoplegia/ 
diplopia (double vision) 
Diplopia 
Intermittently 
symptomatic, intervention 
not indicated 
Symptomatic and 
interfering with function 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL; 
surgical intervention 
indicated 
Disabling 
— 
ALSO CONSIDER: Neuropathy: cranial – Select. 
Optic disc edema 
Optic disc edema 
Asymptomatic 
Decreased visual acuity 
(20/40 or better); visual 
field defect present 
Decreased visual acuity 
(worse than 20/40); 
marked visual field defect 
but sparing the central 20 
degrees 
Blindness  
(20/200 or worse) 
— 
ALSO CONSIDER: Neuropathy: cranial – Select.  
Proptosis/enophthalmos 
Proptosis/enophthalmos 
Asymptomatic, 
intervention not indicated 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
— 
— 
Retinal detachment 
Retinal detachment 
Exudative; no central 
vision loss; intervention 
not indicated 
Exudative and visual 
acuity 20/40 or better but 
intervention not indicated 
Rhegmatogenous or 
exudative detachment; 
operative intervention 
indicated 
Blindness 
(20/200 or worse) 
— 
Retinopathy  
Retinopathy 
Asymptomatic  
Symptomatic with 
moderate decrease in 
visual acuity 
(20/40 or better) 
Symptomatic with marked 
decrease in visual acuity 
(worse than 20/40) 
Blindness 
(20/200 or worse) 
— 

 
OCULAR/VISUAL 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 54 - 
March 31, 2003, Publish Date: August 9, 2006 
Scleral necrosis/melt 
Scleral necrosis 
Asymptomatic or 
symptomatic but not 
interfering with function 
Symptomatic, interfering 
with function but not 
interfering with ADL; 
moderate decrease in 
visual acuity (20/40 or 
better); medical 
intervention indicated 
Symptomatic, interfering 
with ADL; marked 
decrease in visual acuity 
(worse than 20/40); 
operative intervention 
indicated 
Blindness (20/200 or 
worse); painful eye with 
enucleation indicated 
— 
Uveitis  
Uveitis 
Asymptomatic 
Anterior uveitis; medical 
intervention indicated 
Posterior or pan-uveitis; 
operative intervention 
indicated 
Blindness 
(20/200 or worse) 
— 
Vision-blurred vision 
Blurred vision 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
Vision-flashing 
lights/floaters 
Flashing lights 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
Vision-photophobia 
Photophobia 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
Vitreous hemorrhage 
Vitreous hemorrhage 
Asymptomatic, clinical 
findings only 
Symptomatic, interfering 
with function, but not 
interfering with ADL; 
intervention not indicated 
Symptomatic, interfering 
with ADL; vitrectomy 
indicated  
— 
— 
Watery eye (epiphora, 
tearing) 
Watery eye 
Symptomatic, intervention 
not indicated 
Symptomatic, interfering 
with function but not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
— 
— 
Ocular/Visual – Other  
(Specify, __) 
Ocular – Other  
(Specify) 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Blindness 
(20/200 or worse) 
Death 

 
PAIN 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 55 - 
March 31, 2003, Publish Date: August 9, 2006 
Pain  
– Select: 
‘Select’ AEs appear at the 
end of the CATEGORY. 
Pain – Select  
Mild pain not interfering 
with function 
Moderate pain; pain or 
analgesics interfering with 
function, but not 
interfering with ADL 
Severe pain; pain or 
analgesics severely 
interfering with ADL 
Disabling 
— 
Pain – Other 
(Specify, __) 
Pain – Other (Specify) 
Mild pain not interfering 
with function 
Moderate pain; pain or 
analgesics interfering with 
function, but not 
interfering with ADL 
Severe pain; pain or 
analgesics severely 
interfering with ADL 
Disabling 
— 
PAIN – SELECT 
AUDITORY/EAR 
– External ear 
– Middle ear 
CARDIOVASCULAR 
– Cardiac/heart  
– Pericardium 
DERMATOLOGY/SKIN 
– Face 
– Lip 
– Oral-gums 
– Scalp 
– Skin 
GASTROINTESTINAL 
– Abdomen NOS 
– Anus 
– Dental/teeth/peridontal 
– Esophagus 
– Oral cavity 
– Peritoneum 
– Rectum 
– Stomach 
GENERAL 
– Pain NOS 
– Tumor pain  
HEPATOBILIARY/PANCREAS 
– Gallbladder 
– Liver  
LYMPHATIC 
– Lymph node 
MUSCULOSKELETAL 
– Back 
– Bone 
– Buttock 
– Extremity-limb 
– Intestine 
– Joint 
– Muscle 
– Neck 
– Phantom (pain associated with missing limb) 
NEUROLOGY 
– Head/headache 
– Neuralgia/peripheral nerve 
OCULAR 
– Eye 
PULMONARY/UPPER RESPIRATORY 
– Chest wall 
– Chest/thorax NOS 
PULMONARY/UPPER RESPIRATORY (continued) 
– Larynx 
– Pleura 
– Sinus 
– Throat/pharynx/larynx 
RENAL/GENITOURINARY 
– Bladder 
– Kidney 
SEXUAL/REPRODUCTIVE FUNCTION 
– Breast 
– Ovulatory 
– Pelvis 
– Penis 
– Perineum 
– Prostate 
– Scrotum 
– Testicle 
– Urethra 
– Uterus 
– Vagina 
 
 

 
PULMONARY/UPPER RESPIRATORY 
Page 1 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 56 - 
March 31, 2003, Publish Date: August 9, 2006 
Adult Respiratory 
Distress Syndrome 
(ARDS) 
ARDS 
— 
— 
Present, intubation not 
indicated  
Present, intubation 
indicated 
Death 
ALSO CONSIDER: Dyspnea (shortness of breath); Hypoxia; Pneumonitis/pulmonary infiltrates. 
Aspiration 
Aspiration 
Asymptomatic (“silent 
aspiration”); endoscopy 
or radiographic (e.g., 
barium swallow) findings  
Symptomatic (e.g., 
altered eating habits, 
coughing or choking 
episodes consistent with 
aspiration); medical 
intervention indicated 
(e.g., antibiotics, suction 
or oxygen) 
Clinical or radiographic 
signs of pneumonia or 
pneumonitis; unable to 
aliment orally 
Life-threatening (e.g., 
aspiration pneumonia or 
pneumonitis)  
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils 
– Select; Infection with unknown ANC – Select; Laryngeal nerve dysfunction; Neuropathy: cranial – Select; Pneumonitis/pulmonary infiltrates. 
Atelectasis  
Atelectasis  
Asymptomatic  
Symptomatic (e.g., 
dyspnea, cough), medical 
intervention indicated 
(e.g., bronchoscopic 
suctioning, chest 
physiotherapy, 
suctioning)  
Operative (e.g., stent, 
laser) intervention 
indicated  
Life-threatening 
respiratory compromise 
Death 
ALSO CONSIDER: Adult Respiratory Distress Syndrome (ARDS); Cough; Dyspnea (shortness of breath); Hypoxia; Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select; Obstruction/stenosis of airway – 
Select; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes). 
Bronchospasm, 
wheezing  
Bronchospasm 
Asymptomatic  
Symptomatic not 
interfering with function 
Symptomatic interfering 
with function 
Life-threatening 
Death 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever); Dyspnea (shortness of breath).  
Carbon monoxide 
diffusion capacity (DLCO) 
DLCO 
90 – 75% of predicted 
value 
<75 – 50% of predicted 
value 
<50 – 25% of predicted 
value 
<25% of predicted value 
Death 
ALSO CONSIDER: Hypoxia; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes). 
Chylothorax  
Chylothorax 
Asymptomatic 
Symptomatic; 
thoracentesis or tube 
drainage indicated  
Operative intervention 
indicated 
Life-threatening (e.g., 
hemodynamic instability 
or ventilatory support 
indicated) 
Death 
Cough 
Cough 
Symptomatic, non-
narcotic medication only 
indicated  
Symptomatic and 
narcotic medication 
indicated  
Symptomatic and 
significantly interfering 
with sleep or ADL 
— 
— 

 
PULMONARY/UPPER RESPIRATORY 
Page 2 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 57 - 
March 31, 2003, Publish Date: August 9, 2006 
Dyspnea (shortness of 
breath)  
Dyspnea  
Dyspnea on exertion, but 
can walk 1 flight of stairs 
without stopping 
Dyspnea on exertion but 
unable to walk 1 flight of 
stairs or 1 city block 
(0.1km) without stopping 
Dyspnea with ADL 
Dyspnea at rest; 
intubation/ventilator 
indicated  
Death 
ALSO CONSIDER: Hypoxia; Neuropathy: motor; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes). 
Edema, larynx  
Edema, larynx 
Asymptomatic edema by 
exam only 
Symptomatic edema, no 
respiratory distress  
Stridor; respiratory 
distress; interfering with 
ADL 
Life-threatening airway 
compromise; 
tracheotomy, intubation, 
or laryngectomy indicated 
Death 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever). 
FEV1  
FEV1 
90 – 75% of predicted 
value 
<75 – 50% of predicted 
value 
<50 – 25% of predicted 
value 
<25% of predicted 
Death 
Fistula, pulmonary/upper 
respiratory  
– Select: 
– Bronchus 
– Larynx 
– Lung 
– Oral cavity 
– Pharynx  
– Pleura 
– Trachea 
Fistula, pulmonary  
– Select  
Asymptomatic, 
radiographic findings only 
Symptomatic, tube 
thoracostomy or medical 
management indicated; 
associated with altered 
respiratory function but 
not interfering with ADL 
Symptomatic and 
associated with altered 
respiratory function 
interfering with ADL; or 
endoscopic (e.g., stent) 
or primary closure by 
operative intervention 
indicated 
Life-threatening 
consequences; operative 
intervention with 
thoracoplasty, chronic 
open drainage or multiple 
thoracotomies indicated 
Death 
REMARK: A fistula is defined as an abnormal communication between two body cavities, potential spaces, and/or the skin. The site indicated for a fistula should be the site from which 
the abnormal process is believed to have arisen. For example, a tracheo-esophageal fistula arising in the context of a resected or irradiated esophageal cancer should be graded as 
Fistula, GI – esophagus in the GASTROINTESTINAL CATEGORY. 
NAVIGATION NOTE: Hemoptysis is graded as Hemorrhage, pulmonary/upper respiratory – Select in the HEMORRHAGE/BLEEDING CATEGORY.  
Hiccoughs (hiccups, 
singultus) 
Hiccoughs 
Symptomatic, 
intervention not indicated 
Symptomatic, 
intervention indicated  
Symptomatic, 
significantly interfering 
with sleep or ADL 
— 
— 
Hypoxia 
Hypoxia 
— 
Decreased O2 saturation 
with exercise (e.g., pulse 
oximeter <88%); 
intermittent supplemental 
oxygen  
Decreased O2 saturation 
at rest; continuous 
oxygen indicated 
Life-threatening; 
intubation or ventilation 
indicated  
Death 

 
PULMONARY/UPPER RESPIRATORY 
Page 3 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 58 - 
March 31, 2003, Publish Date: August 9, 2006 
Nasal cavity/paranasal 
sinus reactions 
Nasal/paranasal 
reactions 
Asymptomatic mucosal 
crusting, blood-tinged 
secretions 
Symptomatic stenosis or 
edema/narrowing 
interfering with airflow 
Stenosis with significant 
nasal obstruction; 
interfering with ADL 
Necrosis of soft tissue or 
bone 
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils 
– Select; Infection with unknown ANC – Select. 
Obstruction/stenosis of 
airway 
– Select: 
– Bronchus 
– Larynx 
– Pharynx 
– Trachea 
Airway obstruction  
– Select  
Asymptomatic obstruction 
or stenosis on exam, 
endoscopy, or radiograph 
Symptomatic (e.g., noisy 
airway breathing), but 
causing no respiratory 
distress; medical 
management indicated 
(e.g., steroids)  
Interfering with ADL; 
stridor or endoscopic 
intervention indicated 
(e.g., stent, laser)  
Life-threatening airway 
compromise; tracheotomy 
or intubation indicated 
Death 
Pleural effusion 
(non-malignant)  
Pleural effusion 
Asymptomatic 
Symptomatic, 
intervention such as 
diuretics or up to 2 
therapeutic 
thoracenteses indicated 
Symptomatic and 
supplemental oxygen,  
>2 therapeutic 
thoracenteses, tube 
drainage, or pleurodesis 
indicated 
Life-threatening (e.g., 
causing hemodynamic 
instability or ventilatory 
support indicated)  
Death 
ALSO CONSIDER: Atelectasis; Cough; Dyspnea (shortness of breath); Hypoxia; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes).  
NAVIGATION NOTE: Pleuritic pain is graded as Pain – Select in the PAIN CATEGORY. 
Pneumonitis/pulmonary 
infiltrates  
Pneumonitis 
Asymptomatic, 
radiographic findings only 
Symptomatic, not 
interfering with ADL  
Symptomatic, interfering 
with ADL; O2 indicated  
Life-threatening; 
ventilatory support 
indicated 
Death 
ALSO CONSIDER: Adult Respiratory Distress Syndrome (ARDS); Cough; Dyspnea (shortness of breath); Hypoxia; Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select; Pneumonitis/pulmonary infiltrates; 
Pulmonary fibrosis (radiographic changes). 
Pneumothorax  
Pneumothorax  
Asymptomatic, 
radiographic findings only 
Symptomatic; 
intervention indicated 
(e.g., hospitalization for 
observation, tube 
placement without 
sclerosis) 
Sclerosis and/or 
operative intervention 
indicated 
Life-threatening, causing 
hemodynamic instability 
(e.g., tension 
pneumothorax); 
ventilatory support 
indicated 
Death 
Prolonged chest tube 
drainage or air leak after 
pulmonary resection 
Chest tube drainage or 
leak 
— 
Sclerosis or additional 
tube thoracostomy 
indicated 
Operative intervention 
indicated (e.g., 
thoracotomy with stapling 
or sealant application) 
Life-threatening; 
debilitating; organ 
resection indicated 
Death 

 
PULMONARY/UPPER RESPIRATORY 
Page 4 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 59 - 
March 31, 2003, Publish Date: August 9, 2006 
Prolonged intubation 
after pulmonary resection 
(>24 hrs after surgery)  
Prolonged intubation 
— 
Extubated within  
24 – 72 hrs 
postoperatively 
Extubated >72 hrs 
postoperatively, but 
before tracheostomy 
indicated 
Tracheostomy indicated 
Death 
NAVIGATION NOTE: Pulmonary embolism is graded as Grade 4 either as Thrombosis/embolism (vascular access-related) or Thrombosis/thrombus/embolism in the VASCULAR 
CATEGORY.  
Pulmonary fibrosis 
(radiographic changes)  
Pulmonary fibrosis 
Minimal radiographic 
findings (or patchy or bi-
basilar changes) with 
estimated radiographic 
proportion of total lung 
volume that is fibrotic of 
<25% 
Patchy or bi-basilar 
changes with estimated 
radiographic proportion of 
total lung volume that is 
fibrotic of 25 – <50% 
Dense or widespread 
infiltrates/consolidation 
with estimated 
radiographic proportion of 
total lung volume that is 
fibrotic of 50 – <75% 
Estimated radiographic 
proportion of total lung 
volume that is fibrotic is 
≥75%; honeycombing 
Death 
REMARK: Fibrosis is usually a “late effect” seen >3 months after radiation or combined modality therapy (including surgery). It is thought to represent scar/fibrotic lung tissue. It may be 
difficult to distinguish from pneumonitis that is generally seen within 3 months of radiation or combined modality therapy.  
ALSO CONSIDER: Adult Respiratory Distress Syndrome (ARDS); Cough; Dyspnea (shortness of breath); Hypoxia; Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select. 
NAVIGATION NOTE: Recurrent laryngeal nerve dysfunction is graded as Laryngeal nerve dysfunction in the NEUROLOGY CATEGORY. 
Vital capacity  
Vital capacity 
90 – 75% of predicted 
value 
<75 – 50% of predicted 
value 
<50 – 25% of predicted 
value 
<25% of predicted value 
Death 
Voice changes/dysarthria 
(e.g., hoarseness, loss or 
alteration in voice, 
laryngitis)  
Voice changes  
Mild or intermittent 
hoarseness or voice 
change, but fully 
understandable 
Moderate or persistent 
voice changes, may 
require occasional 
repetition but 
understandable on 
telephone 
Severe voice changes 
including predominantly 
whispered speech; may 
require frequent repetition 
or face-to-face contact for 
understandability; 
requires voice aid (e.g., 
electrolarynx) for ≤50% of 
communication 
Disabling; 
non-understandable voice 
or aphonic; requires voice 
aid (e.g., electrolarynx) 
for >50% of 
communication or 
requires >50% written 
communication 
Death 
ALSO CONSIDER: Laryngeal nerve dysfunction; Speech impairment (e.g., dysphasia or aphasia). 
Pulmonary/Upper 
Respiratory – Other 
(Specify, __) 
Pulmonary – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling 
Death 

 
RENAL/GENITOURINARY 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 60 - 
March 31, 2003, Publish Date: August 9, 2006 
Bladder spasms 
Bladder spasms 
Symptomatic, intervention 
not indicated 
Symptomatic, 
antispasmodics indicated 
Narcotics indicated 
Major surgical 
intervention indicated 
(e.g., cystectomy) 
— 
Cystitis 
Cystitis 
Asymptomatic 
Frequency with dysuria; 
macroscopic hematuria 
Transfusion; IV pain 
medications; bladder 
irrigation indicated 
Catastrophic bleeding; 
major non-elective 
intervention indicated 
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils 
– Select; Infection with unknown ANC – Select; Pain – Select. 
Fistula, GU 
– Select:  
– Bladder 
– Genital tract-female 
– Kidney 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
Fistula, GU – Select  
Asymptomatic, 
radiographic findings only 
Symptomatic; 
noninvasive intervention 
indicated  
Symptomatic interfering 
with ADL; invasive 
intervention indicated  
Life-threatening 
consequences; operative 
intervention requiring 
partial or full organ 
resection; permanent 
urinary diversion  
Death 
REMARK: A fistula is defined as an abnormal communication between two body cavities, potential spaces, and/or the skin. The site indicated for a fistula should be the site from which 
the abnormal process is believed to have originated. 
Incontinence, urinary  
Incontinence, urinary 
Occasional (e.g., with 
coughing, sneezing, etc.), 
pads not indicated 
Spontaneous, pads 
indicated  
Interfering with ADL; 
intervention indicated 
(e.g., clamp, collagen 
injections) 
Operative intervention 
indicated (e.g., 
cystectomy or permanent 
urinary diversion) 
— 
Leak (including 
anastomotic), GU 
– Select: 
– Bladder 
– Fallopian tube  
– Kidney 
– Spermatic cord 
– Stoma 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Leak, GU – Select  
Asymptomatic, 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic, interfering 
with GU function; invasive 
or endoscopic 
intervention indicated 
Life-threatening 
Death 
REMARK: Leak (including anastomotic), GU – Select refers to clinical signs and symptoms or radiographic confirmation of anastomotic leak but without development of fistula. 

 
RENAL/GENITOURINARY 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 61 - 
March 31, 2003, Publish Date: August 9, 2006 
Obstruction, GU  
– Select: 
– Bladder 
– Fallopian tube 
– Prostate 
– Spermatic cord 
– Stoma 
– Testes 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Obstruction, GU – Select  
Asymptomatic, 
radiographic or 
endoscopic findings only 
Symptomatic but no 
hydronephrosis, sepsis or 
renal dysfunction; dilation 
or endoscopic repair or 
stent placement indicated 
Symptomatic and altered 
organ function (e.g., 
sepsis or hydronephrosis, 
or renal dysfunction); 
operative intervention 
indicated  
Life-threatening 
consequences; organ 
failure or operative 
intervention requiring 
complete organ resection 
indicated  
Death 
NAVIGATION NOTE: Operative injury is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY CATEGORY.  
Perforation, GU  
– Select: 
– Bladder 
– Fallopian tube 
– Kidney  
– Ovary 
– Prostate 
– Spermatic cord 
– Stoma 
– Testes 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Perforation, GU – Select 
Asymptomatic 
radiographic findings only 
Symptomatic, associated 
with altered renal/GU 
function 
Symptomatic, operative 
intervention indicated 
Life-threatening 
consequences or organ 
failure; operative 
intervention requiring 
organ resection indicated 
Death 
Prolapse of stoma, GU 
Prolapse stoma, GU 
Asymptomatic; special 
intervention, 
extraordinary care not 
indicated 
Extraordinary local care 
or maintenance; minor 
revision under local 
anesthesia indicated 
Dysfunctional stoma; 
operative intervention or 
major stomal revision 
indicated 
Life-threatening 
consequences 
Death 
REMARK: Other stoma complications may be graded as Fistula, GU – Select; Leak (including anastomotic), GU – Select; Obstruction, GU – Select; Perforation, GU – Select; 
Stricture/stenosis (including anastomotic), GU – Select. 
Renal failure  
Renal failure 
— 
— 
Chronic dialysis not 
indicated 
Chronic dialysis or renal 
transplant indicated 
Death 
ALSO CONSIDER: Glomerular filtration rate. 

 
RENAL/GENITOURINARY 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 62 - 
March 31, 2003, Publish Date: August 9, 2006 
Stricture/stenosis 
(including anastomotic), 
GU 
– Select: 
– Bladder 
– Fallopian tube 
– Prostate 
– Spermatic cord 
– Stoma 
– Testes 
– Ureter  
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Stricture, anastomotic, 
GU – Select  
Asymptomatic, 
radiographic or 
endoscopic findings only 
Symptomatic but no 
hydronephrosis, sepsis or 
renal dysfunction; dilation 
or endoscopic repair or 
stent placement indicated 
Symptomatic and altered 
organ function (e.g., 
sepsis or hydronephrosis, 
or renal dysfunction); 
operative intervention 
indicated  
Life-threatening 
consequences; organ 
failure or operative 
intervention requiring 
organ resection indicated  
Death 
ALSO CONSIDER: Obstruction, GU – Select. 
Urinary electrolyte 
wasting (e.g., Fanconi’s 
syndrome, renal tubular 
acidosis) 
Urinary electrolyte 
wasting 
Asymptomatic, 
intervention not indicated 
Mild, reversible and 
manageable with 
replacement 
Irreversible, requiring 
continued replacement  
— 
— 
ALSO CONSIDER: Acidosis (metabolic or respiratory); Bicarbonate, serum-low; Calcium, serum-low (hypocalcemia); Phosphate, serum-low (hypophosphatemia). 
Urinary 
frequency/urgency 
Urinary frequency 
Increase in frequency or 
nocturia up to 2 x normal; 
enuresis 
Increase >2 x normal but 
<hourly 
≥1 x/hr; urgency; catheter 
indicated 
— 
— 
Urinary retention 
(including neurogenic 
bladder)  
Urinary retention 
Hesitancy or dribbling, no 
significant residual urine; 
retention occurring during 
the immediate 
postoperative period 
Hesitancy requiring 
medication; or operative 
bladder atony requiring 
indwelling catheter 
beyond immediate 
postoperative period but 
for <6 weeks 
More than daily 
catheterization indicated; 
urological intervention 
indicated (e.g., TURP, 
suprapubic tube, 
urethrotomy) 
Life-threatening 
consequences; organ 
failure (e.g., bladder 
rupture); operative 
intervention requiring 
organ resection indicated 
Death 
REMARK: The etiology of retention (if known) is graded as Obstruction, GU – Select; Stricture/stenosis (including anastomotic), GU – Select. 
ALSO CONSIDER: Obstruction, GU – Select; Stricture/stenosis (including anastomotic), GU – Select. 
Urine color change  
Urine color change 
Present 
— 
— 
— 
— 
REMARK: Urine color refers to change that is not related to other dietary or physiologic cause (e.g., bilirubin, concentrated urine, and hematuria). 
Renal/Genitourinary – 
Other (Specify, __) 
Renal – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
SECONDARY MALIGNANCY 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 63 - 
March 31, 2003, Publish Date: August 9, 2006 
Secondary Malignancy – 
possibly related to cancer 
treatment (Specify, __)  
Secondary Malignancy 
(possibly related to 
cancer treatment) 
— 
— 
Non-life-threatening basal 
or squamous cell 
carcinoma of the skin 
Solid tumor, leukemia or 
lymphoma  
Death 
REMARK: Secondary malignancy excludes metastasis from initial primary. Any malignancy possibly related to cancer treatment (including AML/MDS) should be reported via the routine 
reporting mechanisms outlined in each protocol. Important: Secondary Malignancy is an exception to NCI Expedited Adverse Event Reporting Guidelines. Secondary Malignancy is 
“Grade 4, present” but NCI does not require AdEERS Expedited Reporting for any (related or unrelated to treatment) Secondary Malignancy. A diagnosis of AML/MDS following 
treatment with an NCI-sponsored investigational agent is to be reported using the form available from the CTEP Web site at http://ctep.cancer.gov. Cancers not suspected of being 
treatment-related are not to be reported here. 

 
SEXUAL/REPRODUCTIVE FUNCTION 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 64 - 
March 31, 2003, Publish Date: August 9, 2006 
Breast function/lactation 
Breast function 
Mammary abnormality, 
not functionally significant 
Mammary abnormality, 
functionally significant 
— 
— 
— 
Breast nipple/areolar 
deformity  
Nipple/areolar 
Limited areolar 
asymmetry with no 
change in nipple/areolar 
projection 
Asymmetry of nipple 
areolar complex with 
slight deviation in nipple 
projection 
Marked deviation of 
nipple projection  
— 
— 
Breast volume/hypoplasia 
Breast 
Minimal asymmetry; 
minimal hypoplasia 
Asymmetry exists, ≤1/3 of 
the breast volume; 
moderate hypoplasia  
Asymmetry exists, >1/3 of 
the breast volume; severe 
hypoplasia 
— 
— 
REMARK: Breast volume is referenced with both arms straight overhead. 
NAVIGATION NOTE: Dysmenorrhea is graded as Pain – Select in the PAIN CATEGORY.  
NAVIGATION NOTE: Dyspareunia is graded as Pain – Select in the PAIN CATEGORY.  
NAVIGATION NOTE: Dysuria (painful urination) is graded as Pain – Select in the PAIN CATEGORY.  
Erectile dysfunction 
Erectile dysfunction 
Decrease in erectile 
function 
(frequency/rigidity of 
erections) but erectile 
aids not indicated 
Decrease in erectile 
function 
(frequency/rigidity of 
erections), erectile aids 
indicated 
Decrease in erectile 
function 
(frequency/rigidity of 
erections) but erectile 
aids not helpful; penile 
prosthesis indicated 
— 
— 
Ejaculatory dysfunction 
Ejaculatory dysfunction 
Diminished ejaculation 
Anejaculation or 
retrograde ejaculation 
— 
— 
— 
NAVIGATION NOTE: Feminization of male is graded in the ENDOCRINE CATEGORY. 
Gynecomastia 
Gynecomastia 
— 
Asymptomatic breast 
enlargement 
Symptomatic breast 
enlargement; intervention 
indicated 
— 
— 
ALSO CONSIDER: Pain – Select.  
Infertility/sterility 
Infertility/sterility 
— 
Male: oligospermia/low 
sperm count 
Female: diminished 
fertility/ovulation 
Male: sterile/azoospermia 
Female: infertile/ 
anovulatory 
— 
— 
Irregular menses  
(change from baseline) 
Irregular menses 
1 – 3 months without 
menses 
>3 – 6 months without 
menses but continuing 
menstrual cycles 
Persistent amenorrhea 
for >6 months 
— 
— 

 
SEXUAL/REPRODUCTIVE FUNCTION 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 65 - 
March 31, 2003, Publish Date: August 9, 2006 
Libido 
Libido 
Decrease in interest but 
not affecting relationship; 
intervention not indicated 
Decrease in interest and 
adversely affecting 
relationship; intervention 
indicated 
— 
— 
— 
NAVIGATION NOTE: Masculinization of female is graded in the ENDOCRINE CATEGORY. 
Orgasmic dysfunction 
Orgasmic function 
Transient decrease 
Decrease in orgasmic 
response requiring 
intervention 
Complete inability of 
orgasmic response; not 
responding to intervention 
— 
— 
NAVIGATION NOTE: Pelvic pain is graded as Pain – Select in the PAIN CATEGORY. 
NAVIGATION NOTE: Ulcers of the labia or perineum are graded as Ulceration in DERMATOLOGY/SKIN CATEGORY. 
Vaginal discharge  
(non-infectious) 
Vaginal discharge 
Mild 
Moderate to heavy; pad 
use indicated 
— 
— 
— 
Vaginal dryness 
Vaginal dryness 
Mild 
Interfering with sexual 
function; dyspareunia; 
intervention indicated 
— 
— 
— 
ALSO CONSIDER: Pain – Select. 
Vaginal mucositis 
Vaginal mucositis 
Erythema of the mucosa; 
minimal symptoms 
Patchy ulcerations; 
moderate symptoms or 
dyspareunia 
Confluent ulcerations; 
bleeding with trauma; 
unable to tolerate vaginal 
exam, sexual intercourse 
or tampon placement  
Tissue necrosis; 
significant spontaneous 
bleeding; life-threatening 
consequences 
— 
Vaginal stenosis/length 
Vaginal stenosis 
Vaginal narrowing and/or 
shortening not interfering 
with function  
Vaginal narrowing and/or 
shortening interfering with 
function  
Complete obliteration; not 
surgically correctable 
— 
— 
Vaginitis (not due to 
infection) 
Vaginitis 
Mild, intervention not 
indicated 
Moderate, intervention 
indicated 
Severe, not relieved with 
treatment; ulceration, but 
operative intervention not 
indicated 
Ulceration and operative 
intervention indicated 
— 
Sexual/Reproductive 
Function – Other 
(Specify, __) 
Sexual – Other (Specify) 
Mild 
Moderate 
Severe 
Disabling 
Death 

 
SURGERY/INTRA-OPERATIVE INJURY 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 66 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Intra-operative hemorrhage is graded as Hemorrhage/bleeding associated with surgery, intra-operative or postoperative in the HEMORRHAGE/BLEEDING 
CATEGORY.  
Intra-operative injury  
– Select Organ or 
Structure 
‘Select’ AEs appear at the 
end of the CATEGORY. 
Intraop injury – Select  
Primary repair of injured 
organ/structure indicated  
Partial resection of 
injured organ/structure 
indicated 
Complete resection or 
reconstruction of injured 
organ/structure indicated 
Life threatening 
consequences; disabling 
— 
REMARK: The ‘Select’ AEs are defined as significant, unanticipated injuries that are recognized at the time of surgery. These AEs do not refer to additional surgical procedures that 
must be performed because of a change in the operative plan based on intra-operative findings. Any sequelae resulting from the intra-operative injury that result in an adverse 
outcome for the patient must also be recorded and graded under the relevant CTCAE Term. 
Intra-operative Injury – 
Other (Specify, __) 
Intraop Injury – Other 
(Specify) 
Primary repair of injured 
organ/structure indicated  
Partial resection of 
injured organ/structure 
indicated 
Complete resection or 
reconstruction of injured 
organ/structure indicated 
Life threatening 
consequences; disabling 
— 
REMARK: Intra-operative Injury – Other (Specify, __) is to be used only to report an organ/structure not included in the ‘Select’ AEs found at the end of the CATEGORY. Any sequelae 
resulting from the intra-operative injury that result in an adverse outcome for the patient must also be recorded and graded under the relevant CTCAE Term. 

 
SURGERY/INTRA-OPERATIVE INJURY – SELECT  
Page 2 of 2 
CTCAE v3.0  
- 67 - 
March 31, 2003, Publish Date: August 9, 2006 
AUDITORY/EAR 
– Inner ear  
– Middle ear  
– Outer ear NOS  
– Outer ear-Pinna  
CARDIOVASCULAR 
– Artery-aorta  
– Artery-carotid  
– Artery-cerebral  
– Artery-extremity (lower)  
– Artery-extremity (upper)  
– Artery-hepatic  
– Artery-major visceral artery  
– Artery-pulmonary  
– Artery NOS 
– Heart  
– Spleen 
– Vein-extremity (lower)  
– Vein-extremity (upper)  
– Vein-hepatic  
– Vein-inferior vena cava  
– Vein-jugular  
– Vein-major visceral vein  
– Vein-portal vein  
– Vein-pulmonary  
– Vein-superior vena cava  
– Vein NOS 
DERMATOLOGY/SKIN 
– Breast  
– Nails  
– Skin 
ENDOCRINE 
– Adrenal gland 
– Parathyroid 
– Pituitary  
ENDOCRINE (continued) 
– Thyroid 
HEAD AND NECK 
– Gingiva  
– Larynx  
– Lip/perioral area  
– Face NOS  
– Nasal cavity  
– Nasopharynx  
– Neck NOS 
– Nose  
– Oral cavity NOS  
– Parotid gland  
– Pharynx  
– Salivary duct  
– Salivary gland  
– Sinus  
– Teeth  
– Tongue  
– Upper aerodigestive NOS 
GASTROINTESTINAL 
– Abdomen NOS  
– Anal sphincter  
– Anus 
– Appendix  
– Cecum  
– Colon  
– Duodenum  
– Esophagus  
– Ileum  
– Jejunum  
– Oral  
– Peritoneal cavity  
– Rectum 
– Small bowel NOS 
GASTROINTESTINAL (continued) 
– Stoma (GI)  
– Stomach  
HEPATOBILIARY/ PANCREAS 
– Biliary tree-common bile  
duct  
– Biliary tree-common hepatic 
duct  
– Biliary tree-left hepatic duct  
– Biliary tree-right hepatic duct  
– Biliary tree NOS  
– Gallbladder  
– Liver 
– Pancreas 
– Pancreatic duct 
MUSCULOSKELETAL 
– Bone  
– Cartilage  
– Extremity-lower 
– Extremity-upper 
– Joint  
– Ligament  
– Muscle  
– Soft tissue NOS 
– Tendon 
NEUROLOGY  
– Brain  
– Meninges  
– Spinal cord 
NERVES: 
– Brachial plexus 
– CN I (olfactory) 
– CN II (optic) 
– CN III (oculomotor) 
– CN IV (trochlear)  
NEUROLOGY (continued) 
NERVES: 
– CN V (trigeminal) motor  
– CN V (trigeminal) sensory  
– CN VI (abducens)  
– CN VII (facial) motor-face  
– CN VII (facial) sensory-
taste  
– CN VIII (vestibulocochlear)  
– CN IX (glossopharyngeal) 
motor pharynx  
– CN IX (glossopharyngeal) 
sensory ear-pharynx-
tongue  
– CN X (vagus)  
– CN XI (spinal accessory)  
– CN XII (hypoglossal)  
– Cranial nerve or branch 
NOS  
– Lingual  
– Lung thoracic  
– Peripheral motor NOS 
– Peripheral sensory NOS 
– Recurrent laryngeal  
– Sacral plexus  
– Sciatic 
– Thoracodorsal 
OCULAR 
– Conjunctiva  
– Cornea  
– Eye NOS 
– Lens 
– Retina 
PULMONARY/UPPER 
RESPIRATORY 
– Bronchus  
– Lung  
– Mediastinum  
– Pleura  
– Thoracic duct  
– Trachea 
– Upper airway NOS 
RENAL/GENITOURINARY 
– Bladder  
– Cervix  
– Fallopian tube  
– Kidney  
– Ovary  
– Pelvis NOS  
– Penis  
– Prostate  
– Scrotum  
– Testis  
– Ureter  
– Urethra  
– Urinary conduit  
– Urinary tract NOS  
– Uterus  
– Vagina  
– Vulva 
 
 

 
SYNDROMES 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 68 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Acute vascular leak syndrome is graded in the VASCULAR CATEGORY. 
NAVIGATION NOTE: Adrenal insufficiency is graded in the ENDOCRINE CATEGORY. 
NAVIGATION NOTE: Adult Respiratory Distress Syndrome (ARDS) is graded in the PULMONARY/UPPER RESPIRATORY CATEGORY. 
Alcohol intolerance 
syndrome (antabuse-like 
syndrome) 
Alcohol intolerance 
syndrome 
— 
— 
Present 
— 
Death 
REMARK: An antabuse-like syndrome occurs with some new anti-androgens (e.g., nilutamide) when patient also consumes alcohol. 
NAVIGATION NOTE: Autoimmune reaction is graded as Autoimmune reaction/hypersensitivity (including drug fever) in the ALLERGY/IMMUNOLOGY CATEGORY. 
Cytokine release 
syndrome/acute infusion 
reaction 
Cytokine release 
syndrome 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDS, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption of 
infusion); recurrence of 
symptoms following initial 
improvement; 
hospitalization indicated 
for other clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates) 
Life-threatening; pressor 
or ventilatory support 
indicated 
Death 
REMARK: Cytokine release syndromes/acute infusion reactions are different from Allergic/hypersensitive reactions, although some of the manifestations are common to both AEs. An 
acute infusion reaction may occur with an agent that causes cytokine release (e.g., monoclonal antibodies or other biological agents). Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hrs of completion of infusion. Signs/symptoms may include: Allergic reaction/hypersensitivity (including drug 
fever); Arthralgia (joint pain); Bronchospasm; Cough; Dizziness; Dyspnea (shortness of breath); Fatigue (asthenia, lethargy, malaise); Headache; Hypertension; Hypotension; Myalgia 
(muscle pain); Nausea; Pruritis/itching; Rash/desquamation; Rigors/chills; Sweating (diaphoresis); Tachycardia; Tumor pain (onset or exacerbation of tumor pain due to treatment); 
Urticaria (hives, welts, wheals); Vomiting.  
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever); Bronchospasm, wheezing; Dyspnea (shortness of breath); Hypertension; Hypotension; Hypoxia; Prolonged 
QTc interval; Supraventricular and nodal arrhythmia – Select; Ventricular arrhythmia – Select.  
NAVIGATION NOTE: Disseminated intravascular coagulation (DIC) is graded in the COAGULATION CATEGORY. 
NAVIGATION NOTE: Fanconi’s syndrome is graded as Urinary electrolyte wasting (e.g., Fanconi’s syndrome, renal tubular acidosis) in the RENAL/GENITOURINARY CATEGORY. 
Flu-like syndrome 
Flu-like syndrome 
Symptoms present but 
not interfering with 
function 
Moderate or causing 
difficulty performing some 
ADL 
Severe symptoms 
interfering with ADL 
Disabling 
Death 
REMARK: Flu-like syndrome represents a constellation of symptoms which may include cough with catarrhal symptoms, fever, headache, malaise, myalgia, prostration, and is to be 
used when the symptoms occur in a cluster consistent with one single pathophysiological process. 
NAVIGATION NOTE: Renal tubular acidosis is graded as Urinary electrolyte wasting (e.g., Fanconi’s syndrome, renal tubular acidosis) in the RENAL/GENITOURINARY CATEGORY. 

 
SYNDROMES 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 69 - 
March 31, 2003, Publish Date: August 9, 2006 
“Retinoic acid syndrome”  
“Retinoic acid syndrome” 
Fluid retention; less than 
3 kg of weight gain; 
intervention with fluid 
restriction and/or diuretics 
indicated 
Mild to moderate signs/ 
symptoms; steroids 
indicated 
Severe signs/symptoms; 
hospitalization indicated 
Life-threatening; 
ventilatory support 
indicated 
Death 
REMARK: Patients with acute promyelocytic leukemia may experience a syndrome similar to “retinoic acid syndrome” in association with other agents such as arsenic trioxide. The 
syndrome is usually manifested by otherwise unexplained fever, weight gain, respiratory distress, pulmonary infiltrates and/or pleural effusion, with or without leukocytosis.  
ALSO CONSIDER: Acute vascular leak syndrome; Pleural effusion (non-malignant); Pneumonitis/pulmonary infiltrates. 
NAVIGATION NOTE: SIADH is graded as Neuroendocrine: ADH secretion abnormality (e.g., SIADH or low ADH) in the ENDOCRINE CATEGORY.  
NAVIGATION NOTE: Stevens-Johnson syndrome is graded as Rash: erythema multiforme (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis) in the DERMATOLOGY/SKIN 
CATEGORY. 
NAVIGATION NOTE: Thrombotic microangiopathy is graded as Thrombotic microangiopathy (e.g., thrombotic thrombocytopenic purpura [TTP] or hemolytic uremic syndrome [HUS]) in 
the COAGULATION CATEGORY. 
Tumor flare 
Tumor flare 
Mild pain not interfering 
with function 
Moderate pain; pain or 
analgesics interfering with 
function, but not 
interfering with ADL 
Severe pain; pain or 
analgesics interfering with 
function and interfering 
with ADL 
Disabling 
Death 
REMARK: Tumor flare is characterized by a constellation of signs and symptoms in direct relation to initiation of therapy (e.g., anti-estrogens/androgens or additional hormones). The 
symptoms/signs include tumor pain, inflammation of visible tumor, hypercalcemia, diffuse bone pain, and other electrolyte disturbances.  
ALSO CONSIDER: Calcium, serum-high (hypercalcemia). 
Tumor lysis syndrome 
Tumor lysis syndrome 
— 
— 
Present 
— 
Death 
ALSO CONSIDER: Creatinine; Potassium, serum-high (hyperkalemia). 
Syndromes – Other 
(Specify, __) 
Syndromes – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
VASCULAR 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 70 - 
March 31, 2003, Publish Date: August 9, 2006 
Acute vascular leak 
syndrome 
Acute vascular leak 
syndrome 
— 
Symptomatic, fluid 
support not indicated 
Respiratory compromise 
or fluids indicated 
Life-threatening; pressor 
support or ventilatory 
support indicated  
Death 
Peripheral arterial 
ischemia 
Peripheral arterial 
ischemia 
— 
Brief (<24 hrs) episode of 
ischemia managed non-
surgically and without 
permanent deficit 
Recurring or prolonged 
(≥24 hrs) and/or invasive 
intervention indicated 
Life-threatening, disabling 
and/or associated with 
end organ damage 
(e.g., limb loss) 
Death 
Phlebitis (including 
superficial thrombosis) 
Phlebitis 
— 
Present 
— 
— 
— 
ALSO CONSIDER: Injection site reaction/extravasation changes. 
Portal vein flow 
Portal flow 
— 
Decreased portal vein 
flow 
Reversal/retrograde 
portal vein flow 
— 
— 
Thrombosis/embolism 
(vascular access-related) 
Thrombosis/embolism 
(vascular access) 
— 
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
not indicated 
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
indicated 
Embolic event including 
pulmonary embolism or 
life-threatening thrombus 
Death 
Thrombosis/thrombus/ 
embolism 
Thrombosis/thrombus/ 
embolism 
— 
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
not indicated  
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
indicated  
Embolic event including 
pulmonary embolism or 
life-threatening thrombus 
Death 
Vessel injury-artery  
– Select:  
– Aorta 
– Carotid 
– Extremity-lower 
– Extremity-upper  
– Other NOS 
– Visceral 
Artery injury – Select 
Asymptomatic diagnostic 
finding; intervention not 
indicated 
Symptomatic (e.g., 
claudication); not 
interfering with ADL; 
repair or revision not 
indicated 
Symptomatic interfering 
with ADL; repair or 
revision indicated 
Life-threatening; 
disabling; evidence of 
end organ damage (e.g., 
stroke, MI, organ or limb 
loss) 
Death 
NAVIGATION NOTE: Vessel injury to an artery intra-operatively is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY 
CATEGORY. 

 
VASCULAR 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 71 - 
March 31, 2003, Publish Date: August 9, 2006 
Vessel injury-vein  
– Select: 
– Extremity-lower  
– Extremity-upper 
– IVC 
– Jugular 
– Other NOS 
– SVC 
– Viscera 
Vein injury – Select 
Asymptomatic diagnostic 
finding; intervention not 
indicated 
Symptomatic (e.g., 
claudication); not 
interfering with ADL; 
repair or revision not 
indicated  
Symptomatic interfering 
with ADL; repair or 
revision indicated 
Life-threatening; 
disabling; evidence of 
end organ damage  
Death 
NAVIGATION NOTE: Vessel injury to a vein intra-operatively is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY CATEGORY. 
Visceral arterial ischemia 
(non-myocardial) 
Visceral arterial ischemia 
— 
Brief (<24 hrs) episode of 
ischemia managed 
medically and without 
permanent deficit 
Prolonged (≥24 hrs) or 
recurring symptoms 
and/or invasive 
intervention indicated 
Life-threatening; 
disabling; evidence of 
end organ damage  
Death 
ALSO CONSIDER: CNS cerebrovascular ischemia.  
Vascular – Other  
(Specify, __) 
Vascular – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
 

Clinical Trial Protocol:  HGT-SAN-067
Study Title:
An Open-Label Extension of Study HGT-SAN-055 Evaluating 
Long-Term Safety and Clinical Outcomes of Intrathecal 
Administration of rhHNS in Patients with Sanfilippo Syndrome
Type A (MPS IIIA)
Study Number:
HGT-SAN-067
Study Phase:
I/II
Product Name:
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Device Names:
SOPH-A-PORT® Mini S, Implantable Access Port, Spinal, Mini 
Unattached, with Guidewire
and
PORT-A-CATH® II Low Profile™Intrathecal Implantable Access 
System (Smiths device)
EudraCT 
Number:
2010-021348-16
Indication:
Sanfilippo Syndrome A
Investigators:
Multicenter
Sponsor:
Shire Human Genetic Therapies, Inc. 
300 Shire Way
Lexington, MA  02421, United States
Medical Monitor:
MD,  PhD
Date
Original Protocol:
21 June 2010
Amendment 1:
27 January 2011
Amendment 2:
13 January 2012
Amendment 3:
28 August 2012
Amendment 4:
3 May 2013
Amendment 5:
17 January 2014
Amendment 6:
10 July 2014
Confidentiality Statement
This document is the proprietary and confidential property of 
Shire Human Genetic Therapies, Inc.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
2
TABLE OF CONTENTS
TABLE OF CONTENTS...........................................................................................................2
SYNOPSIS.................................................................................................................................7
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..........................................14
1
INTRODUCTION ...........................................................................................................18
1.1
Disease Background...............................................................................................18
1.2
Nonclinical Overview............................................................................................20
1.2.1
Toxicology in Monkeys ..............................................................................20
1.2.2
Efficacy in Murine and Canine Models of MPS IIIA.................................21
1.3
HGT-SAN-067 Study Rationale............................................................................21
2
STUDY OBJECTIVES....................................................................................................23
2.1
Primary Objective..................................................................................................23
2.2
Secondary Objectives.............................................................................................23
2.3
Exploratory Objective............................................................................................23
3
STUDY ENDPOINTS.....................................................................................................24
3.1
Primary Endpoint...................................................................................................24
3.2
Secondary Endpoints .............................................................................................24
3.3
SOPH-A-PORT Mini S Assessments....................................................................24
4
INVESTIGATIONAL PLAN..........................................................................................25
4.1
Overall Study Design and Plan..............................................................................25
4.2
Rationale for Study Design and Control Group.....................................................27
4.3
Study Duration and Dates......................................................................................27
5
STUDY POPULATION SELECTION ...........................................................................28
5.1
Study Population....................................................................................................28
5.2
Inclusion Criteria ...................................................................................................28
5.3
Exclusion Criteria ..................................................................................................28
6
STUDY TREATMENT(S)..............................................................................................30
6.1
Description of Treatment(s)...................................................................................30
6.1.1
Study Drug ..................................................................................................30
6.1.2
Intrathecal Drug Delivery Device...............................................................30
6.1.3
Placebo or Control.......................................................................................30
6.2
Treatment Administered ........................................................................................30
6.3
Selection and Timing of Dose for Each Patient.....................................................31
6.3.1
Cerebral Spinal Fluid Sample Procedure....................................................31
6.3.2
Administration of HGT-1410 via Lumbar Puncture Guidance 
Concerning Performance of Lumbar Puncture for Study Drug 
Administration and Cerebrospinal Fluid Sample Collection ......................32
6.4
Method of Assigning Patients to Treatment Groups..............................................33

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
3
6.5
Blinding..................................................................................................................33
6.6
Concomitant Therapy.............................................................................................33
6.7
Restrictions ............................................................................................................33
6.7.1
Prior Therapy ..............................................................................................33
6.7.2
Fluid and Food Intake .................................................................................34
6.7.3
Patient Activity Restrictions .......................................................................34
6.8
Treatment Compliance...........................................................................................34
6.9
Packaging and Labeling.........................................................................................34
6.9.1
Drug Product...............................................................................................34
6.9.2
SOPH-A-PORT Mini S Access Port...........................................................34
6.10
Storage and Accountability....................................................................................34
6.10.1
Investigational Product................................................................................34
6.10.2
Intrathecal Drug Delivery Device...............................................................35
6.10.2.1
PORT-A-CATH IDDD.......................................................................35
6.10.2.2
SOPH-A-PORT Mini S IDDD ...........................................................35
6.11
Investigational Product Retention at Study Site ....................................................35
7
STUDY PROCEDURES .................................................................................................36
7.1
Informed Consent...................................................................................................36
7.2
Physical Examination.............................................................................................36
7.3
Height and Weight .................................................................................................36
7.4
Head Circumference ..............................................................................................36
7.5
Vital Signs..............................................................................................................37
7.6
Electrocardiography...............................................................................................37
7.6.1
Electrocardiograms .....................................................................................37
7.7
Clinical Laboratory Tests.......................................................................................37
7.7.1
Hematology.................................................................................................37
7.7.2
Serum Chemistry.........................................................................................38
7.7.3
Pregnancy Test............................................................................................38
7.7.4
Serum Anti-rhHNS Antibody and Sample Storage ....................................38
7.7.5
Urinalysis ....................................................................................................38
7.7.5.1
Standard Urinalysis.............................................................................39
7.7.5.2
Urine Glycosaminoglycans.................................................................39
7.7.6
Cerebrospinal Fluid Assessments ...............................................................39
7.7.6.1
Cerebrospinal Fluid Cell Counts ........................................................39
7.7.6.2
Cerebrospinal Fluid Heparan Sulfate Levels and Heparan Sulfate 
Derivatives..........................................................................................39
7.7.6.3
Anti-rhHNS Antibodies......................................................................39
7.7.6.4
Cerebrospinal Fluid Biomarkers.........................................................39

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
4
7.7.7
Sample Collection, Storage, and Shipping..................................................39
7.8
Anesthesia..............................................................................................................40
7.9
Audiometry and Auditory Brainstem Response ....................................................40
7.10
Magnetic Resonance Imaging of the Head ............................................................40
7.11
Device Data............................................................................................................40
7.12
Surgical Re-implantation of the IDDD..................................................................41
7.12.1
Restrictions on the Number of Revision and/or re-implantation of the 
IDDD...........................................................................................................41
7.13
Device Related Study Procedures..........................................................................41
7.13.1
IDDD Implantation or Revision Procedures...............................................41
7.13.2
X-ray Verification of Intrathecal Drug Delivery Device Placement ..........42
7.13.3
CSF Sampling Procedure............................................................................42
7.13.4
Device Removal..........................................................................................42
7.14
Cerebrospinal Fluid Opening Pressure Measurement............................................42
7.15
Dispensing Study Drug..........................................................................................43
7.16
Pharmacokinetic Assessments ...............................................................................43
7.17
Neurological Examination .....................................................................................43
7.18
Neurocognitive and Developmental Assessments.................................................43
7.19
Sleep Questionnaire:  Children’s Sleep Habits Rating Scale.................................45
7.20
Age-Dependent, Health-Related Quality of Life in Children................................45
7.20.1
Quality of Life Indicator:  CHQ-50 ............................................................45
7.20.2
Quality of Life Indicator:  CHQ-87 ............................................................45
7.20.3
Quality of Life Indicator:  ITQOL ..............................................................45
7.21
Concomitant Medications, Therapies and Medical/Surgical Procedures ..............45
7.22
Adverse Events ......................................................................................................46
7.22.1
Definitions of Adverse Events and Serious Adverse Events ......................46
7.22.1.1
Adverse Event.....................................................................................46
7.22.1.2
Potential Adverse Events:  Intrathecal recombinant human heparan 
N-sulfatase ..........................................................................................47
7.22.1.3
IDDD-related Adverse Events............................................................47
7.22.1.4
Serious Adverse Event........................................................................48
7.22.2
Device-Associated Definitions....................................................................48
7.22.2.1
Device Revision (Partial and Full) .....................................................48
7.22.2.2
Device Malfunction ............................................................................49
7.22.2.3
Device Failure.....................................................................................49
7.22.3
Classification of Adverse Events and Serious Adverse Events ..................49
7.22.4
Relatedness of Adverse Events and Serious Adverse Events.....................50
7.22.5
Procedures for Recording and Reporting Adverse Events..........................50
7.22.5.1
Reporting Serious Adverse Events Related to Study Procedures.......50

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
5
7.22.5.2
Eliciting Adverse Events ....................................................................52
7.22.5.3
Protocol Deviations for Medical Emergency or Adverse Event ........52
7.23
Abuse, Overdose and Medication Errors...............................................................53
7.24
Safety-related Study Stopping Rules .....................................................................53
7.25
Pregnancy...............................................................................................................53
7.26
Removal of Patients from the Trial or Study Drug................................................54
7.27
Other Study Procedures .........................................................................................55
7.28
Appropriateness of Measurements.........................................................................55
8
STUDY ACTIVITIES .....................................................................................................56
8.1
Screening Visit/Study Start Visit...........................................................................56
8.2
Treatment:  Drug Administration and Weekly Assessments.................................57
8.2.1
Week 1 ........................................................................................................57
8.2.1.1
Day 1 (Pre-treatment) Assessments Performed Prior to Each Dose...57
8.2.1.2
Day 2 (±2 days) Assessments and Administration of HGT-1410 ......58
8.3
End of Study/Early Termination Procedures:  Month 79 ......................................59
8.4
Safety Follow-up (by Telephone or Visit) Month 80 ............................................60
9
QUALITY CONTROL AND ASSURANCE .................................................................61
10
PLANNED STATISTICAL METHODS ........................................................................62
10.1
General Statistical Methodology............................................................................62
10.2
Determination of Sample Size ...............................................................................62
10.3
Analysis Populations..............................................................................................62
10.4
Demographics and Baseline Characteristics..........................................................62
10.5
Statistical Analysis of Pharmacokinetic Variables ................................................63
10.6
Efficacy, Safety, and Pharmacodynamic Evaluations ...........................................63
10.6.1
Primary Analyses ........................................................................................63
10.6.1.1
Safety Analysis ...................................................................................63
10.6.2
Other Observations Related to Safety.........................................................64
10.6.2.1
IDDD Performance.............................................................................64
10.6.3
Secondary Analysis.....................................................................................65
10.6.3.1
Clinical Assessments ..........................................................................65
10.6.3.2
Pharmacodynamic Analyses...............................................................65
10.6.4
Interim Analysis..........................................................................................65
11
ADMINISTRATIVE CONSIDERATIONS....................................................................66
11.1
Investigators and Study Administrative Structure.................................................66
11.2
Institutional Review Board or Independent Ethics Committee Approval .............66
11.3
Ethical Conduct of the Study.................................................................................66
11.4
Patient Information and Consent ...........................................................................66
11.5
Patient Confidentiality...........................................................................................67

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
6
11.6
Study Monitoring...................................................................................................67
11.7
Case Report Forms and Study Records .................................................................68
11.7.1
Critical Documents......................................................................................68
11.8
Device Failure Review Process .............................................................................68
11.9
Protocol Violations/Deviations..............................................................................69
11.10 Access to Source Documentation ..........................................................................69
11.11 Data Generation and Analysis ...............................................................................69
11.12 Premature Closure of the Study.............................................................................70
11.12.1
Study Termination.......................................................................................70
11.12.2
Site Termination..........................................................................................70
11.13 Retention of Data...................................................................................................70
11.14 Financial Disclosure...............................................................................................70
11.15 Publication and Disclosure Policy .........................................................................70
12
LIST OF REFERENCES.................................................................................................72
12.1.2
Interim Analysis..........................................................................................88
LIST OF IN-TEXT TABLES
Table 7-1
Neurodevelopmental Assessments Tests...................................................44
Table 7-2
Sanfilippo-Specific Disability Assessment And Behavior Rating 
Scales .........................................................................................................44
Table 7-3
Adverse Event Severity..............................................................................49
Table 7-4
Adverse Event Relatedness........................................................................50
Table A1-1
HGT-SAN-067 Study Assessments for Patients Who Have Received 
6 Months of HGT-1410 Treatment in Study HGT-SAN-055....................74
Table A2-1
Summary of Neurodevelopmental Outcome Measures .............................77
Table A2-2
Summary of Sanfilippo-specific Assessments...........................................77
LIST OF APPENDICES
Appendix 1
Schedule of Events.....................................................................................74
Appendix 2
Neurodevelopmental and Behavioural Assessments .................................77
Appendix 3
Expected Adverse Device Effects..............................................................81
Appendix 4
Protocol Amendment 6 Summary of Changes...........................................83
Appendix 5
Protocol Signature Page.............................................................................90
Appendix 6
The National Cancer Institute Common Terminology Criteria version 
3.0...............................................................................................................91

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
7
SYNOPSIS
Sponsor:
Shire Human Genetic Therapies, Inc. 
300 Shire Way
Lexington, MA  02421, United States
Name of Finished Product:
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Name of Active Ingredient:
rhHNS, HGT-1410
Name of Inactive Ingredient:
N/A
Names of Devices:  
SOPH-A-PORTMini S, Implantable Access Port, Spinal, Mini Unattached, with 
Guidewire (SOPH-A-PORT Mini S)
and
PORT-A-CATHII Low ProfileIntrathecal Implantable Access System 
(PORT-A-CATH)
Study Title:
An Open-Label Extension of Study HGT-SAN-055 Evaluating Long-Term Safety and 
Clinical Outcomes of Intrathecal Administration of rhHNS in Patients with Sanfilippo 
Syndrome Type A (MPS IIIA) 
Study Number:
HGT-SAN-067
Study Phase:  I/II
Device, Intended Use
The SOPH-A-PORT Mini S is a system intended for implantation by physicians. The 
SOPH-A-PORT Mini S, once implanted, allows healthcare personnel to administer 
HGT-1410 indicated for intrathecal delivery intermittently over a long period of time.
Prior to approval of Amendment 4, patients were implanted with a PORT-A-CATH 
(Smith’s device). After approval of Amendment 4 all PORT-A-CATH IDDDs requiring 
revision or replacement will be replaced with a SOPH-A-PORT at a time judged 
appropriate by the Investigator.
Study Objectives:
Primary Objective: 
The primary objective of this study is:

To collect long-term safety and tolerability data in patients with Sanfilippo Syndrome 
Type A (MPS IIIA) who received HGT-1410 via a surgically implanted intrathecal 
drug delivery device (IDDD) in study HGT-SAN-055 and elected to continue therapy 
in study HGT-SAN-067.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
8
Secondary Objectives:
The secondary objectives of this study are:

To collect as measures of drug efficacy, over an extended treatment period (as change 
from baseline), the following:  clinical, neurological, cognitive, behavioral, 
functional, and quality of life (QoL) assessments, together with potential imaging and 
biochemical biomarkers.
Study Endpoints: 
Primary Endpoints:
The primary endpoints of this study are related to the long-term safety of intrathecal 
HGT-1410 administration. The safety endpoints are:

adverse events (type and severity)

changes in clinical laboratory testing (serum chemistry including  liver function tests, 
hematology, and urinalysis)

electrocardiograms (ECG)

cerebrospinal fluid (CSF) chemistries (including cell counts and inflammatory 
markers)

anti-rhHNS antibodies (in CSF and serum).
Secondary Endpoints:
The secondary endpoints of this study are to collect over an extended treatment period (as 
change from baseline) clinical and potential surrogate biomarker efficacy data:

Standardized neurocognitive and behavioral assessments, Sanfilippo-specific 
behavioral rating scales, gross and fine motor assessments, functional adaptive rating 
scales, quality of life questionnaires, and Children’s Sleep Habits Rating Scale.

Concentration of safety and potential surrogate efficacy biomarkers in CSF, urine, 
and serum.

Concentration of heparan sulfate and heparan sulfate derivatives in CSF and 
glycosaminoglycans (GAG), including heparan sulfate and heparan sulfate 
derivatives, in urine.

Brain magnetic resonance imaging (MRI) and auditory brainstem response (ABR), 
Brainstem Auditory Evoked Potentials).
Study Design:
This study, HGT-SAN-067, is an open-label, long term, multicenter, extension of 
Study HGT-SAN-055.  The study is designed to evaluate the long-term safety, clinical 
activity, and biomarker outcomes of intrathecal (IT) administration of 3 dose levels 
(10 mg, 45 mg, and 90 mg once per month [Q4W]) of HGT-1410 via an IDDD in patients 
with MPS IIIA who successfully complete the Phase I/II study HGT-SAN-055 (including 
end of study [EOS] assessments) and elect to continue to receive HGT-1410 treatment.  
Initially, patients will continue in the same treatment group they were assigned to in the 
HGT-SAN-055 study. Following approval of protocol Amendment 4, patients in the 
10 mg group will have their dose increased to 45 mg per month.
For nomenclature of chronology purposes, the Baseline Visit for this extension study will 
be considered to be the first day the patient received his/her IT dose of HGT-1410 in 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
9
Study HGT-SAN-055.  The HGT-SAN-055 EOS assessment information will provide the 
screening/start of study information for patients who continue into the HGT-SAN-067 
extension study.  Note:  HGT-SAN-055 EOS data must be recorded in the context of the 
HGT-SAN-055 trial, and a copy of those data can be used for HGT-SAN-067 screening.  
Once eligibility is confirmed, informed consent must be obtained prior to performing any 
study-related procedures that are specific to HGT-SAN-067.  
Informed consent will be provided by the patient’s parent(s)/legally authorized 
representative(s) prior to the start of the extension study procedures and again at Month 
54.  Informed consent may be obtained anytime from week 20 in HGT-SAN-055.  This 
would allow a patient to have a nonfunctional IDDD replaced or revised prior to the first 
HGT-1410 dose in HGT-SAN-067.
Enrolled patients will check in to the study center 1 day before each of the scheduled 
HGT-1410 dosing days for safety assessments (designated Day 1). If no safety concerns 
exist, the patient will subsequently receive IT administration of HGT-1410 on Day 2 
(±2 days). However, if feasible and there are no safety concerns in the opinion of the 
investigator, the Day 1 and Day 2 assessments may be combined and performed on 
Day 2; if this is done the results will be recorded as Day 2. Patients will remain in the 
study center for at least 4 hours following dosing with HGT-1410 and will be discharged 
from the unit when deemed clinically stable by the Investigator.
All patients will have received a series of standardized neurodevelopment assessments in 
the HGT-SAN-055 study.  These assessments will have occurred at Baseline and either 
prior to or at the 6-month time point. Patients will continue in HGT-SAN-067 with 
whichever age specific assessment they began with in HGT-SAN-055. If, however, a 
patient’s capability improves and they become capable of completing assessments at a 
higher level, such additional assessments may be added. Any additional assessments 
would be performed after the original assessments (those previously used in study 
HGT-SAN-055) have been carried out. A MRI of the head will be performed at Months 
12, 24, 36, 54, 66 and 78 and ABR testing will be performed at Months 12, 24, and 36
(note that assessment time point nomenclature includes the 6 months in the 
HGT-SAN-055 study). Note: X-rays may be performed to investigate device malfunction, 
and to verify correct catheter and port placement following surgical implantation or 
revision. In addition, fluoroscopy should be employed intraoperatively to guide catheter 
placement. Thus, patients may undergo 3 X-ray examinations in association with each 
episode of IDDD malfunction and subsequent IDDD revision or replacement. Since the 
number of IDDD revisions/replacements is limited to 2 in any 6-month period (including 
the time in the HGT-SAN-055 study), the number of protocol-associated X-ray 
evaluations is limited to 6 exposures in any 6-month period (including time in the 
HGT-SAN-055). Patients will also have X-ray examinations of the device performed at 
the EOS visit if the patient is to continue to receive intrathecal HGT-1410 beyond the end 
of the study.
Patients will be evaluated for safety throughout the study.  Adverse events that occur in 
HGT-SAN-055 and that are ongoing at enrollment in HGT-SAN-067 will be captured in 
the case report forms (CRFs) for study HGT-SAN-067.  Specific safety stopping criteria 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
10
will be applied and will be based on the types and severity of adverse events (AEs) 
reported while on-study.  These data will be reviewed to inform the decision to 
discontinue a patient, a dose group, or the study as a whole. 
All patients will have an EOS visit 30 (±7) days following their last administration of 
HGT-1410 (ie, Month 78).  The EOS procedures will include standard clinical laboratory 
tests (serum chemistry, hematology, and urinalysis) in CSF and blood, protocol specific 
laboratory testing (eg, anti-rhHNS antibody testing), neurodevelopmental testing, child 
health questionnaires, and MRI.  
Use of concomitant medications, therapies, and procedures will be recorded and AEs will 
be monitored. 
All patients will be contacted by telephone or will have a visit for a Final Safety 
Follow-up, to be conducted at 30 (±7) days after the EOS visit (ie, Month 79) to collect
updated information on AEs and concomitant medications, therapies, and procedures. 
It is anticipated that the IDDD will be used to obtain CSF samples and to deliver 
administrations of HGT-1410.  However, if a patient’s IDDD appears nonfunctional or if 
its use is precluded on a scheduled day of dosing, site personnel will refer to the 
operations manual (for PORT-A-CATH) or the IDDD Manual (for SOPH-A-PORT), 
which describes the investigation and management of IDDD-related issues.  This will 
include possible partial revision or complete replacement of the IDDD.  As noted above, 
a maximum of 2 partial revisions and/or complete replacements can occur in any 6 month 
period.  If revision or replacement of the IDDD cannot be scheduled in time to avoid a 
delay of the next scheduled dose of HGT-1410, or if the patient experiences more than 
2 IDDD malfunctions in a 6 month period (including participation in study 
HGT-SAN-055), HGT-1410 will be administered via lumbar puncture (LP).  
If there are medical contra-indications to the re-implantation of a new device, or if the 
patient so desires, repeat monthly lumbar punctures may be considered as an alternative 
way of delivering the study drug and obtaining CSF samples under limited circumstances. 
If no safety risks are identified by the investigator, up to 12 consecutive lumbar punctures 
may be performed across the studies HGT-SAN-055 and HGT-SAN-067. Once a patient 
has reached the maximum of 12 consecutive lumbar punctures, a new IDDD may be 
re-implanted for subsequent dosing, unless, in the opinion of the investigator and medical 
monitor, assessment of risk/benefit favors continued dosing via lumbar puncture.
Continued treatment via lumbar puncture beyond the stipulated 12 consecutive monthly 
doses can be considered only in individual cases where this treatment is very well 
tolerated and the investigator has not identified any safety concerns associated with repeat 
lumbar puncture and repeat sedation/anesthesia. 
If there is no significant safety risk in the opinion of the Investigator, a non-functional 
IDDD may be left in situ for up to 3 months.
In light of the higher than expected complications experienced with the PORT-A-CATH 
IDDD, the SOPH-A-PORT Mini S device will be introduced for those patients requiring 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
11
replacement or revision.  This new device has design features anticipated to reduce 
complications encountered with the PORT-A-CATH IDDD device.  Specific device 
assessments are included in the protocol to collect information with respect to 
information specific to SOPH-A-PORT Mini S device safety and function.  
Patients who discontinue or are withdrawn before receiving 3 monthly IT injections will 
not have to undergo the EOS evaluations but will have their IDDD removed.  
Patients will have the IDDD removed when they discontinue from the study, unless the 
patient is continuing to receive treatment through another mechanism (eg, extension 
study, expanded access, commercially available).
An overview of the study appears in the Schedule of Events.
Study Population: 
A maximum of 12 patients are planned for this study.  To be eligible for participation 
patients will have completed all study requirements in Study HGT-SAN-055, including 
the EOS visit, and will have elected to continue treatment with HGT-1410. 
Test Product; Dose; and Mode of Administration: Recombinant human heparan 
N-sulfatase (rhHNS, HGT-1410) will be administered via an IDDD according to the same 
dose to which the patient was assigned in HGT-SAN-055 (ie, 10 mg, 45 mg, or 90 mg 
monthly). Patients assigned to the 10 mg monthly dose will have their dose increased to 
45 mg once per month (Q4W) at the first administration of HGT-1410 following full 
approval of the protocol amendment.
Reference Therapy; Dose; and Mode of Administration: 
N/A
Diagnosis and Main Criteria for Inclusion
Inclusion Criteria:
Each patient must meet the following criteria to be enrolled in this study.
1. The patient must have completed Study HGT-SAN-055 and, in the opinion of the 
investigator, have no safety or medical issues that contraindicate participation. 
2. The patient, patient’s parent(s) or legally authorized representative(s) has voluntarily 
signed an Institutional Review Board/Independent Ethics Committee-approved 
informed consent (and assent, if applicable) form after all relevant aspects of the 
study have been explained and discussed with them.  Informed consent/assent must be 
obtained prior to any study specific procedures.
3. The patient received at least 5 of the 6 planned infusions of HGT-1410 in the 
HGT-SAN-055 study. 
4. The patient must be medically stable, in the opinion of the Investigator, to 
accommodate the protocol requirements, including travel, assessments, and IDDD 
surgery (if necessary for replacement purposes), without placing an undue burden on 
the patient/patient's family.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
12
Exclusion Criteria: 
Patients will be excluded from the study if there is evidence of any of the following:
1. The patient has experienced an adverse reaction to study drug in Study 
HGT-SAN-055 that contraindicates further treatment with HGT-1410.
2. The patient has a known hypersensitivity to the active ingredient or any excipients in 
HGT-1410 drug product.
3. The patient has non-MPS IIIA related central nervous system (CNS) impairment or 
behavioral disturbances that would confound the scientific integrity or interpretation 
of study assessments, as determined by the Investigator.
4. The patient has MPS IIIA behavioral-related issues, as determined by the 
Investigator, which would preclude performance of study neurocognitive and 
developmental testing procedures.
5. The patient is pregnant, breast feeding, or is a patient of childbearing potential who 
will not or cannot comply with the use of an acceptable method of birth control, such 
as condoms, barrier method, oral contraception, etc.
6. The patient has any known or suspected hypersensitivity to anesthesia or is thought to 
have an unacceptably high risk for anesthesia due to airway compromise or other 
conditions.
7. The patient has a history of a poorly controlled seizure disorder. 
8. The patient is currently receiving psychotropic or other medications, which in the 
Investigator’s opinion, would be likely to substantially confound test results and the 
dose and regimen of which cannot be kept constant throughout the study.
9. The patient cannot sustain absence from aspirin, non-steroidal medications, or 
medications that affect blood clotting within 1 week prior to a relevant study-related 
procedure (eg, device re-implantation if applicable), or has ingested such medications 
within 1 week before any procedures in which any change in clotting activity would 
be deleterious.
10. The patient has received treatment with any investigational drug (other than 
HGT-1410) intended as a treatment for MPS IIIA within the 30 days prior to, during 
the study, or is currently enrolled in another study that involves an investigational 
drug or device (screening through safety follow-up contact).
11. The patient has received a hematopoietic stem cell or bone marrow transplant.
For patients to be implanted with the SOPH-A-PORT Mini S IDDD the following 
conditions are contraindicated, as described in the Instructions for Use: 
1. The patient has had, or may have, an allergic reaction to the materials of construction 
of the SOPH-A-PORT Mini S device
2. The patient’s body size is too small to support the size of the SOPH-A-PORT Mini S 
Access Port, as judged by the Investigator 
3. The patient has a known or suspected local or general infection
4. The patient is at risk of abnormal bleeding due to a medical condition or therapy
5. The patient has one or more spinal abnormalities that could complicate safe 
implantation or fixation
6. The patient has a functioning CSF shunt device

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
13
7. The patient has shown an intolerance to an implanted device
Duration of Treatment: 
The study duration will be 6 years.
Pharmacokinetic Variables:
N/A.
Safety Assessments: 
Safety evaluations will include vital signs, physical examinations, AE assessments, 
electrocardiograms (ECG); serum chemistry, hematology, urine laboratory tests, and 
screening for antibodies to rhHNS (in CSF and serum).  
Statistical Methods: The statistical methodology supporting the trial will focus on 
descriptive rather than inferential approaches, given the early phase and objectives of the 
trial. Data will be plotted and the mean, standard deviation, median, minimum, and 
maximum for each variable will be tabulated by dose group to look for gross trends over 
time, which may be attributed to treatment. For continuous data, 95% confidence interval 
(CI) around the mean will also be estimated and presented.
The analysis population consists of all eligible patients from HGT-SAN-055 who have 
completed Study HGT-SAN-055 and agreed to participate in this extension study.  Safety 
analyses will be performed using the above mentioned population.  The data will be 
presented by dose group.
Date of Original Protocol: 21 June 2010
Date of Amendment 6: 10 July 2014

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
14
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ABR
auditory brainstem response
AE
adverse event
ALB
albumin
ALK-P
alkaline phosphatase
ALT
alanine aminotransferase (SGPT)
AST
aspartate aminotransferase (SGOT)
βhCG
human chorionic gonadotropin
BSID-III
Bayley Scales of Infant Development, Third Edition
BBB
blood brain barrier
BUN
blood urea nitrogen
Ca
calcium
CE
Conformité Européenne
CFR
Code of Federal Regulations
CHQ-50
Child Health Questionnaire™ Parent Form 50
CHQ-87
Child Health Questionnaire™ Child Form 87
CK
creatine kinase
Cl
chloride
CNS
central nervous system
CO2
carbon dioxide
CTCAE
Common Terminology Criteria for Adverse Events
CRO
contract research organization
CRIM
cross-reacting immunologic material 
CS
clinically significant
CSF
cerebrospinal fluid
ECG
electrocardiogram
eCRF
electronic case report form
EDC
Electronic Data Capture 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
15
Abbreviation
Definition
ERT
enzyme replacement therapy
EOS
end of study
EOW
every other week
EU
European Union
FDA
Food and Drug Administration
FPSS/TDS
Four-Point Scoring System/Total Disability Score
GAG
glycosaminoglycan
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
Hct
hematocrit
Hgb
hemoglobin
HS
heparan sulfate
ICH
International Conference on Harmonization 
IDDD
intrathecal drug delivery device
IEC
Independent Ethics Committee
IFU
instructions for use
IND
Investigational New Drug 
IRB
Institutional Review Board
IT
intrathecal
ITQOL
Infant Toddler Quality of Life Questionnaire™
IV
intravenous
K
potassium
KABC-II
Kaufman Assessment Battery for Children, Second Edition
LDH
lactic dehydrogenase
LP
lumbar puncture 
LSD
lysosomal storage disease
M6P
mannose-6-phosphate
MABC-2
Movement Assessment Battery for Children, Second Edition

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
16
Abbreviation
Definition
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MPS
Mucopolysaccharidosis 
MPS IIIA
Mucopolysaccharidosis IIIA or Sanfilippo syndrome Type A
MRI
magnetic resonance imaging
Na
sodium 
NCI
National Cancer Institute
NCS
not clinically significant
PE
pressure-equalization
QoL
quality of life
Q4W
once per month
RBC
red blood cell (count)
rhHNS
recombinant human heparan N-sulfatase
RNA
ribonucleic acid
SAE
serious adverse event
SAP
Statistical Analysis Plan
SBRS
The Sanfilippo Behavior Rating Scale
SGOT
serum glutamic oxaloacetic transaminase (AST)
SGPT
serum glutamic pyruvic transaminase (ALT)
Shire HGT
Shire Human Genetic Therapies, Inc.
TMF
Trial Master File
TX
treatment
UADE
unanticipated adverse device effect
US
United States
VABS-II
Vineland Adaptive Behavior Scales 
WBC
white blood cell (count)

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
17
Abbreviation
Definition
WHO-DD
World Health Organization-Drug Dictionary 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
18
1
INTRODUCTION
The progressive and irreversible nature of lysosomal storage diseases (LSDs) present a challenge 
in the interpretation of clinical benefit derived from treatment in studies using enzyme 
replacement therapy (ERT).  Any short-term improvement and/or stabilization of clinically 
important manifestations of the disease may be viewed as clinically meaningful.  However, the 
demonstration of the different aspects of a long-term, clinically-meaningful improvement may be 
limited by the short duration of treatment in clinical studies. Extended access to treatment 
through extension studies provides an opportunity for further evaluation of long-term safety and 
clinical outcomes for treated patients.  In this extension study, patients who completed study 
HGT-SAN-055, a phase I/II safety and dose-escalation trial, and elected to continue to receive 
recombinant human heparan N-sulfatase (rhHNS), will receive treatment through this extension 
protocol.  Initially, the patient’s treatment group and dosing regimen will be the same as that 
employed in study HGT-SAN-055. Following the analysis of data from HGT-SAN-055, patients 
in the lowest dose group will have their dose increased to 45 mg, as outlined in Section 1.3, 
below.
1.1
Disease Background
Sanfilippo syndrome, or Mucopolysaccharidosis (MPS) III, is LSD caused by loss in activity of 
1 of 4 enzymes necessary for degradation of the glycosaminoglycan (GAG) heparan sulfate (HS) 
in lysosomes.  Four different subtypes (A, B, C, and D) have been identified and are each due to 
a specific enzyme deficiency involved in the lysosomal catabolism of HS.  
Mucopolysaccharidosis IIIA or Sanfilippo syndrome Type A (MPS IIIA) results from deficiency 
of the enzyme heparan N-sulfatase (sulfamidase).  In the absence of this enzyme, intermediates 
of the HS degradation process accumulate in the lysosomes of neurons and glial cells, with lesser 
accumulation outside the brain.  
MPS III is the most prevalent of all mucopolysaccharidoses, with subtype A the most common of 
these.1  The birth prevalence of MPS IIIA has been estimated as 1.28 in 100,000 in Australia, 
1.16 in 100,000 in the Netherlands, and 0.88 in 100,000 in Germany.1-3 In summary, MPS IIIA 
is a rare genetic disorder with apparently widespread geographic distribution and an average 
global birth incidence of approximately 1 in 100,000.
In a recent detailed review of all MPS IIIA patients diagnosed in the Netherlands, it was reported 
that among 81 patients in whom information was available, first symptoms arose at a median of 
2.5 years (range 0.5 to 7 years).4  Owing to the rarity of the disease and the non-specific and 
often subtle nature of its initial manifestations, diagnosis is usually delayed until an average age 
of 4 to 4.5 years.4, 5 Patients present a wide spectrum and severity of clinical symptoms.  The 
central nervous system (CNS) is the most severely affected organ system in patients with MPS 
IIIA, evidenced by deficits in language development, motor skills, and intellectual development.5  
In addition, there are abnormal behaviors including, but not limited to, aggression and excess 
motor activity/hyperactivity that contribute to disturbances in sleep.5 - 7 In contrast with other 
MPS types, the viscera are mildly affected, with transient enlargement of liver and spleen during 
childhood with no evidence of dysfunction.  There are also reports of unexplained, recurrent and 
severe diarrhea.8  Overall, individuals with MPS IIIA have a marked developmental delay and 
significantly reduced lifespan of 15 years of age on average.8  

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
19
A milder variant has recently been identified with slower progression and survival to later age in 
approximately 10% of German patients with MPS IIIA.9
No effective, disease-modifying therapies are currently approved as treatments for this rare, 
devastating and disabling disease.  
A long-range goal of Shire Human Genetic Therapies, Inc. (Shire HGT) is to develop a 
recombinant human sulfamidase ERT for patients with MPS IIIA.  A particular problem for 
LSDs that damage the brain such as MPS III is how to target ERT to the brain.10  In animal 
studies, ERT was administered into the cerebrospinal fluid (CSF) via an intrathecal (IT) route, 
because when administered intravenously (IV), it was shown to not cross the blood brain barrier 
(BBB) after the immediate postnatal period of life.11, 12  
As the CNS in patients with MPS IIIA is the most severely affected body system, the main focus 
of the HGT-1410 clinical development program has been the development of ERT specifically 
for delivery directly to the CNS.  Recombinant human heparan N-sulfatase has been developed 
specifically for delivery into the CSF via an intrathecal drug delivery device (IDDD) due to the 
acknowledged impermeability of the BBB to macromolecules. 
Heparan N-sulfatase is a highly purified recombinant form of the naturally occurring human 
lysosomal enzyme sulfamidase.  It is expressed from the well characterized continuous human 
HT-1080 cell line as a 482 amino acid peptide, following cleavage of the 20 amino acid 
N-terminal signal peptide.  The mature protein in solution is a homodimeric glycoprotein of 
approximately 122 kDa, which undergoes post-translational modifications by conversion of 
Cys50 to formylglycine, required for enzyme activity, and glycosylation at 4 of the 5 potential 
N-linked glycosylation sites.  The rhHNS glycans contain mannose-6-phosphate (M6P) residues 
which target the protein for cellular uptake and internalization in its lysosomal site of action via 
the membrane-bound M6P receptors.13, 14 - 16
The first precedent for intraspinal ERT was recently published and has been shown to be both 
safe and effective for spinal cord compression in MPS I.17  In this study, a patient with MPS I 
received 4 IT doses of enzyme (Laronidase [recombinant α-L- Iduronidase]) at 1-month 
intervals.  Safety evaluations included CSF opening pressure, serum chemistry and CSF protein, 
glucose and cell count, in addition to clinical efficacy studies.  No changes in safety evaluations 
were observed.
In another recent study, a patient with MPS VI and spinal cord compression received IT 
injections of enzyme (Galsulfase) monthly, for 4 months.  CSF analysis revealed no 
inflammatory reaction; no other side effects were noted.18
Several MPS I patients have been treated since 2005 with IT Laronidase in 2 ongoing clinical 
trials (clinicaltrials.gov identifiers NCT00215527 and NCT00786968) studying efficacy on 
spinal cord compression. No results of these trials have yet been published. However, in 
June 2009 a study further investigating the effectiveness of IT ERT as a treatment for another 
neurological symptom in MPS I, cognitive decline, was initiated (clinicaltrials.gov identifier 
NCT00852358). 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
20
This study is a 24-month, open label, prospective, randomized trial in 16 patients with 
MPS I, 6 years of age or older, who have documented evidence of cognitive decline. In this 
study, the clinical safety of the regimen will be assessed by adverse event (AE) monitoring, CSF 
laboratory assessments, and clinical evaluations.  This study is ongoing; no efficacy or safety 
data have yet been published as of October 2011.19 
In addition, there are 4 ongoing Shire-sponsored studies that are evaluating IT administration of 
ERT:  A Phase I/II safety and dose escalation study of monthly idursulfase-IT injection for 
cognitively impaired patients with Hunter syndrome (Study HGT-HIT-045; NCT00920647), the 
open-label extension to this study (HGT-HIT-046); a Phase I/II ascending dose and dose 
frequency study of monthly IT injection of HGT-1410 in patients with Sanfilippo Syndrome 
Type A (Study HGT-SAN-055; NCT01155778), and the open-label extension to this study 
(HGT-SAN-067; NCT 01299727).
In light of the higher than expected complications experienced with the PORT-A-CATH IDDD, 
the SOPH-A-PORT Mini S device will be introduced for those patients requiring replacement or 
revision.  This new device has design features anticipated to reduce complications encountered 
with the PORT-A-CATH IDDD device.  Specific device assessments are included in the protocol 
to collect information with respect to information specific to SOPH-A-PORT Mini S device 
safety and function.  
1.2
Nonclinical Overview
To circumvent the restriction of the BBB, HGT-1410 was administered into the CSF of rats and 
monkeys via an IT route.  The non-clinical data demonstrate that IT administration of HGT-1410 
leads to uptake by target CNS tissues with appropriate efficacy and distribution.  In addition, 
there were no findings noted in the toxicity studies, allowing for a 6.2-fold safety margin from 
the results in the juvenile cynomolgus monkey.  Intermittent bolus injection of HGT-1410 to the 
brain via the IT route of administration is hypothesized to be of benefit in stabilizing, improving, 
or preventing the CNS manifestations of disease. 
The doses tested in the non-clinical studies adequately support the efficacy of the planned doses 
(10, 45 or 90 mg/month, normalized to the brain weight of the human) in the ongoing Phase I/II 
study, HGT-SAN-055.  Specifically, in the San A mouse, the 100 μg dose corresponds to a 
2.2-fold increase (per kg brain weight) from the highest anticipated human dose (90 mg) (human 
brain = 1 kg).  The 20 μg dose given IT every other week (EOW) or monthly, for which efficacy 
was also observed, corresponds to a 40 mg (per kg brain weight) human dose.  In the Huntaway 
(Sanfilippo A) dogs, the 3 mgHGT-1410 given IT weekly (corresponding to a 33 mg/kg of brain 
weight in man), was not only well tolerated but resulted in significant effects on biomarkers of 
disease activity and improved histopathology. 
1.2.1
Toxicology in Monkeys
In the pivotal, 6-month IT toxicity study in juvenile cynomolgus monkeys, and the highest dose 
of HGT-1410 was 8.3 mg given EOW.  This translates into a 138 mg/kg brain-weight dose (ie, 
based on a 60 g juvenile monkey brain).  Since no HGT-1410-related adverse effects were noted, 
the nonclinical study provides for the proposed Phase I/II clinical trial a ~13.8 × safety margin 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
21
relative to the starting clinical dose (10 mg), and a 1.5× safety margin relative to the highest 
clinical dose (90 mg).    
1.2.2
Efficacy in Murine and Canine Models of MPS IIIA
Non-clinical proof of concept efficacy studies were conducted using mouse and dog models of 
MPS IIIA, both of which contain naturally-occurring mutations in the HNS gene.  
In the MPS IIIA mouse, direct injection into the CNS had a beneficial effect on clinical signs, 
impaired neurobehavioral, and the biochemical and histopathologic markers of disease activity.  
In Huntaway (Sanfilippo A) dogs, HGT-1410 (3 mg) given IT weekly had a significant effect on 
biomarkers of disease activity and improved histopathology.
Efficacy has been demonstrated at a range of doses in nonclinical mouse and canine models.  In 
MPS IIIA mice, a dose-dependent reduction in the level of a heparan sulfate-derived monosulfate 
disaccharide was observed within the brain (up to 62% reduction compared with vehicle-treated 
mice) and spinal cord (up to 71% reduction).  An ultrastructural examination revealed a 
reduction in lysosomal vesicle formation in various cell types and fewer (ubiquitin-positive) 
axonal spheroids in several brain regions after repeated injections (5 to 20 µg) of HGT-1410 into 
the CSF of MPS III mutant mice via the cisterna magna (ie, IT).  The biochemical changes were 
accompanied by improved behavior, particularly in mice treated more frequently.20
In the MPS IIIA mutant mouse model, intracisternal (ie, IT) injection of a single dose of 100 µg 
HGT-1410 resulted in a substantial (and sustained) reduction of biomarkers of disease activity 
(heparan sulfate-derived disaccharides, microgliosis and astrogliosis).21   Equally impressive was 
the improvement in neurobehavioral parameters (learning in the Morris water maze, 
normalization of aggression) in these mice post-dose.21  One-hundred µg HGT-1410 per mouse 
translates into 200 mg/kg brain weight (ie, based on a 0.5 g mutant mouse brain).  Efficacy at 
lower doses of HGT-1410 (eg, 20 µg, given IT, EOW or monthly) has been demonstrated.11  A 
20 µg injection translates into a 40 mg human dose (ie, 40 mg per kilogram of brain weight).  
Thus, this data further suggests that efficacy will be seen at the highest clinical dose (90 mg, per 
month) in the proposed Phase I/II study. 
In the tolerized Huntaway (San A) dogs, 3 mg HGT-1410 was initially given IT on a weekly 
basis, then EOW, and had a significant effect on biomarkers of disease activity.22  The 3 mg dose 
in the dog translates into a 33 mg (per kg brain weight) human dose (based on a 90 g Huntaway 
dog brain). 
1.3
HGT-SAN-067 Study Rationale
This extension study (Study HGT-SAN-067) will evaluate the effects of long-term HGT-1410 
administration on safety, clinical activity, and biomarker outcomes in patients who completed 
Study HGT-SAN-055 and elected to continue therapy with HGT-1410.
Patients who were enrolled in Study HGT-SAN-055 through Week 26 and completed the end of 
study (EOS) evaluations are eligible for enrollment in this open-label extension study. All 
patients enrolled in this study will initially receive HGT-1410 at the same dose and schedule as 
they received in Study HGT-SAN-055. Patients assigned to 10 mg monthly will have their dose 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
22
increased to 45 mg monthly once per month (Q4W) at the first administration of HGT-1410 
following full approval of protocol Amendment 4. Based on analyses performed at the 
completion of Study HGT-SAN-055 a decline in the primary pharmacodynamic parameter, CSF 
heparan sulfate, was observed. This response to therapy was exhibited at all dose levels, 
however, the greatest impact was at the 2 higher dose levels. An effect on CSF heparan sulfate 
demonstrated in vivo activity of HGT-1410 in the target anatomical compartment. This effect is 
thought to have central importance in mediating the potential therapeutic benefit of HGT-1410. 
As no apparent difference in safety profile was observed between the 3 dose groups, it was 
believed that the increase in the potential therapeutic benefit of the higher dose outweighed any 
potential increase in risks for this lowest dose group.  
Please refer to the current edition of the Investigator’s Brochure for further information 
concerning the safety and clinical development of HGT-1410 and PORT-A-CATH IDDD and 
SOPH-A-PORT Mini S device.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
23
2
STUDY OBJECTIVES
2.1
Primary Objective 
The primary objective of this study is:

To collect long-term safety and tolerability data in patients with Sanfilippo Syndrome 
Type A (MPS IIIA) who received HGT-1410 via a surgically implanted IDDD in study 
HGT-SAN-055 and elect to continue therapy in study HGT-SAN-067.
2.2
Secondary Objectives 
The secondary objectives of this study are:

To collect, as measures of drug efficacy, over an extended treatment period (as change from 
baseline), the following:  clinical, neurological, cognitive, behavioral, functional, and quality 
of life (QoL) assessments, together with potential imaging and biochemical biomarkers.
2.3
Exploratory Objective
An exploratory objective of this study is:


Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
24
3
STUDY ENDPOINTS
3.1
Primary Endpoint
The primary endpoints of this study are related to the long-term safety of intrathecal HGT-1410 
administration. The safety endpoints are:

adverse events (type and severity)

changes in clinical laboratory testing (serum chemistry including  liver function tests, 
hematology, and urinalysis)

electrocardiograms (ECG)

CSF chemistries (including cell counts and inflammatory markers)

anti-rhHNS antibodies (in CSF and serum).
3.2
Secondary Endpoints 
The secondary endpoints of this study are to collect over an extended treatment period (as the 
change from baseline [defined as the start of the HGT-SAN-055 study]) clinical and potential 
surrogate biomarker efficacy data: 

Measures of standardized neurocognitive and behavioral assessments, Sanfilippo-specific 
behavioral rating scales, gross and fine motor assessments, functional adaptive rating scales, 
QoL questionnaires, and Children’s Sleep Habits Rating Scale.

Concentration of safety and potential surrogate efficacy biomarkers in CSF, urine, and 
serum.

Concentration of heparan sulfate and heparan sulfate derivatives in CSF and GAG, including 
heparan sulfate and heparan sulfate derivatives, in urine.

Brain magnetic resonance imaging (MRI) and auditory brainstem response (ABR), (also 
known as Brainstem Auditory Evoked Potentials).
3.3
SOPH-A-PORT Mini S Assessments

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
25
4
INVESTIGATIONAL PLAN
4.1
Overall Study Design and Plan
Study HGT-SAN-067, is an open-label, long term, multicenter, extension of Study 
HGT-SAN-055.  This study is designed to evaluate the long-term safety, clinical activity, and 
biomarker outcomes of IT administration of 3 dose levels (10 mg, 45 mg, and 90 mg once per 
month [Q4W]) of HGT-1410 via an IDDD in patients with MPS IIIA who successfully 
completed HGT-SAN-055 (including the EOS assessments) and elect to continue to receive 
uninterrupted HGT-1410 treatment.  Patients will initially continue in the same treatment group 
they were assigned to in the HGT-SAN-055 study: 

Group 1:  HGT-1410 administered by IT injection 10 mg once per month (Q4W) 

Group 2:  HGT-1410 administered by IT injection 45 mg once per month (Q4W)

Group 3:  HGT-1410 administered by IT injection 90 mg once per month (Q4W) 
Patients assigned to Group 1 will initially receive 10 mg monthly but will have their dose 
increased to 45 mg monthly (Q4W) at the first administration of HGT-1410 following full 
approval of protocol Amendment 4.
In order to maintain a nomenclature system based on study chronology across the original 
HGT-SAN-055 study and this extension study, the Baseline Visit for this extension study will be 
considered to be the day the patient received their first IT dose of HGT-1410 in 
Study HGT-SAN-055.  The HGT-SAN-055 EOS assessment information will provide the 
screening/start of study information for patients who continue into the HGT-SAN-067 extension 
study.  Note: HGT-SAN-055 EOS data must be recorded in the context of the HGT-SAN-055 
trial, and a copy of those data can be used for HGT-SAN-067 screening.  Once eligibility is 
confirmed, informed consent (and assent, if applicable), provided by the patient’s 
parent(s)/legally authorized representative(s), must be obtained prior to performing any 
HGT-SAN-067 study-related procedures.  Informed consent may be obtained anytime from 
Week 20 in HGT-SAN-055.  This would allow a patient to have a nonfunctional IDDD replaced 
or revised prior to the first HGT-1410 dose in HGT-SAN-067.
Enrolled patients will check in to the study center 1 day before each of the scheduled HGT-1410 
dosing days for safety assessments (designated Day 1).  If no safety concerns exist, the patient 
will subsequently receive IT administration of HGT-1410 on Day 2 (±2 days).  However, if 
feasible and there are no safety concerns in the opinion of the investigator, the Day 1 and Day 2 
assessments may be combined and performed on Day 2; if this is done the results will be 
recorded as Day 2.  Patients will remain in the study center for at least 4 hours following dosing 
with HGT-1410 and will be discharged from the unit when deemed clinically stable by the 
Investigator.  
All patients will have received a series of standardized neurodevelopment assessments; in the 
HGT-SAN-055 study, these will have occurred at Baseline and either prior to or at the 6-month 
time point.  Patients will continue in HGT-SAN-067 with whichever age specific assessment 
they began with in HGT-SAN-055.  If, however, a patient’s capability improves and they 
become capable of completing assessments at a higher level, such additional assessments may be 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
26
added.  Any additional assessments are to be performed after the original assessments (those 
used in study HGT-SAN-055) have been carried out.  
A MRI of the head will be performed at Months 12, 24, 36, 54, 66 and 78 and ABR testing will 
be performed at Months 12, 24, 36 and 54 (note that assessment time point nomenclature 
includes the 6 months in the HGT-SAN-055 study).
In the event of a device malfunction, X-rays may be performed to investigate, as well as to verify 
correct catheter and port placement following surgical IDDD implantation or revision.  In 
addition, fluoroscopy may be employed intra-operatively to guide catheter placement.  Patients 
may undergo 3 X-ray examinations in association with each episode of IDDD malfunction and 
subsequent IDDD revision or replacement.  The number of IDDD revisions/replacements is 
limited to 2 in any 6-month period (including the time in the HGT-SAN-055 study), and the 
number of protocol-associated X-ray evaluations is limited to 6 exposures in any 6-month period 
(including time in study HGT-SAN-055). If patients are to continue to receive HGT-1410 using 
the IDDD beyond the duration of this study, they will also have X-ray examinations of the 
device performed at the EOS visit, to document correct positioning.
Patients will be evaluated for safety throughout the study.  Adverse events that occur in 
HGT-SAN-055 and are ongoing at enrollment in HGT-SAN-067 will be captured as ongoing in 
the HGT-SAN-055 study and also be reported as a concurrent condition in the HGT-SAN-067 
eCRFs.  Specific safety stopping criteria will be applied and will be based on the types and 
severity of AEs reported while on-study.  These data will be reviewed to inform the decision to 
discontinue a patient, a dose group, or the study as a whole. 
All patients will have an EOS visit 30 (±7) days following their last administration of HGT-1410 
(ie, Month 78).  The EOS procedures will include standard clinical laboratory tests (serum 
chemistry, hematology, and urinalysis) in CSF and blood, protocol specific laboratory testing 
(eg, anti-rhHNS antibody testing), neurodevelopmental testing, child health questionnaires, and 
MRI.  Use of concomitant medications, therapies, and procedures will be recorded and AEs will 
be monitored. 
All patients will be contacted by telephone or will have a visit for a Final Safety Follow-up, 
conducted at 30 (±7) days after the EOS visit (ie, Month 79) to collect updated information on 
AEs and concomitant medications, therapies, and procedures. 
It is anticipated that the IDDD will be used to obtain CSF samples and to administer HGT-1410. 
However, if a patient’s PORT-A-CATH IDDD appears nonfunctional or if its use is precluded 
on a scheduled day of dosing, site personnel will refer to the PORT-A-CATH Instructions for 
Use (IFU), which describes the investigation and management of IDDD-related issues with this 
device. This will include possible partial revision or complete replacement of the PORT-A-
CATH IDDD with a SOPH-A-PORT IDDD. For malfunctions involving the SOPH-A-PORT 
Mini S, site personnel will refer to the SOPH-A-PORT IFU.  For either IDDD, a maximum of 
2 partial revisions and/or complete replacements are permitted in any 6 month period (including 
participation in study HGT-SAN-055). If a revision or replacement of the IDDD cannot be 
scheduled in time to avoid a delay of the next scheduled dose of HGT-1410, or if the patient 
experiences more than 2 IDDD malfunctions in a 6 month period, HGT-1410 will be 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
27
administered via lumbar puncture (LP). If implantation of a replacement IDDD is not possible, 
investigational drug may be administered by LP for a maximum of 12 successive monthly doses.  
At that point, a safety discussion needs to take place between the investigator and the Sponsor to 
determine the risk/benefit of further dosing by LP.
If there is no significant safety risk in the opinion of the Investigator, a non-functional IDDD 
may be left in situ for up to 3 months.
Patients who discontinue or are withdrawn before receiving 3 monthly IT injections will not have 
to undergo the EOS evaluations but will have their IDDD removed.  
If a patient discontinues, or withdraws from the study, or the study is stopped by the Sponsor, the 
IDDD will be removed as part of the EOS Procedures. 
An overview of the study appears in the Schedule of Events (Appendix 1).
4.2
Rationale for Study Design and Control Group
The original study, Study HGT-SAN-055, is an ongoing Phase I/II safety and ascending dose 
ranging study of IT administration of HGT-1410 via an IDDD, in patients 3 years of age and 
older with MPS IIIA and early cognitive impairment.  This extension study is proposed to 
continue evaluation of the effects of IT HGT-1410 administration on long-term safety and 
clinical outcomes for patients who completed Study HGT-SAN-055 and elected to continue 
treatment with HGT-1410 in the HGT-SAN-067 study. 
In order to traverse the blood-brain barrier, Shire is evaluating HGT-1410 delivered directly to 
the CNS using an IDDD. The advantage of using an IDDD is that it obviates the need for 
multiple lumbar punctures for drug delivery. Drug products will be administered through this 
port or, if the IDDD is non functional, via lumbar puncture.
If patients in the study require revision and/or replacement of the PORT-A-CATH IDDD, it will 
be removed and replaced with the SOPH-A-PORT Mini S device at a time judged appropriate by 
the Investigator.
4.3
Study Duration and Dates
The study duration will be 6 years.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
28
5
STUDY POPULATION SELECTION
5.1
Study Population
Patients who have completed all study requirements in Study-HGT-SAN-055 and who elected to 
continue HGT-1410 treatment will be eligible to participate; a maximum of 12 patients are 
planned for this study. 
5.2
Inclusion Criteria
Each patient must meet the following criteria to be considered eligible for enrollment in this 
study.
1. The patient must have completed Study HGT-SAN-055 and, in the opinion of the 
investigator, have no safety or medical issues that contraindicate participation. 
2. The patient, patient’s parent(s) or legally authorized representative(s) has voluntarily signed 
an Institutional Review Board/Independent Ethics Committee-approved informed consent 
(and assent, if applicable) form after all relevant aspects of the study have been explained and 
discussed with them.  Informed consent/assent must be obtained prior to any study specific 
procedures.
3. The patient has received at least 5 of the 6 planned infusions of HGT-1410 in the 
HGT-SAN-055 study. 
4. The patient must be medically stable, in the opinion of the Investigator, to accommodate the 
protocol requirements, including travel, assessments, and IDDD surgery (if necessary for 
replacement purposes), without placing an undue burden on the patient/patient's family.
5.3
Exclusion Criteria
Patients will be excluded from the study if there is evidence of any of the following: 
1. The patient has experienced an adverse reaction to study drug in Study HGT-SAN-055 that 
contraindicates further treatment with HGT-1410.
2. The patient has a known hypersensitivity to the active ingredient or any excipients in 
HGT-1410 drug product.
3. The patient has significant non-MPS IIIA related central nervous system impairment or 
behavioral disturbances that would confound the scientific integrity or interpretation of study 
assessments, as determined by the Investigator.
4. The patient has MPS IIIA behavioral-related issues, as determined by the Investigator, which 
would preclude performance of study neurocognitive and developmental testing procedures.
5. The patient is pregnant, breast feeding, or is of childbearing potential who will not or cannot 
comply with the use of an acceptable method of birth control, such as condoms, barrier 
method, oral contraception, etc.
6. The patient has any known or suspected hypersensitivity to anesthesia or is thought to have 
an unacceptably high risk for anesthesia due to airway compromise or other conditions.
7. The patient has a history of a poorly controlled seizure disorder. 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
29
8. The patient is currently receiving psychotropic or other medications, which in the 
Investigator’s opinion, would be likely to substantially confound test results and the dose and 
regimen of which cannot be kept constant throughout the study.
9. The patient cannot sustain absence of aspirin, non-steroidal medications, or medications that 
affect blood clotting within 1 week prior to a relevant study-related procedure (eg, device 
re-implantation if applicable), or has ingested such medications within 1 week before any 
procedures in which any change in clotting activity would be deleterious.
10. The patient has received treatment with any investigational drug (other than HGT-1410) 
intended as a treatment for MPS IIIA within the 30 days prior to, during the study, or is 
currently enrolled in another study that involves an investigational drug or device (screening 
through safety follow-up contact).
11. The patient has received a hematopoietic stem cell or bone marrow transplant.
For patients to be implanted with the SOPH-A-PORT Mini S IDDD the following conditions are 
contraindicated, as described in the Instructions for Use: 
1. The patient has had, or may have, an allergic reaction to the materials of construction of the 
SOPH-A-PORT Mini S device
2. The patient’s body size is too small to support the size of the SOPH-A-PORT Mini S Access 
Port, as judged by the Investigator 
3. The patient has a known or suspected local or general infection
4. The patient is at risk of abnormal bleeding due to a medical condition or therapy
5. The patient has one or more spinal abnormalities that could complicate safe implantation or 
fixation
6. The patient has a functioning CSF shunt device
7. The patient has shown an intolerance to an implanted device

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
30
6
STUDY TREATMENT(S)
6.1
Description of Treatment(s)
6.1.1
Study Drug
Recombinant human heparan N-sulfatase (HGT-1410 drug product) formulation is a sterile 
solution for injection in single-use vials for IT administration.  It is formulated in an aqueous 
isotonic solution containing 15.0 mg/mL HGT-1410 in 145 mM sodium chloride, 0.02% (v/v) 
polysorbate 20, 5 mM sodium phosphate at pH 7.0.
6.1.2
Intrathecal Drug Delivery Device
The PORT-A-CATH will continue to be used for the administration of drug product for each 
patient until such time as an IDDD replacement may be required. Following implementation of 
protocol Amendment 4, any replacements will be performed using the SOPH-A-PORT Mini S.   
After IDDD replacement the drug product will be administered via the SOPH-A-PORT Mini S 
Implantable Access Port.  The SOPH-A-PORT Mini S device is intended for long-term, 
intermittent access to the IT space for the delivery of investigational drug.
The SOPH-A-PORT Mini S is comprised of the following 7 components:

One SOPH-A-PORT Mini S Access Port

One intrathecal port closed-tip catheter

One guidewire

Two suture wings

One 14-gauge Tuohy needle

One 22-gauge non-coring Huber needle

One Luer lock Connector.
Further details are provided in the Instructions for Use.
6.1.3
Placebo or Control
This study will not employ a placebo or control.  
6.2
Treatment Administered
HGT-1410 for IT administration will be provided by Shire.  HGT-1410 will be administered by 
an IDDD.  Following the review and signing of informed consent (and assent, if applicable), 
eligible patients will initially receive the same dose of HGT-1410 they received in Study HGT-
SAN-055:

Group 1:  HGT-1410 administered by IT injection 10 mg once per month (Q4W) 

Group 2:  HGT-1410 administered by IT injection 45 mg once per month (Q4W)

Group 3:  HGT-1410 administered by IT injection 90 mg once per month (Q4W)

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
31
Patients assigned to Group 1 will have their dose increased to 45 mg once per month (Q4W) at 
the first administration of HGT-1410 following full approval of protocol Amendment 4.
The study drug will be administered through an IDDD.
The initial implantation and revision and/or explantation of the PORT-A-CATH IDDD or 
SOPH-A-PORT Mini S will be performed by pediatric or general neurosurgeons or 
anesthesiologists who have experience in port and catheter implant procedures and 
intrathecal-access procedures. Please refer to the relevant IFU for further details.
Drug administration will be performed in a clinical setting by appropriately trained and skilled 
healthcare providers (nurses or physicians) with knowledge of the patient’s drug regimen and 
experienced in accessing vascular or CNS ports or CNS infusion pumps. Patients and patients’ 
families will not be directly using the device to administer drugs and will have limited direct 
interaction with the device as there is minimal care required during the immediate postoperative 
period as the implant site heals, or at times of drug administration.
6.3
Selection and Timing of Dose for Each Patient
Patients will check into the study center 1 day prior to IT HGT-1410 dosing for safety 
assessments, designated Day 1, on each HGT-1410 treatment week, and if no safety concerns 
exist, will receive IT administration of HGT-1410 on Day 2 (±2 days).  However, if feasible and 
there are no safety concerns in the opinion of the Investigator, the Day 1 and Day 2 assessments 
and dosing may be combined and performed on Day 2; if this is done the results will be recorded 
as Day 2.  Patients will remain in the study center for at least 4 hours following dosing with 
HGT-1410 and will be discharged from the unit when deemed clinically stable by the 
Investigator. 
The IT injections are to be administered every 28 days (±7 days).  If a patient’s IDDD becomes 
nonfunctional, it may be revised (partial or complete) (a maximum of twice in a 6 month period) 
so that the patient can remain on study (see Section 7.12 for details).
6.3.1
Cerebral Spinal Fluid Sample Procedure
CSF samples will be obtained prior to each injection for clinical laboratory evaluation and 
potential biomarker studies.  The IDDD will be used for CSF sampling and a topical anesthetic 
agent may be applied over the skin covering the IDDD reservoir prior to sampling. Site 
personnel should refer to the operations manual for instructions on the use of topical anesthesia 
prior to accessing the IDDD reservoir.
If use of the IDDD is precluded on a scheduled day of dosing, CSF samples may be obtained by 
LP, as described in the IDDD Manual and Section 6.3.2. Intrathecal Administration of 
HGT-1410
A visual examination of both the port and catheter track will be performed before each IT 
injection.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
32
HGT-1410 will be administered using an IDDD.  After appropriate pre-procedure assessments 
are completed, anesthesia cream will be applied to the skin over the port.  Patients may receive 
sedation as necessary to alleviate anxiety and/or to facilitate drug delivery.
Patients will receive HGT-1410 via slow push/injection through an appropriately sized syringe 
(see the Pharmacy Manual).  Replacement of fluid, including drug, to the CSF will be an 
approximate equal volume to that removed.  The patient’s vital signs will be continuously 
monitored.  The patient will also be monitored closely during study drug administration and 
through the next 4 hours for any adverse clinical reactions.  The patient will be encouraged to lie 
down comfortably for 1 to 3 hours post injection, although this may be difficult for the most 
hyperactive patients.
For the Soph-A-Port Mini S, a 22-gauge Huber non-coring needle is to be used for access to the 
implanted port; standard hypodermic needles would damage the septum and may cause leakage. 
If no needle-free connector is present, either a stopcock of the Huber needle infusion set’s clamp 
is to be used to prevent CSF backflow and to mitigate the risk of air entering the system. It is 
possible to use other brands of Huber non-coring needles, provided that their specifications are 
identical to that of the Huber needle supplied by Sophysa in the SOPH-A-PORT Mini S (22G).
The injection date, injection start/stop time, planned dose, injection volume, and flush volume 
will be recorded on the patient’s eCRF.  
In the event of IDDD malfunction, CSF collection and study drug administration may be 
performed via LP (see Section 6.3.2). The investigation and management of a malfunctioning 
IDDD is detailed in the PORT-A-CATH or SOPH-A-PORT IFUs. Partial or complete 
replacement of the IDDD may be necessary (only permitted twice in a 6-month period, including 
the time a patient was in study HGT-SAN-055), and will require scheduling of the appropriate 
procedure.  The definitive diagnosis of the cause of IDDD failure may not be possible until the 
time of exploratory surgery.  Surgery will take place at the earliest convenience, so the patient 
may remain on, or as close as possible to their treatment schedule. 
6.3.2
Administration of HGT-1410 via Lumbar Puncture Guidance Concerning 
Performance of Lumbar Puncture for Study Drug Administration and 
Cerebrospinal Fluid Sample Collection
It is intended that the IDDD will be used to deliver all IT injections of study drug and to obtain 
CSF samples.  If the IDDD appears to be nonfunctional, or if its use is precluded on a scheduled 
day of dosing, site personnel will refer to the IDDD manual (s), which provides details on the 
investigation and management of any IDDD-related issues.  This may include possible partial 
revision or complete replacement of the IDDD as indicated.  If the nonfunctional IDDD is a 
PORT-A-CATH device, then it will be replaced by a SOPH-A-PORT Mini S device. 
If there are medical contra-indication to the re-implantation of a new device, or if the patient so 
desires, repeat monthly lumbar punctures may be considered as an alternative way of delivering 
the study drug and obtaining CSF samples under limited circumstances.  If no safety risks are 
identified by the investigator, up to 12 consecutive lumbar punctures may be performed across 
studies HGT-SAN-055 and HGT-SAN-067.  Once a patient has reached the maximum of 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
33
12 consecutive lumbar punctures, a new IDDD will be re-implanted for subsequent dosing, 
unless, in the opinion of the investigator and medical monitor, assessment of risk/benefit favors 
continued dosing via lumbar puncture.
Continued treatment via repeat lumbar puncture beyond the stipulated 12 consecutive monthly 
doses can be considered only in individual cases of patients where this treatment is very well 
tolerated and the investigator has not identified any safety concerns associated with repeat 
lumbar puncture and repeat sedation/anesthesia.
6.4
Method of Assigning Patients to Treatment Groups
This is an open-label, non-randomized study; all patients enrolled in this study will be treated 
with HGT-1410. Patients will initially receive the same dose of HGT-1410 they received in 
Study HGT-SAN-055. Patients assigned to Group 1 (10 mg once per month [Q4W]) will have 
their dose increased to 45 mg once per month (Q4W) at the first administration of HGT-1410 
following full approval of protocol Amendment 4.
6.5
Blinding
Not applicable; as this trial is not blinded.
6.6
Concomitant Therapy
All non-protocol treatments and procedures that occur from the time of informed consent (and 
assent, if applicable) through the safety follow-up contact are regarded as concomitant and will 
be documented on the appropriate pages of the eCRF.  Concomitant therapy includes 
medications (including Genistein), therapies/interventions administered to patients, and 
medical/surgical procedures performed on the patients. 
Every effort should be made to keep the patient’s symptomatic Sanfilippo syndrome Type A 
treatment constant throughout the study.  However, changes in medications are acceptable if 
necessary according to clinical judgment.  All changes will be recorded on the appropriate eCRF.  
Concomitant medication will be coded using World Health Organization Drug Dictionary 
(WHO-DD).
6.7
Restrictions
6.7.1
Prior Therapy
Prior therapy excluded for this study consists of the following:

Psychotropic or other medications, which in the Investigator’s opinion would be likely to 
substantially confound test results, and the dose and regimen of which cannot be kept 
constant throughout the study.

The patient cannot sustain absence from aspirin, non-steroidal medications, or medications 
that affect blood clotting within 1 week prior to a relevant study related procedure (eg, device 
implantation if applicable) or medications within 1 week before any procedures in which any 
change in clotting activity would be deleterious.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
34

The patient has received any investigational drug or device intended as a treatment for 
MPS IIIA within the 30 days prior to the study other than HGT-1410 or is enrolled in another 
study that involves an investigational drug or device.

Hematopoietic stem cell or bone marrow transplant.
6.7.2
Fluid and Food Intake 
Food and fluid intake are not restricted over the course of the study, with the exception of 
hospital standard pre-anesthesia dietary restrictions.
6.7.3
Patient Activity Restrictions
For patients implanted with the SOPH-A-PORT Mini S please refer to the SOPH-A-PORT Mini 
S IFU for details regarding patient activity restrictions for patients to be implanted with this 
device.
6.8
Treatment Compliance
HGT-1410 is administered under controlled conditions by the Investigator; therefore, full patient 
compliance with study treatment is anticipated in this study. 
6.9
Packaging and Labeling
6.9.1
Drug Product
Drug product will be supplied in a 3 mL clear, colorless glass (Type 1) vial. Each vial holds an 
extractable volume of 1 mL of HGT-1410. The closure is a gray, 13 mm stopper composed of 
butyl rubber with a fluoro resin lamination. The overseal is an aluminium seal with a flip-off, 
plastic, tamper evident cap. 
See the Pharmacy Manual for additional details.
6.9.2
SOPH-A-PORT Mini S Access Port
The SOPH-A-PORT Mini S Access Port is available in one size, individually packaged, with 
other SOPH-A-PORT Mini S components in double peel-off, sterile, pyrogen-free packaging, 
sterilized with Ethylene Oxide.  Instructions for use are also included in the packaging. A 
guidewire is provided in separate double pouch, sterile, pyrogen-free packaging.
Labels are provided on the outer carton, and on both the SOPH-A-PORT Mini S box and 
guidewire/cannula package inside.
6.10
Storage and Accountability
6.10.1
Investigational Product
Drug product should be stored refrigerated (2°C to 8°C); drug product may not be stored beyond 
the expiration date on the vial.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
35
All HGT-1410 study drug delivered to an Investigator will be recorded and accounted for 
throughout the study.  All HGT-1410 study drug must be recorded on a patient-by-patient basis.  
The lot number of the IDDD and the date and time of administration of the study medication will 
be documented on the appropriate eCRF.
All unused study medication and other study materials are to be returned to the Sponsor or its 
designee or disposed of after Sponsor approval per site policy after study completion.
6.10.2
Intrathecal Drug Delivery Device
6.10.2.1
PORT-A-CATH IDDD
Please refer to the operations manual for return instructions.
6.10.2.2
SOPH-A-PORT Mini S IDDD
The disposition of all SOPH-A-PORT Mini S intrathecal drug delivery devices delivered to a 
Principal Investigator must be recorded on a patient-by-patient basis by completing the 
Accountability Log.  The date and time of administration of the investigational product and use 
of the SOPH-A-PORT Mini S device must be documented on the patient’s appropriate eCRF.
The Principal Investigator, Clinical Research Coordinator, or designee (eg, Pharmacist) must 
ensure that all documentation regarding receipt, storage, dispensing, loss/damaged 
SOPH-A-PORT Mini S intrathecal drug delivery devices and return of used/unused intrathecal 
drug delivery devices) is complete, accurate, and ready for review at each monitoring visit and/or 
audit.  The sites must ensure that the SOPH-A-PORT Mini S devices are available for the 
monitor to inventory and prepare for return shipment to the Sponsor or designee, if required.
The SOPH-A-PORT Mini S and its components are sterile, single-use devices.
Please refer to the relevant IDDD Manual for device return instructions.
6.11
Investigational Product Retention at Study Site
All HGT-1410 study drug delivered to an Investigator will be recorded and accounted for 
throughout the study.  All HGT-1410 study drug must be recorded on a patient-by-patient basis.  
The lot number of the IDDD and the date and time of administration of the study medication will 
be documented on the appropriate eCRF.
All unused study medication and other study materials are to be returned to the Sponsor or its 
designee or disposed of after Sponsor approval per site policy after study completion.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
36
7
STUDY PROCEDURES
7.1
Informed Consent
Study procedures will be conducted only after written informed consent for the patient to 
participate in this study is provided by the parent(s) or the patient’s legally authorized 
representative(s) and assent from the patient (if applicable).  Detailed descriptions of patient 
evaluations required for this protocol are described in this section.  These evaluations will be 
performed during the indicated days and weeks of each study month (see Appendix 1 Schedule 
of Events).
All data collected are to be recorded on the appropriate eCRF. Blood, urine and CSF volumes to 
be collected for each clinical laboratory measurement are described in detail in the Laboratory 
Manual.
7.2
Physical Examination
A full physical examination or a symptom-directed physical examination of each patient will be 
performed at time points detailed in Appendix 1 Schedule of Events.
Any changes from the screening physical examination will be captured as AEs in the eCRF.
Note:  if the patient’s hearing cannot be assessed during the physical examination, the patient 
will have an Ears, Nose, and Throat Evaluation performed under anesthesia at the screening/start 
of study visit.  If it is determined that the patient requires pressure-equalization (PE) tubes, they 
may be implanted during that evaluation (see Section 7.9).  Note:  PE tubes may be re-implanted 
if they fall out during this study.
The physical examination findings will be recorded on the eCRF and will include a review of the 
patient’s general appearance as well as the following evaluations:
-
Head and neck
-
Eyes, ears, nose, and throat
-
Chest and lungs
-
Cardiovascular
-
Abdomen
-
Skin
-
Lymphatic
-
Musculoskeletal
-
Neurological
-
Endocrine
-
Genitourinary
7.3
Height and Weight
Height or length (cm), and weight (kg) will be measured once and recorded on the eCRF.
7.4
Head Circumference
Head circumference (cm) will be measured and recorded on the eCRF.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
37
7.5
Vital Signs
Vital signs (blood pressure, heart rate, respiratory rate, and temperature measurements) will be 
measured and recorded on the eCRF.
7.6
Electrocardiography
7.6.1
Electrocardiograms
An ECG will be performed.  Each ECG will include an assessment of heart rate, sinus rhythm, 
atrial or ventricular hypertrophy, PR, QRS, QT, and QTc intervals.  The ECGs will be conducted 
in accordance with the clinical site’s standard practice(s), and will be read locally at the clinical 
site.  Identification of any clinically significant findings and/or conduction abnormalities will be 
recorded on the eCRF. 
7.7
Clinical Laboratory Tests
Blood, urine, and CSF samples will be collected as described below for clinical laboratory 
testing. Procedures for collection and handling of samples are included in the Laboratory 
Manual. The conduct of a clinical trial in an extremely rare disease such as MPS IIIA provides a 
unique opportunity to collect samples for potential biomarker research. In the context of this 
study, a biomarker is defined as a characteristic that is objectively measured and evaluated as an 
indicator of the MPS IIIA pathogenic process, or a pharmacologic response to experimental 
therapy with HGT-1410. In addition to exploration of potential biomarkers, as part of the 
assessment of the SOPH-A-PORT Mini S, it may be necessary to determine the levels of 
leachables from the device into the CSF and blood. 
Patients will be in a seated or supine position during blood collection.  Clinical laboratory tests 
will include hematology, serum chemistry, and urinalysis.
Laboratory Parameters 
Clinical laboratory tests will be performed at a central laboratory.  Clinical laboratory tests will 
include the following:
7.7.1
Hematology

Hematocrit (Hct)

Hemoglobin (Hgb)

Mean corpuscular hemoglobin (MCH)

Mean corpuscular hemoglobin 
concentration (MCHC)

Mean corpuscular volume (MCV)

Platelet count

Red blood cell (RBC) count 

White blood cell (WBC) count with 
differential 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
38
7.7.2
Serum Chemistry

Albumin (ALB)

Alkaline phosphatase (ALK-P)

Alanine aminotransferase (ALT; SGPT)

Aspartate aminotransferase (AST; 
SGOT)

Blood urea nitrogen (BUN)

Calcium (Ca)

Carbon dioxide (CO2)

Chloride (Cl)

Creatinine

Creatine kinase (CK) and subtypes

Gamma-glutamyl transferase (GGT)

Globulin

Glucose

Lactate dehydrogenase (LDH)

Phosphorus

Potassium (K)

Sodium (Na)

Total bilirubin

Direct bilirubin

Total cholesterol

Total protein

Triglycerides

Uric acid

Human Chorionic Gonadotropin 
(βhCG) Pregnancy Test
In addition a leukocyte pellet will be prepared, stored frozen, and will be used for additional 
disease-related laboratory studies, including possible assessment of cross-reactive immunologic 
material (CRIM).
7.7.3
Pregnancy Test
A pregnancy test will be performed on Day 1 of each dosing week.  Pregnancy testing will be 
performed using either a serum or urine sample (at the discretion of the site), and only on 
females who have reached menarche.  All pregnancy testing and the reporting of results will be 
performed locally by the clinical site staff.  Study drug must not be administered in the event of a 
positive or inconclusive pregnancy result. 
7.7.4
Serum Anti-rhHNS Antibody and Sample Storage 
Blood samples will be collected and evaluated at Shire or Shire-designated laboratories for the 
determination of anti-rhHNS antibodies. Samples will be reserved in accordance with local 
regulations for potential future MPS IIIA research that may determine biomarkers of disease 
severity and progression.
Two blood samples will be collected from each patient at each designated time point. One 
sample will be collected in tubes intended for serum specimens, while the second sample will be 
collected in tubes intended for plasma specimens. Blood sample collection, processing, and 
shipping instructions will be provided in the Laboratory Manual.
7.7.5
Urinalysis 
Patient catheterization may be required for obtaining urine samples (if deemed necessary by the 
Investigator).  

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
39
7.7.5.1
Standard Urinalysis
The following urinalysis parameters will be performed at a central laboratory:  pH, macroscopic 
and microscopic evaluations.
7.7.5.2
Urine Glycosaminoglycans 
A urine sample will be collected for the determination of GAG (including heparan sulfate and 
heparan sulfate derivatives) and the analysis will be performed at Shire, or Shire designated 
laboratories. A urine sample from each visit will be reserved for possible exploratory biomarker 
studies that may provide new indicators or markers of MPS IIIA disease severity or progression.
7.7.6
Cerebrospinal Fluid Assessments
Cerebrospinal fluid sample collection, processing, and shipping instructions will be provided in 
the Laboratory Manual. A CSF sample will be reserved for possible exploratory biomarker 
studies for MPS IIIA disease.
Each CSF sample collected will be assessed for appearance and will be analyzed using the assays 
listed in Sections 7.7.6.1, 7.7.6.2, and 7.7.6.4.  In addition, as more is learned about Sanfilippo 
CNS pathology and etiology, future exploratory assays of CSF metabolites, protein or 
ribonucleic acid (RNA) may become used as they become available in the future.
7.7.6.1
Cerebrospinal Fluid Cell Counts
An aliquot of each CSF sample collected will be evaluated for CSF standard chemistries, 
glucose, protein, and cell counts.  These assessments will be performed at the local laboratory.
7.7.6.2
Cerebrospinal Fluid Heparan Sulfate Levels and Heparan Sulfate Derivatives
An aliquot of each CSF sample collected will be quick frozen as per the Laboratory Manual for 
subsequent determination of CSF heparan sulfate and heparan sulfate derivatives at Shire 
designated laboratories.
7.7.6.3
Anti-rhHNS Antibodies
An aliquot of each CSF sample collected will be quick frozen as per the Laboratory Manual for 
subsequent determination of anti-rhHNS antibodies at Shire or Shire designated laboratories.
7.7.6.4
Cerebrospinal Fluid Biomarkers 
An aliquot of each CSF sample collected will be quick frozen as per the Laboratory Manual for 
subsequent determination of MPS exploratory biomarkers at Shire or Shire-designated 
laboratories.
7.7.7
Sample Collection, Storage, and Shipping
Sample collection, processing, and shipping instructions will be provided in the Laboratory 
Manual to be provided by Shire.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
40
CSF, urine, and serum samples may be reserved for potential, future, biomarker studies.  
Samples will be stored securely to ensure patient confidentiality.  
7.8
Anesthesia
Administration of anesthesia/sedation will be given prior to obtaining CSF (when the use of the 
IDDD is precluded), prior to performing a MRI of the head, the ABR, the CSF opening pressure, 
and the partial revision or replacement of the IDDD (if applicable).  
See Appendix 1 for the Schedule of Events. When logistically feasible, the MRI, ABR, and 
surgical implantation of the IDDD may be performed together to reduce exposure to 
general anesthesia.
Note:  The neurologic exam and the neurocognitive and developmental assessments must be 
performed prior to the administration of anesthesia.
7.9
Audiometry and Auditory Brainstem Response
The rare attenuated patients with MPS IIIA with high levels of cognitive functioning will have 
hearing tests via clinical audiometry measurement performed using age-appropriate testing 
methods based on the child’s developmental age at the time of the testing.  It is anticipated that 
most of the cognitively-impaired and/or behaviorally-deteriorated patients with Sanfilippo A will 
be unable to cooperate with a (conscious) hearing evaluation.  In these instances, the Investigator 
will utilize his best clinical judgment to estimate the extent of hearing loss (if any) during the 
physical examination.  In this situation, a specific evaluation of hearing loss will occur during an 
examination of waveforms in the ABR (see below).  If the patient has a history of multiple 
instances of otitis media or evidence of clinically-significant otitis media on physical 
examination, which the Investigator believes causes significant conductive hearing loss and 
impairment of daily living, the Investigator will discuss and offer the parent or legally authorized 
representative(s) placement of PE tubes as part of the scheduled anesthesia.  A patient’s PE tubes 
may be replaced if they fall out during the course of this study.
The ABR will be conducted under anesthesia.  The ABR findings will be considered within 
normal limits if, after applying appropriate correction factors, the waveforms reveal normal 
morphology. 
7.10
Magnetic Resonance Imaging of the Head
The regional brain volume will be assessed through a MRI, of the head.  The patient will be 
under general anesthesia for this assessment.  All MRIs will be centrally read by the University 
of Minnesota Medical Center.  Refer to the Study Operations Manual for specific procedures and 
precautions.
7.11
Device Data

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
41
7.12
Surgical Re-implantation of the IDDD
If a patient’s IDDD becomes nonfunctional or infected, it will be replaced or revised so that the 
patient can remain on study. After full approval of protocol Amendment 4, all IDDD 
replacements will be made with the SOPH-A-PORT IDDD. If the IDDD device is a 
PORT-A-CATH IDDD, it will be replaced by a SOPH-A PORT IDDD. Management details for 
the PORT-A- CATH IDDD or for the SOPH-A PORT IDDD are provided in the respective 
device's IFU. Procedures for implantation are detailed in the relevant device’s Instructions for 
Use Manual and in the training materials provided by Shire. The patient will be under general 
anesthesia for this procedure. Standard hospital procedure for surgery will be followed and will 
include an X-ray to confirm that the device has been (1) surgically implanted correctly, and (2) 
positioned so that the intrathecal catheter tip is at the mid-thoracic level (a check list is provided 
in the IDDD Manual). 
A post-operative check of the IDDD and incision will be performed on Day 4 following surgery.  
X-rays may be performed to check placement of the device, as needed, throughout the study (see 
Section 7.12.1 for limits on the number of x-rays and IDDD revisions and or replacement).
7.12.1
Restrictions on the Number of Revision and/or re-implantation of the IDDD
A non-functional IDDD can be replaced or revised twice in a 6-month period, including the time 
a patient was in study HGT-SAN-055.  Similarly, 6 X-rays may be taken in a 6-month period 
(including the time in HGT-SAN-055).
7.13
Device Related Study Procedures
7.13.1
IDDD Implantation or Revision Procedures
The IDDD will be surgically implanted or revised at the clinical site. Procedures for implantation 
and revision are detailed in the device’s IFU. Standard hospital procedures for surgery will be 
followed; the patient will be under general anesthesia for this procedure.
An additional medical device, the catheter passer, is necessary for the implantation procedure, 
for patients receiving the SOPH-A-PORT Mini S.  The catheter passer is a sterile, single use 
device that will be used in the subcutaneous placement of the catheter.  The Phoenix Neuro 
Disposable Catheter Passer, manufactured by Sophysa is CE marked in the European Union 
(EU) and cleared under K853370 in the United States (US). Other catheter passers that are 
compatible with the SOPH-A-PORT Mini S may be used.
Details of the implantation/revision and malfunctions/failure for the SOPH-A-PORT will be 
documented on the patient’s eCRF.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
42
7.13.2
X-ray Verification of Intrathecal Drug Delivery Device Placement 
A postoperative x-ray check of the IDDD will be performed following surgery to verify proper 
installation and confirmation of IDDD placement at the mid-thoracic level. The x-rays may be 
performed to check placement of the device, as needed, throughout the study. If the patient is to 
receive intrathecal HGT-1410 beyond the end of the study, an X-ray will be performed at the end 
of the study to verify that the IDDD is in the correct position. At a minimum, the date of the 
x-ray verifying correct IDDD placement will be documented on the patient’s eCRF. If the device 
requires revision or replacement during the study, additional x-rays will be taken to document 
proper positioning of the device. If an IDDD malfunctions, an X-ray may be performed to assess 
the potential cause of malfunction. Fluoroscopy may be used during device implant or revision 
procedures.
7.13.3
CSF Sampling Procedure
Cerebrospinal fluid will be sampled via the device. If this is not possible, and if CSF sampling is 
necessary, either for adherence to the protocol, or to investigate clinical concerns, an LP may be 
performed to sample CSF, either with or without administration of drug afterwards. 
7.13.4
Device Removal
If at the time of a scheduled dosing it is not possible to administer a full medication dosage as 
per the standard administration steps detailed in the device’s IFU due to a device-related issue, 
the IDDD will be declared a device malfunction. If the device malfunction is irreversible and 
cannot be corrected without a device surgical intervention, the IDDD will be declared a device 
failure, starting from the date of the initial malfunction. 
The IDDD will then be surgically removed or revised and a new device and/or device 
components will be re-implanted at the earliest possible opportunity, preferably at the same time. 
Patients who have a PORT-A-CATH IDDD device failure will have this device replaced by a 
SOPH-A-PORT Mini S.
Details of the device removal will be recorded in the patient’s eCRF. Refer to the relevant IFU 
for further details.
If the IT space is not accessible via the IDDD, study drug may be administered by LP up to 
5 times.
Patients will have the IDDD removed when they discontinue from the study, unless the patient is 
continuing to receive treatment through another mechanism (eg, extension study, expanded 
access, commercially available).
7.14
Cerebrospinal Fluid Opening Pressure Measurement
A CSF opening pressure measurement (cm of H2O) will be conducted as per standard hospital 
practice.  The measurement will be obtained whenever a LP is performed and an IDDD revision 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
43
or replacement is done. Following implementation of Amendment 6 the CSF opening pressure 
measurement will not be required with the LP.
7.15
Dispensing Study Drug
A visual examination of both the port and catheter track will be performed before each IT 
injection.
HGT-1410 will be administered IT by means of an IDDD (or via LP if necessary) to patients on 
Day 2 (±2 days) of Week 1 of each treatment month. 
The patient may be sedated for this procedure.  HGT-1410 will be administered through an 
appropriately sized syringe (see the Pharmacy Manual).  If the IT space is not accessible via the 
IDDD, HGT-1410 may be administered via LP.  See Section 6.3.2 for details.
For the Soph-A-Port Mini S, a 22-gauge Huber non-coring needle is to be used for access to the 
implanted port; standard hypodermic needles would damage the septum and may cause leakage. 
If no needle-free connector is present, either a stopcock or the Huber needle infusion set’s clamp 
is to be used to prevent CSF backflow and to mitigate the risk of air entering the system. It is 
possible to use other brands of Huber non-coring needles, provided that their specifications are 
identical to that of the Huber needle supplied by Sophysa in the SOPH-A-PORT Mini S (22G).
7.16
Pharmacokinetic Assessments
Pharmacokinetic assessments are not included in this study.
7.17
Neurological Examination
A neurological examination to monitor CNS changes in a patient’s neurological status will be 
conducted during this study.  See Appendix 2 for a complete list of the neurological 
examinations.
The neurological exam should not occur sooner than 4 hours after study drug administration or 
before the patient has fully recovered from any anesthesia administered for the dosing, 
whichever occurs later.
7.18
Neurocognitive and Developmental Assessments
Patients will undergo neurocognitive and neurobehavioral development testing.  The assessments 
are estimated to last between 2 and 4 hours and must be conducted prior to sedation or 
anesthesia. 
A full neurodevelopmental assessment, including global development, cognition, adaptive 
behavior, receptive and expressive language, and gross motor function, will be evaluated using 
standardized developmental and behavioral tests to provide a surrogate and quantifiable measure 
of global CNS neurodevelopmental/neurobehavioral function. 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
44
All patients will have received a series of standardized neurodevelopment assessments; in the 
HGT-SAN-055 study, patients in HGT-SAN-067 will continue with the age specific assessment 
they began with in HGT-SAN-055.  If, however, a patient’s capability improves and they 
become capable of completing assessments at a higher level, any such additional assessments 
may be added.  Any additional assessments would be performed after the original assessments 
have been carried out.  
For this study, outcome measures will be computed for each patient enrolled.  The psychometric 
instruments and Sanfilippo-specific assessments are summarized below in Table 7-1 and 
Table 7-2, respectively.  See Appendix 2 for details on these assessments.
Table 7-1
Neurodevelopmental Assessments Tests 
Developmental or Cognitive 
Domain(s)
Patient Age:  Representative Cognitive Test or 
Scale
COGNITIVE DEVELOPMENT ASSESSMENT
Summary score and sub-domains:
- Cognitive
- Motor
- Social/emotional
0 to 42 months:  Bayley Scales of Infant Development-III 
Bayley Scales of Infant Development, Third Edition 
(BSID-III)23
- Cognitive 
- Processing skills
3 to 18 years:  Kaufman Assessment Battery for Children, 
Second Edition (KABC-II)24  
GROSS AND FINE MOTOR SKILLS ASSESSMENT AND VOLUNTARY MOVEMENT
Motor
3.0 to 16:11 years:  Movement Assessment Battery for 
Children II (MABC-2)25
- Cognitive
- Motor
0 to 5 ½ years:  Bayley Scales of Infant Development III 
(BSID-III)23
ADAPTIVE BEHAVIOR
Communication
Daily Living
Socialization
Motor Skills
0 to 90 years:  Vineland Adaptive Behavior Scales (VABS-II)  
Second Edition26
Table 7-2
Sanfilippo-Specific Disability Assessment And Behavior Rating Scales
DEVELOPMENTAL OR COGNITIVE 
DOMAIN(S)
SANFILIPPO SPECIFIC ASSESSMENTS
Parent-scored behavioral inventory
- communication:  understanding
- communication:  expression
- tantrums
- specific behaviors inventory
- mood & emotions inventory
Sanfilippo Behavior Rating Scale (SBRS)
MPS-specific disability score 
- cognitive functioning
- expressive language
- motor score
Four-Point Scoring System/Total Disability Score 
(FPSS/TDS)5

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
45
7.19
Sleep Questionnaire:  Children’s Sleep Habits Rating Scale 
A sleep questionnaire, Children’s Sleep Habits Rating Scale, will be administered to the patient's 
parent(s)/legally authorized representative(s).
7.20
Age-Dependent, Health-Related Quality of Life in Children
The Quality of Life questionnaires will be administered as outlined in Sections 7.20.1, 7.20.2, 
and 7.20.3.
7.20.1
Quality of Life Indicator:  CHQ-50
The Child Health Questionnaire™ Parent Form 50 Questions (CHQ-50) will be administered 
during the study.  The questionnaire is a generic quality of life instrument, measuring 14 unique 
physical and psychosocial concepts, which was developed for children from 5 to 18 years of age.
7.20.2
Quality of Life Indicator:  CHQ-87
The Child Health Questionnaire™ Child Form 87 (CHQ-87) will be administered during the 
study.  The CHQ-87 is a child and adolescent self-report, developed for ages 10 and older, which 
assesses the child’s self-perceived physical and psychosocial well-being.
7.20.3
Quality of Life Indicator:  ITQOL
The Infant Toddler Quality of Life Questionnaire™ (ITQOL) will be administered during the 
study.  The ITQOL was developed for children at least 2 months of age up to 5 years and 
assesses the physical, mental, and social well being of the child and assesses the quality of the 
parent/legally authorized representative(s) life.  
7.21
Concomitant Medications, Therapies and Medical/Surgical Procedures
All non-protocol treatments that occur from the time of informed consent (and assent, if 
applicable) through the safety follow-up contact are regarded as concomitant and will be 
documented on the appropriate pages of the eCRF.  Concomitant therapy includes medication 
(including Genistein), therapies/interventions administered to patients, and medical/surgical 
procedures performed on the patients.
Every effort should be made to keep symptomatic Sanfilippo syndrome Type A treatment 
constant throughout the study.  However, changes in medications are acceptable if necessary 
according to clinical judgment.  All changes will be recorded on the appropriate eCRF.  
Concomitant medication will be coded using WHO-DD.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
46
7.22
Adverse Events
7.22.1
Definitions of Adverse Events and Serious Adverse Events
7.22.1.1
Adverse Event
An AE is any noxious, pathologic, or unintended change in anatomical, physiologic, or 
metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in 
any phase of a clinical study, whether or not considered study drug-related.  This includes an 
exacerbation of a pre-existing condition.  Once the informed consent is signed and dated, any 
adverse event prior to the start of study drug must be reported. 
AEs include:

Worsening (change in nature, severity, or frequency) of conditions present at the onset of the 
study

Intercurrent illnesses

Drug interactions

Events related to or possibly related to concomitant medications

Abnormal laboratory values (this includes significant shifts from baseline  within the range 
of normal that the Investigator considers to be clinically important)

Clinically significant abnormalities in physical examination, vital signs, and weight
Throughout the study, the Investigator must record all AEs on the AE eCRF, regardless of the 
severity or relationship to study drug.  The Investigator should treat patients with AEs 
appropriately and observe them at suitable intervals until the events stabilize or resolve.  AEs 
may be discovered through observation or examination of the patient, questioning of the patient, 
complaint by the patient, or by abnormal clinical laboratory values.
In addition, AEs may also include laboratory values that become significantly out of range.  In 
the event of an out-of-range value, the laboratory test should be repeated until it returns to 
normal or can be explained and the patient’s safety is not at risk.  
All AEs should be recorded with causality assessment.
The information presented below is intended to provide issues to consider for AEs associated 
with intrathecal injections of HGT-1410.  In general, these AEs can be classified as follows: 

Adverse events due to systemic exposure to HGT-1410 caused by the drug diffusion from the 
CSF to the peripheral circulation; 

Adverse events related to the direct delivery of HGT-1410 to the intrathecal CSF space and 
meninges, and subsequent diffusion into brain parenchyma, via an intrathecal route 

IDDD–related AEs  
Note:  the classification of potential AEs and the examples presented below are based on purely 
theoretical considerations and/or published literature as there is limited human experience with 
intrathecal HGT-1410 therapy to date.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
47
7.22.1.2
Potential Adverse Events:  Intrathecal recombinant human heparan 
N-sulfatase 
ADVERSE EVENTS RELATED TO THE DIRECT DELIVERY OF HGT-1410 TO THE CNS THROUGH 
INTRATHECAL ADMINISTRATION
Examples of AEs observed in other published clinical trials with intrathecally-administered 
peptides or proteins, include, but are not limited to the following:  headache, fever, feeling of 
warmth, sensory paresthesias (including feelings of warmth, tingling, or pain) or autonomic 
symptoms such as dry mouth or gustatory abnormalities (including loss of smell and metallic 
taste).  Changes in mental cognitive status or level of consciousness that are not caused by 
pre-medication may either occur acutely or develop post-injection, over time
ADVERSE EVENTS DUE TO SYSTEMIC EXPOSURE TO HGT-1410
Although HGT-1410 is given intrathecally only, some proportion of the drug will diffuse from 
the CSF into the peripheral circulation.  The resulting systemic exposure may cause events that 
are typically seen in patients receiving ERT via an intravenous administration, known as 
infusion-related reactions.  An infusion-related reaction is defined as an adverse event that 
(1) begins either during or within 24 hours after the start of the infusion, and (2) is judged as 
possibly or probably related to study drug.  Other AEs that occur prior to the infusion, along with 
AEs associated with protocol-defined testing and assessments (laboratory testing and physical 
examinations) that were performed prior to the infusion will not be defined as infusion-related 
reactions.
7.22.1.3
IDDD-related Adverse Events 
IDDD ADVERSE EVENTS
Examples of AEs related to use of the IDDD include, but are not limited to, the following: device 
failure, device malfunction, incorrect connection of IDDD components, erosion of the 
portal/catheter through the skin, fibrin sheath formation around the catheter tip, hematoma, 
implant rejection, migration of the portal/catheter, occlusion of the portal/catheter, portal site, or 
subcutaneous tract infection. The device may also need to be replaced or repaired as needed. A 
malfunction of the device (defined in Section 7.22.2.2) should not be entered as an AE unless it 
has physiological consequences.  In the event of a device failure (defined in Section7.22.2.3), the 
device may need to be replaced or repaired. Hospitalization for such a procedure will be reported 
as a serious adverse event (SAE).  Details of the cause of IDDD malfunction or failure will be 
recorded on the Device Malfunction/Failure CRF.  A list of the more common IDDD AEs is 
included in Appendix 3.
DEVICE SURGICAL PROCEDURE-RELATED ADVERSE EVENTS
Examples of AEs related to device surgical procedures include, but are not limited to, the 
following: events that occur during or following IDDD implant/explant, IDDD adjustment, full 
revision, partial revision, IDDD removal, and delayed re-implantation after previous IDDD 
removal (such as complications of anesthesia, excessive bleeding, wound hematoma) and post 
operative complications (such as post-operative infection).

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
48
IT ADMINISTRATION PROCESS ADVERSE EVENTS 
Intrathecal administration process AEs include those caused by anesthesia during drug 
administration, drug administration issues (eg, extravasation during infusion or hematoma due to 
Huber needle) or complications of lumbar puncture.
7.22.1.4
Serious Adverse Event
1. An SAE is any AE occurring at any dose of investigational drug or at any procedure that 
results in any of the following outcomes:

Death

Is life-threatening

Requires inpatient hospitalization

Requires prolongation of existing hospitalization

A persistent or significant disability or incapacity 

A congenital anomaly or birth defect
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization. Hospitalizations, which are the 
result of elective or previously scheduled surgery for pre-existing conditions, which have not 
worsened after initiation of treatment, should not be classified as SAEs. For example, an 
admission for a previously scheduled ventral hernia repair would not be classified as an SAE; 
however, complication(s) resulting from a hospitalization for an elective or previously scheduled 
surgery that meet(s) serious criteria must be reported as SAE(s). Furthermore, this does not 
apply to device failures resulting in scheduled surgical revisions, which should be reported as 
SAEs.”
2.  Unanticipated Adverse Device Effect (UADE) - Any serious adverse effect on health or 
safety or any life-threatening problem or death caused by, or associated with, a device, if that 
effect, problem, or death was not previously identified in nature, severity, or degree of incidence 
in the investigational plan or application (including a supplementary plan or application), or any 
other unanticipated serious problem associated with a device that relates to the rights, safety, or 
welfare of patients. (21CFR812.3[s] or other regulatory requirements, as applicable).
7.22.2
Device-Associated Definitions
7.22.2.1
Device Revision (Partial and Full)
Partial device revision: surgical revision/replacement of one or more component(s) of the device; 
other component(s) of the original device remain implanted and are not affected (eg, port 
revision).

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
49
Full device revision: the device is removed (explanted) in its entirety and a completely new 
device is implanted.
7.22.2.2
Device Malfunction
The device does not perform as intended, based on the description in the device’s IFU, but does 
not require either a partial or full device revision.
7.22.2.3
Device Failure
The device irreversibly fails to perform as intended and requires either a partial or full device 
revision or removal.
7.22.3
Classification of Adverse Events and Serious Adverse Events
The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
version 3.0 grading scale should be referenced when assessing the severity of an AE (see 
Appendix 6).  If an AE is not described in the NCI CTC, the severity should be recorded based 
on the scale provided in Table 7-3. The severity of all AEs/SAEs should be recorded on the 
appropriate eCRF page. Adverse events are graded as Grade 1, 2, 3, 4, or 5 corresponding, 
respectively, to a severity of mild, moderate, severe, life-threatening, or death. 
Table 7-3
Adverse Event Severity
Severity
Definition
Grade 1 (Mild)
No limitation of usual activities.
Grade 2 (Moderate)
Some limitation of usual activities.
Grade 3 (Severe)
Inability to carry out usual activities.
Grade 4 (Life-threatening)
Immediate risk of death.
Grade 5 (Death related to an AE)
Death

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
50
7.22.4
Relatedness of Adverse Events and Serious Adverse Events
Relationship of an AE or SAE to investigational product, device, device surgical procedure, or 
IT administration process is to be determined by the Investigator based on the definitions in 
Table 7-4:
Table 7-4
Adverse Event Relatedness
Relationship to Product(s)
Definition
Not Related
Unrelated to study drug, device, device surgical procedure, or IT 
administration process.
Possibly Related
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of study drug, device, device surgical 
procedure, or IT administration process but which could also be 
explained by concurrent disease or other drugs or chemicals.
Probably Related
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of study drug, device, device surgical 
procedure, or IT administration process unlikely to be attributable to 
concurrent disease or other drugs and chemicals and which follows a 
clinically reasonable response on de-challenge.  The association of the 
clinical event or laboratory abnormality must also have some biologic 
plausibility, at least on theoretical grounds.
Definitely Related
The event follows a reasonable temporal sequence from administration 
of the medication,  device, device surgical procedure, or IT 
administration process follows a known or suspected response pattern 
to the medication, is confirmed by improvement upon stopping the 
medication (dechallenge) and reappears upon repeated exposure 
(rechallenge).  
Note that this is not to be construed as requiring re-exposure of the 
patient to study drug; however, the determination of definitely related 
can only be used when recurrence of event is observed.
7.22.5
Procedures for Recording and Reporting Adverse Events
7.22.5.1
Reporting Serious Adverse Events Related to Study Procedures
Any SAE regardless of relationship to investigational product, device, device surgical procedure, 
or IT administration process that occurs in a patient after informed consent (and assent if 
applicable) should be recorded by the clinical site on an SAE form that is to be transmitted to the 
Shire Medical Monitor and to the Shire Pharmacovigilance and Risk Management Department at 
the contact number provided below.  The SAE must be completely described on the patient’s 
eCRF, including the judgment of the Investigator as to the relationship of the SAE to the 
investigational product and or device.  The Investigator will promptly supply all information 
identified and requested by the Sponsor (and/or contract research organization [CRO]) regarding 
the SAE as to the relationship of the SAE to study drug, device, or procedure. 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
51
The Investigator must report the SAE to the Shire Pharmacovigilance and Risk Management 
Department AND to the Shire Medical Monitor on an SAE form.  The SAE form must be 
completed and FAXED or scanned and EMAILED (PDF sent by e-mail) within 24 hours of the 
Investigator’s learning of the event to: 
Any follow-up information must also be completed on an SAE form and faxed or scanned to the 
same numbers or e-mail address listed above.
In the event of a severe and unexpected, fatal, or life-threatening SAE, the clinical site must 
contact the Shire Medical Monitor by telephone; this is in addition to completing and 
transmitting the SAE form as stated above.  The following provides contact information for the 
Shire Medical Monitor.
If an SAE is assessed as severe and unexpected, or life-threatening, contact:
  MD, PhD 
Shire Human Genetic Therapies, Inc.
300 Shire Way
Lexington, MA  02421,  United States
Telephone: 
Fax: 
(United States)
Mobile: 
 (24-hour access)
Shire Pharmacovigilance and Risk Management Department:
International FAX: 
United Kingdom OR 
United States FAX: 
Email: 
AND
Shire HGT Medical Monitor:
FAX: 
(United States)
The Investigator may also call the Medical Monitor directly (optional):
Shire HGT Medical Monitor: 
,  MD, PhD
Shire HGT
Work:
Cell:
(24 hour access)
Email: 
AND
Clinical Project Manager CC’d: 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
52
The Investigator must promptly report all required information to the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC).  It is the responsibility of the Sponsor to ensure that 
each Investigator receives a copy of any CIOMS I/MedWatch report that has been submitted to 
the appropriate regulatory agencies notifying them of an unexpected related SAE.  The 
Investigator or Sponsor must ensure that the IRB/IEC receives a copy of the report and that a 
copy is also filed within their study files.  In addition, the Sponsor will also notify the 
Investigators and IRBs/IECs of all deaths that occur during the study, irrespective of relationship 
to study medication
7.22.5.2
Eliciting Adverse Events
Patients should be asked non-leading questions (eg, “How do you feel?”) and further questions 
should be posed if there is indication of an AE.  The questioning should be conducted with due 
regard for objectivity and, in particular, the questioner should gather information regarding AEs 
from questioning the patient, the patient’s parent/guardian, spontaneous report by the patient or 
parent/guardian, laboratory reports, and any health care provider’s observations.
The onset date, resolution date, treatment administered, and outcome of each AE must be 
recorded on the appropriate eCRF. The relationship of each AE to study medication must be 
recorded. In addition AEs may be considered to be related to the IDDD, the IDDD surgical 
procedure, or the IT administration process. Since the AE may be deemed to be related to more 
than one of these factors, as many of these IDDD-related options as apply should be indicated on 
the eCRF.
7.22.5.3
Protocol Deviations for Medical Emergency or Adverse Event
During and following a patient’s participation in the study, the Investigator should ensure that 
adequate medical care is provided to a patient for any AEs, including clinically significant 
laboratory test results.  
The Investigator should inform the patient, the patient’s parent(s), or the patient’s legally 
authorized representative when medical care is needed for intercurrent illness(es) of which the 
Investigator becomes aware.  In an emergency situation, the Investigator should contact the Shire 
Medical Monitor (see Section 7.22.5.1).
Only when an emergency occurs that requires an immediate deviation from the protocol for the 
safety of a patient, will there be such a deviation and this will be only for that patient.  
The Investigator or other physician in attendance in such an emergency must contact the Shire 
Medical Monitor as soon as possible.  
The Investigator, along with the Shire Medical Monitor, will make a decision as to whether or 
not the patient should continue in the study prior to the next scheduled dose.  The departure from 
the protocol and the grounds for it should be stated in the eCRF.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
53
7.23
Abuse, Overdose and Medication Errors
Abuse, misuse, overdose or medication error must be reported to the Sponsor according to the 
SAE reporting procedure whether or not they result in an AE/SAE as described in Section 7.22.

Abuse – Persistent or sporadic intentional intake of investigational medicinal product at a 
dose higher than prescribed per protocol (but below the dose defined for overdose) or when 
used for non-medical purpose (eg, altering one’s state of consciousness)

Misuse – Intentional or unintentional use of investigational medicinal product other than as 
directed or indicated at any dose, which is at or below the dose defined for overdose (Note: 
This includes a situation where the test article is not used as directed at the dose prescribed 
by the protocol)

Overdose – Overdosage with adverse clinical consequences is not anticipated with the use of 
HGT-1410. Additionally, HGT-1410 will be given in a clinical setting by a health care 
provider. 

Medication Error – A mistake made in prescribing, dispensing, administration and/or use of 
the investigational medicinal product.
7.24
Safety-related Study Stopping Rules
If any patient experiences a life-threatening (Grade 4) adverse event or death which is considered 
by the sponsor to be possibly, probably, or definitely related to study drug or the IDDD, or if 
2 or more patients experience a Grade 3 adverse event during the trial that is considered by the 
sponsor to be possibly, probably, or definitely related to the study drug or the IDDD, then the 
site will be instructed to halt further HGT-1410 administration to all patients and the safety data 
reviewed. Following a review of safety data, the study will be either:

Resumed unchanged

Resumed with modifications to the protocol or

Terminated
Patient safety will be monitored on a continuous basis during this study until the last patient 
completes his or her last scheduled study visit/assessment.  
7.25
Pregnancy
Pregnancy and breast feeding are exclusion criteria.  Only female patients who have 
reached menarche will be tested for pregnancy in HGT-SAN-067.  If applicable, this will occur 
at study start and before each dose of HGT-1410 throughout the study.  Pregnancy testing will be 
performed on a blood or urine sample.  Patients with a positive or inconclusive result will not be 
eligible for this study.
At study start, a pregnancy test will be performed if more than 30 days have passed since the 
initial screening sample.  Throughout the study pregnancy testing will occur prior to each dose of 
HGT-1410.  The clinical site’s local laboratory will analyze and report all pregnancy testing 
results.  If a pregnancy test is positive the patient will be discontinued from the study, and the 
Investigator must contact the Shire Medical Monitor. 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
54
Pregnancy is not to be reported as an AE; the Pregnancy Reporting Form, found in the Study 
Operations Manual along with instructions for completion, should be used to report the 
pregnancy.  The pregnancy will be followed up through delivery or final outcome.
7.26
Removal of Patients from the Trial or Study Drug
The patient's parent or legally authorized representative acting on behalf of the patient is free to 
withdraw consent and discontinue participation in the study at any time without prejudice to 
further treatment.  Since this is an extension trial, there will be no replacement of patients who 
discontinue the study for any reason.
A patient’s participation in the study may be discontinued at any time at the discretion of the 
Investigator, Sponsor, or Medical Monitor.  The following may be justifiable reasons for the 
Investigator, Sponsor, or Medical Monitor to remove a patient from the study:

Adverse Event:  If a patient experiences an AE which, in the judgment of the investigator, the 
sponsor, or the medical monitor, presents an unacceptable consequence or risk to the patient.

Adverse Laboratory Experience:  If a patient has an adverse laboratory experience which, in 
the judgment of the investigator, the Sponsor, or the medical monitor, presents an 
unacceptable consequence or risk to the patient, the patient may be withdrawn from the 
study.

Comorbidity:  If a patient develops comorbidity during the course of the study that is 
independent of the study indication, and treatment is required that is not consistent with 
protocol requirements. 

Intercurrent Illness:  If a patient develops an illness during the course of the study that is not 
associated with the condition under study, and which requires treatment that is not consistent 
with protocol requirements.

Refusal of Treatment:  If the patient, the patient’s parent(s) or legally authorized 
representative(s) discontinues participation in the study, or the patient is discontinued by the 
Investigator, reasonable efforts will be made to follow the patient through the end of study 
assessments.  The reason for refusal will be documented on the eCRF.  

Withdrawal of Informed Consent:  A patient’s parent or legally authorized representative 
may withdraw his informed consent to participate in the study at any time.

Cerebrospinal fluid leukocyte count >100 cells per cubic millimeter for 2 consecutive 
months.

New onset seizure.

Anaphylactic reaction beyond reasonable management as described in the Investigator’s 
Brochure.

Clinically problematic intubations or extubations, which may preclude safe airway 
management and anesthesia.

Development of refractory spinal fluid leakage. 

Clinically significant prolonged (eg, greater than 24 to 48 hours) worsening in mental status, 
including development of new focal or non-focal neurological symptoms, or recurrence of a 
previously stable prior medical problem judged due to study drug or participation that is 
exclusive of effects from anesthesia.

Non-compliance, including failure to appear at 1 or more study visits.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
55

The patient was erroneously included in the study.

The patient develops an exclusion criterion.

The study is terminated by the Sponsor.

The patient becomes pregnant during the trial.
If a patient discontinues the study the Patient Completion/Discontinuation eCRF describing the 
reason for discontinuation must be completed.  Any AE’s experienced up to the point of 
discontinuation must be documented on the AE eCRF.  
If AEs are present when the patient withdraws from the study, the patient will be re-evaluated 
within 30 days of withdrawal.  All ongoing SAEs at the time of withdrawal will be followed until 
resolution.
At the time of discontinuation or withdrawal, patients will be asked to participate in all safety 
and efficacy evaluations required for the end of study visit and for the safety follow-up visit.  
Participation in these EOS procedures will be strongly encouraged, but is voluntary for those 
patients electing to discontinue from the study.  The patient will be scheduled for the removal of 
the IDDD. 
7.27
Other Study Procedures
This section is not applicable.
7.28
Appropriateness of Measurements
The neurocognitive and developmental assessments are intended to gauge which domains can be 
accurately measured, with which specific tools, despite the considerable behavioral and cognitive 
challenges in Sanfilippo syndrome.  The evaluation of these domains and the analysis of CSF, 
serum, and urine biomarkers may provide the pivotal data necessary to inform the clinical 
assessments and biomarkers used in possible future Sanfilippo syndrome ERT trials.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
56
8
STUDY ACTIVITIES
Patients who participated in Study HGT-SAN-055 through Week 26 and completed the EOS 
evaluations may be eligible for enrollment in this open-label extension study.  Informed consent 
(and assent, if applicable) must be obtained prior to performing any study related procedures that 
are specific to HGT-SAN-067.  Informed consent may be obtained anytime from Week 20 in 
HGT-SAN-055.  This would allow a patient to have a nonfunctional IDDD replaced or revised 
prior to the first HGT-1410 dose in HGT-SAN-067.
8.1
Screening Visit/Study Start Visit 
All Screening assessments for this study are to have been performed during the Week 26 EOS 
procedures in HGT-SAN-055 (ie, 30 [±7] days after the last HGT-1410 administration).  If less 
than 60 days have elapsed since completion of the EOS assessments for HGT-SAN-055, and the 
start of HGT-SAN-067, the assessments detailed in this Screening visit do not need to be 
repeated.  The Baseline visit for this study will be the first day the patient received their first 
dose of HGT-1410 in the HGT-SAN-055 Study.  
If more than 60 days have elapsed following the HGT-SAN-055 EOS procedures, patients will 
be evaluated for enrollment in HGT-SAN-067 on a case-by-case basis by the Investigator.  A 
decision about enrollment will be made following discussion with the Medical Monitor.  If the 
patient is enrolled, the following assessments are to be repeated within 30 days prior to the first 
scheduled intrathecal HGT-1410 dose:

Physical examination

Height and weight

Head circumference

ECG

Vital signs

Hematology 

Leukocyte pellet preparation to be used for additional disease-related laboratory studies, 
including possible assessment of cross-reactive immunologic material (if this is not collected 
at baseline, it can be collected at any subsequent pre-dosing time point)

Serum chemistry 

Pregnancy testing (for post menarche premenopausal females only)

Urinalysis 

Urine GAG, including heparan sulfate and heparan sulfate derivatives

Plasma collection for biomarkers

Anti-rhHNS antibody testing (serum and CSF)

General anesthesia:  administration of anesthesia will be given prior to the following 
assessments:

ABR

MRI of the head

Neurological examination (performed prior to the administration of anesthesia)

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
57

Full Neurodevelopmental assessments, including Vineland Adaptive Behavior Scales, 
Second Edition (VABS-II; all assessments performed prior to the administration of 
anesthesia)

CSF sample collection (chemistry, cell count, heparan sulfate and heparan sulfate derivatives, 
and other MPS exploratory biomarkers) via the IDDD

Children’s Sleep Habits Rating Scale 

CHQ-50

CHQ-87

ITQOL

Concomitant medications, therapies, and procedures

AE assessments
8.2
Treatment:  Drug Administration and Weekly Assessments
Patients will receive HGT-1410 IDDD monthly (Q4W), on Day 2 (±2 days), Week 1.  
Patient assessments for safety, biochemical, and neurological baseline measures (Day 1, Week 1) 
will occur on the day before the first IT injection.  Note:  Day 1 assessments may be performed 
on the same day as the administration of study drug (Day 2).  This can occur if it is feasible for 
the patient to arrive at the study site early in the day, and if it is deemed clinically appropriate by 
the Investigator.  If the procedures on Day 1 and Day 2 are combined in this way, the 
assessments will be recorded as occurring on Day 2.
CSF samples will be obtained from these patients on Day 2, immediately prior to the first IT 
study drug injection.  
8.2.1
Week 1 
8.2.1.1
Day 1 (Pre-treatment) Assessments Performed Prior to Each Dose

Physical examination

Height and weight

Vital signs

Hematology (after Month 54 frequency reduced to Q3 Months)

Serum chemistry (after Month 54 frequency reduced to Q3 Months)

Urinalysis (after Month 54 frequency reduced to Q3 Months)

Pregnancy testing (applicable females only)

Neurological examination (performed prior to the administration of anesthesia and the 
HGT-1410 IT injection)

Concomitant medications, therapies, and procedures

AE assessments

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
58
Note: If the HGT-SAN-055 EOS (or HGT-SAN-067 Screening) assessments were performed 
within 7 days of first intrathecal HGT-1410 treatment in this study, the pre-treatment 
assessments described in this section do not need to be completed prior to the first treatment in 
study HGT-SAN-067.
DAY 1 (PRE-TREATMENT) ADDITIONAL ASSESSMENTS PERFORMED AT MONTHS 12, 24, 36, 54,
66, AND 78

Head circumference

Visual and hearing assessments 

Urine GAG, including heparan sulfate and heparan sulfate derivatives (also performed at 
Month 60 and Month 72, ie, Q6 Months following Month 54)

Plasma collection for biomarkers

Anti-rhHNS antibody testing (also performed at Month 60 and Month 72,  ie, Q6 Months 
following Month 54)

ABR (not performed after Month 54, ie not on Month 66 or 78)

MRI of the head 

Full neurodevelopmental testing, including VABS-II (performed prior to the administration 
of anesthesia and the HGT-1410 IT injection)

Children’s Sleep Habits Rating Scale 

Child health questionnaire-50 

Child health questionnaire-87 

Infant toddler QoL Questionnaire 
8.2.1.2
Day 2 (±2 days) Assessments and Administration of HGT-1410
Patients may be discharged from the clinical site 4 hours after dosing, if deemed stable by the 
Investigator.

Physical examination (after Month 54 the full physical examination will be performed at 
Months 54, 66, and 78. The remainder of the physical examinations will be symptom-
directed)

ECG (performed following IT study drug injection)(after Month 54 performed Q3 months)

Vital signs

CSF sample collection (obtained prior to IT study drug injection)

HGT-1410 IT injection (Day 2 ±2 days)

Neurological examination 

Concomitant medications, therapies, and procedures

AE assessments
The neurological exam should not occur sooner than 4 hours after study drug administration or 
before the patient has fully recovered from any anesthesia administered for the dosing, 
whichever occurs later.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
59
8.3
End of Study/Early Termination Procedures:  Month 79
Patients who complete the study or who discontinue prior to the end of the study, will have EOS 
assessments performed 30 (±7 days) after their last dose of HGT-1410.  
Patients who discontinue or are withdrawn prior to study completion will be asked to participate 
in the EOS procedures at the time of discontinuation.  Participation in these EOS procedures will 
be strongly encouraged, but is voluntary for those patients electing to discontinue from the study.  
Note:  Patients will have the IDDD removed when they discontinue from the study, unless the 
patient is continuing to receive treatment through another mechanism (eg, expanded access, 
commercially available).

Physical examination

Height and weight

Head circumference

Visual and hearing assessment

ECG

Vital signs

Hematology

Serum chemistries

Urinalysis

Urine GAG, including heparan sulfate and heparan sulfate derivatives 

Anti-rhHNS antibody testing (serum and CSF)

MRI of the head (unless performed at Month 78)

CSF sample collection (unless performed at Month 78)

Neurological examination

Full neurodevelopmental testing, including VABS-II 

Children’s Sleep Habits Rating Scale 

CHQ-50 

CHQ-87 

Infant toddler QoL Questionnaire 

Concomitant medications, therapies, and procedures

AE assessments
All patients who discontinue the study early will have their IDDD removed.  
Patients who withdraw or discontinue after having received fewer than 3 IT injections will not 
need to complete the EOS visit.  
Patients who withdraw or discontinue from the study after having received 3 or more IT 
injections, will be asked to complete the EOS visit and undergo all the scheduled assessments.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
60
8.4
Safety Follow-up (by Telephone or Visit) Month 80
Patients who complete the study or withdraw early will have a safety follow-up telephone call or 
visit 30 Days (±7 days) after the last study visit.  This will assess:

Concomitant medications, therapies, and procedures

AE assessments

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
61
9
QUALITY CONTROL AND ASSURANCE
Training will occur at an investigator meeting or at the site initiation visit or both, and instruction 
manuals (eg, laboratory manuals and pharmacy manuals) will be provided to aid consistency in 
data collection and reporting across sites.
Clinical sites will be monitored by Shire or its designee to ensure the accuracy of data against 
source documents.  The required data will be captured in a validated clinical data management 
system that is compliant with the Food and Drug Administration (FDA) 21 Code of Federal 
Regulations (CFR) Part 11 Guidance.  The clinical trial database will include an audit trail to 
document any evidence of data processing or activity on each data field by each user.  Users will 
be trained and given restricted access, based on their role in the study, through a password 
protected environment.  
Data entered in the system will be reviewed manually for validity and completeness against the 
source documents by a clinical monitor from Shire or its designee.  If necessary, the study site 
will be contacted for corrections or clarifications; all missing data will be accounted for.
SAE information captured in the clinical trial database will be reconciled with the information 
captured in the Pharmacovigilance database.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
62
10
PLANNED STATISTICAL METHODS
10.1
General Statistical Methodology
This is an open-label extension of study HGT-SAN-055 to evaluate the long-term safety and 
clinical outcomes of intrathecal administration of HGT-1410 in patients with MPS IIIA.  The 
statistical methodology supporting the trial will focus on descriptive rather than inferential 
approaches, given the early phase and objectives of this trial. 
Data will be summarized by dose group (10 mg, 45 mg, and 90 mg) with respect to demographic 
and baseline characteristics, efficacy variables, and safety variables. Summary statistics for 
continuous variables will include the n, mean, standard deviation, median, minimum and 
maximum. Categorical variables will be summarized in a contingency table by the frequency and 
percentage of patients in each category. Data will be plotted to assess trends across time as 
appropriate.
No a priori hypotheses will be tested.  Exploratory hypotheses may emerge from the data 
analysis, in which case, appropriate testing methods will be applied and specified in the 
statistical analysis plan.
There are no formal hypotheses associated with the evaluation of the safety and performance of 
the IDDD device (SOPH-A-PORT Mini S). All analyses of device safety and performance will 
be descriptive and no statistical testing will be performed. Device related analyses will be based 
on patients for whom the device implant procedure was performed and are described in the 
sections below.
10.2
Determination of Sample Size
Since this is an extension study, sample size is determined by the number of patients who 
completed HGT-SAN-055 (maximum of 12 patients) and elected to continue treatment with 
HGT-1410 in this study. Hence no statistical estimation of the sample size was performed.
10.3
Analysis Populations
The primary analysis population consists of all eligible patients from HGT-SAN-055 who have 
agreed to participate in the extension study. This population will be used to perform both safety 
and efficacy analyses. The collection of detailed data pertaining to the SOPH-A-PORT mini S 
will permit device-related analyses to be conducted in the subset of patients in the primary 
analysis population who had the SOPH-A-PORT Mini S implant procedure performed.
10.4
Demographics and Baseline Characteristics
Patient disposition for those enrolled will be presented in a summary table using number and 
percentage of patients enrolled, completed or discontinued/withdrew. The reasons for 
discontinuation/withdrawal will also be presented.
Demographic and baseline characteristics (eg, age, race, ethnicity, medical history, and surgical 
history) will be reported in summary tables.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
63
10.5
Statistical Analysis of Pharmacokinetic Variables
Not applicable.
10.6
Efficacy, Safety, and Pharmacodynamic Evaluations    
10.6.1
Primary Analyses
10.6.1.1
Safety Analysis
In general, safety assessments will be based on all assessments post-baseline.  The assessment of 
safety will be based primarily on the frequency of AEs, and on the frequency of clinically 
notable abnormal vital sign and laboratory values.  Changes from baseline will be calculated by 
subtracting the baseline value from the post-baseline value.
All enrolled patients who had an IDDD surgical procedure and/or received administration of 
HGT-1410 will be included in the safety analysis.  
Adverse events will be recorded throughout the study and at early termination.  Adverse events 
and medical conditions will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). 
Adverse events will be summarized by presenting, for each dose group, the number and 
percentage of patients having any AE, having an AE in system organ class, and having each 
individual AE. In addition, those events which resulted in death or were otherwise classified as 
serious will be presented in a separate listing. The incidence of treatment-emergent adverse 
events , defined as all AEs from the time of the surgery for IDDD implantation to the last follow 
up contact, ie, 30 days after the last HGT-1410 administration, (new or worsened from baseline)
will be summarized by system organ class, severity, type of adverse event and relationship to 
trial medication/procedure. 
Treatment-emergent AEs deemed related to HGT-1410 administration will be summarized 
separately.
IDDD and procedure-related AEs will be summarized within system organ class by preferred 
term. IDDD and procedure-related AEs will be tabulated by severity (mild, moderate, severe) 
and degree of relatedness.  Separate tabulations will be provided for adverse events related to the 
IDDD, device surgical procedure (including post-implant infections) and IT administration 
process.  These summaries will be presented by device and overall, as appropriate. 
Descriptive summaries of clinical laboratory evaluations (hematology, serum chemistry, 
urinalysis and CSF) results will be presented in summary tables by evaluation visit.  Changes 
from baseline will be summarized for each post-baseline visit.  Each laboratory result will be 
categorized as a patient having had (1) an Abnormal and Clinically Significant (CS) value at any 
time, (2) no CS values at any time but had at least one Abnormal and not CS (NCS) value, and 
(3) no CS or NCS values at any time; the number and percentage in each category will be 
presented.  For any patient who experiences a CS laboratory result at any time that was not CS at 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
64
baseline (or the most recent non-missing value prior to the start of the treatment), their entire 
profile for that particular laboratory parameter will be presented as a listing.
The observed values and changes from baseline for vital sign data will be summarized for each 
dose group.  Shift tables may be presented, utilizing reference ranges.  Patients with notably 
abnormal values will be identified and listed separately along with their values.
The observed values and changes from baseline for ECG data will be summarized for each dose 
group.  Patients with any clinically significant findings and/or conduction abnormalities will be 
listed separately along with their values. 
Anti-rhHNS antibody formation will be monitored throughout the study.  Results will be 
presented in summary tables by number and percentage of positive and negative specimens by 
evaluation visit, and number and percentage of positive and negative specimens overall.  The 
effect of antibodies on other safety parameters will be assessed by presenting summary tables by 
antibody status.  
For those patients who fail to complete the study, the reason for discontinuation will be listed by 
patient and dose group. 
Listings of all study safety data will be presented.
10.6.2
Other Observations Related to Safety
10.6.2.1
IDDD Performance
IDDD safety and performance will be summarized in detail for patients implanted with the 
SOPH-A-PORT Mini S. Difficulties associated with the implant procedure (e.g. excessive 
bleeding, CSF leakage, etc.) will be summarized.  A summary of abnormal findings from the 
IDDD radiological assessments will also be presented.  
The proportion of patients with at least one IDDD failure and/or malfunction, as well as the 
number of and reasons for IDDD failures/malfunctions will be summarized.  The rate of IDDD 
failures/malfunctions and 95% confidence interval will also be estimated.  The time from initial 
implant surgery to first IDDD failure and/or malfunction will be summarized.  Patients without
an IDDD failure/malfunction will be censored at their last study drug injection date.  A by-
patient listing of the device failure/malfunction data will be displayed.
The proportion of patients for whom a successful first injection of study drug occurred will be 
reported among those for whom a first injection was attempted (i.e. those who had an apparently 
successful implantation and did not suffer a device removal or revision prior to first scheduled 
injection). The proportion of patients who had no failed injection attempts during the study will 
also be summarized. The corresponding 95% confidence intervals of the proportion of interest 
will be estimated, where appropriate. Injections not given for patient reasons (e.g. patient 
uncooperative, competing medical issue, etc) will not be included in the determination of these 
success proportions.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
65
10.6.3
Secondary Analysis
10.6.3.1
Clinical Assessments
The change from baseline in neurocognitive assessment based scores will be examined by dose 
group.  Furthermore, the effect of HGT-1410 administration on QoL measures will be examined 
by presenting mean change from baseline by dose groups.  Other relevant assessments which 
might help in the understanding of clinical activity will also be analyzed.
10.6.3.2
Pharmacodynamic Analyses
To determine the effects of HGT-1410 administration on biomarkers, mean change from baseline 
will be assessed at selected time points.  The heparan sulfate reduction (in CSF) will be 
examined using mean change and the corresponding 95% confidence interval.  Other exploratory 
biomarkers in CSF, serum, and urine may also be examined.
The effect of anti- rhHNS antibodies on the changes in CSF biomarkers may also be examined 
by presenting summary tables by antibody status.
10.6.4
Interim Analysis
No formal analysis or interim statistical testing for early stopping of the trial is planned.  
Descriptive analyses of the data before trial completion may be performed for safety monitoring, 
regulatory reporting, or general planning purposes.
The planned final analyses and presentations will be defined in the Statistical Analysis Plan 
(SAP).

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
66
11
ADMINISTRATIVE CONSIDERATIONS
11.1
Investigators and Study Administrative Structure
Before initiation of the study, the Investigators must provide the Sponsor with a completed Form 
FDA 1572 or Investigator Agreement.  Study medications may be administered only under the 
supervision of the Investigators listed on this form.  Curriculum vitae must be provided for the 
Investigators and sub-investigators listed on Form FDA 1572 or Investigator Agreement.
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, any amendments to the protocol, the study treatments, and their study related 
duties and functions.  The Investigator must maintain a list of sub-investigators and other 
appropriately qualified persons to whom he or she has delegated significant study related duties.
11.2
Institutional Review Board or Independent Ethics Committee Approval
Before initiation of the study, the Investigator must provide the Sponsor with a copy of the 
written IRB or IEC approval of the protocol and the informed consent form.  This approval must 
refer to the informed consent form and to the study title, study number, and version and date of 
issue of the study protocol, as given by the Sponsor on the cover page of the protocol.  
Status reports must be submitted to the IRB/IEC at least once per year.  The IRB/IEC must be 
notified of completion of the study.  Within 3 months of study completion or termination, a final 
report must be provided to the IRB/IEC.  A copy of these reports will be sent to the study clinical 
monitor.  The Investigators must maintain an accurate and complete record of all submissions 
made to the IRB/IEC, including a list of all reports and documents submitted.  AEs which are 
reported to the US FDA or other Regulatory agencies (Investigational New Drug [IND] Safety 
Reports) must be submitted promptly to the IRB/IEC.
11.3
Ethical Conduct of the Study
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor and Investigators abide by 
good clinical practice (GCP) as described in the 21 CFR Parts 50, 56, and 312 and the 
International Conference on Harmonization (ICH) GCP Guidelines. 
11.4
Patient Information and Consent
Before enrolling in the clinical study, the patient’s parent(s), or the patient’s legally authorized 
representative(s) must consent to participate after the nature, scope, and possible consequences 
of the clinical study have been explained in a form understandable to him or her.  An informed 
consent form that includes information about the study will be prepared and given to the 
patient’s parent(s), or the patient’s legally authorized representative(s).  This document will 
contain all FDA and ICH-required elements.  
The informed consent form must be in a language understandable to the patient’s parent(s), or 
the patient’s legally authorized representative(s) and must specify who informed the patient’s 
parent(s) or the patient’s legally authorized representative.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
67
After reading the informed consent document, the patient, patient’s parent(s), or the patient’s 
legally authorized representative(s) must give consent in writing.  The patient’s consent must be 
confirmed at the time of consent by the personally dated signature of the patient, patient’s 
parent(s) or the patient’s legally authorized representative(s) and by the personally dated 
signature of the person conducting the informed consent discussions.  If the patient, patient’s 
parent(s), or the patient’s legally authorized representative(s) is unable to read, oral presentation 
and explanation of the written informed consent form and information to be supplied must take 
place in the presence of an impartial witness.  Consent (or assent) must be confirmed at the time 
of consent orally and by the personally dated signature of the patient, patient’s parent(s) or by the 
patient’s legally authorized representative(s).  The witness and the person conducting the 
informed consent discussions must also sign and personally date the informed consent document.  
It should also be recorded and dated in the source document that consent was given.
A copy of the signed and dated consent document(s) must be given to the patient’s parent(s), or 
the patient’s legally authorized representative(s).  The original signed and dated consent 
document will be retained by the Investigator.
The Investigator will not undertake any measures specifically required solely for the clinical 
study until valid consent has been obtained.
A model of the informed consent form to be used in this study will be provided to the sites 
separately from this protocol.  
Where applicable, signed assent(s) to participate in the study must be obtained.
11.5
Patient Confidentiality
Patient names will not be supplied to the Sponsor.  Only the patient number and patient initials 
will be recorded in the eCRF, and if the patient name appears on any other document, it must be 
obliterated before a copy of the document is supplied to the Sponsor.  Study findings stored on a 
computer will be stored in accordance with local data protection laws.  The patients will be told 
that representatives of the Sponsor, a designated CRO, the IRB/IEC, or regulatory authorities 
may inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws.  The Investigator will maintain a personal patient 
identification list (patient numbers with the corresponding patient names) to enable records to be 
identified.
11.6
Study Monitoring
Monitoring procedures that comply with current GCP guidelines will be followed.  On-site 
review of the eCRFs for completeness and clarity, cross-checking with source documents, and 
clarification of administrative matters will be performed.
The study will be monitored by the Sponsor or its designee.  On site monitoring will be 
performed by a representative of the Sponsor (Clinical Study Monitor) who will review the CRFs 
and source documents.  The site monitor will ensure that the investigation is conducted 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
68
according to protocol design and regulatory requirements by frequent site visits and 
communications (letter, telephone, and facsimile).
11.7
Case Report Forms and Study Records
Case report forms are provided for each patient in electronic format.  Electronic Data Capture 
(EDC) will be used for this study.  The study data will be recorded from the source documents 
into the eCRF.  The electronic files will be considered as the CRFs. 
All forms must be filled out by authorized study personnel.  All corrections to the original eCRF 
entry must indicate the reason for change.  The Investigator is required to sign the eCRF after all 
data have been captured for each patient.  If corrections are made after review and signature by 
the Investigator, he or she must be made aware of the changes, and his or her awareness 
documented by re-signing the eCRF.   
11.7.1
Critical Documents
Before Shire initiates the trial (ie, obtains informed consent [assent if applicable] from the first 
patient), it is the responsibility of the Investigator to ensure that the following documents are 
available to Shire or their designee:

Curricula vitae of Investigator and sub-investigator(s) (current, dated and signed or supported 
by an official regulatory document)

Current medical license of Investigator and sub investigator(s)

Signed and dated agreement of the final protocol

Signed and dated agreement of any amendment(s), if applicable

Approval/favorable opinion from the IRB/IEC clearly identifying the documents reviewed:  
protocol, any amendments, Patient Information/Informed Consent Form (Assent form if 
applicable), and any other written information to be provided regarding patients recruitment 
procedures

Copy of IRB/IEC approved Patient Information/Informed Consent Form (Assent Form if 
applicable)/any other written information/advertisement

Any additional regulatory approvals, ie national regulatory approvals

List of IRB/IEC Committee members/constitution

Financial agreement(s)

Documentation from central or local laboratory as applicable
•
Reference ranges
•
Certification/QA scheme/other documentation
Regulatory approval and notification as required must also be available; these are the 
responsibility of Shire.  All trial documents will be available in a Trial Master File (TMF) at the 
Investigator/trial site and at Shire.     
11.8
Device Failure Review Process
The final cause for device failures will be reviewed by a Shire team by examining the clinical
database, safety database, and manufacturer investigation of returned devices.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
69
11.9
Protocol Violations/Deviations
The Investigator will conduct the study in compliance with the protocol.  The protocol will not 
be initiated until the IRB/IEC and the appropriate regulatory authorities have given 
approval/favorable opinion.  Modifications to the protocol will not be made without agreement 
of the Sponsor.  Changes to the protocol will require written IRB/IEC approval/favorable opinion 
prior to implementation, except when the modification is needed to eliminate an immediate 
hazard(s) to patients.  The IRB/IEC may provide, if applicable regulatory authorities permit, 
expedited review and approval/favorable opinion for minor change(s) in ongoing studies that 
have the approval/favorable opinion of the IRB/IEC.  The Sponsor will submit all protocol 
modifications to the regulatory authorities in accordance with the governing regulations.  A 
record of patients screened, but not entered into the study, is also to be maintained.  There will be 
no protocol exemptions granted for this study.
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
patients, the Investigator will contact the Sponsor or its designee, if circumstances permit, to 
discuss the planned course of action.  Any departures from the protocol must be fully 
documented as a protocol deviation.  Protocol deviations will need to be reviewed by the medical 
monitor and may also be required to be submitted to the IRB/IEC.
Protocol modifications will only be initiated by the Sponsor and must be approved by the 
IRB/IEC and submitted to the FDA or other applicable international regulatory authority before 
initiation.
11.10 Access to Source Documentation
Regulatory authorities, the IEC/IRB, or the Sponsor may request access to all source documents, 
CRFs, and other study documentation for on-site audit or inspection.  Direct access to these 
documents must be guaranteed by the Investigator, who must provide support at all times for 
these activities.  Monitoring and auditing procedures that comply with current GCP guidelines 
will be followed.  On-site review of the CRFs for completeness and clarity, crosschecking with 
source documents, and clarification of administrative matters will be performed.
11.11 Data Generation and Analysis
The clinical database will be developed and maintained by a contract research organization or an 
electronic data capture technology provider as designated by Shire.  Shire or its designee will be 
responsible for performing study data management activities. 
Adverse events will be coded using MedDRA.  Concomitant medication will be coded using 
WHO-DD.  Centralized laboratories will be employed as described in the study manual to aid in 
consistent measurement of efficacy and safety parameters.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
70
11.12 Premature Closure of the Study
11.12.1
Study Termination
If the Sponsor or an Investigator discovers conditions arising during the study which indicate that 
the clinical investigation should be halted due to an unacceptable patient risk, the study may be 
terminated after appropriate consultation between Shire and the Investigators.  In addition, a 
decision on the part of Shire to suspend or discontinue development of the study material may be 
made at any time.
11.12.2
Site Termination
A specific site may be terminated separate from the general study for, but not limited to, the 
following conditions:

The discovery of an unexpected, significant, or unacceptable risk to the patients enrolled at 
the site.

Failure of the Investigator to enter patients at an acceptable rate.

Insufficient adherence by the Investigator to protocol requirements.
11.13 Retention of Data
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application and until there are no pending or contemplated marketing applications or 
at least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product.  The Sponsor will notify the Investigator if these documents must be 
retained for a longer period of time.  It is the responsibility of the Sponsor to inform the 
Investigator or institution as to when these documents no longer need to be retained. 
Biological samples may be reserved for potential, future, biomarker studies (see Section 7.7.7).  
11.14 Financial Disclosure
The Investigator should disclose any financial interests in the Sponsor as described in 21 CFR 
Part 54 prior to beginning this study.  The appropriate form will be provided to the Investigator 
by the Sponsor, which will be signed and dated by the Investigator, prior to the start of the study. 
11.15 Publication and Disclosure Policy
All information concerning the study material, such as patent applications, manufacturing 
processes, basic scientific data, and formulation information supplied by the Sponsor and not 
previously published are considered confidential and will remain the sole property of the 
Sponsor.  The Investigator agrees to use this information only in accomplishing this study and 
will not use it for other purposes.
It is understood by the Investigator that the information developed in the clinical study may be 
disclosed as required to the authorized regulatory authorities and governmental agencies.  

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
71
In order to allow for the use of the information derived from the clinical studies, it is understood 
that there is an obligation to provide the Sponsor with complete test results and all data 
developed in the study in a timely manner.
The Investigator and any other clinical personnel associated with this study will not publish the 
results of the study, in whole or in part, at any time, unless they have consulted with Shire, 
provided Shire a copy of the draft document intended for publication, and obtained Shire’s 
written consent for such publication.  All information obtained during the conduct of this study 
will be regarded as confidential.  Shire will use the information for registration purposes and for 
the general development of the drug.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
72
12
LIST OF REFERENCES
1. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. 
JAMA : the journal of the American Medical Association 1999;281:249-54.
2. Poorthuis BJ, Wevers RA, Kleijer WJ, et al. The frequency of lysosomal storage diseases in 
The Netherlands. Human genetics 1999;105:151-6.
3. Baehner F, Schmiedeskamp C, Krummenauer F, et al. Cumulative incidence rates of the 
mucopolysaccharidoses in Germany. J Inherit Metab Dis 2005;28:1011-7.
4. Valstar MJ, Bruggenwirth HT, Olmer R, et al. Mucopolysaccharidosis type IIIB may 
predominantly present with an attenuated clinical phenotype. Journal of inherited metabolic 
disease 2010;33:759-67.
5. Meyer A, Kossow K, Gal A, et al. Scoring evaluation of the natural course of 
mucopolysaccharidosis type IIIA (Sanfilippo syndrome type A). Pediatrics 
2007;120:e1255-61.
6. Cleary MA, Wraith JE. Management of mucopolysaccharidosis type III. Arch Dis Child 
1993;69:403-6.
7. Fraser J, Wraith JE, Delatycki MB. Sleep disturbance in mucopolysaccharidosis type III 
(Sanfilippo syndrome): a survey of managing clinicians. Clin Genet 2002;62:418-21.
8. Neufeld E, Muenzer J. The Mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, 
Valle D, eds. The metabolic and molecular bases of inherited disease. 8th ed. New York: 
McGraw-Hill; 2001:4 v. (xivii, 6338, I-104 p.).
9. Meyer A, Kossow K, Gal A, et al. The mutation p.Ser298Pro in the sulphamidase gene 
(SGSH) is associated with a slowly progressive clinical phenotype in mucopolysaccharidosis 
type IIIA (Sanfilippo A syndrome). Hum Mutat 2008;29:770.
10. Vellodi A. Lysosomal storage disorders. Br J Haematol 2005;128:413-31.
11. Hemsley KM, Beard H, King BM, Hopwood JJ. Effect of high dose, repeated intra-CSF 
injection of sulphamidase on neuropathology in MPS IIIA mice. Genes Brain Behav 2008.
12. Urayama A, Grubb JH, Sly WS, Banks WA. Mannose 6-phosphate receptor-mediated 
transport of sulfamidase across the blood-brain barrier in the newborn mouse. Mol Ther 
2008;16:1261-6.
13. Bielicki J, Hopwood JJ, Melville EL, Anson DS. Recombinant human sulphamidase: 
expression, amplification, purification and characterization. Biochem J 1998;329 ( Pt 
1):145-50.
14. Di Natale P, Vanacore B, Daniele A, Esposito S. Heparan N-sulfatase: in vitro mutagenesis 
of potential N-glycosylation sites. Biochem Biophys Res Commun 2001;280:1251-7.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
73
15. Daniele A, Di Natale P. Heparan N-sulfatase: cysteine 70 plays a role in the enzyme catalysis 
and processing. FEBS Lett 2001;505:445-8.
16. Perkins KJ, Byers S, Yogalingam G, Weber B, Hopwood JJ. Expression and characterization 
of wild type and mutant recombinant human sulfamidase. Implications for Sanfilippo 
(Mucopolysaccharidosis IIIA) syndrome. J Biol Chem 1999;274:37193-9.
17. Munoz-Rojas MV, Vieira T, Costa R, et al. Intrathecal enzyme replacement therapy in a 
patient with mucopolysaccharidosis type I and symptomatic spinal cord compression. Am J 
Med Genet A 2008;146A:2538-44.
18. Muñoz-Rojas M, Dain D, Horovitz G, et al. Intrathecal administration of recombinant human 
N-acetylgalactosamine 4-sulfatase to a MPS VI patient with pachymeningitis cervicalis. 
Molecular Genetics and Metabolism 2010;99:346-50.
19. Chen A, Dickson P, Shapiro E, Lyons B, Kan S, Guillaume D. A study of intrathecal enzyme 
replacement for cognitivedecline in mucopolysaccharidosis. Mol Genet Metab 
2010;99:S13-S4.
20. Hemsley K, King B, Hopwood J. Injection of recombinant human sulfamidase into the CSF 
via the cerebellomedullary cistern in MPS IIIA mice. Mol Genet Metab 2007;90:313-28.
21. Hemsley KM, Luck AJ, Crawley AC, et al. Examination of intravenous and intra-CSF 
protein delivery for treatment of neurological disease. Eur J Neurosci 2009;29:1197-214.
22. Hemsley KM, Norman EJ, Crawley AC, et al. Effect of cisternal sulfamidase delivery in 
MPS IIIA Huntaway dogs-A proof of principle study. Mol Genet Metab 2009.
23. Bayley N. Bayley Scales of Infant and Toddler Development: Third Edition. San Antonio, 
TX The Psychological Corporation; 2005.
24. Kaufman S, Kaufman N. Kaufman Assessment Battery for Children (KABC-II). 2nd ed.
25. Henderson S, Sugden D, Barnett A. Movement Assessment Battery for Children (second 
ed.). London: Harcourt Assessment; 2007.
26. Sparrow S, Balla D, Cicchetti D. Vineland Adaptive Behavior Scales (Second Edition). 4201 
Woodland Road Circle Pines, MN 55014-1796: American Guidance Service, Inc; 2005.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
74
Appendix 1
Schedule of Events 
Table A1-1
HGT-SAN-067 Study Assessments for Patients Who Have Received 6 Months of HGT-1410 Treatment in Study 
HGT-SAN-055
Month 7 through Month 80 (from the start of HGT-SAN-055)
Dosed every 28 (±7) days (ie, 
Q4W)
Assessment
Screening/or 
HGT-SAN-
055 EOS Visitj
(Month 6 
from the start 
of HGT-SAN-
055)
Pre-Tx
Day 1a
IT dosing
Day 2 (±2)
Months 12, 24, 
36, 
54, 60, 72 and
78 
(from the start 
of 
HGT-SAN-05
5)
Months 9, 15, 
18, 21, 27, 30, 
33, 39, 42, 45, 
48, and 51 
(from the start 
of HGT-SAN-
055)
EOSe
Month 79 
(from the start 
of HGT-SAN-
055)
Month 80 
Safety Follow-
upf
Informed Consent/Enrollment
●
●r
Physical Examination
●
●p
●p
●p
Symptom-Directed Physical Examination
●p
●p
●
Neurological Examinationh
●
●
●
●
Height and Weight
●
●
●
Head Circumference
●
●
●
Visual and Hearing Assessment
●
●
ECG
●
●b
Vital Signs
●
●
●
●
Hematology
●
●
●
Serum Chemistry
●
●
●
anti-rhHNS antibody testing (serum)k
●
●
●
Plasma storage for biomarkers
●
●
●
●
Pregnancy Testingl
●
●
●
Urinalysis
●
●
●
Urine GAGS
●
●e
●
Leukocyte pellet preparationm
●
CSF chemistry and cell countsc
●
●
●
CSF sample storagec,o
●
●
●
CSF Heparan Sulfate and Heparan Sulfate 
Derivativesc
●
●
●
Anti-rhHNS antibody testing (CSF) c
●
●
●

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
75
Table A1-1
HGT-SAN-067 Study Assessments for Patients Who Have Received 6 Months of HGT-1410 Treatment in Study 
HGT-SAN-055
Month 7 through Month 80 (from the start of HGT-SAN-055)
Dosed every 28 (±7) days (ie, 
Q4W)
Assessment
Screening/or 
HGT-SAN-
055 EOS Visitj
(Month 6 
from the start 
of HGT-SAN-
055)
Pre-Tx
Day 1a
IT dosing
Day 2 (±2)
Months 12, 24, 
36, 
54, 60, 72 and
78 
(from the start 
of 
HGT-SAN-05
5)
Months 9, 15, 
18, 21, 27, 30, 
33, 39, 42, 45, 
48, and 51 
(from the start 
of HGT-SAN-
055)
EOSe
Month 79 
(from the start 
of HGT-SAN-
055)
Month 80 
Safety Follow-
upf
Auditory Brainstem Response (ABR)q
●
●
MRI of the Head
●
●
●n
HGT-1410 dosing: every 28 (7) days d, g , 
●
Full Neurodevelopmental Testingi
●
●
●
Children’s Sleep Habits Rating Scale
●
●
●
Child Health Questionnaire-50
●
●
●
Child Health Questionnaire-87
●
●
●
Infant Toddler QOL Questionnaire
●
●
●
Concomitant Medications, Therapies, and 
Procedures
●
●
●
●
●
Adverse Event Monitoring
●
●
●
●
●
Abbreviations:
ABR = Auditory brainstem response; CSF = cerebrospinal fluid; EOS  = end of study ; ECG = electrocardiogram; IT = intrathecal; 
MRI = Magnetic resonance imaging; TX = treatment
Note:
The timing of assessments is calculated from the start of HGT-SAN-055. Therefore, for example, the end-of-study visit, as presented here at Month 78, 
corresponds to Month 72 in HGT-SAN-067, but represents a total of 78 months of study treatment (72 months in HGT-SAN-067 + 6 months in HGT-SAN-055).
a
Week 1 only, and only performed  if >7 days have elapsed since  HGT-SAN-055 EOS visit assessments.
b
ECG to be performed following administration of study drug, after Month 54 it is to be performed every 3 months.
c
CSF samples will be obtained according to the process with in the study laboratory manual. An attempt will be made to obtain a CSF sample via the IDDD 
prior to each administration of HGT-1410 and at the End of Study visit. If it is not possible to obtain a CSF using the IDDD, the IDDD may be replaced (up 
to twice in a 6 month period [including the time in the HGT-SAN-055 study]) or a LP may be performed.
d
Patients may be discharged as early as 4 hours post HGT-1410 infusion (ie, on Day 2) when deemed clinically stable by the Investigator. 
e
All patients who complete the study will have end of study assessments performed 30 (±7 days) after their last dose of study drug.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
76
Table A1-1
HGT-SAN-067 Study Assessments for Patients Who Have Received 6 Months of HGT-1410 Treatment in Study 
HGT-SAN-055
Month 7 through Month 80 (from the start of HGT-SAN-055)
Dosed every 28 (±7) days (ie, 
Q4W)
Assessment
Screening/or 
HGT-SAN-
055 EOS Visitj
(Month 6 
from the start 
of HGT-SAN-
055)
Pre-Tx
Day 1a
IT dosing
Day 2 (±2)
Months 12, 24, 
36, 
54, 60, 72 and
78 
(from the start 
of 
HGT-SAN-05
5)
Months 9, 15, 
18, 21, 27, 30, 
33, 39, 42, 45, 
48, and 51 
(from the start 
of HGT-SAN-
055)
EOSe
Month 79 
(from the start 
of HGT-SAN-
055)
Month 80 
Safety Follow-
upf
f
A safety follow up telephone call will be made 30 (±7 days) after End of Study Procedures.
g
If a patient’s IDDD becomes nonfunctional or infected; it will be replaced (up to 2 times in a 6 month period; including the time in Study HGT-SAN-055).
h
The neurological exam should not occur sooner than 4 hours after administration of study drug or before the patient has fully recovered from any anesthesia 
administered for the dosing, whichever occurs later.
i
Full neurodevelopmental testing includes an assessment with the Vineland Adaptive Behavior Scales, Second Edition (VABS-II)
j
Assessments will be required only if more than 60 days have elapsed following the HGT-SAN-055 procedures.  These assessments would be repeated 
within 30 days prior to the first scheduled HGT-1410 IT dose.
k
Blood sample drawn before IT injection of HGT-1410.
l
A pregnancy test will be carried out on pre-treatment Day 1 in females who are postmenarche to premenopause (childbearing).  The results must be negative 
before study drug can be administered.
m
A blood sample for leukocyte pellet preparation is to be taken at baseline, before dosing.  This pellet should be stored frozen, and will be used for additional 
disease-related laboratory studies, including possible assessment of cross-reactive immunologic material.  If this is not drawn at baseline, it can be drawn at 
any subsequent visit, but it must be taken before dosing.  This only needs to be taken once during the study.
n
These assessments are not to be performed at an EOS visit conducted at Month 79 if they were performed at the Month 78 visit
o
CSF samples will be tested for MPS exploratory biomarkers, and possibly extractables and leachables.
p
After Month 54 the Symptom-Directed PE is to be done monthly. Full PE is done monthly to Month 54 and then at least yearly, or more frequently at the 
investigator’s discretion.
q
ABR will not be performed after Month 54
r
Informed consent will be obtained at Screening and Month 54

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
77
Appendix 2
Neurodevelopmental and Behavioural Assessments 
Tables A2-1 and A2-2 detail the specific psychometric instruments that will be used to provide 
measures of each of relevant neurobehavioral or developmental domain assessed.  The tables 
also summarize the rules used to select a test for a patient, the subtests included in each test, and 
the subscales generated by the test battery.
Table A2-1
Summary of Neurodevelopmental Outcome Measures
Domain
Age
Test
Summary score and 
subdomains:
- Cognitive
- Motor
- Social/Emotional
0 to 42 months
Bayley Scales of Infant Development, Third 
Edition (BSID-III)23
- Cognitive 
- Processing skills
3 to 18 years
Kaufman Assessment Battery for Children, 
Second Edition (KABC-II)24  
Motor
3.0 to 16:11 
years
Movement Assessment Battery for Children, 
Second Edition (MABC-2)25  
Communication
Daily Living
Socialization
Motor Skills
0 to 90 years
Vineland Adaptive Behavior Scales, Second 
Edition (VABS-II)26
Table A2-2
Summary of Sanfilippo-specific Assessments
Domain
Assessment
Parent-scored behavioral inventory
- communication:  understanding
- communication:  expression
- tantrums
- specific behaviors inventory
- mood & emotions inventory
Sanfilippo Behavior Rating Scale
MPS-specific four-point scoring 
system/total disability score
- cognition
- expressive language
- motor score
Four-Point Scoring System/Total Disability 
Score (FPSS/TDS)5
The term “neurodevelopmental” refers to the process by which the neurological system matures 
and changes over time.  Assessing these changes in a population of children whose neurological 
system is progressively more affected can be very challenging.  
Typically, neurodevelopmental progress is reflected by the child’s abilities to perform certain 
skills (sitting, walking, and talking).  

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
78
However, a child with a neurological disorder may be able to perform age appropriate skills, but 
with atypical patterns.  For example, the child may be able to walk, but his gait is not normal.  
Most assessments will therefore measure the skills, but are not designed to capture the 
abnormalities in pattern or quality of the skill.  
These qualitative differences will be evident to the skilled test administrator/clinician who is 
familiar with the disorder.  However, only longitudinal tracking and repeated measures will 
reveal the significance of these abnormalities in overall function to the less experienced clinician.   
The rate at which different skills develop or regress over time will give insight into the disease 
process.  The next step is to determine how the learned skills are used for daily functional 
activities so that as the children grow up they become independent from caregivers.  These 
functional skills can be tracked to reflect quality of life issues for both parents and children. 
Neurodevelopmental assessments described below will be scheduled for administration in the 
morning and estimated to last between 2 and 4 hours.
The list of assessments and algorithm is discussed in detail in the Study Operations Manual and 
includes:
Bayley Scales of Infant Development, Third Edition (BSID-III) 23
The Bayley Scales of Infant Development is a standard series of measurements used primarily to 
assess the motor (fine and gross), language (receptive and expressive), and cognitive 
development of infants and toddlers, ages 0 to 42 months.  This measure consists of a series of 
developmental play tasks and takes between 45 and 60 minutes to administer.  Raw scores of 
successfully completed items are converted to scale scores and to composite scores.  These 
scores are used to determine the child's performance compared with norms taken from typically 
developing children of their age (in months).  The assessment is often used in conjunction with 
the Social-Emotional Adaptive Behavior Questionnaire.  Completed by the parent or caregiver, 
this questionnaire establishes the range of adaptive behaviors that the child can currently achieve 
and enables comparison with age norms.
Kaufman Assessment Battery for Children, Second Edition (KABC-II) 24
Purpose:
The KABC-II measures a child’s cognitive ability and processing skills and was designed to 
minimize verbal instructions and responses.  In addition, the assessment contains little cultural 
content to provide a more accurate assessment of children from diverse backgrounds.  Thus 
language difficulties or cultural differences are minimized in the test battery’s results.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
79
Description:
Investigators may choose either the Cattell-Horn-Carroll or the Luria model for a patient’s 
assessment.  
The Cattell-Horn-Carroll model is used with children from a mainstream cultural and language 
background and the Luria model is used for children with significantly limited verbal ability.  
Subtests are administered on four or five ability scales and interpreted using the chosen model. 
Movement Assessment Battery for Children, Second Edition (MABC-2)25
Purpose:
The Movement Assessment Battery for Children, Second Edition identifies, describes and guides 
treatment of motor impairment in children from 3.0 to 16:11 years of age.
Description:
The MABC-2 checklist is administered individually over approximately 30 minutes.  It yields 
both normative and qualitative measures of movement competence, manual dexterity, ball skills, 
static and dynamic balance.
Vineland Adaptive Behavior Scales, Second Edition (VABS-II) 26
Purpose:
The test measures adaptive behaviors, including the ability to cope with environmental changes, 
to learn new everyday skills and to demonstrate independence.  It is an instrument that supports 
the diagnosis of intellectual and developmental disabilities.  It encompasses ages from birth to 
90 years. 
Description:
Adaptive behavior is a composite of various dimensions.  This test measures 5 domains:  
communication, daily living skills, socialization, motor skills, and maladaptive behavior 
(optional) and is administered in a semi-structured interview in through a questionnaire.  The 
scales of the VABS-II were organized within a 3-domain structure:  Communication, Daily 
Living, and Socialization.  This structure corresponds to the 3 broad domains of adaptive 
functioning by the American Association of Intellectual and Developmental Disabilities:  
Conceptual, Practical, and Social.  In addition, VABS-II offers a Motor Skills Domain and an 
optional Maladaptive Behavior Index.  The scores are interpreted by means of score equivalents 
for the raw scores in each domain, percentile ranks, age equivalents, adaptive levels, and 
maladaptive levels.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
80
Sanfilippo Behavior Rating Scale (SBRS)
The Sanfilippo Behavior Rating Scale (SBRS) is a newly-developed scale designed by Drs. Elsa 
Shapiro and Michael Potegal to measure a cluster of behaviors known to occur in Sanfilippo 
syndrome.  The SBRS is a parent-scored behavioral inventory measuring (1) comprehensive 
language skills, (2) expressive language skills, (3) tantrums, (4) mood and emotions, and 
(5) other behaviors not otherwise classified.
Four-Point Scoring System/Total Disability Score (FPSS/TDS) 5
The FPSS assesses motor function, expressive language, and cognitive function on a 0 to 3 point 
scale and can be used for individuals of all ages. The total disability score is the average of the 
motor function, speech, and cognitive function scores.

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
81
Appendix 3
Expected Adverse Device Effects
Procedure-Related Complications

Components handled improperly before, during, or after implantation 

Access port implanted incorrectly

Catheter positioned improperly

Injection through septum performed incorrectly

Injection of incorrect medication through access port

Injection outside the access port into pocket or subcutaneous tissue or extravasation

Pocket seroma, hematoma, erosion, or infection
Intrathecal Access Complications

Surgical complications such as hemorrhage or hematoma

Infection of the implant site or catheter track

Radiculitis or arachnoiditis

Intrathecal space infection resulting in meningitis or encephalitis

Bleeding 

Spinal cord damage or trauma to the spinal cord or nerve roots

Post-lumbar puncture, cerebrospinal fluid (CSF) leak, leading to headache, or  subcutaneous 
CSF collection

Epidural instead of intrathecal placement of catheter

Inflammatory mass resulting in neurological impairment, including paralysis

Pain on injection

Complications of anesthesia

Pseudomeningocele

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
82
System-Related Complications

Improperly positioned access port

Erosion of the skin because of the underlying access port or the catheter

Wound dehiscence

Access port migration, fracture, breakage or occlusion

Catheter damage, dislodgement, migration, disconnection, kinking or occlusion, fibrosis, or 
hygroma, resulting in tissue damage or a loss of or change in therapy, or other potentially 
serious adverse health consequences

Catheter breakage and migration of residual catheter fragments, potentially resulting in 
serious adverse health consequences and the need for surgical removal 

Local immunological or fibrous reaction to the presence of a foreign body (the device)

End of device service life or component failure, requiring surgical replacement

Component failure, resulting in loss of therapy

Access port inversion (“flipping”), rotation, or extrusion

Access port or catheter rejection 

Fibrin sheath formation around catheter tip

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
83
Appendix 4
Protocol Amendment 6 Summary of Changes 
AMENDMENT SUMMARY AND RATIONALE
Clinical protocol HGT-SAN-067 has been amended to extend the study and provide treatment 
with HGT-1410 for an additional 24 months (to Month 79 from start of study HGT-SAN-055); 
the frequency of hematology, serum chemistry and urinalysis assessments and the frequency of 
the ECG were reduced to Q3 months and the frequency of urine and plasma heparan sulfate and 
anti-rhHNS assessments was changed to Q6 months within this extended period.
replaced
in the role of Medical Monitor. The potential for determination of the 
levels of leachables from the IDDD in the CSF was added to the protocol. Other clarifications 
related to the IDDD use were added. Language clarifying that no formal interim analysis or 
interim statistical testing for early stopping is planned was added.
Previous Amendment:  Amendment 5; 17 January 2014
DETAILED SUMMARY OF CHANGES FOR THE AMENDMENT 
This is a section that has been updated to describe the changes from the previous protocol 
version.  Significant changes and additions to the protocol text are captured below.  Bold text 
indicates new text.  Strikethrough text indicates deleted text.
Change:  Replacement of 
by
as Medical Monitor
Section impacted by this change: Title page
Other sections impacted by this change: Synopsis, Section 7.22.5.1, Appendix 5 Signature 
Page
Change:  Removal of the concentration of inflammatory cytokines in serum and CSF as a 
secondary endpoint
Section impacted by this change: Section 3.2

Concentration of inflammatory cytokines in serum and CSF.
Other sections impacted by this change: Synopsis, Section 10.6.3.2
Change:  Addition of MRI of the head at Months 66 and 78 and deletion of ABR testing at 
Month 54
Section impacted by this change: Section 4.1
A MRI of the head will be performed at Months 12, 24, 36, 54, 66 and 78 and ABR 
testing will be performed at Months 12, 24, and 36 and 54 (note that assessment time 
point nomenclature includes the 6 months in the HGT-SAN-055 study).
Other sections impacted by this change: Synopsis; Appendix 1 Table A1-1 Schedule of 
Events

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
84
Change:  Last planned administration of HGT-1410 designated as Month 78 and EOS 
study procedures designated as Month 79
Section impacted by this change: Section 4.1
All patients will have an EOS visit 30 (±7) days following their last administration of 
HGT-1410 (ie, Month 55 78).
All patients will be contacted by telephone or will have a visit for a Final Safety 
Follow-up, to be conducted at 30 (±7) days after the EOS visit (ie, Month 56 79) to collect 
updated information on AEs and concomitant medications, therapies, and procedures. 
Other sections impacted by this change: Synopsis; Section 8.3, Appendix 1 Table A1-1
Schedule of Events
Change:  Elimination of ABR after Month 36 and elimination of the x-ray of the device 
at end of study
Section impacted by this change: Section 4.1
The EOS procedures will include standard clinical laboratory tests (serum chemistry, 
hematology, and urinalysis) in CSF and blood, protocol specific laboratory testing (eg, 
anti-rhHNS antibody testing), neurodevelopmental testing, ABR, child health 
questionnaires, and MRI and an X-ray examination of the device.  
Other sections impacted by this change: Synopsis, Appendix  1 Table A1-1 Schedule of 
Events
Change:  Removal of limitation of number lumbar punctures to 5 and replaced with 
language that limits to 12 LP and consultation with Sponsor if more needed
Section impacted by this change: Section 4.1
Study drug may be administered via LP for a maximum of 5 successive monthly doses, 
after which, IDDD re-implantation or revision must occur.
If there are medical contra-indications to the re-implantation of a new device, or if 
the patient so desires, repeat monthly lumbar punctures may be considered as an 
alternative way of delivering the study drug and obtaining CSF samples under 
limited circumstances.  If no safety risks are identified by the investigator, up to 12 
consecutive lumbar punctures may be performed across the studies HGT-SAN-055 
and HGT-SAN-067.  Once a patient has reached the maximum of 12 consecutive 
lumbar punctures, a new IDDD may be re-implanted for subsequent dosing, unless, 
in the opinion of the investigator and medical monitor, assessment of risk/benefit 
favors continued dosing via lumbar puncture.
Continued treatment via lumbar puncture beyond the stipulated 12 consecutive 
monthly doses can be considered only in individual cases where this treatment is 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
85
very well tolerated and the investigator has not identified any safety concerns 
associated with repeat lumbar puncture and repeat sedation/anesthesia. 
Other sections impacted by this change: Synopsis; Section 6.3; Section 6.3.1, Section 
6.3.3
Change:  Study duration changed from 4 years to 6 years
Section impacted by this change: Section 4.3
The study duration will be 4 6 years.
Other sections impacted by this change: Synopsis; Appendix 1 Table A1-1 Schedule of 
Events
Change:  Changes from screening physical exam to be added as AEs.  Symptom-directed 
physical exam added.
Section impacted by this change: Section 7.2
A full physical examination or a symptom-directed physical examination of each 
patient will be performed at time points detailed in Appendix 1 Schedule of Events.
Any changes from the screening physical examination will be captured as AEs in the 
eCRF.
Other sections impacted by this change: Synopsis; Appendix 1 Table A1-1 Schedule of 
Events
Change:  Statement that it may be necessary to determine the levels of leachables from the 
device into the CSF and blood
Section impacted by this change: Section 7.7
The conduct of a clinical trial in an extremely rare disease such as MPS IIIA 
provides a unique opportunity to collect samples for potential biomarker research. 
In the context of this study, a biomarker is defined as a characteristic that is 
objectively measured and evaluated as an indicator of the MPS IIIA pathogenic 
process, or a pharmacologic response to experimental therapy with HGT-1410. In 
addition to exploration of potential biomarkers, as part of the assessment of the 
SOPH-A-PORT Mini S, it may be necessary to determine the levels of leachables 
from the device into the CSF and blood.
Other sections impacted by this change: Appendix 1 Table A1-1 Schedule of Events 
footnotes
Change:  Addition of urine glycosaminoglycans and serum anti-rhHNS antibody 
assessments at Month 60 and 72 (Q6 Months after Month 54) and clarification that urine 

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
86
assessments include all glycosaminoglycans and not only heparan sulfate and its 
derivatives. Removal of plasma or serum assessments of heparan sulfate and its 
derivatives
Section impacted by this change:  Section 7.7.4

Urine GAG, including heparan sulfate and heparan sulfate derivatives (also 
performed at Month 60 and Month 72, ie, Q6 Months following Month 54)

Plasma and /or serum heparan sulfate and heparan sulfate derivatives 

Anti-rhHNS antibody testing (also performed at Month 60 and Month 72,  ie, Q6 
Months following Month 54)
Other sections impacted by this change: Sections 7.7.5.2; 8.1, 8.2.1.1, 8.3,  Appendix 1 
Table A1-1 Schedule of Events
Change:  Statement that catheters other than the Phoenix Neuro Disposable that are 
compatible with the device may be used.
Section impacted by this change: Section 7.13.1
Other catheter passers that are compatible with the SOPH-A-PORT Mini S may be 
used.
Other sections impacted by this change: None
Change:  Statement that fluoroscopy will be used during all device implantation 
procedures during x-ray verification.
Section impacted by this change: Section 7.13.3
Fluoroscopy will be used during all device implantation procedures.
Other sections impacted by this change: None
Change:  Elimination of measurement of CSF opening pressure at the time of an IDDD 
revision or replacement or lumbar puncture 
Section impacted by this change: Section 7.14
A CSF opening pressure measurement (cm of H2O) will be conducted as per standard 
hospital practice.  The measurement will be obtained whenever a LP is performed and an 
IDDD revision or replacement is done. Following implementation of Amendment 6 
the CSF opening pressure measurement will not be required with the LP.
. 
Other sections impacted by this change: Sections 6.3.1, 7.12,

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
87
Change:  Clarification of when  a malfunction of the device should be reported as an AE 
Section impacted by this change: Section 7.22.1.3
A malfunction of the device (defined in Section 7.23.2.1) should not be entered as an 
AE unless it has physiological consequences.  In the event of a device failure 
(defined in Section 7.23.2.2), the device may need to be replaced or repaired. 
Hospitalization for such a procedure will be reported as a SAE.  Details of the cause 
of IDDD malfunction or failure will be recorded on the Device Malfunction/Failure 
CRF.  A list of the more common IDDD AEs is included in Appendix 3.
If the patient is admitted to the hospital in association with an IDDD event (eg for 
subsequent revision or replacement) the surgery will be recorded as a SAE.
DEVICE SURGICAL PROCEDURE-RELATED ADVERSE EVENTS
Examples of AEs related to device surgical procedures include, but are not limited to, the 
following: events that occur during or following IDDD implant/explant, IDDD 
adjustment, full revision, partial revision, IDDD removal, and delayed re-implantation 
after previous IDDD removal (such as complications of anesthesia, excessive 
bleeding, wound hematoma) and post operative complications (such as post-
operative infection).
Other sections impacted by this change: none
Change:  Additional SAE language
Section impacted by this change: Section 7.22.5.1
The Investigator must report the SAE to the Shire Pharmacovigilance and Risk 
Management Department AND to the Shire Medical Monitor on an SAE form.  The 
SAE form must be completed and FAXED or scanned and EMAILED (PDF sent by e-
mail) within 24 hours
Other sections impacted by this change: None
Change:  Change in frequency of hematology, serum chemistry and urinalysis 
assessments from monthly to every third month.
Section impacted by this change: Section 8.2.1.1

Hematology (after Month 54 frequency reduced to Q3 Months)

Serum chemistry (after Month 54 frequency reduced to Q3 Months)

Urinalysis (after Month 54 frequency reduced to Q3 Months)

Pregnancy testing (applicable females only)
Other sections impacted by this change: Appendix  1 Table A1-1 Schedule of Events

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
88
Change:  Frequency of ECG changed from Q4 weeks to Q3 Months
Section impacted by this change: Section 8.2.1.2

ECG (performed following IT study drug injection)(after Month 54 performed Q3 
months)
Other sections impacted by this change: Appendix 1 Table A1-1 Schedule of Events
Change:  Indication that actions taken would not be captured for IDDD failures or 
malfunctions
Section impacted by this change: Section 10.6.2.1
The proportion of patients with at least one IDDD failure and/or malfunction, as well as 
the number of and reasons for IDDD failures/malfunctions and actions taken will be 
summarized.  
The proportion of patients for whom a successful first injection of study drug occurred 
will be reported among those for whom a first injection was attempted (i.e. those who 
had an apparently successful implantation and did not suffer a device removal or revision 
prior to first scheduled injection). The proportion of patients who had no failed injection 
attempts during the study will also be summarized. The corresponding 95% confidence 
intervals of the proportion of interest will be estimated, where appropriate. Injections not 
given for patient reasons (e.g. patient uncooperative, competing medical issue, etc) will 
not be included in the determination of these success proportions. The frequency and 
reasons for unsuccessful injection attempts will be reported.
Other sections impacted by this change: None
Change:  Addition of language to clarify that interim analyses were not intended to 
provide data for early stopping of the trial  
Section impacted by this change: Section 10.6.4
12.1.2
Interim Analysis
No formal analysis or interim statistical testing for early stopping of the trial is 
planned.  Descriptive analyses of the data before trial completion may be performed 
for safety monitoring, regulatory reporting, or general planning purposes.
Other sections impacted by this change: None
Change:  Clarification that device failures will be reviewed by a Shire team  
Section impacted by this change: Section 11.8

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
89
The final cause for device failures will be reviewed adjudicated by a Shire team by 
examining the clinical database, safety database, and manufacturer investigation of 
returned devices.
Other sections impacted by this change: None
Change:  Addition of informed consent at Month 54
Section impacted by this change: Appendix 1 Table A1-1 Schedule of Events
Informed consent will be provided by the patient’s parent(s)/legally authorized 
representative(s) prior to the start of the extension study procedures and again at Month 
54.  
Other sections impacted by this change: Appendix 1 Table A1-1 Schedule of Events,
Synopsis

Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Clinical Trial Protocol: HGT-SAN-067 Amendment 6
10 July 2014
Shire
Confidential
91
Appendix 6
The National Cancer Institute Common Terminology Criteria version 3.0

Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, Version 3.0, DCTD, NCI, NIH, DHHS 
 
March 31, 2003 (http://ctep.cancer.gov), Publish Date: August 9, 2006 
Common Terminology Criteria for Adverse Events v3.0 (CTCAE) 
Publish Date: August 9, 2006 
Quick Reference 
The NCI Common Terminology Criteria for Adverse Events 
v3.0 is a descriptive terminology which can be utilized for 
Adverse Event (AE) reporting. A grading (severity) scale is 
provided for each AE term. 
Components and Organization  
CATEGORY 
A CATEGORY is a broad classification of AEs based on 
anatomy and/or pathophysiology. Within each CATEGORY, 
AEs are listed accompanied by their descriptions of severity 
(Grade). 
Adverse Event Terms 
An AE is any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medical treatment or procedure 
that may or may not be considered related to the medical 
treatment or procedure. An AE is a term that is a unique 
representation of a specific event used for medical 
documentation and scientific analyses. Each AE term is 
mapped to a MedDRA term and code. AEs are listed 
alphabetically within CATEGORIES. 
Short AE Name 
The ‘SHORT NAME’ column is new and it is used to simplify 
documentation of AE names on Case Report Forms.   
Supra-ordinate Terms  
A supra-ordinate term is located within a CATEGORY and is a 
grouping term based on disease process, signs, symptoms, 
or diagnosis. A supra-ordinate term is followed by the word 
‘Select’ and is accompanied by specific AEs that are all 
related to the supra-ordinate term. Supra-ordinate terms 
provide clustering and consistent representation of Grade for 
related AEs. Supra-ordinate terms are not AEs, are not 
mapped to a MedDRA term and code, cannot be graded and 
cannot be used for reporting. 
REMARK 
A ‘REMARK’ is a clarification of an AE. 
ALSO CONSIDER 
An ‘ALSO CONSIDER’ indicates additional AEs that are to be 
graded if they are clinically significant. 
NAVIGATION NOTE 
A ‘NAVIGATION NOTE’ indicates the location of an AE term 
within the CTCAE document. It lists signs/symptoms 
alphabetically and the CTCAE term will appear in the same 
CATEGORY unless the ‘NAVIGATION NOTE’ states differently. 
Grades 
Grade refers to the severity of the AE. The CTCAE v3.0 
displays Grades 1 through 5 with unique clinical descriptions 
of severity for each AE based on this general guideline: 
Grade 1 
Mild AE  
Grade 2 
Moderate AE 
Grade 3 
Severe AE 
Grade 4 
Life-threatening or disabling AE 
Grade 5 
Death related to AE 
A Semi-colon indicates ‘or’ within the description of the grade. 
An ‘Em dash’ (—) indicates a grade not available. 
Not all Grades are appropriate for all AEs. Therefore, some 
AEs are listed with fewer than five options for Grade 
selection. 
Grade 5 
Grade 5 (Death) is not appropriate for some AEs and 
therefore is not an option. 
The DEATH CATEGORY is new. Only one Supra-ordinate 
term is listed in this CATEGORY: ‘Death not associated with 
CTCAE term – Select’ with 4 AE options: Death NOS; 
Disease progression NOS; Multi-organ failure; Sudden death. 
Important: 
• 
Grade 5 is the only appropriate Grade 
• 
This AE is to be used in the situation where 
a death  
1. cannot be reported using a CTCAE v3.0 
term associated with Grade 5, or 
2. cannot be reported within a CTCAE 
CATEGORY as ‘Other (Specify)’ 
 
 
 
 
 
Contents 
ALLERGY/IMMUNOLOGY ............................................1 
AUDITORY/EAR............................................................2 
BLOOD/BONE MARROW .............................................4 
CARDIAC ARRHYTHMIA..............................................5 
CARDIAC GENERAL ....................................................7 
COAGULATION ..........................................................10 
CONSTITUTIONAL SYMPTOMS................................11 
DEATH ........................................................................13 
DERMATOLOGY/SKIN ...............................................14 
ENDOCRINE...............................................................17 
GASTROINTESTINAL.................................................19 
GROWTH AND DEVELOPMENT................................29 
HEMORRHAGE/BLEEDING ....................................... 30 
HEPATOBILIARY/PANCREAS ................................... 34 
INFECTION................................................................. 35 
LYMPHATICS ............................................................. 38 
METABOLIC/LABORATORY ...................................... 40 
MUSCULOSKELETAL/SOFT TISSUE........................ 43 
NEUROLOGY ............................................................. 47 
OCULAR/VISUAL........................................................ 52 
PAIN............................................................................ 55 
PULMONARY/UPPER RESPIRATORY...................... 56 
RENAL/GENITOURINARY.......................................... 60 
SECONDARY MALIGNANCY..................................... 63 
SEXUAL/REPRODUCTIVE FUNCTION ..................... 64 
SURGERY/INTRA-OPERATIVE INJURY ................... 66 
SYNDROMES............................................................. 68 
VASCULAR................................................................. 70 
 

 
ALLERGY/IMMUNOLOGY 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 1 - 
March 31, 2003, Publish Date: August 9, 2006 
Allergic reaction/ 
hypersensitivity  
(including drug fever) 
Allergic reaction 
Transient flushing or 
rash; drug fever <38°C 
(<100.4°F) 
Rash; flushing; urticaria; 
dyspnea; drug fever 
≥38°C (≥100.4°F) 
Symptomatic 
bronchospasm, with or 
without urticaria; 
parenteral medication(s) 
indicated; allergy-related 
edema/angioedema; 
hypotension 
Anaphylaxis 
Death 
REMARK: Urticaria with manifestations of allergic or hypersensitivity reaction is graded as Allergic reaction/hypersensitivity (including drug fever). 
ALSO CONSIDER: Cytokine release syndrome/acute infusion reaction. 
Allergic rhinitis  
(including sneezing, 
nasal stuffiness, 
postnasal drip) 
Rhinitis 
Mild, intervention not 
indicated  
Moderate, intervention 
indicated 
— 
— 
— 
REMARK: Rhinitis associated with obstruction or stenosis is graded as Obstruction/stenosis of airway – Select in the PULMONARY/UPPER RESPIRATORY CATEGORY. 
Autoimmune reaction 
Autoimmune reaction 
Asymptomatic and 
serologic or other 
evidence of autoimmune 
reaction, with normal 
organ function and 
intervention not indicated 
Evidence of autoimmune 
reaction involving a non-
essential organ or 
function (e.g., 
hypothyroidism) 
Reversible autoimmune 
reaction involving function 
of a major organ or other 
adverse event (e.g., 
transient colitis or 
anemia)  
Autoimmune reaction with 
life-threatening 
consequences 
Death 
ALSO CONSIDER: Colitis; Hemoglobin; Hemolysis (e.g., immune hemolytic anemia, drug-related hemolysis); Thyroid function, low (hypothyroidism). 
Serum sickness 
Serum sickness 
— 
— 
Present 
— 
Death 
NAVIGATION NOTE: Splenic function is graded in the BLOOD/BONE MARROW CATEGORY. 
NAVIGATION NOTE: Urticaria as an isolated symptom is graded as Urticaria (hives, welts, wheals) in the DERMATOLOGY/SKIN CATEGORY. 
Vasculitis 
Vasculitis 
Mild, intervention not 
indicated 
Symptomatic, non-
steroidal medical 
intervention indicated 
Steroids indicated 
Ischemic changes; 
amputation indicated 
Death 
Allergy/Immunology – 
Other (Specify, __) 
Allergy – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
AUDITORY/EAR 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 2 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Earache (otalgia) is graded as Pain – Select in the PAIN CATEGORY. 
Hearing:  
patients with/without 
baseline audiogram and 
enrolled in a monitoring 
program1 
Hearing (monitoring 
program) 
Threshold shift or loss of 
15 – 25 dB relative to 
baseline, averaged at 2 
or more contiguous test 
frequencies in at least 
one ear; or subjective 
change in the absence of 
a Grade 1 threshold shift 
Threshold shift or loss of 
>25 – 90 dB, averaged at 
2 contiguous test 
frequencies in at least 
one ear 
Adult only: Threshold shift 
of >25 – 90 dB, averaged 
at 3 contiguous test 
frequencies in at least 
one ear  
Pediatric:  
Hearing loss sufficient to 
indicate therapeutic 
intervention, including 
hearing aids (e.g., ≥20 dB 
bilateral HL in the speech 
frequencies; ≥30 dB 
unilateral HL; and 
requiring additional 
speech-language related 
services) 
Adult only: Profound 
bilateral hearing loss 
(>90 dB) 
Pediatric:  
Audiologic indication for 
cochlear implant and 
requiring additional 
speech-language related 
services  
— 
REMARK: Pediatric recommendations are identical to those for adults, unless specified. For children and adolescents (≤18 years of age) without a baseline test, pre-exposure/pre-
treatment hearing should be considered to be <5 dB loss. 
Hearing: 
patients without baseline 
audiogram and not 
enrolled in a monitoring 
program1  
Hearing (without 
monitoring program) 
— 
Hearing loss not requiring 
hearing aid or 
intervention (i.e., not 
interfering with ADL) 
Hearing loss requiring 
hearing aid or 
intervention (i.e., 
interfering with ADL) 
Profound bilateral hearing 
loss (>90 dB) 
— 
REMARK: Pediatric recommendations are identical to those for adults, unless specified. For children and adolescents (≤18 years of age) without a baseline test, pre-exposure/pre-
treatment hearing should be considered to be <5 dB loss. 
Otitis, external ear 
(non-infectious) 
Otitis, external  
External otitis with 
erythema or dry 
desquamation  
External otitis with moist 
desquamation, edema, 
enhanced cerumen or 
discharge; tympanic 
membrane perforation; 
tympanostomy 
External otitis with 
mastoiditis; stenosis or 
osteomyelitis 
Necrosis of soft tissue or 
bone 
Death 
ALSO CONSIDER: Hearing: patients with/without baseline audiogram and enrolled in a monitoring program1; Hearing: patients without baseline audiogram and not enrolled in a 
monitoring program1.  
Otitis, middle ear  
(non-infectious) 
Otitis, middle 
Serous otitis  
Serous otitis, medical 
intervention indicated 
Otitis with discharge; 
mastoiditis  
Necrosis of the canal soft 
tissue or bone 
Death 

 
AUDITORY/EAR 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 3 - 
March 31, 2003, Publish Date: August 9, 2006 
Tinnitus 
Tinnitus 
— 
Tinnitus not interfering 
with ADL 
Tinnitus interfering with 
ADL 
Disabling 
— 
ALSO CONSIDER: Hearing: patients with/without baseline audiogram and enrolled in a monitoring program1; Hearing: patients without baseline audiogram and not enrolled in a 
monitoring program1. 
Auditory/Ear – Other 
(Specify, __) 
Auditory/Ear – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
 
 
 
 
 
 
                                            
1 Drug-induced ototoxicity should be distinguished from age-related threshold decrements or unrelated cochlear insult. When considering whether an adverse event has occurred, it is 
first necessary to classify the patient into one of two groups. (1) The patient is under standard treatment/enrolled in a clinical trial <2.5 years, and has a 15 dB or greater threshold 
shift averaged across two contiguous frequencies; or (2) The patient is under standard treatment/enrolled in a clinical trial >2.5 years, and the difference between the expected age-
related and the observed threshold shifts is 15 dB or greater averaged across two contiguous frequencies. Consult standard references for appropriate age- and gender-specific 
hearing norms, e.g., Morrell, et al. Age- and gender-specific reference ranges for hearing level and longitudinal changes in hearing level. Journal of the Acoustical Society of America 
100:1949-1967, 1996; or Shotland, et al. Recommendations for cancer prevention trials using potentially ototoxic test agents. Journal of Clinical Oncology 19:1658-1663, 2001.  
In the absence of a baseline prior to initial treatment, subsequent audiograms should be referenced to an appropriate database of normals. ANSI. (1996) 
American National Standard: Determination of occupational noise exposure and estimation of noise-induced hearing impairment, ANSI S 3.44-1996. (Standard S 3.44). New York: 
American National Standards Institute. The recommended ANSI S3.44 database is Annex B. 

 
BLOOD/BONE MARROW 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 4 - 
March 31, 2003, Publish Date: August 9, 2006 
Bone marrow cellularity 
Bone marrow cellularity 
Mildly hypocellular or  
≤25% reduction from 
normal cellularity for age 
Moderately hypocellular 
or >25 – ≤50% reduction 
from normal cellularity for 
age  
Severely hypocellular or 
>50 – ≤75% reduction 
cellularity from normal for 
age  
— 
Death 
CD4 count  
CD4 count 
<LLN – 500/mm3 
<LLN – 0.5 x 109 /L 
<500 – 200/mm3  
<0.5 – 0.2 x 109 /L 
<200 – 50/mm3  
<0.2 x 0.05 – 109 /L 
<50/mm3  
<0.05 x 109 /L 
Death 
Haptoglobin  
Haptoglobin 
<LLN  
— 
Absent 
— 
Death 
Hemoglobin  
Hemoglobin 
<LLN – 10.0 g/dL  
<LLN – 6.2 mmol/L  
<LLN – 100 g/L 
<10.0 – 8.0 g/dL 
<6.2 – 4.9 mmol/L  
<100 – 80g/L 
<8.0 – 6.5 g/dL 
<4.9 – 4.0 mmol/L 
<80 – 65 g/L 
<6.5 g/dL 
<4.0 mmol/L  
<65 g/L 
Death 
Hemolysis (e.g., immune 
hemolytic anemia, drug-
related hemolysis) 
Hemolysis 
Laboratory evidence of 
hemolysis only (e.g., 
direct antiglobulin test 
[DAT, Coombs’] 
schistocytes) 
Evidence of red cell 
destruction and ≥2 gm 
decrease in hemoglobin, 
no transfusion 
Transfusion or medical 
intervention (e.g., 
steroids) indicated 
Catastrophic 
consequences of 
hemolysis (e.g., renal 
failure, hypotension, 
bronchospasm, 
emergency splenectomy) 
Death 
ALSO CONSIDER: Haptoglobin; Hemoglobin. 
Iron overload 
Iron overload 
— 
Asymptomatic iron 
overload, intervention not 
indicated  
Iron overload, 
intervention indicated  
Organ impairment (e.g., 
endocrinopathy, 
cardiopathy) 
Death 
Leukocytes (total WBC) 
Leukocytes 
<LLN – 3000/mm3 
<LLN – 3.0 x 109 /L  
<3000 – 2000/mm3 
<3.0 – 2.0 x 109 /L 
<2000 – 1000/mm3 
<2.0 – 1.0 x 109 /L 
<1000/mm3  
<1.0 x 109 /L 
Death 
Lymphopenia  
Lymphopenia 
<LLN – 800/mm3 
<LLN x 0.8 – 109 /L 
<800 – 500/mm3 
<0.8 – 0.5 x 109 /L 
<500 – 200 mm3 
<0.5 – 0.2 x 109 /L 
<200/mm3 
<0.2 x 109 /L 
Death 
Myelodysplasia 
Myelodysplasia 
— 
— 
Abnormal marrow 
cytogenetics (marrow 
blasts ≤5%)  
RAEB or RAEB-T 
(marrow blasts >5%) 
Death 
Neutrophils/granulocytes 
(ANC/AGC) 
Neutrophils 
<LLN – 1500/mm3  
<LLN – 1.5 x 109 /L 
<1500 – 1000/mm3 
<1.5 – 1.0 x 109 /L  
<1000 – 500/mm3 
<1.0 – 0.5 x 109 /L 
<500/mm3 
<0.5 x 109 /L 
Death 
Platelets 
Platelets 
<LLN – 75,000/mm3 
<LLN – 75.0 x 109 /L 
<75,000 – 50,000/mm3 
<75.0 – 50.0 x 109 /L 
<50,000 – 25,000/mm3  
<50.0 – 25.0 x 109 /L 
<25,000/mm3  
<25.0 x 109 /L 
Death 
Splenic function 
Splenic function 
Incidental findings (e.g., 
Howell-Jolly bodies) 
Prophylactic antibiotics 
indicated 
—  
Life-threatening 
consequences 
Death 
Blood/Bone Marrow – 
Other (Specify, __) 
Blood – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
CARDIAC ARRHYTHMIA 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 5 - 
March 31, 2003, Publish Date: August 9, 2006 
Conduction abnormality/ 
atrioventricular heart 
block  
– Select:  
Conduction abnormality 
– Select 
Asymptomatic, 
intervention not indicated 
– Asystole 
– AV Block-First degree 
– AV Block-Second degree Mobitz Type I (Wenckebach)  
– AV Block-Second degree Mobitz Type II 
– AV Block-Third degree (Complete AV block) 
– Conduction abnormality NOS 
– Sick Sinus Syndrome  
– Stokes-Adams Syndrome 
– Wolff-Parkinson-White Syndrome 
Non-urgent medical 
intervention indicated 
Incompletely controlled 
medically or controlled  
with device (e.g., 
pacemaker) 
Life-threatening (e.g., 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
Death 
Palpitations 
Palpitations 
Present 
Present with associated 
symptoms (e.g., 
lightheadedness, 
shortness of breath) 
— 
— 
— 
REMARK: Grade palpitations only in the absence of a documented arrhythmia. 
Prolonged QTc interval 
Prolonged QTc 
QTc >0.45 – 0.47 second 
 QTc >0.47 – 0.50 
second; ≥0.06 second 
above baseline 
QTc >0.50 second 
QTc >0.50 second; life-
threatening signs or 
symptoms (e.g., 
arrhythmia, CHF, 
hypotension, shock 
syncope); Torsade de 
pointes 
Death 
Supraventricular and 
nodal arrhythmia  
– Select: 
Supraventricular 
arrhythmia – Select 
Asymptomatic, 
intervention not indicated 
Non-urgent medical 
intervention indicated 
– Atrial fibrillation 
– Atrial flutter  
– Atrial tachycardia/Paroxysmal Atrial Tachycardia 
– Nodal/Junctional 
– Sinus arrhythmia  
– Sinus bradycardia 
– Sinus tachycardia  
– Supraventricular arrhythmia NOS 
– Supraventricular extrasystoles (Premature Atrial Contractions; Premature Nodal/Junctional Contractions) 
– Supraventricular tachycardia 
Symptomatic and 
incompletely controlled 
medically, or controlled 
with device (e.g., 
pacemaker) 
Life-threatening (e.g., 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
Death 
NAVIGATION NOTE: Syncope is graded as Syncope (fainting) in the NEUROLOGY CATEGORY. 

 
CARDIAC ARRHYTHMIA 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 6 - 
March 31, 2003, Publish Date: August 9, 2006 
Vasovagal episode 
Vasovagal episode 
— 
Present without loss of 
consciousness 
Present with loss of 
consciousness 
Life-threatening 
consequences  
Death 
Ventricular arrhythmia 
– Select: 
Ventricular arrhythmia 
– Select 
– Bigeminy 
– Idioventricular rhythm 
– PVCs 
– Torsade de pointes 
– Trigeminy 
– Ventricular arrhythmia NOS 
– Ventricular fibrillation  
– Ventricular flutter 
– Ventricular tachycardia 
Asymptomatic, no 
intervention indicated 
Non-urgent medical 
intervention indicated 
Symptomatic and 
incompletely controlled 
medically or controlled 
with device (e.g., 
defibrillator) 
Life-threatening (e.g., 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
Death 
Cardiac Arrhythmia  
– Other (Specify, __) 
Cardiac Arrhythmia – 
Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling  
Death 

 
CARDIAC GENERAL 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 7 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Angina is graded as Cardiac ischemia/infarction in the CARDIAC GENERAL CATEGORY. 
Cardiac 
ischemia/infarction 
Cardiac 
ischemia/infarction 
Asymptomatic arterial 
narrowing without 
ischemia 
Asymptomatic and testing 
suggesting ischemia; 
stable angina  
Symptomatic and testing 
consistent with ischemia; 
unstable angina; 
intervention indicated 
Acute myocardial 
infarction 
Death 
Cardiac troponin I (cTnI) 
cTnI 
— 
— 
Levels consistent with 
unstable angina as 
defined by the 
manufacturer 
Levels consistent with 
myocardial infarction as 
defined by the 
manufacturer 
Death 
Cardiac troponin T (cTnT) 
cTnT 
0.03 – <0.05 ng/mL 
0.05 – <0.1 ng/mL 
0.1 – <0.2 ng/mL 
0.2 ng/mL 
Death 
Cardiopulmonary arrest, 
cause unknown 
(non-fatal) 
Cardiopulmonary arrest 
— 
— 
— 
Life-threatening  
— 
REMARK: Grade 4 (non-fatal) is the only appropriate grade. CTCAE provides three alternatives for reporting Death: 
1. A CTCAE term associated with Grade 5.  
2. A CTCAE 'Other (Specify, __)’ within any CATEGORY. 
3. Death not associated with CTCAE term – Select in the DEATH CATEGORY. 
NAVIGATION NOTE: Chest pain (non-cardiac and non-pleuritic) is graded as Pain – Select in the PAIN CATEGORY. 
NAVIGATION NOTE: CNS ischemia is graded as CNS cerebrovascular ischemia in the NEUROLOGY CATEGORY. 
Hypertension 
Hypertension 
Asymptomatic, transient 
(<24 hrs) increase by >20 
mmHg (diastolic) or to 
>150/100 if previously 
WNL; intervention not 
indicated  
Pediatric: 
Asymptomatic, transient 
(<24 hrs) BP increase 
>ULN; intervention not 
indicated 
Recurrent or persistent 
(≥24 hrs) or symptomatic 
increase by >20 mmHg 
(diastolic) or to >150/100 
if previously WNL; 
monotherapy may be 
indicated  
Pediatric: 
Recurrent or persistent 
(≥24 hrs) BP >ULN; 
monotherapy may be 
indicated 
Requiring more than one 
drug or more intensive 
therapy than previously 
Pediatric: 
Same as adult 
Life-threatening 
consequences (e.g., 
hypertensive crisis) 
Pediatric: 
Same as adult 
Death 
REMARK: Use age and gender-appropriate normal values >95th percentile ULN for pediatric patients. 

 
CARDIAC GENERAL 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 8 - 
March 31, 2003, Publish Date: August 9, 2006 
Hypotension 
Hypotension 
Changes, intervention not 
indicated 
Brief (<24 hrs) fluid 
replacement or other 
therapy; no physiologic 
consequences 
Sustained (≥24 hrs) 
therapy, resolves without 
persisting physiologic 
consequences 
Shock (e.g., acidemia; 
impairment of vital organ 
function)  
Death 
ALSO CONSIDER: Syncope (fainting). 
Left ventricular diastolic 
dysfunction 
Left ventricular diastolic 
dysfunction 
Asymptomatic diagnostic 
finding; intervention not 
indicated 
Asymptomatic, 
intervention indicated 
Symptomatic CHF 
responsive to intervention 
Refractory CHF, poorly 
controlled; intervention 
such as ventricular assist 
device or heart transplant 
indicated  
Death 
Left ventricular systolic 
dysfunction 
Left ventricular systolic 
dysfunction 
Asymptomatic, resting 
ejection fraction (EF)  
<60 – 50%; shortening 
fraction (SF) <30 – 24% 
Asymptomatic, resting  
EF <50 – 40%; 
SF <24 – 15% 
Symptomatic CHF 
responsive to 
intervention; 
EF <40 – 20% 
SF <15% 
Refractory CHF or poorly 
controlled; EF <20%; 
intervention such as 
ventricular assist device, 
ventricular reduction 
surgery, or heart 
transplant indicated 
Death 
NAVIGATION NOTE: Myocardial infarction is graded as Cardiac ischemia/infarction in the CARDIAC GENERAL CATEGORY. 
Myocarditis 
Myocarditis 
— 
— 
CHF responsive to 
intervention 
Severe or refractory CHF 
Death 
Pericardial effusion 
(non-malignant) 
Pericardial effusion 
Asymptomatic effusion  
—  
Effusion with physiologic 
consequences 
Life-threatening 
consequences (e.g., 
tamponade); emergency 
intervention indicated 
Death 
Pericarditis 
Pericarditis 
Asymptomatic, ECG or 
physical exam (rub) 
changes consistent with 
pericarditis 
Symptomatic pericarditis 
(e.g., chest pain) 
Pericarditis with 
physiologic 
consequences (e.g., 
pericardial constriction) 
Life-threatening 
consequences; 
emergency intervention 
indicated 
Death 
NAVIGATION NOTE: Pleuritic pain is graded as Pain – Select in the PAIN CATEGORY. 
Pulmonary hypertension 
Pulmonary hypertension 
Asymptomatic without 
therapy 
Asymptomatic, therapy 
indicated 
Symptomatic 
hypertension, responsive 
to therapy 
Symptomatic 
hypertension, poorly 
controlled 
Death 
Restrictive 
cardiomyopathy  
Restrictive 
cardiomyopathy  
Asymptomatic, therapy 
not indicated 
Asymptomatic, therapy 
indicated 
Symptomatic CHF 
responsive to intervention 
Refractory CHF, poorly 
controlled; intervention 
such as ventricular assist 
device, or heart 
transplant indicated  
Death 

 
CARDIAC GENERAL 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 9 - 
March 31, 2003, Publish Date: August 9, 2006 
Right ventricular 
dysfunction 
(cor pulmonale) 
Right ventricular 
dysfunction 
Asymptomatic without 
therapy 
Asymptomatic, therapy 
indicated 
Symptomatic cor 
pulmonale, responsive to 
intervention 
Symptomatic cor 
pulmonale poorly 
controlled; intervention 
such as ventricular assist 
device, or heart 
transplant indicated  
Death 
Valvular heart disease 
Valvular heart disease 
Asymptomatic valvular 
thickening with or without 
mild valvular regurgitation 
or stenosis; treatment 
other than endocarditis 
prophylaxis not indicated 
Asymptomatic; moderate 
regurgitation or stenosis 
by imaging 
Symptomatic; severe 
regurgitation or stenosis; 
symptoms controlled with 
medical therapy 
Life-threatening; 
disabling; intervention 
(e.g., valve replacement, 
valvuloplasty) indicated 
Death 
Cardiac General – Other 
(Specify, __) 
Cardiac General – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
COAGULATION 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 10 - 
March 31, 2003, Publish Date: August 9, 2006 
DIC (disseminated 
intravascular coagulation) 
DIC 
— 
Laboratory findings with 
no bleeding 
Laboratory findings and 
bleeding 
Laboratory findings, life-
threatening or disabling 
consequences (e.g., CNS 
hemorrhage, organ 
damage, or 
hemodynamically 
significant blood loss) 
Death 
REMARK: DIC (disseminated intravascular coagulation) must have increased fibrin split products or D-dimer.  
ALSO CONSIDER: Platelets. 
 
Fibrinogen  
Fibrinogen 
<1.0 – 0.75 x LLN 
or <25% decrease from 
baseline 
<0.75 – 0.5 x LLN 
or 25 – <50% decrease 
from baseline 
<0.5 – 0.25 x LLN 
or 50 – <75% decrease 
from baseline 
<0.25 x LLN  
or 75% decrease from 
baseline or absolute 
value <50 mg/dL  
Death 
REMARK: Use % decrease only when baseline is <LLN (local laboratory value). 
INR (International 
Normalized Ratio of 
prothrombin time) 
INR 
 
>1 – 1.5 x ULN 
>1.5 – 2 x ULN 
>2 x ULN 
— 
— 
ALSO CONSIDER: Hemorrhage, CNS; Hemorrhage, GI – Select; Hemorrhage, GU – Select; Hemorrhage, pulmonary/upper respiratory – Select. 
PTT (Partial 
Thromboplastin Time)  
PTT 
>1 – 1.5 x ULN 
>1.5 – 2 x ULN 
>2 x ULN 
— 
— 
ALSO CONSIDER: Hemorrhage, CNS; Hemorrhage, GI – Select; Hemorrhage, GU – Select; Hemorrhage, pulmonary/upper respiratory – Select. 
Thrombotic 
microangiopathy (e.g., 
thrombotic 
thrombocytopenic 
purpura [TTP] or 
hemolytic uremic 
syndrome [HUS]) 
Thrombotic 
microangiopathy 
Evidence of RBC 
destruction 
(schistocytosis) without 
clinical consequences 
— 
Laboratory findings 
present with clinical 
consequences (e.g., renal 
insufficiency, petechiae) 
Laboratory findings and 
life-threatening or 
disabling consequences, 
(e.g., CNS hemorrhage/ 
bleeding or thrombosis/ 
embolism or renal failure) 
Death 
REMARK: Must have microangiopathic changes on blood smear (e.g., schistocytes, helmet cells, red cell fragments). 
ALSO CONSIDER: Creatinine; Hemoglobin; Platelets. 
Coagulation – Other 
(Specify, __) 
Coagulation – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
CONSTITUTIONAL SYMPTOMS 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 11 - 
March 31, 2003, Publish Date: August 9, 2006 
Fatigue  
(asthenia, lethargy, 
malaise) 
Fatigue 
Mild fatigue over baseline 
Moderate or causing 
difficulty performing some 
ADL 
Severe fatigue interfering 
with ADL 
Disabling 
— 
Fever  
(in the absence of 
neutropenia, where 
neutropenia is defined as 
ANC <1.0 x 109/L) 
Fever 
38.0 – 39.0°C  
(100.4 – 102.2°F) 
>39.0 – 40.0°C 
(102.3 – 104.0°F)  
>40.0°C 
(>104.0°F) for ≤24 hrs  
>40.0°C 
(>104.0°F) for >24 hrs 
Death 
REMARK: The temperature measurements listed are oral or tympanic. 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever).  
NAVIGATION NOTE: Hot flashes are graded as Hot flashes/flushes in the ENDOCRINE CATEGORY. 
Hypothermia 
Hypothermia 
— 
35 – >32°C 
95 – >89.6°F 
32 – >28°C  
89.6 – >82.4° F 
≤28 °C  
82.4°F or life-threatening 
consequences (e.g., 
coma, hypotension, 
pulmonary edema, 
acidemia, ventricular 
fibrillation) 
Death 
Insomnia 
Insomnia 
Occasional difficulty 
sleeping, not interfering 
with function 
Difficulty sleeping, 
interfering with function 
but not interfering with 
ADL 
Frequent difficulty 
sleeping, interfering with 
ADL 
Disabling 
— 
REMARK: If pain or other symptoms interfere with sleep, do NOT grade as insomnia. Grade primary event(s) causing insomnia. 
Obesity2 
Obesity 
— 
BMI 25 – 29.9 kg/m2 
BMI 30 – 39.99 kg/m2 
BMI ≥40 kg/m2 
— 
REMARK: BMI = (weight [kg]) / (height [m])2 
Odor  
(patient odor) 
Patient odor 
Mild odor 
Pronounced odor 
— 
— 
— 
Rigors/chills 
Rigors/chills 
Mild 
Moderate, narcotics 
indicated 
Severe or prolonged, not 
responsive to narcotics 
— 
— 
                                            
2 NHLBI Obesity Task Force. "Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults," The Evidence Report, Obes Res 6:51S-
209S, 1998.  

 
CONSTITUTIONAL SYMPTOMS 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 12 - 
March 31, 2003, Publish Date: August 9, 2006 
Sweating  
(diaphoresis) 
Sweating  
Mild and occasional 
Frequent or drenching 
— 
— 
— 
ALSO CONSIDER: Hot flashes/flushes.  
Weight gain  
Weight gain 
5 – <10% of baseline 
10 – <20% of baseline 
≥20% of baseline 
— 
— 
REMARK: Edema, depending on etiology, is graded in the CARDIAC GENERAL or LYMPHATICS CATEGORIES. 
ALSO CONSIDER: Ascites (non-malignant); Pleural effusion (non-malignant). 
Weight loss 
Weight loss 
5 to <10% from baseline; 
intervention not indicated 
10 – <20% from baseline; 
nutritional support 
indicated 
≥20% from baseline; tube 
feeding or TPN indicated 
— 
— 
Constitutional Symptoms 
– Other (Specify, __) 
Constitutional Symptoms 
– Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
DEATH 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 13 - 
March 31, 2003, Publish Date: August 9, 2006 
Death not associated with 
CTCAE term  
– Select: 
Death not associated with 
CTCAE term – Select 
– Death NOS 
– Disease progression NOS 
– Multi-organ failure 
– Sudden death 
— 
— 
— 
— 
Death 
REMARK: Grade 5 is the only appropriate grade. 'Death not associated with CTCAE term – Select' is to be used where a death: 
1. Cannot be attributed to a CTCAE term associated with Grade 5. 
2. Cannot be reported within any CATEGORY using a CTCAE 'Other (Specify, __)’.  

 
DERMATOLOGY/SKIN 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 14 - 
March 31, 2003, Publish Date: August 9, 2006 
Atrophy, skin 
Atrophy, skin 
Detectable 
Marked 
— 
— 
— 
Atrophy, subcutaneous 
fat 
Atrophy, subcutaneous 
fat 
Detectable 
Marked 
— 
— 
— 
ALSO CONSIDER: Induration/fibrosis (skin and subcutaneous tissue). 
Bruising  
(in absence of Grade 3 or 
4 thrombocytopenia) 
Bruising  
Localized or in a 
dependent area 
Generalized 
— 
— 
— 
Burn 
Burn 
Minimal symptoms; 
intervention not indicated  
Medical intervention; 
minimal debridement 
indicated  
Moderate to major 
debridement or 
reconstruction indicated  
Life-threatening 
consequences 
Death 
REMARK: Burn refers to all burns including radiation, chemical, etc. 
Cheilitis 
Cheilitis 
Asymptomatic 
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
— 
— 
Dry skin 
Dry skin 
Asymptomatic 
Symptomatic, not 
interfering with ADL 
Interfering with ADL 
— 
— 
Flushing 
Flushing 
Asymptomatic 
Symptomatic 
— 
— 
— 
Hair loss/alopecia 
(scalp or body) 
Alopecia 
Thinning or patchy 
Complete 
— 
— 
— 
Hyperpigmentation 
Hyperpigmentation 
Slight or localized 
Marked or generalized 
— 
— 
— 
Hypopigmentation 
Hypopigmentation 
Slight or localized 
Marked or generalized 
— 
— 
— 
Induration/fibrosis 
(skin and subcutaneous 
tissue) 
Induration  
Increased density on 
palpation 
Moderate impairment of 
function not interfering 
with ADL; marked 
increase in density and 
firmness on palpation 
with or without minimal 
retraction 
Dysfunction interfering 
with ADL; very marked 
density, retraction or 
fixation 
— 
— 
ALSO CONSIDER: Fibrosis-cosmesis; Fibrosis-deep connective tissue.  
Injection site reaction/ 
extravasation changes 
Injection site reaction 
Pain; itching; erythema 
Pain or swelling, with 
inflammation or phlebitis 
Ulceration or necrosis 
that is severe; operative 
intervention indicated  
— 
— 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever); Ulceration. 

 
DERMATOLOGY/SKIN 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 15 - 
March 31, 2003, Publish Date: August 9, 2006 
Nail changes 
Nail changes 
Discoloration; ridging 
(koilonychias); pitting 
Partial or complete loss of 
nail(s); pain in nailbed(s) 
Interfering with ADL  
— 
— 
NAVIGATION NOTE: Petechiae is graded as Petechiae/purpura (hemorrhage/bleeding into skin or mucosa) in the HEMORRHAGE/BLEEDING CATEGORY. 
Photosensitivity 
Photosensitivity 
Painless erythema 
Painful erythema 
Erythema with 
desquamation 
Life-threatening; disabling 
Death 
Pruritus/itching 
Pruritus 
Mild or localized 
Intense or widespread 
Intense or widespread 
and interfering with ADL  
— 
— 
ALSO CONSIDER: Rash/desquamation. 
Rash/desquamation  
Rash 
Macular or papular 
eruption or erythema 
without associated 
symptoms 
Macular or papular 
eruption or erythema with 
pruritus or other 
associated symptoms; 
localized desquamation 
or other lesions covering 
<50% of body surface 
area (BSA) 
Severe, generalized 
erythroderma or macular, 
papular or vesicular 
eruption; desquamation 
covering ≥50% BSA 
Generalized exfoliative, 
ulcerative, or bullous 
dermatitis 
Death 
REMARK: Rash/desquamation may be used for GVHD. 
Rash:  
acne/acneiform 
Acne 
Intervention not indicated  
Intervention indicated 
Associated with pain, 
disfigurement, ulceration, 
or desquamation 
— 
Death 
Rash:  
dermatitis associated with 
radiation  
– Select: 
– Chemoradiation 
– Radiation 
Dermatitis – Select  
Faint erythema or dry 
desquamation 
Moderate to brisk 
erythema; patchy moist 
desquamation, mostly 
confined to skin folds and 
creases; moderate 
edema 
Moist desquamation other 
than skin folds and 
creases; bleeding 
induced by minor trauma 
or abrasion 
Skin necrosis or 
ulceration of full thickness 
dermis; spontaneous 
bleeding from involved 
site  
Death 
Rash:  
erythema multiforme 
(e.g., Stevens-Johnson 
syndrome, toxic 
epidermal necrolysis) 
Erythema multiforme 
— 
Scattered, but not 
generalized eruption 
Severe (e.g., generalized 
rash or painful stomatitis); 
IV fluids, tube feedings, 
or TPN indicated 
Life-threatening; disabling 
Death 
Rash:  
hand-foot skin reaction 
Hand-foot 
Minimal skin changes or 
dermatitis (e.g., 
erythema) without pain  
Skin changes (e.g., 
peeling, blisters, 
bleeding, edema) or pain, 
not interfering with 
function  
Ulcerative dermatitis or 
skin changes with pain 
interfering with function  
— 
— 

 
DERMATOLOGY/SKIN 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 16 - 
March 31, 2003, Publish Date: August 9, 2006 
Skin breakdown/ 
decubitus ulcer 
Decubitus  
— 
Local wound care; 
medical intervention 
indicated 
Operative debridement or 
other invasive 
intervention indicated 
(e.g., hyperbaric oxygen)  
Life-threatening 
consequences; major 
invasive intervention 
indicated (e.g., tissue 
reconstruction, flap, or 
grafting) 
Death 
REMARK: Skin breakdown/decubitus ulcer is to be used for loss of skin integrity or decubitus ulcer from pressure or as the result of operative or medical intervention. 
Striae 
Striae 
Mild 
Cosmetically significant 
— 
— 
— 
Telangiectasia 
Telangiectasia 
Few 
Moderate number 
Many and confluent 
— 
— 
Ulceration 
Ulceration 
— 
Superficial ulceration  
<2 cm size; local wound 
care; medical intervention 
indicated 
Ulceration ≥2 cm size; 
operative debridement, 
primary closure or other 
invasive intervention 
indicated (e.g., hyperbaric 
oxygen)  
Life-threatening 
consequences; major 
invasive intervention 
indicated (e.g., complete 
resection, tissue 
reconstruction, flap, or 
grafting) 
Death 
Urticaria  
(hives, welts, wheals) 
Urticaria 
Intervention not indicated 
Intervention indicated for 
<24 hrs 
Intervention indicated for 
≥24 hrs 
— 
— 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever). 
Wound complication, 
non-infectious  
Wound complication, 
non-infectious 
Incisional separation of  
≤25% of wound, no 
deeper than superficial 
fascia 
Incisional separation 
>25% of wound with local 
care; asymptomatic 
hernia 
Symptomatic hernia 
without evidence of 
strangulation; fascial 
disruption/dehiscence 
without evisceration; 
primary wound closure or 
revision by operative 
intervention indicated; 
hospitalization or 
hyperbaric oxygen 
indicated 
Symptomatic hernia with 
evidence of strangulation; 
fascial disruption with 
evisceration; major 
reconstruction flap, 
grafting, resection, or 
amputation indicated 
Death 
REMARK: Wound complication, non-infectious is to be used for separation of incision, hernia, dehiscence, evisceration, or second surgery for wound revision. 
Dermatology/Skin – Other 
(Specify, __) 
Dermatology – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
ENDOCRINE 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 17 - 
March 31, 2003, Publish Date: August 9, 2006 
Adrenal insufficiency 
Adrenal insufficiency 
Asymptomatic, 
intervention not indicated 
Symptomatic, intervention 
indicated 
Hospitalization  
Life-threatening; disabling 
Death 
REMARK: Adrenal insufficiency includes any of the following signs and symptoms: abdominal pain, anorexia, constipation, diarrhea, hypotension, pigmentation of mucous membranes, 
pigmentation of skin, salt craving, syncope (fainting), vitiligo, vomiting, weakness, weight loss. Adrenal insufficiency must be confirmed by laboratory studies (low cortisol frequently 
accompanied by low aldosterone). 
ALSO CONSIDER: Potassium, serum-high (hyperkalemia); Thyroid function, low (hypothyroidism). 
Cushingoid appearance 
(e.g., moon face, buffalo 
hump, centripetal obesity, 
cutaneous striae) 
Cushingoid  
— 
Present 
— 
— 
— 
ALSO CONSIDER: Glucose, serum-high (hyperglycemia); Potassium, serum-low (hypokalemia). 
Feminization of male 
Feminization of male 
— 
— 
Present 
— 
— 
NAVIGATION NOTE: Gynecomastia is graded in the SEXUAL/REPRODUCTIVE FUNCTION CATEGORY. 
Hot flashes/flushes3 
Hot flashes 
Mild  
Moderate  
Interfering with ADL 
— 
— 
Masculinization of female 
Masculinization of female 
— 
— 
Present 
— 
— 
Neuroendocrine: 
ACTH deficiency 
ACTH  
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL; hospitalization 
indicated 
Life-threatening 
consequences (e.g., 
severe hypotension) 
Death 
Neuroendocrine: 
ADH secretion 
abnormality (e.g., SIADH 
or low ADH) 
ADH 
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL 
Life-threatening 
consequences 
Death 
Neuroendocrine: 
gonadotropin secretion 
abnormality 
Gonadotropin 
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL; osteopenia; 
fracture; infertility 
— 
— 
Neuroendocrine:  
growth hormone 
secretion abnormality 
Growth hormone  
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
— 
— 
— 
Neuroendocrine:  
prolactin hormone 
secretion abnormality 
Prolactin  
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL; amenorrhea; 
galactorrhea 
— 
Death 
                                            
3 Sloan JA, Loprinzi CL, Novotny PJ, Barton DL, Lavasseur BI, Windschitl HJ, "Methodologic Lessons Learned from Hot Flash Studies," J Clin Oncol 2001 Dec 1;19(23):4280-90 

 
ENDOCRINE 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 18 - 
March 31, 2003, Publish Date: August 9, 2006 
Pancreatic endocrine:  
glucose intolerance 
Diabetes 
Asymptomatic, 
intervention not indicated 
Symptomatic; dietary 
modification or oral agent 
indicated 
Symptoms interfering with 
ADL; insulin indicated 
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar non-ketotic 
coma)  
Death 
Parathyroid function, low 
(hypoparathyroidism) 
Hypoparathyroidism 
Asymptomatic, 
intervention not indicated 
Symptomatic; intervention 
indicated 
— 
— 
— 
Thyroid function, high 
(hyperthyroidism, 
thyrotoxicosis) 
Hyperthyroidism  
Asymptomatic, 
intervention not indicated 
Symptomatic, not 
interfering with ADL; 
thyroid suppression 
therapy indicated 
Symptoms interfering with 
ADL; hospitalization 
indicated  
Life-threatening 
consequences (e.g., 
thyroid storm) 
Death 
Thyroid function, low 
(hypothyroidism) 
Hypothyroidism 
Asymptomatic, 
intervention not indicated 
Symptomatic, not 
interfering with ADL; 
thyroid replacement 
indicated 
Symptoms interfering with 
ADL; hospitalization 
indicated  
Life-threatening 
myxedema coma 
Death 
Endocrine – Other  
(Specify, __) 
Endocrine – Other  
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
GASTROINTESTINAL 
Page 1 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 19 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Abdominal pain or cramping is graded as Pain – Select in the PAIN CATEGORY. 
Anorexia 
Anorexia 
Loss of appetite without 
alteration in eating habits 
Oral intake altered 
without significant weight 
loss or malnutrition; oral 
nutritional supplements 
indicated 
Associated with 
significant weight loss or 
malnutrition (e.g., 
inadequate oral caloric 
and/or fluid intake); IV 
fluids, tube feedings or 
TPN indicated 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Weight loss. 
Ascites (non-malignant) 
Ascites 
Asymptomatic 
Symptomatic, medical 
intervention indicated 
Symptomatic, invasive 
procedure indicated 
Life-threatening 
consequences 
Death 
REMARK: Ascites (non-malignant) refers to documented non-malignant ascites or unknown etiology, but unlikely malignant, and includes chylous ascites. 
Colitis 
Colitis 
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain; mucus 
or blood in stool 
Abdominal pain, fever, 
change in bowel habits 
with ileus; peritoneal 
signs 
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis, toxic 
megacolon) 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select.  
Constipation 
Constipation 
Occasional or intermittent 
symptoms; occasional 
use of stool softeners, 
laxatives, dietary 
modification, or enema 
Persistent symptoms with 
regular use of laxatives 
or enemas indicated 
Symptoms interfering 
with ADL; obstipation 
with manual evacuation 
indicated  
Life-threatening 
consequences (e.g., 
obstruction, toxic 
megacolon) 
Death 
ALSO CONSIDER: Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation); Obstruction, GI – Select. 
Dehydration 
Dehydration 
Increased oral fluids 
indicated; dry mucous 
membranes; diminished 
skin turgor 
IV fluids indicated <24 
hrs 
IV fluids indicated ≥24 hrs 
Life-threatening 
consequences (e.g., 
hemodynamic collapse) 
Death 
ALSO CONSIDER: Diarrhea; Hypotension; Vomiting. 
Dental:  
dentures or prosthesis 
Dentures  
Minimal discomfort, no 
restriction in activities  
Discomfort preventing 
use in some activities 
(e.g., eating), but not 
others (e.g., speaking) 
Unable to use dentures 
or prosthesis at any time 
— 
— 

 
GASTROINTESTINAL 
Page 2 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 20 - 
March 31, 2003, Publish Date: August 9, 2006 
Dental:  
periodontal disease  
Periodontal  
Gingival recession or 
gingivitis; limited bleeding 
on probing; mild local 
bone loss 
Moderate gingival 
recession or gingivitis; 
multiple sites of bleeding 
on probing; moderate 
bone loss 
Spontaneous bleeding; 
severe bone loss with or 
without tooth loss; 
osteonecrosis of maxilla 
or mandible  
— 
— 
REMARK: Severe periodontal disease leading to osteonecrosis is graded as Osteonecrosis (avascular necrosis) in the MUSCULOSKELETAL CATEGORY. 
Dental: 
teeth  
Teeth 
Surface stains; dental 
caries; restorable, without 
extractions 
Less than full mouth 
extractions; tooth fracture 
or crown amputation or 
repair indicated 
Full mouth extractions 
indicated 
— 
— 
Dental:  
teeth development 
Teeth development 
Hypoplasia of tooth or 
enamel not interfering 
with function 
Functional impairment 
correctable with oral 
surgery 
Maldevelopment with 
functional impairment not 
surgically correctable 
— 
— 
Diarrhea 
Diarrhea 
Increase of <4 stools per 
day over baseline; mild 
increase in ostomy output 
compared to baseline 
Increase of 4 – 6 stools 
per day over baseline; IV 
fluids indicated <24hrs; 
moderate increase in 
ostomy output compared 
to baseline; not 
interfering with ADL 
Increase of ≥7 stools per 
day over baseline; 
incontinence; IV fluids 
≥24 hrs; hospitalization; 
severe increase in 
ostomy output compared 
to baseline; interfering 
with ADL 
Life-threatening 
consequences (e.g., 
hemodynamic collapse) 
Death 
REMARK: Diarrhea includes diarrhea of small bowel or colonic origin, and/or ostomy diarrhea. 
ALSO CONSIDER: Dehydration; Hypotension. 
Distension/bloating, 
abdominal 
Distension 
Asymptomatic  
Symptomatic, but not 
interfering with GI 
function 
Symptomatic, interfering 
with GI function 
— 
— 
ALSO CONSIDER: Ascites (non-malignant); Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation); Obstruction, GI – Select.  

 
GASTROINTESTINAL 
Page 3 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 21 - 
March 31, 2003, Publish Date: August 9, 2006 
Dry mouth/salivary gland 
(xerostomia) 
Dry mouth 
Symptomatic (dry or thick 
saliva) without significant 
dietary alteration; 
unstimulated saliva flow 
>0.2 ml/min 
Symptomatic and 
significant oral intake 
alteration (e.g., copious 
water, other lubricants, 
diet limited to purees 
and/or soft, moist foods); 
unstimulated saliva 
0.1 to 0.2 ml/min 
Symptoms leading to 
inability to adequately 
aliment orally; IV fluids, 
tube feedings, or TPN 
indicated; unstimulated 
saliva <0.1 ml/min 
— 
— 
REMARK: Dry mouth/salivary gland (xerostomia) includes descriptions of grade using both subjective and objective assessment parameters. Record this event consistently throughout 
a patient’s participation on study. If salivary flow measurements are used for initial assessment, subsequent assessments must use salivary flow. 
ALSO CONSIDER: Salivary gland changes/saliva.  
Dysphagia 
(difficulty swallowing) 
Dysphagia 
Symptomatic, able to eat 
regular diet  
Symptomatic and altered 
eating/swallowing (e.g., 
altered dietary habits, 
oral supplements); IV 
fluids indicated <24 hrs 
Symptomatic and 
severely altered 
eating/swallowing (e.g., 
inadequate oral caloric or 
fluid intake); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences (e.g., 
obstruction, perforation) 
 
Death 
REMARK: Dysphagia (difficulty swallowing) is to be used for swallowing difficulty from oral, pharyngeal, esophageal, or neurologic origin. Dysphagia requiring dilation is graded as 
Stricture/stenosis (including anastomotic), GI – Select. 
ALSO CONSIDER: Dehydration; Esophagitis. 
Enteritis  
(inflammation of the small 
bowel) 
Enteritis 
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain; mucus 
or blood in stool 
Abdominal pain, fever, 
change in bowel habits 
with ileus; peritoneal 
signs 
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis) 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select; Typhlitis (cecal inflammation).  
Esophagitis 
Esophagitis 
Asymptomatic pathologic, 
radiographic, or 
endoscopic findings only 
Symptomatic; altered 
eating/swallowing (e.g., 
altered dietary habits, 
oral supplements); IV 
fluids indicated <24 hrs 
Symptomatic and 
severely altered 
eating/swallowing (e.g., 
inadequate oral caloric or 
fluid intake); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences 
Death 
REMARK: Esophagitis includes reflux esophagitis.  
ALSO CONSIDER: Dysphagia (difficulty swallowing). 

 
GASTROINTESTINAL 
Page 4 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 22 - 
March 31, 2003, Publish Date: August 9, 2006 
Fistula, GI 
– Select: 
Fistula, GI – Select  
– Abdomen NOS 
– Anus 
– Biliary tree  
– Colon/cecum/appendix 
– Duodenum 
– Esophagus 
– Gallbladder  
– Ileum 
– Jejunum 
– Oral cavity 
– Pancreas 
– Pharynx 
– Rectum 
– Salivary gland  
– Small bowel NOS 
– Stomach 
Asymptomatic, 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, diarrhea, 
or GI fluid loss); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered GI 
function (e.g., altered 
dietary habits, diarrhea, 
or GI fluid loss); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences  
Death 
REMARK: A fistula is defined as an abnormal communication between two body cavities, potential spaces, and/or the skin. The site indicated for a fistula should be the site from which 
the abnormal process is believed to have originated. For example, a tracheo-esophageal fistula arising in the context of a resected or irradiated esophageal cancer is graded as 
Fistula, GI – esophagus. 
Flatulence 
Flatulence 
Mild 
Moderate 
— 
— 
— 
Gastritis (including bile 
reflux gastritis) 
Gastritis 
Asymptomatic 
radiographic or 
endoscopic findings only 
Symptomatic; altered 
gastric function (e.g., 
inadequate oral caloric or 
fluid intake); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered gastric 
function (e.g., inadequate 
oral caloric or fluid 
intake); IV fluids, tube 
feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., gastrectomy)  
Death 
ALSO CONSIDER: Hemorrhage, GI – Select; Ulcer, GI – Select. 
NAVIGATION NOTE: Head and neck soft tissue necrosis is graded as Soft tissue necrosis – Select in the MUSCULOSKELETAL/SOFT TISSUE CATEGORY. 
Heartburn/dyspepsia 
Heartburn 
Mild 
Moderate 
Severe 
— 
— 
Hemorrhoids 
Hemorrhoids 
Asymptomatic 
Symptomatic; banding or 
medical intervention 
indicated 
Interfering with ADL; 
interventional radiology, 
endoscopic, or operative 
intervention indicated 
Life-threatening 
consequences 
Death 

 
GASTROINTESTINAL 
Page 5 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 23 - 
March 31, 2003, Publish Date: August 9, 2006 
Ileus, GI (functional 
obstruction of bowel, i.e., 
neuroconstipation) 
Ileus 
Asymptomatic, 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered GI 
function; IV fluids, tube 
feeding, or TPN indicated 
≥24 hrs 
Life-threatening 
consequences 
Death 
REMARK: Ileus, GI is to be used for altered upper or lower GI function (e.g., delayed gastric or colonic emptying). 
ALSO CONSIDER: Constipation; Nausea; Obstruction, GI – Select; Vomiting. 
Incontinence, anal 
Incontinence, anal 
Occasional use of pads 
required 
Daily use of pads 
required 
Interfering with ADL; 
operative intervention 
indicated 
Permanent bowel 
diversion indicated 
Death 
REMARK: Incontinence, anal is to be used for loss of sphincter control as sequelae of operative or therapeutic intervention. 
Leak (including 
anastomotic), GI 
– Select: 
– Biliary tree 
– Esophagus 
– Large bowel 
– Leak NOS 
– Pancreas 
– Pharynx 
– Rectum 
– Small bowel  
– Stoma 
– Stomach 
Leak, GI – Select  
Asymptomatic 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and 
interfering with GI 
function; invasive or 
endoscopic intervention 
indicated  
Life-threatening 
consequences 
Death 
REMARK: Leak (including anasomotic), GI – Select is to be used for clinical signs/symptoms or radiographic confirmation of anastomotic or conduit leak (e.g., biliary, esophageal, 
intestinal, pancreatic, pharyngeal, rectal), but without development of fistula. 
Malabsorption  
Malabsorption 
— 
Altered diet; oral 
therapies indicated (e.g., 
enzymes, medications, 
dietary supplements)  
Inability to aliment 
adequately via GI tract 
(i.e., TPN indicated) 
Life-threatening 
consequences 
Death 

 
GASTROINTESTINAL 
Page 6 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 24 - 
March 31, 2003, Publish Date: August 9, 2006 
Mucositis/stomatitis 
(clinical exam)  
– Select: 
– Anus 
– Esophagus 
– Large bowel 
– Larynx 
– Oral cavity 
– Pharynx 
– Rectum 
– Small bowel 
– Stomach 
– Trachea 
Mucositis (clinical exam) 
– Select  
Erythema of the mucosa 
Patchy ulcerations or 
pseudomembranes  
Confluent ulcerations or 
pseudomembranes; 
bleeding with minor 
trauma 
Tissue necrosis; 
significant spontaneous 
bleeding; life-threatening 
consequences 
Death 
REMARK: Mucositis/stomatitis (functional/symptomatic) may be used for mucositis of the upper aero-digestive tract caused by radiation, agents, or GVHD.  
Mucositis/stomatitis 
(functional/symptomatic)  
– Select: 
– Anus 
– Esophagus 
– Large bowel 
– Larynx 
– Oral cavity 
– Pharynx 
– Rectum 
– Small bowel 
– Stomach 
– Trachea 
Mucositis (functional/ 
symptomatic) – Select  
Upper aerodigestive tract 
sites: Minimal symptoms, 
normal diet; minimal 
respiratory symptoms but 
not interfering with 
function 
Lower GI sites: 
Minimal discomfort, 
intervention not indicated 
Upper aerodigestive tract 
sites: Symptomatic but 
can eat and swallow 
modified diet; respiratory 
symptoms interfering with 
function but not 
interfering with ADL 
Lower GI sites:  
Symptomatic, medical 
intervention indicated but 
not interfering with ADL 
Upper aerodigestive tract 
sites: Symptomatic and 
unable to adequately 
aliment or hydrate orally; 
respiratory symptoms 
interfering with ADL 
Lower GI sites: 
Stool incontinence or 
other symptoms 
interfering with ADL 
Symptoms associated 
with life-threatening 
consequences  
Death 
Nausea 
Nausea 
Loss of appetite without 
alteration in eating habits 
Oral intake decreased 
without significant weight 
loss, dehydration or 
malnutrition; IV fluids 
indicated <24 hrs 
Inadequate oral caloric or 
fluid intake; IV fluids, tube 
feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Anorexia; Vomiting. 

 
GASTROINTESTINAL 
Page 7 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 25 - 
March 31, 2003, Publish Date: August 9, 2006 
Necrosis, GI 
– Select:  
Necrosis, GI – Select  
– Anus 
– Colon/cecum/appendix 
– Duodenum 
– Esophagus 
– Gallbladder 
– Hepatic 
– Ileum 
– Jejunum 
– Oral 
– Pancreas 
– Peritoneal cavity 
– Pharynx  
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
— 
— 
Inability to aliment 
adequately by GI tract 
(e.g., requiring enteral or 
parenteral nutrition); 
interventional radiology, 
endoscopic, or operative 
intervention indicated  
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., total colectomy)  
Death 
ALSO CONSIDER: Visceral arterial ischemia (non-myocardial). 
Obstruction, GI 
– Select: 
– Cecum 
– Colon 
– Duodenum 
– Esophagus 
– Gallbladder 
– Ileum 
– Jejunum 
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
Obstruction, GI – Select 
Asymptomatic 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, vomiting, 
diarrhea, or GI fluid loss); 
IV fluids indicated <24 
hrs 
Symptomatic and 
severely altered GI 
function (e.g., altered 
dietary habits, vomiting, 
diarrhea, or GI fluid loss); 
IV fluids, tube feedings, 
or TPN indicated ≥24 hrs; 
operative intervention 
indicated 
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., total colectomy)  
Death 
NAVIGATION NOTE: Operative injury is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY CATEGORY. 
NAVIGATION NOTE: Pelvic pain is graded as Pain – Select in the PAIN CATEGORY. 

 
GASTROINTESTINAL 
Page 8 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 26 - 
March 31, 2003, Publish Date: August 9, 2006 
Perforation, GI 
– Select: 
– Appendix 
– Biliary tree 
– Cecum 
– Colon 
– Duodenum 
– Esophagus 
– Gallbladder 
– Ileum 
– Jejunum 
– Rectum 
– Small bowel NOS 
– Stomach 
Perforation, GI – Select 
Asymptomatic 
radiographic findings only 
Medical intervention 
indicated; IV fluids 
indicated <24 hrs 
IV fluids, tube feedings, 
or TPN indicated ≥24 hrs; 
operative intervention 
indicated 
Life-threatening 
consequences 
Death 
Proctitis  
Proctitis 
Rectal discomfort, 
intervention not indicated 
Symptoms not interfering 
with ADL; medical 
intervention indicated  
Stool incontinence or 
other symptoms 
interfering with ADL; 
operative intervention 
indicated 
Life-threatening 
consequences (e.g., 
perforation) 
Death 
Prolapse of stoma, GI 
Prolapse of stoma, GI 
Asymptomatic  
Extraordinary local care 
or maintenance; minor 
revision indicated 
Dysfunctional stoma; 
major revision indicated  
Life-threatening 
consequences 
Death 
REMARK: Other stoma complications may be graded as Fistula, GI – Select; Leak (including anastomotic), GI – Select; Obstruction, GI – Select; Perforation, GI – Select; 
Stricture/stenosis (including anastomotic), GI – Select. 
NAVIGATION NOTE: Rectal or perirectal pain (proctalgia) is graded as Pain – Select in the PAIN CATEGORY.  
Salivary gland 
changes/saliva 
Salivary gland changes 
Slightly thickened saliva; 
slightly altered taste (e.g., 
metallic) 
Thick, ropy, sticky saliva; 
markedly altered taste; 
alteration in diet 
indicated; secretion-
induced symptoms not 
interfering with ADL 
Acute salivary gland 
necrosis; severe 
secretion-induced 
symptoms interfering with 
ADL  
Disabling 
— 
ALSO CONSIDER: Dry mouth/salivary gland (xerostomia); Mucositis/stomatitis (clinical exam) – Select; Mucositis/stomatitis (functional/symptomatic) – Select; Taste alteration 
(dysgeusia). 
NAVIGATION NOTE: Splenic function is graded in the BLOOD/BONE MARROW CATEGORY. 

 
GASTROINTESTINAL 
Page 9 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 27 - 
March 31, 2003, Publish Date: August 9, 2006 
Stricture/stenosis 
(including anastomotic), 
GI 
– Select:  
Stricture, GI – Select  
– Anus 
– Biliary tree 
– Cecum 
– Colon  
– Duodenum  
– Esophagus 
– Ileum 
– Jejunum 
– Pancreas/pancreatic duct 
– Pharynx 
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
Asymptomatic 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, vomiting, 
bleeding, diarrhea); IV 
fluids indicated <24 hrs 
Symptomatic and 
severely altered GI 
function (e.g., altered 
dietary habits, diarrhea, 
or GI fluid loss); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs; 
operative intervention 
indicated 
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., total colectomy)  
Death 
Taste alteration 
(dysgeusia) 
Taste alteration 
Altered taste but no 
change in diet 
Altered taste with change 
in diet (e.g., oral 
supplements); noxious or 
unpleasant taste; loss of 
taste 
— 
— 
— 
Typhlitis 
(cecal inflammation) 
Typhlitis 
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain; mucus 
or blood in stool 
Abdominal pain, fever, 
change in bowel habits 
with ileus; peritoneal 
signs 
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis); 
operative intervention 
indicated 
Death 
ALSO CONSIDER: Colitis; Hemorrhage, GI – Select ; Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation).  

 
GASTROINTESTINAL 
Page 10 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 28 - 
March 31, 2003, Publish Date: August 9, 2006 
Ulcer, GI 
– Select: 
– Anus 
– Cecum 
– Colon 
– Duodenum 
– Esophagus 
– Ileum 
– Jejunum 
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
Ulcer, GI – Select 
Asymptomatic, 
radiographic or 
endoscopic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, oral 
supplements); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered GI 
function (e.g., inadequate 
oral caloric or fluid 
intake); IV fluids, tube 
feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select. 
Vomiting 
Vomiting 
1 episode in 24 hrs 
2 – 5 episodes in 24 hrs; 
IV fluids indicated  
<24 hrs 
≥6 episodes in 24 hrs; IV 
fluids, or TPN indicated 
≥24 hrs 
Life-threatening 
consequences  
Death 
ALSO CONSIDER: Dehydration. 
Gastrointestinal – Other 
(Specify, __) 
GI – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling 
Death 

 
GROWTH AND DEVELOPMENT 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 29 - 
March 31, 2003, Publish Date: August 9, 2006 
Bone age 
(alteration in bone age) 
Bone age 
— 
+2 SD (standard 
deviation) from normal 
— 
— 
— 
Bone growth: 
femoral head; slipped 
capital femoral epiphysis 
Femoral head growth 
Mild valgus/varus 
deformity 
Moderate valgus/varus 
deformity, symptomatic, 
interfering with function 
but not interfering with 
ADL 
Mild slipped capital 
femoral epiphysis; 
operative intervention 
(e.g., fixation) indicated; 
interfering with ADL 
Disabling; severe slipped 
capital femoral epiphysis 
>60%; avascular necrosis 
— 
Bone growth: 
limb length discrepancy 
Limb length  
Mild length discrepancy 
<2 cm 
Moderate length 
discrepancy 2 – 5 cm; 
shoe lift indicated 
Severe length 
discrepancy >5 cm; 
operative intervention 
indicated; interfering with 
ADL 
Disabling; epiphysiodesis 
— 
Bone growth: 
spine kyphosis/lordosis 
Kyphosis/lordosis 
Mild radiographic 
changes  
Moderate accentuation; 
interfering with function 
but not interfering with 
ADL 
Severe accentuation; 
operative intervention 
indicated; interfering with 
ADL 
Disabling (e.g., cannot lift 
head) 
— 
Growth velocity 
(reduction in growth 
velocity) 
Reduction in growth 
velocity 
10 – 29% reduction in 
growth from the baseline 
growth curve 
30 – 49% reduction in 
growth from the baseline 
growth curve 
≥50% reduction in growth 
from the baseline growth 
curve  
— 
— 
Puberty (delayed) 
Delayed puberty 
— 
No breast development 
by age 13 yrs for females; 
no Tanner Stage 2 
development by age 14.5 
yrs for males 
No sexual development 
by age 14 yrs for girls, 
age 16 yrs for boys; 
hormone replacement 
indicated 
— 
— 
REMARK: Do not use testicular size for Tanner Stage in male cancer survivors. 
Puberty (precocious)  
Precocious puberty 
— 
Physical signs of puberty 
<7 years for females,  
<9 years for males 
— 
— 
— 
Short stature 
Short stature 
Beyond two standard 
deviations of age and 
gender mean height 
Altered ADL 
— 
— 
— 
REMARK: Short stature is secondary to growth hormone deficiency. 
ALSO CONSIDER: Neuroendocrine: growth hormone secretion abnormality. 
Growth and Development 
– Other (Specify, __) 
Growth and Development 
– Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
HEMORRHAGE/BLEEDING 
Page 1 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 30 - 
March 31, 2003, Publish Date: August 9, 2006 
Hematoma  
Hematoma 
Minimal symptoms, 
invasive intervention not 
indicated  
Minimally invasive 
evacuation or aspiration 
indicated 
Transfusion, 
interventional radiology, 
or operative intervention 
indicated 
Life-threatening 
consequences; major 
urgent intervention 
indicated 
Death 
REMARK: Hematoma refers to extravasation at wound or operative site or secondary to other intervention. Transfusion implies pRBC.  
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Hemorrhage/bleeding 
associated with surgery, 
intra-operative or 
postoperative 
Hemorrhage with surgery 
— 
— 
Requiring transfusion of  
2 units non-autologous 
(10 cc/kg for pediatrics) 
pRBCs beyond protocol 
specification; 
postoperative 
interventional radiology, 
endoscopic, or operative 
intervention indicated 
Life-threatening 
consequences  
Death 
REMARK: Postoperative period is defined as ≤72 hours after surgery. Verify protocol-specific acceptable guidelines regarding pRBC transfusion. 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Hemorrhage, CNS 
CNS hemorrhage 
Asymptomatic, 
radiographic findings only 
Medical intervention 
indicated  
Ventriculostomy, ICP 
monitoring, 
intraventricular 
thrombolysis, or operative 
intervention indicated 
Life-threatening 
consequences; 
neurologic deficit or 
disability 
Death 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 

 
HEMORRHAGE/BLEEDING 
Page 2 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 31 - 
March 31, 2003, Publish Date: August 9, 2006 
Hemorrhage, GI  
– Select: 
– Abdomen NOS 
– Anus 
– Biliary tree  
– Cecum/appendix  
– Colon 
– Duodenum 
– Esophagus 
– Ileum 
– Jejunum 
– Liver 
– Lower GI NOS 
– Oral cavity 
– Pancreas 
– Peritoneal cavity 
– Rectum 
– Stoma 
– Stomach 
– Upper GI NOS 
– Varices (esophageal) 
– Varices (rectal) 
Hemorrhage, GI – Select 
Mild, intervention (other 
than iron supplements) 
not indicated 
Symptomatic and medical 
intervention or minor 
cauterization indicated 
Transfusion, 
interventional radiology, 
endoscopic, or operative 
intervention indicated; 
radiation therapy (i.e., 
hemostasis of bleeding 
site) 
Life-threatening 
consequences; major 
urgent intervention 
indicated  
Death 
REMARK: Transfusion implies pRBC. 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 

 
HEMORRHAGE/BLEEDING 
Page 3 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 32 - 
March 31, 2003, Publish Date: August 9, 2006 
Hemorrhage, GU  
– Select:  
– Bladder 
– Fallopian tube 
– Kidney 
– Ovary 
– Prostate  
– Retroperitoneum  
– Spermatic cord 
– Stoma 
– Testes 
– Ureter 
– Urethra 
– Urinary NOS 
– Uterus 
– Vagina 
– Vas deferens 
Hemorrhage, GU – Select 
Minimal or microscopic 
bleeding; intervention not 
indicated 
Gross bleeding, medical 
intervention, or urinary 
tract irrigation indicated 
Transfusion, 
interventional radiology, 
endoscopic, or operative 
intervention indicated; 
radiation therapy (i.e., 
hemostasis of bleeding 
site) 
Life-threatening 
consequences; major 
urgent intervention 
indicated 
Death 
REMARK: Transfusion implies pRBC. 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Hemorrhage, pulmonary/ 
upper respiratory  
– Select: 
Hemorrhage pulmonary  
– Select 
– Bronchopulmonary NOS 
– Bronchus  
– Larynx  
– Lung  
– Mediastinum 
– Nose 
– Pharynx 
– Pleura 
– Respiratory tract NOS 
– Stoma 
– Trachea 
Mild, intervention not 
indicated 
Symptomatic and 
medical intervention 
indicated 
Transfusion, 
interventional radiology, 
endoscopic, or operative 
intervention indicated; 
radiation therapy (i.e., 
hemostasis of bleeding 
site) 
Life-threatening 
consequences; major 
urgent intervention 
indicated 
Death 
REMARK: Transfusion implies pRBC.  
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Petechiae/purpura 
(hemorrhage/bleeding 
into skin or mucosa) 
Petechiae 
Few petechiae 
Moderate petechiae; 
purpura 
Generalized petechiae or 
purpura 
— 
— 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 

 
HEMORRHAGE/BLEEDING 
Page 4 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 33 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Vitreous hemorrhage is graded in the OCULAR/VISUAL CATEGORY. 
Hemorrhage/Bleeding – 
Other (Specify, __) 
Hemorrhage – Other 
(Specify) 
Mild without transfusion 
— 
Transfusion indicated 
Catastrophic bleeding, 
requiring major non-
elective intervention 
Death 

 
HEPATOBILIARY/PANCREAS 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 34 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Biliary tree damage is graded as Fistula, GI – Select; Leak (including anastomotic), GI – Select; Necrosis, GI – Select; Obstruction, GI – Select; Perforation, GI – 
Select; Stricture/stenosis (including anastomotic), GI – Select in the GASTROINTESTINAL CATEGORY. 
Cholecystitis 
Cholecystitis 
Asymptomatic, 
radiographic findings only 
Symptomatic, medical 
intervention indicated 
Interventional radiology, 
endoscopic, or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
sepsis or perforation)  
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection 
with unknown ANC – Select.  
Liver dysfunction/failure 
(clinical)  
Liver dysfunction  
— 
Jaundice  
Asterixis 
Encephalopathy or coma 
Death 
REMARK: Jaundice is not an AE, but occurs when the liver is not working properly or when a bile duct is blocked. It is graded as a result of liver dysfunction/failure or elevated bilirubin. 
ALSO CONSIDER: Bilirubin (hyperbilirubinemia). 
Pancreas, exocrine 
enzyme deficiency 
Pancreas, exocrine 
enzyme deficiency 
— 
Increase in stool 
frequency, bulk, or odor; 
steatorrhea 
Sequelae of absorption 
deficiency (e.g., weight 
loss)  
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Diarrhea. 
Pancreatitis  
Pancreatitis 
Asymptomatic, enzyme 
elevation and/or 
radiographic findings  
Symptomatic, medical 
intervention indicated 
Interventional radiology or 
operative intervention 
indicated 
Life-threatening 
consequences 
(e.g., circulatory failure, 
hemorrhage, sepsis) 
Death 
ALSO CONSIDER: Amylase. 
NAVIGATION NOTE: Stricture (biliary tree, hepatic or pancreatic) is graded as Stricture/stenosis (including anastomotic), GI – Select in the GASTROINTESTINAL CATEGORY. 
Hepatobiliary/Pancreas – 
Other (Specify, __) 
Hepatobiliary – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
INFECTION 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 35 - 
March 31, 2003, Publish Date: August 9, 2006 
Colitis, infectious 
(e.g., Clostridium difficile) 
Colitis, infectious  
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain with 
mucus and/or blood in 
stool 
IV antibiotics or TPN 
indicated  
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis or 
toxic megacolon); 
operative resection or 
diversion indicated 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select; Typhlitis (cecal inflammation).  
Febrile neutropenia 
(fever of unknown origin 
without clinically or 
microbiologically 
documented infection) 
(ANC <1.0 x 109/L, fever 
≥38.5°C) 
Febrile neutropenia 
— 
— 
Present 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
ALSO CONSIDER: Neutrophils/granulocytes (ANC/AGC). 
Infection  
(documented clinically or 
microbiologically) with 
Grade 3 or 4 neutrophils  
(ANC <1.0 x 109/L) 
– Select  
‘Select’ AEs appear at the 
end of the CATEGORY. 
Infection (documented 
clinically) with Grade 3 or 
4 ANC – Select 
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
REMARK: Fever with Grade 3 or 4 neutrophils in the absence of documented infection is graded as Febrile neutropenia (fever of unknown origin without clinically or microbiologically 
documented infection). 
ALSO CONSIDER: Neutrophils/granulocytes (ANC/AGC). 
Infection with normal 
ANC or Grade 1 or 2 
neutrophils  
– Select  
‘Select’ AEs appear at the 
end of the CATEGORY. 
Infection with normal 
ANC – Select 
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 

 
INFECTION 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 36 - 
March 31, 2003, Publish Date: August 9, 2006 
Infection with unknown 
ANC 
– Select  
‘Select’ AEs appear at the 
end of the CATEGORY. 
Infection with unknown 
ANC – Select 
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
REMARK: Infection with unknown ANC – Select is to be used in the rare case when ANC is unknown. 
Opportunistic infection 
associated with ≥Grade 2 
Lymphopenia 
Opportunistic infection  
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
ALSO CONSIDER: Lymphopenia. 
Viral hepatitis 
Viral hepatitis 
Present; transaminases 
and liver function normal 
Transaminases 
abnormal, liver function 
normal  
Symptomatic liver 
dysfunction; fibrosis by 
biopsy; compensated 
cirrhosis 
Decompensated liver 
function (e.g., ascites, 
coagulopathy, 
encephalopathy, coma) 
Death 
REMARK: Non-viral hepatitis is graded as Infection – Select. 
ALSO CONSIDER: Albumin, serum-low (hypoalbuminemia); ALT, SGPT (serum glutamic pyruvic transaminase); AST, SGOT (serum glutamic oxaloacetic transaminase); Bilirubin 
(hyperbilirubinemia); Encephalopathy. 
Infection – Other 
(Specify, __) 
Infection – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
INFECTION – SELECT 
Page 3 of 3 
CTCAE v3.0  
- 37 - 
March 31, 2003, Publish Date: August 9, 2006 
AUDITORY/EAR 
– External ear (otitis externa) 
– Middle ear (otitis media) 
CARDIOVASCULAR 
– Artery 
– Heart (endocarditis) 
– Spleen 
– Vein 
DERMATOLOGY/SKIN  
– Lip/perioral 
– Peristomal 
– Skin (cellulitis) 
– Ungual (nails) 
GASTROINTESTINAL  
– Abdomen NOS 
– Anal/perianal 
– Appendix 
– Cecum 
– Colon 
– Dental-tooth 
– Duodenum 
– Esophagus 
– Ileum 
– Jejunum 
– Oral cavity-gums (gingivitis) 
– Peritoneal cavity 
– Rectum 
– Salivary gland 
– Small bowel NOS 
– Stomach 
GENERAL 
– Blood 
– Catheter-related 
– Foreign body (e.g., graft, implant,  
prosthesis, stent) 
– Wound  
HEPATOBILIARY/PANCREAS 
– Biliary tree 
– Gallbladder (cholecystitis) 
– Liver 
– Pancreas 
LYMPHATIC 
– Lymphatic 
MUSCULOSKELETAL 
– Bone (osteomyelitis) 
– Joint 
– Muscle (infection myositis) 
– Soft tissue NOS 
NEUROLOGY 
– Brain (encephalitis, infectious) 
– Brain + Spinal cord (encephalomyelitis) 
– Meninges (meningitis) 
– Nerve-cranial 
– Nerve-peripheral 
– Spinal cord (myelitis) 
OCULAR 
– Conjunctiva 
– Cornea 
– Eye NOS 
– Lens 
PULMONARY/UPPER RESPIRATORY 
– Bronchus 
– Larynx 
– Lung (pneumonia) 
– Mediastinum NOS 
– Mucosa 
– Neck NOS 
– Nose 
– Paranasal 
– Pharynx 
– Pleura (empyema) 
– Sinus 
– Trachea 
– Upper aerodigestive NOS 
– Upper airway NOS  
RENAL/GENITOURINARY  
– Bladder (urinary) 
– Kidney 
– Prostate 
– Ureter 
– Urethra 
– Urinary tract NOS 
SEXUAL/REPRODUCTIVE FUNCTION 
– Cervix 
– Fallopian tube 
– Pelvis NOS 
– Penis 
– Scrotum 
– Uterus 
– Vagina 
– Vulva 
 

 
LYMPHATICS 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 38 - 
March 31, 2003, Publish Date: August 9, 2006 
Chyle or lymph leakage  
Chyle or lymph leakage 
Asymptomatic, clinical or 
radiographic findings 
Symptomatic, medical 
intervention indicated  
Interventional radiology 
or operative intervention 
indicated 
Life-threatening 
complications 
Death 
ALSO CONSIDER: Chylothorax. 
Dermal change 
lymphedema, 
phlebolymphedema  
Dermal change 
Trace thickening or faint 
discoloration 
Marked discoloration; 
leathery skin texture; 
papillary formation 
— 
— 
— 
REMARK: Dermal change lymphedema, phlebolymphedema refers to changes due to venous stasis. 
ALSO CONSIDER: Ulceration.  
Edema: 
head and neck 
Edema: head and neck 
Localized to dependent 
areas, no disability or 
functional impairment 
Localized facial or neck 
edema with functional 
impairment 
Generalized facial or 
neck edema with 
functional impairment 
(e.g., difficulty in turning 
neck or opening mouth 
compared to baseline) 
Severe with ulceration or 
cerebral edema; 
tracheotomy or feeding 
tube indicated 
Death 
Edema: 
limb 
Edema: limb 
5 – 10% inter-limb 
discrepancy in volume or 
circumference at point of 
greatest visible 
difference; swelling or 
obscuration of anatomic 
architecture on close 
inspection; pitting edema 
>10 – 30% inter-limb 
discrepancy in volume or 
circumference at point of 
greatest visible 
difference; readily 
apparent obscuration of 
anatomic architecture; 
obliteration of skin folds; 
readily apparent 
deviation from normal 
anatomic contour  
>30% inter-limb 
discrepancy in volume; 
lymphorrhea; gross 
deviation from normal 
anatomic contour; 
interfering with ADL 
Progression to 
malignancy (i.e., 
lymphangiosarcoma); 
amputation indicated; 
disabling 
Death 
Edema: 
trunk/genital 
Edema: trunk/genital 
Swelling or obscuration 
of anatomic architecture 
on close inspection; 
pitting edema 
Readily apparent 
obscuration of anatomic 
architecture; obliteration 
of skin folds; readily 
apparent deviation from 
normal anatomic contour 
Lymphorrhea; interfering 
with ADL; gross deviation 
from normal anatomic 
contour 
Progression to 
malignancy (i.e., 
lymphangiosarcoma); 
disabling  
Death 
Edema: 
viscera 
Edema: viscera 
Asymptomatic; clinical or 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and unable 
to aliment adequately 
orally; interventional 
radiology or operative 
intervention indicated  
Life-threatening 
consequences 
Death 

 
LYMPHATICS 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 39 - 
March 31, 2003, Publish Date: August 9, 2006 
Lymphedema-related 
fibrosis 
Lymphedema-related 
fibrosis 
Minimal to moderate 
redundant soft tissue, 
unresponsive to elevation 
or compression, with 
moderately firm texture or 
spongy feel 
Marked increase in 
density and firmness, 
with or without tethering 
Very marked density and 
firmness with tethering 
affecting ≥40% of the 
edematous area 
— 
— 
Lymphocele 
Lymphocele 
Asymptomatic, clinical or 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and 
interventional radiology 
or operative intervention 
indicated 
— 
— 
Phlebolymphatic cording  
Phlebolymphatic cording 
Asymptomatic, clinical 
findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and leading 
to contracture or reduced 
range of motion 
— 
— 
Lymphatics – Other  
(Specify, __) 
Lymphatics – Other  
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling 
Death 

 
METABOLIC/LABORATORY 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 40 - 
March 31, 2003, Publish Date: August 9, 2006 
Acidosis  
(metabolic or respiratory) 
Acidosis  
pH <normal, but ≥7.3 
— 
pH <7.3 
pH <7.3 with life-
threatening 
consequences 
Death 
Albumin, serum-low 
(hypoalbuminemia)  
Hypoalbuminemia 
<LLN – 3 g/dL  
<LLN – 30 g/L 
<3 – 2 g/dL 
<30 – 20 g/L  
<2 g/dL  
<20 g/L 
— 
Death 
Alkaline phosphatase 
Alkaline phosphatase 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Alkalosis  
(metabolic or respiratory) 
Alkalosis 
pH >normal, but ≤7.5 
— 
pH >7.5 
pH >7.5 with life-
threatening 
consequences 
Death 
ALT, SGPT  
(serum glutamic pyruvic 
transaminase) 
ALT 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Amylase 
Amylase 
>ULN – 1.5 x ULN 
>1.5 – 2.0 x ULN 
>2.0 – 5.0 x ULN 
>5.0 x ULN 
— 
AST, SGOT 
(serum glutamic 
oxaloacetic 
transaminase) 
AST 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Bicarbonate, serum-low  
Bicarbonate, serum-low 
<LLN – 16 mmol/L 
<16 – 11 mmol/L 
<11 – 8 mmol/L 
<8 mmol/L 
Death 
Bilirubin 
(hyperbilirubinemia) 
Bilirubin 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x ULN 
>3.0 – 10.0 x ULN 
>10.0 x ULN 
— 
REMARK: Jaundice is not an AE, but may be a manifestation of liver dysfunction/failure or elevated bilirubin. If jaundice is associated with elevated bilirubin, grade bilirubin. 
Calcium, serum-low 
(hypocalcemia) 
Hypocalcemia 
<LLN – 8.0 mg/dL 
<LLN – 2.0 mmol/L 
Ionized calcium: 
<LLN – 1.0 mmol/L 
<8.0 – 7.0 mg/dL 
<2.0 – 1.75 mmol/L 
Ionized calcium: 
<1.0 – 0.9 mmol/L 
<7.0 – 6.0 mg/dL 
<1.75 – 1.5 mmol/L 
Ionized calcium: 
<0.9 – 0.8 mmol/L 
<6.0 mg/dL 
<1.5 mmol/L 
Ionized calcium: 
<0.8 mmol/L 
Death 
REMARK: Calcium can be falsely low if hypoalbuminemia is present. Serum albumin is <4.0 g/dL, hypocalcemia is reported after the following corrective calculation has been 
performed: Corrected Calcium (mg/dL) = Total Calcium (mg/dL) – 0.8 [Albumin (g/dL) – 4] 4. Alternatively, direct measurement of ionized calcium is the definitive method to diagnose 
metabolically relevant alterations in serum calcium. 
                                            
4Crit Rev Clin Lab Sci 1984;21(1):51-97 

 
METABOLIC/LABORATORY 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 41 - 
March 31, 2003, Publish Date: August 9, 2006 
Calcium, serum-high 
(hypercalcemia) 
Hypercalcemia 
>ULN – 11.5 mg/dL 
>ULN – 2.9 mmol/L 
Ionized calcium: 
>ULN – 1.5 mmol/L 
>11.5 – 12.5 mg/dL 
>2.9 – 3.1 mmol/L 
Ionized calcium: 
>1.5 – 1.6 mmol/L 
>12.5 – 13.5 mg/dL 
>3.1 – 3.4 mmol/L 
Ionized calcium: 
>1.6 – 1.8 mmol/L 
>13.5 mg/dL 
>3.4 mmol/L 
Ionized calcium: 
>1.8 mmol/L 
Death 
Cholesterol, serum-high 
(hypercholesteremia) 
Cholesterol 
>ULN – 300 mg/dL 
>ULN – 7.75 mmol/L 
>300 – 400 mg/dL 
>7.75 – 10.34 mmol/L 
>400 – 500 mg/dL 
>10.34 – 12.92 mmol/L 
>500 mg/dL 
>12.92 mmol/L 
Death 
CPK (creatine 
phosphokinase) 
CPK 
>ULN – 2.5 x ULN 
>2.5 x ULN – 5 x ULN 
>5 x ULN – 10 x ULN 
>10 x ULN 
Death 
Creatinine 
Creatinine 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x ULN 
>3.0 – 6.0 x ULN 
>6.0 x ULN 
Death 
REMARK: Adjust to age-appropriate levels for pediatric patients.  
ALSO CONSIDER: Glomerular filtration rate. 
GGT (γ-Glutamyl 
transpeptidase) 
GGT 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Glomerular filtration rate  
GFR 
<75 – 50% LLN 
<50 – 25% LLN 
<25% LLN, chronic 
dialysis not indicated 
Chronic dialysis or renal 
transplant indicated 
Death 
ALSO CONSIDER: Creatinine. 
Glucose, serum-high 
(hyperglycemia)  
Hyperglycemia 
>ULN – 160 mg/dL 
>ULN – 8.9 mmol/L 
>160 – 250 mg/dL 
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL 
>13.9 – 27.8 mmol/L 
>500 mg/dL 
>27.8 mmol/L or acidosis 
Death 
REMARK: Hyperglycemia, in general, is defined as fasting unless otherwise specified in protocol. 
Glucose, serum-low 
(hypoglycemia) 
Hypoglycemia 
<LLN – 55 mg/dL 
<LLN – 3.0 mmol/L 
<55 – 40 mg/dL 
<3.0 – 2.2 mmol/L 
<40 – 30 mg/dL 
<2.2 – 1.7 mmol/L 
<30 mg/dL 
<1.7 mmol/L 
Death 
Hemoglobinuria 
Hemoglobinuria 
Present 
— 
— 
— 
Death 
Lipase 
Lipase 
>ULN – 1.5 x ULN 
>1.5 – 2.0 x ULN 
>2.0 – 5.0 x ULN 
>5.0 x ULN 
— 
Magnesium, serum-high 
(hypermagnesemia) 
Hypermagnesemia 
>ULN – 3.0 mg/dL 
>ULN – 1.23 mmol/L 
— 
>3.0 – 8.0 mg/dL 
>1.23 – 3.30 mmol/L 
>8.0 mg/dL 
>3.30 mmol/L 
Death 
Magnesium, serum-low 
(hypomagnesemia)  
Hypomagnesemia 
<LLN – 1.2 mg/dL 
<LLN – 0.5 mmol/L 
<1.2 – 0.9 mg/dL 
<0.5 – 0.4 mmol/L 
<0.9 – 0.7 mg/dL 
<0.4 – 0.3 mmol/L 
<0.7 mg/dL 
<0.3 mmol/L 
Death 
Phosphate, serum-low 
(hypophosphatemia)  
Hypophosphatemia 
<LLN – 2.5 mg/dL 
<LLN – 0.8 mmol/L 
<2.5 – 2.0 mg/dL  
<0.8 – 0.6 mmol/L 
<2.0 – 1.0 mg/dL 
<0.6 – 0.3 mmol/L 
<1.0 mg/dL 
<0.3 mmol/L 
Death 
Potassium, serum-high 
(hyperkalemia) 
Hyperkalemia 
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L 
>6.0 – 7.0 mmol/L 
>7.0 mmol/L 
Death 

 
METABOLIC/LABORATORY 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 42 - 
March 31, 2003, Publish Date: August 9, 2006 
Potassium, serum-low 
(hypokalemia)  
Hypokalemia 
<LLN – 3.0 mmol/L 
— 
<3.0 – 2.5 mmol/L 
<2.5 mmol/L 
Death 
Proteinuria 
Proteinuria 
1+ or 
0.15 – 1.0 g/24 hrs 
2+ to 3+ or 
>1.0 – 3.5 g/24 hrs  
4+ or 
>3.5 g/24 hrs 
Nephrotic syndrome 
Death 
Sodium, serum-high 
(hypernatremia) 
Hypernatremia 
>ULN – 150 mmol/L 
>150 – 155 mmol/L 
>155 – 160 mmol/L 
>160 mmol/L 
Death 
Sodium, serum-low 
(hyponatremia) 
Hyponatremia 
<LLN – 130 mmol/L 
— 
<130 – 120 mmol/L 
<120 mmol/L 
Death 
Triglyceride, serum-high 
(hypertriglyceridemia) 
Hypertriglyceridemia 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 10 x ULN 
>10 x ULN 
Death 
Uric acid, serum-high 
(hyperuricemia) 
Hyperuricemia 
>ULN – 10 mg/dL 
≤0.59 mmol/L without 
physiologic 
consequences 
— 
>ULN – 10 mg/dL 
≤0.59 mmol/L with 
physiologic 
consequences 
>10 mg/dL 
>0.59 mmol/L 
Death 
ALSO CONSIDER: Creatinine; Potassium, serum-high (hyperkalemia); Renal failure; Tumor lysis syndrome. 
Metabolic/Laboratory – 
Other (Specify, __) 
Metabolic/Lab – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
MUSCULOSKELETAL/SOFT TISSUE 
Page 1 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 43 - 
March 31, 2003, Publish Date: August 9, 2006 
Arthritis (non-septic) 
Arthritis 
Mild pain with 
inflammation, erythema, 
or joint swelling, but not 
interfering with function 
Moderate pain with 
inflammation, erythema, 
or joint swelling 
interfering with function, 
but not interfering with 
ADL 
Severe pain with 
inflammation, erythema, 
or joint swelling and 
interfering with ADL 
Disabling 
Death 
REMARK: Report only when the diagnosis of arthritis (e.g., inflammation of a joint or a state characterized by inflammation of joints) is made. Arthralgia (sign or symptom of pain in a 
joint, especially non-inflammatory in character) is graded as Pain – Select in the PAIN CATEGORY.  
Bone: 
spine-scoliosis 
Scoliosis  
≤20 degrees; clinically 
undetectable 
>20 – 45 degrees; visible 
by forward flexion; 
interfering with function 
but not interfering with 
ADL 
>45 degrees; scapular 
prominence in forward 
flexion; operative 
intervention indicated; 
interfering with ADL 
Disabling (e.g., interfering 
with cardiopulmonary 
function) 
Death 
Cervical spine-range of 
motion 
Cervical spine ROM 
Mild restriction of rotation 
or flexion between  
60 – 70 degrees 
Rotation <60 degrees to 
right or left; <60 degrees 
of flexion 
Ankylosed/fused over 
multiple segments with 
no C-spine rotation 
— 
— 
REMARK: 60 – 65 degrees of rotation is required for reversing a car; 60 – 65 degrees of flexion is required to tie shoes. 
Exostosis 
Exostosis 
Asymptomatic 
Involving multiple sites; 
pain or interfering with 
function  
Excision indicated 
Progression to 
malignancy (i.e., 
chondrosarcoma) 
Death 
Extremity-lower 
(gait/walking) 
Gait/walking 
Limp evident only to 
trained observer and able 
to walk ≥1 kilometer; 
cane indicated for 
walking 
Noticeable limp, or 
limitation of limb function, 
but able to walk ≥0.1 
kilometer (1 city block); 
quad cane indicated for 
walking 
Severe limp with stride 
modified to maintain 
balance (widened base of 
support, marked 
reduction in step length); 
ambulation limited to 
walker; crutches 
indicated 
Unable to walk 
— 
ALSO CONSIDER: Ataxia (incoordination); Muscle weakness, generalized or specific area (not due to neuropathy) – Select.  
Extremity-upper 
(function)  
Extremity-upper 
(function) 
Able to perform most 
household or work 
activities with affected 
limb 
Able to perform most 
household or work 
activities with 
compensation from 
unaffected limb 
Interfering with ADL  
Disabling; no function of 
affected limb 
— 
Fibrosis-cosmesis 
Fibrosis-cosmesis 
Visible only on close 
examination 
Readily apparent but not 
disfiguring 
Significant disfigurement; 
operative intervention 
indicated if patient 
chooses 
— 
— 

 
MUSCULOSKELETAL/SOFT TISSUE 
Page 2 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 44 - 
March 31, 2003, Publish Date: August 9, 2006 
Fibrosis-deep connective 
tissue 
Fibrosis-deep connective 
tissue  
Increased density, 
“spongy” feel 
Increased density with 
firmness or tethering 
Increased density with 
fixation of tissue; 
operative intervention 
indicated; interfering with 
ADL 
Life-threatening; 
disabling; loss of limb; 
interfering with vital organ 
function 
Death 
ALSO CONSIDER: Induration/fibrosis (skin and subcutaneous tissue); Muscle weakness, generalized or specific area (not due to neuropathy) – Select; Neuropathy: motor; Neuropathy: 
sensory. 
Fracture 
Fracture 
Asymptomatic, 
radiographic findings only 
(e.g., asymptomatic rib 
fracture on plain x-ray, 
pelvic insufficiency 
fracture on MRI, etc.) 
Symptomatic but non-
displaced; immobilization 
indicated 
Symptomatic and 
displaced or open wound 
with bone exposure; 
operative intervention 
indicated 
Disabling; amputation 
indicated 
Death 
Joint-effusion 
Joint-effusion 
Asymptomatic, clinical or 
radiographic findings only 
Symptomatic; interfering 
with function but not 
interfering with ADL 
Symptomatic and 
interfering with ADL 
Disabling 
Death 
ALSO CONSIDER: Arthritis (non-septic). 
Joint-function5 
Joint-function 
Stiffness interfering with 
athletic activity; ≤25% 
loss of range of motion 
(ROM) 
Stiffness interfering with 
function but not 
interfering with ADL;  
>25 – 50% decrease in 
ROM 
Stiffness interfering with 
ADL; >50 – 75% 
decrease in ROM  
Fixed or non-functional 
joint (arthrodesis); 
>75% decrease in ROM 
— 
ALSO CONSIDER: Arthritis (non-septic). 
Local complication –
device/prosthesis-related 
Device/prosthesis 
Asymptomatic  
Symptomatic, but not 
interfering with ADL; local 
wound care; medical 
intervention indicated 
Symptomatic, interfering 
with ADL; operative 
intervention indicated 
(e.g., hardware/device 
replacement or removal, 
reconstruction)  
Life-threatening; 
disabling; loss of limb or 
organ 
Death 
Lumbar spine-range of 
motion 
Lumbar spine ROM 
Stiffness and difficulty 
bending to the floor to 
pick up a very light object 
but able to do activity 
Some lumbar spine 
flexion but requires a 
reaching aid to pick up a 
very light object from the 
floor 
Ankylosed/fused over 
multiple segments with 
no L-spine flexion (i.e., 
unable to reach to floor to 
pick up a very light 
— 
— 
                                            
5 Adapted from the International SFTR Method of Measuring and Recording Joint Motion, International Standard Orthopedic Measurements (ISOM), Jon J. Gerhardt and Otto A. 
Russee, Bern, Switzerland, Han Huber 9 Publisher), 1975. 

 
MUSCULOSKELETAL/SOFT TISSUE 
Page 3 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 45 - 
March 31, 2003, Publish Date: August 9, 2006 
object) 
Muscle weakness, 
generalized or specific 
area (not due to 
neuropathy)  
– Select: 
Muscle weakness  
– Select  
– Extraocular 
– Extremity-lower  
– Extremity-upper 
– Facial 
– Left-sided 
– Ocular 
– Pelvic 
– Right-sided 
– Trunk 
– Whole body/generalized  
Asymptomatic, weakness 
on physical exam 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Life-threatening; disabling 
Death 
ALSO CONSIDER: Fatigue (asthenia, lethargy, malaise). 
Muscular/skeletal 
hypoplasia 
Muscular/skeletal 
hypoplasia 
Cosmetically and 
functionally insignificant 
hypoplasia  
Deformity, hypoplasia, or 
asymmetry able to be 
remediated by prosthesis 
(e.g., shoe insert) or 
covered by clothing  
Functionally significant 
deformity, hypoplasia, or 
asymmetry, unable to be 
remediated by prosthesis 
or covered by clothing  
Disabling 
— 
Myositis 
(inflammation/damage of 
muscle) 
Myositis 
Mild pain, not interfering 
with function 
Pain interfering with 
function, but not 
interfering with ADL 
Pain interfering with ADL 
Disabling 
Death 
REMARK: Myositis implies muscle damage (i.e., elevated CPK). 
ALSO CONSIDER: CPK (creatine phosphokinase); Pain – Select. 
Osteonecrosis  
(avascular necrosis) 
Osteonecrosis 
Asymptomatic, 
radiographic findings only 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL; minimal bone 
removal indicated (i.e., 
minor sequestrectomy)  
Symptomatic and 
interfering with ADL; 
operative intervention or 
hyperbaric oxygen 
indicated 
Disabling  
Death 

 
MUSCULOSKELETAL/SOFT TISSUE 
Page 4 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 46 - 
March 31, 2003, Publish Date: August 9, 2006 
Osteoporosis6 
Osteoporosis 
Radiographic evidence of 
osteoporosis or Bone 
Mineral Density (BMD) 
t-score –1 to –2.5 
(osteopenia) and no loss 
of height or therapy 
indicated 
BMD t-score < –2.5; loss 
of height <2 cm; anti-
osteoporotic therapy 
indicated 
Fractures; loss of height 
≥2 cm 
Disabling 
Death 
Seroma 
Seroma 
Asymptomatic 
Symptomatic; medical 
intervention or simple 
aspiration indicated 
Symptomatic, 
interventional radiology 
or operative intervention 
indicated 
— 
— 
Soft tissue necrosis 
– Select: 
– Abdomen 
– Extremity-lower 
– Extremity-upper  
– Head 
– Neck 
– Pelvic 
– Thorax 
Soft tissue necrosis 
– Select 
— 
Local wound care; 
medical intervention 
indicated 
Operative debridement or 
other invasive 
intervention indicated 
(e.g., hyperbaric oxygen)  
Life-threatening 
consequences; major 
invasive intervention 
indicated (e.g., tissue 
reconstruction, flap, or 
grafting) 
Death 
Trismus (difficulty, 
restriction or pain when 
opening mouth) 
Trismus 
Decreased range of 
motion without impaired 
eating  
Decreased range of 
motion requiring small 
bites, soft foods or 
purees 
Decreased range of 
motion with inability to 
adequately aliment or 
hydrate orally 
— 
— 
NAVIGATION NOTE: Wound-infectious is graded as Infection – Select in the INFECTION CATEGORY. 
NAVIGATION NOTE: Wound non-infectious is graded as Wound complication, non-infectious in the DERMATOLOGY/SKIN CATEGORY.  
Musculoskeletal/Soft 
Tissue – Other 
(Specify, __) 
Musculoskeletal – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
                                            
6 "Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis," Report of a WHO Study Group Technical Report Series, No. 843, 1994, v + 129 
pages [C*, E, F, R, S], ISBN 92 4 120843 0, Sw.fr. 22.-/US $19.80; in developing countries: Sw.fr. 15.40, Order no. 1100843 

 
NEUROLOGY 
Page 1 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 47 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: ADD (Attention Deficit Disorder) is graded as Cognitive disturbance. 
NAVIGATION NOTE: Aphasia, receptive and/or expressive, is graded as Speech impairment (e.g., dysphasia or aphasia). 
Apnea 
Apnea 
— 
— 
Present 
Intubation indicated  
Death 
Arachnoiditis/ 
meningismus/radiculitis 
Arachnoiditis 
Symptomatic, not 
interfering with function; 
medical intervention 
indicated 
Symptomatic (e.g., 
photophobia, nausea) 
interfering with function 
but not interfering with 
ADL  
Symptomatic, interfering 
with ADL 
Life-threatening; disabling 
(e.g., paraplegia) 
Death 
ALSO CONSIDER: Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 109/L); Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select; Pain – Select; Vomiting. 
Ataxia (incoordination) 
Ataxia 
Asymptomatic  
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL; mechanical 
assistance indicated  
Disabling 
Death 
REMARK: Ataxia (incoordination) refers to the consequence of medical or operative intervention. 
Brachial plexopathy 
Brachial plexopathy 
Asymptomatic 
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
Disabling 
Death 
CNS cerebrovascular 
ischemia 
CNS ischemia 
— 
Asymptomatic, 
radiographic findings only 
Transient ischemic event 
or attack (TIA) ≤24 hrs 
duration 
Cerebral vascular 
accident (CVA, stroke), 
neurologic deficit 
>24 hrs  
Death 
NAVIGATION NOTE: CNS hemorrhage/bleeding is graded as Hemorrhage, CNS in the HEMORRHAGE/BLEEDING CATEGORY.  
CNS necrosis/cystic 
progression 
CNS necrosis 
Asymptomatic, 
radiographic findings only 
Symptomatic, not 
interfering with ADL; 
medical intervention 
indicated 
Symptomatic and 
interfering with ADL; 
hyperbaric oxygen 
indicated 
Life-threatening; 
disabling; operative 
intervention indicated to 
prevent or treat CNS 
necrosis/cystic 
progression 
Death 
Cognitive disturbance 
Cognitive disturbance 
Mild cognitive disability; 
not interfering with 
work/school/life 
performance; specialized 
educational 
services/devices not 
indicated 
Moderate cognitive 
disability; interfering with 
work/school/life 
performance but capable 
of independent living; 
specialized resources on 
part-time basis indicated 
Severe cognitive 
disability; significant 
impairment of 
work/school/life 
performance 
Unable to perform ADL; 
full-time specialized 
resources or 
institutionalization 
indicated 
Death 
REMARK: Cognitive disturbance may be used for Attention Deficit Disorder (ADD). 

 
NEUROLOGY 
Page 2 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 48 - 
March 31, 2003, Publish Date: August 9, 2006 
Confusion 
Confusion 
Transient confusion, 
disorientation, or attention 
deficit 
Confusion, disorientation, 
or attention deficit 
interfering with function, 
but not interfering with 
ADL 
Confusion or delirium 
interfering with ADL 
Harmful to others or self; 
hospitalization indicated 
Death 
REMARK: Attention Deficit Disorder (ADD) is graded as Cognitive disturbance. 
NAVIGATION NOTE: Cranial neuropathy is graded as Neuropathy-cranial – Select. 
Dizziness  
Dizziness 
With head movements or 
nystagmus only; not 
interfering with function 
Interfering with function, 
but not interfering with 
ADL 
Interfering with ADL 
Disabling 
— 
REMARK: Dizziness includes disequilibrium, lightheadedness, and vertigo. 
ALSO CONSIDER: Neuropathy: cranial – Select; Syncope (fainting). 
NAVIGATION NOTE: Dysphasia, receptive and/or expressive, is graded as Speech impairment (e.g., dysphasia or aphasia). 
Encephalopathy 
Encephalopathy 
— 
Mild signs or symptoms; 
not interfering with ADL 
Signs or symptoms 
interfering with ADL; 
hospitalization indicated 
Life-threatening; disabling 
Death 
ALSO CONSIDER: Cognitive disturbance; Confusion; Dizziness; Memory impairment; Mental status; Mood alteration – Select; Psychosis (hallucinations/delusions); 
Somnolence/depressed level of consciousness. 
Extrapyramidal/ 
involuntary movement/ 
restlessness 
Involuntary movement 
Mild involuntary 
movements not 
interfering with function 
Moderate involuntary 
movements interfering 
with function, but not 
interfering with ADL 
Severe involuntary 
movements or torticollis 
interfering with ADL 
Disabling 
 
Death 
NAVIGATION NOTE: Headache/neuropathic pain (e.g., jaw pain, neurologic pain, phantom limb pain, post-infectious neuralgia, or painful neuropathies) is graded as Pain – Select in the 
PAIN CATEGORY. 
Hydrocephalus 
Hydrocephalus 
Asymptomatic, 
radiographic findings only 
Mild to moderate 
symptoms not interfering 
with ADL 
Severe symptoms or 
neurological deficit 
interfering with ADL 
Disabling  
Death 
Irritability (children <3 
years of age) 
Irritability 
Mild; easily consolable 
Moderate; requiring 
increased attention 
Severe; inconsolable 
— 
— 
Laryngeal nerve 
dysfunction  
Laryngeal nerve 
Asymptomatic, weakness 
on clinical 
examination/testing only 
Symptomatic, but not 
interfering with ADL; 
intervention not indicated 
Symptomatic, interfering 
with ADL; intervention 
indicated (e.g., 
thyroplasty, vocal cord 
injection) 
Life-threatening; 
tracheostomy indicated 
 
Death 

 
NEUROLOGY 
Page 3 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 49 - 
March 31, 2003, Publish Date: August 9, 2006 
Leak, cerebrospinal fluid 
(CSF) 
CSF leak 
Transient headache; 
postural care indicated 
Symptomatic, not 
interfering with ADL; 
blood patch indicated 
Symptomatic, interfering 
with ADL; operative 
intervention indicated 
Life-threatening; disabling 
Death 
REMARK: Leak, cerebrospinal fluid (CSF) may be used for CSF leak associated with operation and persisting >72 hours. 
Leukoencephalopathy 
(radiographic findings) 
Leukoencephalopathy  
Mild increase in 
subarachnoid space 
(SAS); mild 
ventriculomegaly; small 
(+/- multiple) focal T2 
hyperintensities, involving 
periventricular white 
matter or <1/3 of 
susceptible areas of 
cerebrum 
Moderate increase in 
SAS; moderate 
ventriculomegaly; focal 
T2 hyperintensities 
extending into centrum 
ovale or involving 1/3 to 
2/3 of susceptible areas 
of cerebrum 
Severe increase in SAS; 
severe ventriculomegaly; 
near total white matter T2 
hyperintensities or diffuse 
low attenuation (CT) 
— 
— 
REMARK: Leukoencephalopathy is a diffuse white matter process, specifically NOT associated with necrosis. Leukoencephalopathy (radiographic findings) does not include lacunas, 
which are areas that become void of neural tissue.  
Memory impairment 
Memory impairment 
Memory impairment not 
interfering with function 
Memory impairment 
interfering with function, 
but not interfering with 
ADL 
Memory impairment 
interfering with ADL 
Amnesia 
— 
Mental status7 
Mental status 
— 
1 – 3 point below age  
and educational norm in 
Folstein Mini-Mental 
Status Exam (MMSE) 
>3 point below age and 
educational norm in 
Folstein MMSE  
— 
— 
Mood alteration  
– Select: 
– Agitation 
– Anxiety 
– Depression 
– Euphoria 
Mood alteration – Select 
Mild mood alteration not 
interfering with function 
Moderate mood alteration 
interfering with function, 
but not interfering with 
ADL; medication 
indicated 
Severe mood alteration 
interfering with ADL 
Suicidal ideation; danger 
to self or others 
Death 
Myelitis 
Myelitis 
Asymptomatic, mild signs 
(e.g., Babinski’s or 
Lhermitte’s sign) 
Weakness or sensory 
loss not interfering with 
ADL 
Weakness or sensory 
loss interfering with ADL 
Disabling 
Death 
                                            
7 Folstein MF, Folstein, SE and McHugh PR (1975) "Mini-Mental State: A Practical Method for Grading the State of Patients for the Clinician," Journal of Psychiatric Research, 12: 
189-198 

 
NEUROLOGY 
Page 4 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 50 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Neuropathic pain is graded as Pain – Select in the PAIN CATEGORY.  
Neuropathy: 
cranial  
– Select: 
Neuropathy: cranial  
– Select 
Asymptomatic, detected 
on exam/testing only 
– CN I  
Smell 
– CN II  Vision 
– CN III  Pupil, upper eyelid, extra ocular movements 
– CN IV  Downward, inward movement of eye 
– CN V  Motor-jaw muscles; Sensory-facial 
– CN VI  Lateral deviation of eye 
– CN VII Motor-face; Sensory-taste 
– CN VIII Hearing and balance 
– CN IX Motor-pharynx; Sensory-ear, pharynx, tongue 
– CN X 
Motor-palate; pharynx, larynx 
– CN XI Motor-sternomastoid and trapezius 
– CN XII Motor-tongue 
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
Life-threatening; disabling 
Death 
Neuropathy: 
motor  
Neuropathy-motor 
Asymptomatic, weakness 
on exam/testing only 
Symptomatic weakness 
interfering with function, 
but not interfering with 
ADL 
Weakness interfering with 
ADL; bracing or 
assistance to walk (e.g., 
cane or walker) indicated 
Life-threatening; disabling 
(e.g., paralysis)  
Death 
REMARK: Cranial nerve motor neuropathy is graded as Neuropathy: cranial – Select. 
ALSO CONSIDER: Laryngeal nerve dysfunction; Phrenic nerve dysfunction.  
Neuropathy: 
sensory 
Neuropathy-sensory 
Asymptomatic; loss of 
deep tendon reflexes or 
paresthesia (including 
tingling) but not 
interfering with function 
Sensory alteration or 
paresthesia (including 
tingling), interfering with 
function, but not 
interfering with ADL 
Sensory alteration or 
paresthesia interfering 
with ADL  
Disabling  
Death 
REMARK: Cranial nerve sensory neuropathy is graded as Neuropathy: cranial – Select. 
Personality/behavioral 
Personality 
Change, but not 
adversely affecting 
patient or family 
Change, adversely 
affecting patient or family  
Mental health intervention 
indicated 
Change harmful to others 
or self; hospitalization 
indicated 
Death 
Phrenic nerve dysfunction  Phrenic nerve 
Asymptomatic weakness 
on exam/testing only 
Symptomatic but not 
interfering with ADL; 
intervention not indicated 
Significant dysfunction; 
intervention indicated 
(e.g., diaphragmatic 
plication) 
Life-threatening 
respiratory compromise; 
mechanical ventilation 
indicated 
Death 
Psychosis (hallucinations/ 
delusions) 
Psychosis 
— 
Transient episode 
Interfering with ADL; 
medication, supervision 
Harmful to others or self; 
life-threatening 
Death 

 
NEUROLOGY 
Page 5 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 51 - 
March 31, 2003, Publish Date: August 9, 2006 
or restraints indicated  
consequences 
Pyramidal tract 
dysfunction (e.g., ↑ tone, 
hyperreflexia, positive 
Babinski, ↓ fine motor 
coordination) 
Pyramidal tract 
dysfunction 
Asymptomatic, 
abnormality on exam or 
testing only  
Symptomatic; interfering 
with function but not 
interfering with ADL 
Interfering with ADL 
Disabling; paralysis 
Death 
Seizure 
Seizure 
— 
One brief generalized 
seizure; seizure(s) well 
controlled by 
anticonvulsants or 
infrequent focal motor 
seizures not interfering 
with ADL 
Seizures in which 
consciousness is altered; 
poorly controlled seizure 
disorder, with 
breakthrough generalized 
seizures despite medical 
intervention 
Seizures of any kind 
which are prolonged, 
repetitive, or difficult to 
control (e.g., status 
epilepticus, intractable 
epilepsy) 
Death 
Somnolence/depressed 
level of consciousness 
Somnolence 
— 
Somnolence or sedation 
interfering with function, 
but not interfering with 
ADL 
Obtundation or stupor; 
difficult to arouse; 
interfering with ADL 
Coma 
Death 
Speech impairment  
(e.g., dysphasia or 
aphasia)  
Speech impairment 
— 
Awareness of receptive 
or expressive dysphasia, 
not impairing ability to 
communicate 
Receptive or expressive 
dysphasia, impairing 
ability to communicate 
Inability to communicate 
— 
REMARK: Speech impairment refers to a primary CNS process, not neuropathy or end organ dysfunction. 
ALSO CONSIDER: Laryngeal nerve dysfunction; Voice changes/dysarthria (e.g., hoarseness, loss, or alteration in voice, laryngitis). 
Syncope (fainting) 
Syncope (fainting) 
— 
— 
Present 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: CNS cerebrovascular ischemia; Conduction abnormality/atrioventricular heart block – Select; Dizziness; Supraventricular and nodal arrhythmia – Select; Vasovagal 
episode; Ventricular arrhythmia – Select. 
NAVIGATION NOTE: Taste alteration (CN VII, IX) is graded as Taste alteration (dysgeusia) in the GASTROINTESTINAL CATEGORY. 
Tremor 
Tremor 
Mild and brief or 
intermittent but not 
interfering with function 
Moderate tremor 
interfering with function, 
but not interfering with 
ADL 
Severe tremor interfering 
with ADL 
Disabling 
— 
Neurology – Other 
(Specify, __) 
Neurology – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
OCULAR/VISUAL 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 52 - 
March 31, 2003, Publish Date: August 9, 2006 
Cataract 
Cataract 
Asymptomatic, detected 
on exam only  
Symptomatic, with 
moderate decrease in 
visual acuity  
(20/40 or better); 
decreased visual function 
correctable with glasses  
Symptomatic with marked 
decrease in visual acuity 
(worse than 20/40); 
operative intervention 
indicated (e.g., cataract 
surgery) 
— 
— 
Dry eye syndrome  
Dry eye 
Mild, intervention not 
indicated 
Symptomatic, interfering 
with function but not 
interfering with ADL; 
medical intervention 
indicated  
Symptomatic or decrease 
in visual acuity interfering 
with ADL; operative 
intervention indicated 
— 
— 
Eyelid dysfunction  
Eyelid dysfunction 
Asymptomatic  
Symptomatic, interfering 
with function but not ADL; 
requiring topical agents or 
epilation 
Symptomatic; interfering 
with ADL; surgical 
intervention indicated 
— 
— 
REMARK: Eyelid dysfunction includes canalicular stenosis, ectropion, entropion, erythema, madarosis, symblepharon, telangiectasis, thickening, and trichiasis. 
ALSO CONSIDER: Neuropathy: cranial – Select. 
Glaucoma  
Glaucoma 
Elevated intraocular 
pressure (EIOP) with 
single topical agent for 
intervention; no visual 
field deficit 
EIOP causing early visual 
field deficit (i.e., nasal 
step or arcuate deficit); 
multiple topical or oral 
agents indicated 
EIOP causing marked 
visual field deficits (i.e., 
involving both superior 
and inferior visual fields); 
operative intervention 
indicated 
EIOP resulting in 
blindness (20/200 or 
worse); enucleation 
indicated 
— 
Keratitis (corneal 
inflammation/corneal 
ulceration) 
Keratitis 
Abnormal ophthalmologic 
changes only; 
intervention not indicated 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL; 
operative intervention 
indicated 
Perforation or blindness 
(20/200 or worse)  
— 
NAVIGATION NOTE: Ocular muscle weakness is graded as Muscle weakness, generalized or specific area (not due to neuropathy) – Select in the MUSCULOSKELETAL/SOFT TISSUE 
CATEGORY.  
Night blindness 
(nyctalopia) 
Nyctalopia 
Symptomatic, not 
interfering with function 
Symptomatic and 
interfering with function 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL  
Disabling 
— 

 
OCULAR/VISUAL 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 53 - 
March 31, 2003, Publish Date: August 9, 2006 
Nystagmus 
Nystagmus 
Asymptomatic 
Symptomatic and 
interfering with function 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
ALSO CONSIDER: Neuropathy: cranial – Select; Ophthalmoplegia/diplopia (double vision). 
Ocular surface disease  
Ocular surface disease  
Asymptomatic or 
minimally symptomatic 
but not interfering with 
function 
Symptomatic, interfering 
with function but not 
interfering with ADL; 
topical antibiotics or other 
topical intervention 
indicated 
Symptomatic, interfering 
with ADL; operative 
intervention indicated 
— 
— 
REMARK: Ocular surface disease includes conjunctivitis, keratoconjunctivitis sicca, chemosis, keratinization, and palpebral conjunctival epithelial metaplasia. 
Ophthalmoplegia/ 
diplopia (double vision) 
Diplopia 
Intermittently 
symptomatic, intervention 
not indicated 
Symptomatic and 
interfering with function 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL; 
surgical intervention 
indicated 
Disabling 
— 
ALSO CONSIDER: Neuropathy: cranial – Select. 
Optic disc edema 
Optic disc edema 
Asymptomatic 
Decreased visual acuity 
(20/40 or better); visual 
field defect present 
Decreased visual acuity 
(worse than 20/40); 
marked visual field defect 
but sparing the central 20 
degrees 
Blindness  
(20/200 or worse) 
— 
ALSO CONSIDER: Neuropathy: cranial – Select.  
Proptosis/enophthalmos 
Proptosis/enophthalmos 
Asymptomatic, 
intervention not indicated 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
— 
— 
Retinal detachment 
Retinal detachment 
Exudative; no central 
vision loss; intervention 
not indicated 
Exudative and visual 
acuity 20/40 or better but 
intervention not indicated 
Rhegmatogenous or 
exudative detachment; 
operative intervention 
indicated 
Blindness 
(20/200 or worse) 
— 
Retinopathy  
Retinopathy 
Asymptomatic  
Symptomatic with 
moderate decrease in 
visual acuity 
(20/40 or better) 
Symptomatic with marked 
decrease in visual acuity 
(worse than 20/40) 
Blindness 
(20/200 or worse) 
— 

 
OCULAR/VISUAL 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 54 - 
March 31, 2003, Publish Date: August 9, 2006 
Scleral necrosis/melt 
Scleral necrosis 
Asymptomatic or 
symptomatic but not 
interfering with function 
Symptomatic, interfering 
with function but not 
interfering with ADL; 
moderate decrease in 
visual acuity (20/40 or 
better); medical 
intervention indicated 
Symptomatic, interfering 
with ADL; marked 
decrease in visual acuity 
(worse than 20/40); 
operative intervention 
indicated 
Blindness (20/200 or 
worse); painful eye with 
enucleation indicated 
— 
Uveitis  
Uveitis 
Asymptomatic 
Anterior uveitis; medical 
intervention indicated 
Posterior or pan-uveitis; 
operative intervention 
indicated 
Blindness 
(20/200 or worse) 
— 
Vision-blurred vision 
Blurred vision 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
Vision-flashing 
lights/floaters 
Flashing lights 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
Vision-photophobia 
Photophobia 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
Vitreous hemorrhage 
Vitreous hemorrhage 
Asymptomatic, clinical 
findings only 
Symptomatic, interfering 
with function, but not 
interfering with ADL; 
intervention not indicated 
Symptomatic, interfering 
with ADL; vitrectomy 
indicated  
— 
— 
Watery eye (epiphora, 
tearing) 
Watery eye 
Symptomatic, intervention 
not indicated 
Symptomatic, interfering 
with function but not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
— 
— 
Ocular/Visual – Other  
(Specify, __) 
Ocular – Other  
(Specify) 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Blindness 
(20/200 or worse) 
Death 

 
PAIN 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 55 - 
March 31, 2003, Publish Date: August 9, 2006 
Pain  
– Select: 
‘Select’ AEs appear at the 
end of the CATEGORY. 
Pain – Select  
Mild pain not interfering 
with function 
Moderate pain; pain or 
analgesics interfering with 
function, but not 
interfering with ADL 
Severe pain; pain or 
analgesics severely 
interfering with ADL 
Disabling 
— 
Pain – Other 
(Specify, __) 
Pain – Other (Specify) 
Mild pain not interfering 
with function 
Moderate pain; pain or 
analgesics interfering with 
function, but not 
interfering with ADL 
Severe pain; pain or 
analgesics severely 
interfering with ADL 
Disabling 
— 
PAIN – SELECT 
AUDITORY/EAR 
– External ear 
– Middle ear 
CARDIOVASCULAR 
– Cardiac/heart  
– Pericardium 
DERMATOLOGY/SKIN 
– Face 
– Lip 
– Oral-gums 
– Scalp 
– Skin 
GASTROINTESTINAL 
– Abdomen NOS 
– Anus 
– Dental/teeth/peridontal 
– Esophagus 
– Oral cavity 
– Peritoneum 
– Rectum 
– Stomach 
GENERAL 
– Pain NOS 
– Tumor pain  
HEPATOBILIARY/PANCREAS 
– Gallbladder 
– Liver  
LYMPHATIC 
– Lymph node 
MUSCULOSKELETAL 
– Back 
– Bone 
– Buttock 
– Extremity-limb 
– Intestine 
– Joint 
– Muscle 
– Neck 
– Phantom (pain associated with missing limb) 
NEUROLOGY 
– Head/headache 
– Neuralgia/peripheral nerve 
OCULAR 
– Eye 
PULMONARY/UPPER RESPIRATORY 
– Chest wall 
– Chest/thorax NOS 
PULMONARY/UPPER RESPIRATORY (continued) 
– Larynx 
– Pleura 
– Sinus 
– Throat/pharynx/larynx 
RENAL/GENITOURINARY 
– Bladder 
– Kidney 
SEXUAL/REPRODUCTIVE FUNCTION 
– Breast 
– Ovulatory 
– Pelvis 
– Penis 
– Perineum 
– Prostate 
– Scrotum 
– Testicle 
– Urethra 
– Uterus 
– Vagina 
 
 

 
PULMONARY/UPPER RESPIRATORY 
Page 1 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 56 - 
March 31, 2003, Publish Date: August 9, 2006 
Adult Respiratory 
Distress Syndrome 
(ARDS) 
ARDS 
— 
— 
Present, intubation not 
indicated  
Present, intubation 
indicated 
Death 
ALSO CONSIDER: Dyspnea (shortness of breath); Hypoxia; Pneumonitis/pulmonary infiltrates. 
Aspiration 
Aspiration 
Asymptomatic (“silent 
aspiration”); endoscopy 
or radiographic (e.g., 
barium swallow) findings  
Symptomatic (e.g., 
altered eating habits, 
coughing or choking 
episodes consistent with 
aspiration); medical 
intervention indicated 
(e.g., antibiotics, suction 
or oxygen) 
Clinical or radiographic 
signs of pneumonia or 
pneumonitis; unable to 
aliment orally 
Life-threatening (e.g., 
aspiration pneumonia or 
pneumonitis)  
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils 
– Select; Infection with unknown ANC – Select; Laryngeal nerve dysfunction; Neuropathy: cranial – Select; Pneumonitis/pulmonary infiltrates. 
Atelectasis  
Atelectasis  
Asymptomatic  
Symptomatic (e.g., 
dyspnea, cough), medical 
intervention indicated 
(e.g., bronchoscopic 
suctioning, chest 
physiotherapy, 
suctioning)  
Operative (e.g., stent, 
laser) intervention 
indicated  
Life-threatening 
respiratory compromise 
Death 
ALSO CONSIDER: Adult Respiratory Distress Syndrome (ARDS); Cough; Dyspnea (shortness of breath); Hypoxia; Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select; Obstruction/stenosis of airway – 
Select; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes). 
Bronchospasm, 
wheezing  
Bronchospasm 
Asymptomatic  
Symptomatic not 
interfering with function 
Symptomatic interfering 
with function 
Life-threatening 
Death 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever); Dyspnea (shortness of breath).  
Carbon monoxide 
diffusion capacity (DLCO) 
DLCO 
90 – 75% of predicted 
value 
<75 – 50% of predicted 
value 
<50 – 25% of predicted 
value 
<25% of predicted value 
Death 
ALSO CONSIDER: Hypoxia; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes). 
Chylothorax  
Chylothorax 
Asymptomatic 
Symptomatic; 
thoracentesis or tube 
drainage indicated  
Operative intervention 
indicated 
Life-threatening (e.g., 
hemodynamic instability 
or ventilatory support 
indicated) 
Death 
Cough 
Cough 
Symptomatic, non-
narcotic medication only 
indicated  
Symptomatic and 
narcotic medication 
indicated  
Symptomatic and 
significantly interfering 
with sleep or ADL 
— 
— 

 
PULMONARY/UPPER RESPIRATORY 
Page 2 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 57 - 
March 31, 2003, Publish Date: August 9, 2006 
Dyspnea (shortness of 
breath)  
Dyspnea  
Dyspnea on exertion, but 
can walk 1 flight of stairs 
without stopping 
Dyspnea on exertion but 
unable to walk 1 flight of 
stairs or 1 city block 
(0.1km) without stopping 
Dyspnea with ADL 
Dyspnea at rest; 
intubation/ventilator 
indicated  
Death 
ALSO CONSIDER: Hypoxia; Neuropathy: motor; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes). 
Edema, larynx  
Edema, larynx 
Asymptomatic edema by 
exam only 
Symptomatic edema, no 
respiratory distress  
Stridor; respiratory 
distress; interfering with 
ADL 
Life-threatening airway 
compromise; 
tracheotomy, intubation, 
or laryngectomy indicated 
Death 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever). 
FEV1  
FEV1 
90 – 75% of predicted 
value 
<75 – 50% of predicted 
value 
<50 – 25% of predicted 
value 
<25% of predicted 
Death 
Fistula, pulmonary/upper 
respiratory  
– Select: 
– Bronchus 
– Larynx 
– Lung 
– Oral cavity 
– Pharynx  
– Pleura 
– Trachea 
Fistula, pulmonary  
– Select  
Asymptomatic, 
radiographic findings only 
Symptomatic, tube 
thoracostomy or medical 
management indicated; 
associated with altered 
respiratory function but 
not interfering with ADL 
Symptomatic and 
associated with altered 
respiratory function 
interfering with ADL; or 
endoscopic (e.g., stent) 
or primary closure by 
operative intervention 
indicated 
Life-threatening 
consequences; operative 
intervention with 
thoracoplasty, chronic 
open drainage or multiple 
thoracotomies indicated 
Death 
REMARK: A fistula is defined as an abnormal communication between two body cavities, potential spaces, and/or the skin. The site indicated for a fistula should be the site from which 
the abnormal process is believed to have arisen. For example, a tracheo-esophageal fistula arising in the context of a resected or irradiated esophageal cancer should be graded as 
Fistula, GI – esophagus in the GASTROINTESTINAL CATEGORY. 
NAVIGATION NOTE: Hemoptysis is graded as Hemorrhage, pulmonary/upper respiratory – Select in the HEMORRHAGE/BLEEDING CATEGORY.  
Hiccoughs (hiccups, 
singultus) 
Hiccoughs 
Symptomatic, 
intervention not indicated 
Symptomatic, 
intervention indicated  
Symptomatic, 
significantly interfering 
with sleep or ADL 
— 
— 
Hypoxia 
Hypoxia 
— 
Decreased O2 saturation 
with exercise (e.g., pulse 
oximeter <88%); 
intermittent supplemental 
oxygen  
Decreased O2 saturation 
at rest; continuous 
oxygen indicated 
Life-threatening; 
intubation or ventilation 
indicated  
Death 

 
PULMONARY/UPPER RESPIRATORY 
Page 3 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 58 - 
March 31, 2003, Publish Date: August 9, 2006 
Nasal cavity/paranasal 
sinus reactions 
Nasal/paranasal 
reactions 
Asymptomatic mucosal 
crusting, blood-tinged 
secretions 
Symptomatic stenosis or 
edema/narrowing 
interfering with airflow 
Stenosis with significant 
nasal obstruction; 
interfering with ADL 
Necrosis of soft tissue or 
bone 
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils 
– Select; Infection with unknown ANC – Select. 
Obstruction/stenosis of 
airway 
– Select: 
– Bronchus 
– Larynx 
– Pharynx 
– Trachea 
Airway obstruction  
– Select  
Asymptomatic obstruction 
or stenosis on exam, 
endoscopy, or radiograph 
Symptomatic (e.g., noisy 
airway breathing), but 
causing no respiratory 
distress; medical 
management indicated 
(e.g., steroids)  
Interfering with ADL; 
stridor or endoscopic 
intervention indicated 
(e.g., stent, laser)  
Life-threatening airway 
compromise; tracheotomy 
or intubation indicated 
Death 
Pleural effusion 
(non-malignant)  
Pleural effusion 
Asymptomatic 
Symptomatic, 
intervention such as 
diuretics or up to 2 
therapeutic 
thoracenteses indicated 
Symptomatic and 
supplemental oxygen,  
>2 therapeutic 
thoracenteses, tube 
drainage, or pleurodesis 
indicated 
Life-threatening (e.g., 
causing hemodynamic 
instability or ventilatory 
support indicated)  
Death 
ALSO CONSIDER: Atelectasis; Cough; Dyspnea (shortness of breath); Hypoxia; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes).  
NAVIGATION NOTE: Pleuritic pain is graded as Pain – Select in the PAIN CATEGORY. 
Pneumonitis/pulmonary 
infiltrates  
Pneumonitis 
Asymptomatic, 
radiographic findings only 
Symptomatic, not 
interfering with ADL  
Symptomatic, interfering 
with ADL; O2 indicated  
Life-threatening; 
ventilatory support 
indicated 
Death 
ALSO CONSIDER: Adult Respiratory Distress Syndrome (ARDS); Cough; Dyspnea (shortness of breath); Hypoxia; Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select; Pneumonitis/pulmonary infiltrates; 
Pulmonary fibrosis (radiographic changes). 
Pneumothorax  
Pneumothorax  
Asymptomatic, 
radiographic findings only 
Symptomatic; 
intervention indicated 
(e.g., hospitalization for 
observation, tube 
placement without 
sclerosis) 
Sclerosis and/or 
operative intervention 
indicated 
Life-threatening, causing 
hemodynamic instability 
(e.g., tension 
pneumothorax); 
ventilatory support 
indicated 
Death 
Prolonged chest tube 
drainage or air leak after 
pulmonary resection 
Chest tube drainage or 
leak 
— 
Sclerosis or additional 
tube thoracostomy 
indicated 
Operative intervention 
indicated (e.g., 
thoracotomy with stapling 
or sealant application) 
Life-threatening; 
debilitating; organ 
resection indicated 
Death 

 
PULMONARY/UPPER RESPIRATORY 
Page 4 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 59 - 
March 31, 2003, Publish Date: August 9, 2006 
Prolonged intubation 
after pulmonary resection 
(>24 hrs after surgery)  
Prolonged intubation 
— 
Extubated within  
24 – 72 hrs 
postoperatively 
Extubated >72 hrs 
postoperatively, but 
before tracheostomy 
indicated 
Tracheostomy indicated 
Death 
NAVIGATION NOTE: Pulmonary embolism is graded as Grade 4 either as Thrombosis/embolism (vascular access-related) or Thrombosis/thrombus/embolism in the VASCULAR 
CATEGORY.  
Pulmonary fibrosis 
(radiographic changes)  
Pulmonary fibrosis 
Minimal radiographic 
findings (or patchy or bi-
basilar changes) with 
estimated radiographic 
proportion of total lung 
volume that is fibrotic of 
<25% 
Patchy or bi-basilar 
changes with estimated 
radiographic proportion of 
total lung volume that is 
fibrotic of 25 – <50% 
Dense or widespread 
infiltrates/consolidation 
with estimated 
radiographic proportion of 
total lung volume that is 
fibrotic of 50 – <75% 
Estimated radiographic 
proportion of total lung 
volume that is fibrotic is 
≥75%; honeycombing 
Death 
REMARK: Fibrosis is usually a “late effect” seen >3 months after radiation or combined modality therapy (including surgery). It is thought to represent scar/fibrotic lung tissue. It may be 
difficult to distinguish from pneumonitis that is generally seen within 3 months of radiation or combined modality therapy.  
ALSO CONSIDER: Adult Respiratory Distress Syndrome (ARDS); Cough; Dyspnea (shortness of breath); Hypoxia; Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select. 
NAVIGATION NOTE: Recurrent laryngeal nerve dysfunction is graded as Laryngeal nerve dysfunction in the NEUROLOGY CATEGORY. 
Vital capacity  
Vital capacity 
90 – 75% of predicted 
value 
<75 – 50% of predicted 
value 
<50 – 25% of predicted 
value 
<25% of predicted value 
Death 
Voice changes/dysarthria 
(e.g., hoarseness, loss or 
alteration in voice, 
laryngitis)  
Voice changes  
Mild or intermittent 
hoarseness or voice 
change, but fully 
understandable 
Moderate or persistent 
voice changes, may 
require occasional 
repetition but 
understandable on 
telephone 
Severe voice changes 
including predominantly 
whispered speech; may 
require frequent repetition 
or face-to-face contact for 
understandability; 
requires voice aid (e.g., 
electrolarynx) for ≤50% of 
communication 
Disabling; 
non-understandable voice 
or aphonic; requires voice 
aid (e.g., electrolarynx) 
for >50% of 
communication or 
requires >50% written 
communication 
Death 
ALSO CONSIDER: Laryngeal nerve dysfunction; Speech impairment (e.g., dysphasia or aphasia). 
Pulmonary/Upper 
Respiratory – Other 
(Specify, __) 
Pulmonary – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling 
Death 

 
RENAL/GENITOURINARY 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 60 - 
March 31, 2003, Publish Date: August 9, 2006 
Bladder spasms 
Bladder spasms 
Symptomatic, intervention 
not indicated 
Symptomatic, 
antispasmodics indicated 
Narcotics indicated 
Major surgical 
intervention indicated 
(e.g., cystectomy) 
— 
Cystitis 
Cystitis 
Asymptomatic 
Frequency with dysuria; 
macroscopic hematuria 
Transfusion; IV pain 
medications; bladder 
irrigation indicated 
Catastrophic bleeding; 
major non-elective 
intervention indicated 
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils 
– Select; Infection with unknown ANC – Select; Pain – Select. 
Fistula, GU 
– Select:  
– Bladder 
– Genital tract-female 
– Kidney 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
Fistula, GU – Select  
Asymptomatic, 
radiographic findings only 
Symptomatic; 
noninvasive intervention 
indicated  
Symptomatic interfering 
with ADL; invasive 
intervention indicated  
Life-threatening 
consequences; operative 
intervention requiring 
partial or full organ 
resection; permanent 
urinary diversion  
Death 
REMARK: A fistula is defined as an abnormal communication between two body cavities, potential spaces, and/or the skin. The site indicated for a fistula should be the site from which 
the abnormal process is believed to have originated. 
Incontinence, urinary  
Incontinence, urinary 
Occasional (e.g., with 
coughing, sneezing, etc.), 
pads not indicated 
Spontaneous, pads 
indicated  
Interfering with ADL; 
intervention indicated 
(e.g., clamp, collagen 
injections) 
Operative intervention 
indicated (e.g., 
cystectomy or permanent 
urinary diversion) 
— 
Leak (including 
anastomotic), GU 
– Select: 
– Bladder 
– Fallopian tube  
– Kidney 
– Spermatic cord 
– Stoma 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Leak, GU – Select  
Asymptomatic, 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic, interfering 
with GU function; invasive 
or endoscopic 
intervention indicated 
Life-threatening 
Death 
REMARK: Leak (including anastomotic), GU – Select refers to clinical signs and symptoms or radiographic confirmation of anastomotic leak but without development of fistula. 

 
RENAL/GENITOURINARY 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 61 - 
March 31, 2003, Publish Date: August 9, 2006 
Obstruction, GU  
– Select: 
– Bladder 
– Fallopian tube 
– Prostate 
– Spermatic cord 
– Stoma 
– Testes 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Obstruction, GU – Select  
Asymptomatic, 
radiographic or 
endoscopic findings only 
Symptomatic but no 
hydronephrosis, sepsis or 
renal dysfunction; dilation 
or endoscopic repair or 
stent placement indicated 
Symptomatic and altered 
organ function (e.g., 
sepsis or hydronephrosis, 
or renal dysfunction); 
operative intervention 
indicated  
Life-threatening 
consequences; organ 
failure or operative 
intervention requiring 
complete organ resection 
indicated  
Death 
NAVIGATION NOTE: Operative injury is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY CATEGORY.  
Perforation, GU  
– Select: 
– Bladder 
– Fallopian tube 
– Kidney  
– Ovary 
– Prostate 
– Spermatic cord 
– Stoma 
– Testes 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Perforation, GU – Select 
Asymptomatic 
radiographic findings only 
Symptomatic, associated 
with altered renal/GU 
function 
Symptomatic, operative 
intervention indicated 
Life-threatening 
consequences or organ 
failure; operative 
intervention requiring 
organ resection indicated 
Death 
Prolapse of stoma, GU 
Prolapse stoma, GU 
Asymptomatic; special 
intervention, 
extraordinary care not 
indicated 
Extraordinary local care 
or maintenance; minor 
revision under local 
anesthesia indicated 
Dysfunctional stoma; 
operative intervention or 
major stomal revision 
indicated 
Life-threatening 
consequences 
Death 
REMARK: Other stoma complications may be graded as Fistula, GU – Select; Leak (including anastomotic), GU – Select; Obstruction, GU – Select; Perforation, GU – Select; 
Stricture/stenosis (including anastomotic), GU – Select. 
Renal failure  
Renal failure 
— 
— 
Chronic dialysis not 
indicated 
Chronic dialysis or renal 
transplant indicated 
Death 
ALSO CONSIDER: Glomerular filtration rate. 

 
RENAL/GENITOURINARY 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 62 - 
March 31, 2003, Publish Date: August 9, 2006 
Stricture/stenosis 
(including anastomotic), 
GU 
– Select: 
– Bladder 
– Fallopian tube 
– Prostate 
– Spermatic cord 
– Stoma 
– Testes 
– Ureter  
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Stricture, anastomotic, 
GU – Select  
Asymptomatic, 
radiographic or 
endoscopic findings only 
Symptomatic but no 
hydronephrosis, sepsis or 
renal dysfunction; dilation 
or endoscopic repair or 
stent placement indicated 
Symptomatic and altered 
organ function (e.g., 
sepsis or hydronephrosis, 
or renal dysfunction); 
operative intervention 
indicated  
Life-threatening 
consequences; organ 
failure or operative 
intervention requiring 
organ resection indicated  
Death 
ALSO CONSIDER: Obstruction, GU – Select. 
Urinary electrolyte 
wasting (e.g., Fanconi’s 
syndrome, renal tubular 
acidosis) 
Urinary electrolyte 
wasting 
Asymptomatic, 
intervention not indicated 
Mild, reversible and 
manageable with 
replacement 
Irreversible, requiring 
continued replacement  
— 
— 
ALSO CONSIDER: Acidosis (metabolic or respiratory); Bicarbonate, serum-low; Calcium, serum-low (hypocalcemia); Phosphate, serum-low (hypophosphatemia). 
Urinary 
frequency/urgency 
Urinary frequency 
Increase in frequency or 
nocturia up to 2 x normal; 
enuresis 
Increase >2 x normal but 
<hourly 
≥1 x/hr; urgency; catheter 
indicated 
— 
— 
Urinary retention 
(including neurogenic 
bladder)  
Urinary retention 
Hesitancy or dribbling, no 
significant residual urine; 
retention occurring during 
the immediate 
postoperative period 
Hesitancy requiring 
medication; or operative 
bladder atony requiring 
indwelling catheter 
beyond immediate 
postoperative period but 
for <6 weeks 
More than daily 
catheterization indicated; 
urological intervention 
indicated (e.g., TURP, 
suprapubic tube, 
urethrotomy) 
Life-threatening 
consequences; organ 
failure (e.g., bladder 
rupture); operative 
intervention requiring 
organ resection indicated 
Death 
REMARK: The etiology of retention (if known) is graded as Obstruction, GU – Select; Stricture/stenosis (including anastomotic), GU – Select. 
ALSO CONSIDER: Obstruction, GU – Select; Stricture/stenosis (including anastomotic), GU – Select. 
Urine color change  
Urine color change 
Present 
— 
— 
— 
— 
REMARK: Urine color refers to change that is not related to other dietary or physiologic cause (e.g., bilirubin, concentrated urine, and hematuria). 
Renal/Genitourinary – 
Other (Specify, __) 
Renal – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
SECONDARY MALIGNANCY 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 63 - 
March 31, 2003, Publish Date: August 9, 2006 
Secondary Malignancy – 
possibly related to cancer 
treatment (Specify, __)  
Secondary Malignancy 
(possibly related to 
cancer treatment) 
— 
— 
Non-life-threatening basal 
or squamous cell 
carcinoma of the skin 
Solid tumor, leukemia or 
lymphoma  
Death 
REMARK: Secondary malignancy excludes metastasis from initial primary. Any malignancy possibly related to cancer treatment (including AML/MDS) should be reported via the routine 
reporting mechanisms outlined in each protocol. Important: Secondary Malignancy is an exception to NCI Expedited Adverse Event Reporting Guidelines. Secondary Malignancy is 
“Grade 4, present” but NCI does not require AdEERS Expedited Reporting for any (related or unrelated to treatment) Secondary Malignancy. A diagnosis of AML/MDS following 
treatment with an NCI-sponsored investigational agent is to be reported using the form available from the CTEP Web site at http://ctep.cancer.gov. Cancers not suspected of being 
treatment-related are not to be reported here. 

 
SEXUAL/REPRODUCTIVE FUNCTION 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 64 - 
March 31, 2003, Publish Date: August 9, 2006 
Breast function/lactation 
Breast function 
Mammary abnormality, 
not functionally significant 
Mammary abnormality, 
functionally significant 
— 
— 
— 
Breast nipple/areolar 
deformity  
Nipple/areolar 
Limited areolar 
asymmetry with no 
change in nipple/areolar 
projection 
Asymmetry of nipple 
areolar complex with 
slight deviation in nipple 
projection 
Marked deviation of 
nipple projection  
— 
— 
Breast volume/hypoplasia 
Breast 
Minimal asymmetry; 
minimal hypoplasia 
Asymmetry exists, ≤1/3 of 
the breast volume; 
moderate hypoplasia  
Asymmetry exists, >1/3 of 
the breast volume; severe 
hypoplasia 
— 
— 
REMARK: Breast volume is referenced with both arms straight overhead. 
NAVIGATION NOTE: Dysmenorrhea is graded as Pain – Select in the PAIN CATEGORY.  
NAVIGATION NOTE: Dyspareunia is graded as Pain – Select in the PAIN CATEGORY.  
NAVIGATION NOTE: Dysuria (painful urination) is graded as Pain – Select in the PAIN CATEGORY.  
Erectile dysfunction 
Erectile dysfunction 
Decrease in erectile 
function 
(frequency/rigidity of 
erections) but erectile 
aids not indicated 
Decrease in erectile 
function 
(frequency/rigidity of 
erections), erectile aids 
indicated 
Decrease in erectile 
function 
(frequency/rigidity of 
erections) but erectile 
aids not helpful; penile 
prosthesis indicated 
— 
— 
Ejaculatory dysfunction 
Ejaculatory dysfunction 
Diminished ejaculation 
Anejaculation or 
retrograde ejaculation 
— 
— 
— 
NAVIGATION NOTE: Feminization of male is graded in the ENDOCRINE CATEGORY. 
Gynecomastia 
Gynecomastia 
— 
Asymptomatic breast 
enlargement 
Symptomatic breast 
enlargement; intervention 
indicated 
— 
— 
ALSO CONSIDER: Pain – Select.  
Infertility/sterility 
Infertility/sterility 
— 
Male: oligospermia/low 
sperm count 
Female: diminished 
fertility/ovulation 
Male: sterile/azoospermia 
Female: infertile/ 
anovulatory 
— 
— 
Irregular menses  
(change from baseline) 
Irregular menses 
1 – 3 months without 
menses 
>3 – 6 months without 
menses but continuing 
menstrual cycles 
Persistent amenorrhea 
for >6 months 
— 
— 

 
SEXUAL/REPRODUCTIVE FUNCTION 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 65 - 
March 31, 2003, Publish Date: August 9, 2006 
Libido 
Libido 
Decrease in interest but 
not affecting relationship; 
intervention not indicated 
Decrease in interest and 
adversely affecting 
relationship; intervention 
indicated 
— 
— 
— 
NAVIGATION NOTE: Masculinization of female is graded in the ENDOCRINE CATEGORY. 
Orgasmic dysfunction 
Orgasmic function 
Transient decrease 
Decrease in orgasmic 
response requiring 
intervention 
Complete inability of 
orgasmic response; not 
responding to intervention 
— 
— 
NAVIGATION NOTE: Pelvic pain is graded as Pain – Select in the PAIN CATEGORY. 
NAVIGATION NOTE: Ulcers of the labia or perineum are graded as Ulceration in DERMATOLOGY/SKIN CATEGORY. 
Vaginal discharge  
(non-infectious) 
Vaginal discharge 
Mild 
Moderate to heavy; pad 
use indicated 
— 
— 
— 
Vaginal dryness 
Vaginal dryness 
Mild 
Interfering with sexual 
function; dyspareunia; 
intervention indicated 
— 
— 
— 
ALSO CONSIDER: Pain – Select. 
Vaginal mucositis 
Vaginal mucositis 
Erythema of the mucosa; 
minimal symptoms 
Patchy ulcerations; 
moderate symptoms or 
dyspareunia 
Confluent ulcerations; 
bleeding with trauma; 
unable to tolerate vaginal 
exam, sexual intercourse 
or tampon placement  
Tissue necrosis; 
significant spontaneous 
bleeding; life-threatening 
consequences 
— 
Vaginal stenosis/length 
Vaginal stenosis 
Vaginal narrowing and/or 
shortening not interfering 
with function  
Vaginal narrowing and/or 
shortening interfering with 
function  
Complete obliteration; not 
surgically correctable 
— 
— 
Vaginitis (not due to 
infection) 
Vaginitis 
Mild, intervention not 
indicated 
Moderate, intervention 
indicated 
Severe, not relieved with 
treatment; ulceration, but 
operative intervention not 
indicated 
Ulceration and operative 
intervention indicated 
— 
Sexual/Reproductive 
Function – Other 
(Specify, __) 
Sexual – Other (Specify) 
Mild 
Moderate 
Severe 
Disabling 
Death 

 
SURGERY/INTRA-OPERATIVE INJURY 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 66 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Intra-operative hemorrhage is graded as Hemorrhage/bleeding associated with surgery, intra-operative or postoperative in the HEMORRHAGE/BLEEDING 
CATEGORY.  
Intra-operative injury  
– Select Organ or 
Structure 
‘Select’ AEs appear at the 
end of the CATEGORY. 
Intraop injury – Select  
Primary repair of injured 
organ/structure indicated  
Partial resection of 
injured organ/structure 
indicated 
Complete resection or 
reconstruction of injured 
organ/structure indicated 
Life threatening 
consequences; disabling 
— 
REMARK: The ‘Select’ AEs are defined as significant, unanticipated injuries that are recognized at the time of surgery. These AEs do not refer to additional surgical procedures that 
must be performed because of a change in the operative plan based on intra-operative findings. Any sequelae resulting from the intra-operative injury that result in an adverse 
outcome for the patient must also be recorded and graded under the relevant CTCAE Term. 
Intra-operative Injury – 
Other (Specify, __) 
Intraop Injury – Other 
(Specify) 
Primary repair of injured 
organ/structure indicated  
Partial resection of 
injured organ/structure 
indicated 
Complete resection or 
reconstruction of injured 
organ/structure indicated 
Life threatening 
consequences; disabling 
— 
REMARK: Intra-operative Injury – Other (Specify, __) is to be used only to report an organ/structure not included in the ‘Select’ AEs found at the end of the CATEGORY. Any sequelae 
resulting from the intra-operative injury that result in an adverse outcome for the patient must also be recorded and graded under the relevant CTCAE Term. 

 
SURGERY/INTRA-OPERATIVE INJURY – SELECT  
Page 2 of 2 
CTCAE v3.0  
- 67 - 
March 31, 2003, Publish Date: August 9, 2006 
AUDITORY/EAR 
– Inner ear  
– Middle ear  
– Outer ear NOS  
– Outer ear-Pinna  
CARDIOVASCULAR 
– Artery-aorta  
– Artery-carotid  
– Artery-cerebral  
– Artery-extremity (lower)  
– Artery-extremity (upper)  
– Artery-hepatic  
– Artery-major visceral artery  
– Artery-pulmonary  
– Artery NOS 
– Heart  
– Spleen 
– Vein-extremity (lower)  
– Vein-extremity (upper)  
– Vein-hepatic  
– Vein-inferior vena cava  
– Vein-jugular  
– Vein-major visceral vein  
– Vein-portal vein  
– Vein-pulmonary  
– Vein-superior vena cava  
– Vein NOS 
DERMATOLOGY/SKIN 
– Breast  
– Nails  
– Skin 
ENDOCRINE 
– Adrenal gland 
– Parathyroid 
– Pituitary  
ENDOCRINE (continued) 
– Thyroid 
HEAD AND NECK 
– Gingiva  
– Larynx  
– Lip/perioral area  
– Face NOS  
– Nasal cavity  
– Nasopharynx  
– Neck NOS 
– Nose  
– Oral cavity NOS  
– Parotid gland  
– Pharynx  
– Salivary duct  
– Salivary gland  
– Sinus  
– Teeth  
– Tongue  
– Upper aerodigestive NOS 
GASTROINTESTINAL 
– Abdomen NOS  
– Anal sphincter  
– Anus 
– Appendix  
– Cecum  
– Colon  
– Duodenum  
– Esophagus  
– Ileum  
– Jejunum  
– Oral  
– Peritoneal cavity  
– Rectum 
– Small bowel NOS 
GASTROINTESTINAL (continued) 
– Stoma (GI)  
– Stomach  
HEPATOBILIARY/ PANCREAS 
– Biliary tree-common bile  
duct  
– Biliary tree-common hepatic 
duct  
– Biliary tree-left hepatic duct  
– Biliary tree-right hepatic duct  
– Biliary tree NOS  
– Gallbladder  
– Liver 
– Pancreas 
– Pancreatic duct 
MUSCULOSKELETAL 
– Bone  
– Cartilage  
– Extremity-lower 
– Extremity-upper 
– Joint  
– Ligament  
– Muscle  
– Soft tissue NOS 
– Tendon 
NEUROLOGY  
– Brain  
– Meninges  
– Spinal cord 
NERVES: 
– Brachial plexus 
– CN I (olfactory) 
– CN II (optic) 
– CN III (oculomotor) 
– CN IV (trochlear)  
NEUROLOGY (continued) 
NERVES: 
– CN V (trigeminal) motor  
– CN V (trigeminal) sensory  
– CN VI (abducens)  
– CN VII (facial) motor-face  
– CN VII (facial) sensory-
taste  
– CN VIII (vestibulocochlear)  
– CN IX (glossopharyngeal) 
motor pharynx  
– CN IX (glossopharyngeal) 
sensory ear-pharynx-
tongue  
– CN X (vagus)  
– CN XI (spinal accessory)  
– CN XII (hypoglossal)  
– Cranial nerve or branch 
NOS  
– Lingual  
– Lung thoracic  
– Peripheral motor NOS 
– Peripheral sensory NOS 
– Recurrent laryngeal  
– Sacral plexus  
– Sciatic 
– Thoracodorsal 
OCULAR 
– Conjunctiva  
– Cornea  
– Eye NOS 
– Lens 
– Retina 
PULMONARY/UPPER 
RESPIRATORY 
– Bronchus  
– Lung  
– Mediastinum  
– Pleura  
– Thoracic duct  
– Trachea 
– Upper airway NOS 
RENAL/GENITOURINARY 
– Bladder  
– Cervix  
– Fallopian tube  
– Kidney  
– Ovary  
– Pelvis NOS  
– Penis  
– Prostate  
– Scrotum  
– Testis  
– Ureter  
– Urethra  
– Urinary conduit  
– Urinary tract NOS  
– Uterus  
– Vagina  
– Vulva 
 
 

 
SYNDROMES 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 68 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Acute vascular leak syndrome is graded in the VASCULAR CATEGORY. 
NAVIGATION NOTE: Adrenal insufficiency is graded in the ENDOCRINE CATEGORY. 
NAVIGATION NOTE: Adult Respiratory Distress Syndrome (ARDS) is graded in the PULMONARY/UPPER RESPIRATORY CATEGORY. 
Alcohol intolerance 
syndrome (antabuse-like 
syndrome) 
Alcohol intolerance 
syndrome 
— 
— 
Present 
— 
Death 
REMARK: An antabuse-like syndrome occurs with some new anti-androgens (e.g., nilutamide) when patient also consumes alcohol. 
NAVIGATION NOTE: Autoimmune reaction is graded as Autoimmune reaction/hypersensitivity (including drug fever) in the ALLERGY/IMMUNOLOGY CATEGORY. 
Cytokine release 
syndrome/acute infusion 
reaction 
Cytokine release 
syndrome 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDS, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption of 
infusion); recurrence of 
symptoms following initial 
improvement; 
hospitalization indicated 
for other clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates) 
Life-threatening; pressor 
or ventilatory support 
indicated 
Death 
REMARK: Cytokine release syndromes/acute infusion reactions are different from Allergic/hypersensitive reactions, although some of the manifestations are common to both AEs. An 
acute infusion reaction may occur with an agent that causes cytokine release (e.g., monoclonal antibodies or other biological agents). Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hrs of completion of infusion. Signs/symptoms may include: Allergic reaction/hypersensitivity (including drug 
fever); Arthralgia (joint pain); Bronchospasm; Cough; Dizziness; Dyspnea (shortness of breath); Fatigue (asthenia, lethargy, malaise); Headache; Hypertension; Hypotension; Myalgia 
(muscle pain); Nausea; Pruritis/itching; Rash/desquamation; Rigors/chills; Sweating (diaphoresis); Tachycardia; Tumor pain (onset or exacerbation of tumor pain due to treatment); 
Urticaria (hives, welts, wheals); Vomiting.  
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever); Bronchospasm, wheezing; Dyspnea (shortness of breath); Hypertension; Hypotension; Hypoxia; Prolonged 
QTc interval; Supraventricular and nodal arrhythmia – Select; Ventricular arrhythmia – Select.  
NAVIGATION NOTE: Disseminated intravascular coagulation (DIC) is graded in the COAGULATION CATEGORY. 
NAVIGATION NOTE: Fanconi’s syndrome is graded as Urinary electrolyte wasting (e.g., Fanconi’s syndrome, renal tubular acidosis) in the RENAL/GENITOURINARY CATEGORY. 
Flu-like syndrome 
Flu-like syndrome 
Symptoms present but 
not interfering with 
function 
Moderate or causing 
difficulty performing some 
ADL 
Severe symptoms 
interfering with ADL 
Disabling 
Death 
REMARK: Flu-like syndrome represents a constellation of symptoms which may include cough with catarrhal symptoms, fever, headache, malaise, myalgia, prostration, and is to be 
used when the symptoms occur in a cluster consistent with one single pathophysiological process. 
NAVIGATION NOTE: Renal tubular acidosis is graded as Urinary electrolyte wasting (e.g., Fanconi’s syndrome, renal tubular acidosis) in the RENAL/GENITOURINARY CATEGORY. 

 
SYNDROMES 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 69 - 
March 31, 2003, Publish Date: August 9, 2006 
“Retinoic acid syndrome”  
“Retinoic acid syndrome” 
Fluid retention; less than 
3 kg of weight gain; 
intervention with fluid 
restriction and/or diuretics 
indicated 
Mild to moderate signs/ 
symptoms; steroids 
indicated 
Severe signs/symptoms; 
hospitalization indicated 
Life-threatening; 
ventilatory support 
indicated 
Death 
REMARK: Patients with acute promyelocytic leukemia may experience a syndrome similar to “retinoic acid syndrome” in association with other agents such as arsenic trioxide. The 
syndrome is usually manifested by otherwise unexplained fever, weight gain, respiratory distress, pulmonary infiltrates and/or pleural effusion, with or without leukocytosis.  
ALSO CONSIDER: Acute vascular leak syndrome; Pleural effusion (non-malignant); Pneumonitis/pulmonary infiltrates. 
NAVIGATION NOTE: SIADH is graded as Neuroendocrine: ADH secretion abnormality (e.g., SIADH or low ADH) in the ENDOCRINE CATEGORY.  
NAVIGATION NOTE: Stevens-Johnson syndrome is graded as Rash: erythema multiforme (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis) in the DERMATOLOGY/SKIN 
CATEGORY. 
NAVIGATION NOTE: Thrombotic microangiopathy is graded as Thrombotic microangiopathy (e.g., thrombotic thrombocytopenic purpura [TTP] or hemolytic uremic syndrome [HUS]) in 
the COAGULATION CATEGORY. 
Tumor flare 
Tumor flare 
Mild pain not interfering 
with function 
Moderate pain; pain or 
analgesics interfering with 
function, but not 
interfering with ADL 
Severe pain; pain or 
analgesics interfering with 
function and interfering 
with ADL 
Disabling 
Death 
REMARK: Tumor flare is characterized by a constellation of signs and symptoms in direct relation to initiation of therapy (e.g., anti-estrogens/androgens or additional hormones). The 
symptoms/signs include tumor pain, inflammation of visible tumor, hypercalcemia, diffuse bone pain, and other electrolyte disturbances.  
ALSO CONSIDER: Calcium, serum-high (hypercalcemia). 
Tumor lysis syndrome 
Tumor lysis syndrome 
— 
— 
Present 
— 
Death 
ALSO CONSIDER: Creatinine; Potassium, serum-high (hyperkalemia). 
Syndromes – Other 
(Specify, __) 
Syndromes – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 

 
VASCULAR 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 70 - 
March 31, 2003, Publish Date: August 9, 2006 
Acute vascular leak 
syndrome 
Acute vascular leak 
syndrome 
— 
Symptomatic, fluid 
support not indicated 
Respiratory compromise 
or fluids indicated 
Life-threatening; pressor 
support or ventilatory 
support indicated  
Death 
Peripheral arterial 
ischemia 
Peripheral arterial 
ischemia 
— 
Brief (<24 hrs) episode of 
ischemia managed non-
surgically and without 
permanent deficit 
Recurring or prolonged 
(≥24 hrs) and/or invasive 
intervention indicated 
Life-threatening, disabling 
and/or associated with 
end organ damage 
(e.g., limb loss) 
Death 
Phlebitis (including 
superficial thrombosis) 
Phlebitis 
— 
Present 
— 
— 
— 
ALSO CONSIDER: Injection site reaction/extravasation changes. 
Portal vein flow 
Portal flow 
— 
Decreased portal vein 
flow 
Reversal/retrograde 
portal vein flow 
— 
— 
Thrombosis/embolism 
(vascular access-related) 
Thrombosis/embolism 
(vascular access) 
— 
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
not indicated 
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
indicated 
Embolic event including 
pulmonary embolism or 
life-threatening thrombus 
Death 
Thrombosis/thrombus/ 
embolism 
Thrombosis/thrombus/ 
embolism 
— 
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
not indicated  
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
indicated  
Embolic event including 
pulmonary embolism or 
life-threatening thrombus 
Death 
Vessel injury-artery  
– Select:  
– Aorta 
– Carotid 
– Extremity-lower 
– Extremity-upper  
– Other NOS 
– Visceral 
Artery injury – Select 
Asymptomatic diagnostic 
finding; intervention not 
indicated 
Symptomatic (e.g., 
claudication); not 
interfering with ADL; 
repair or revision not 
indicated 
Symptomatic interfering 
with ADL; repair or 
revision indicated 
Life-threatening; 
disabling; evidence of 
end organ damage (e.g., 
stroke, MI, organ or limb 
loss) 
Death 
NAVIGATION NOTE: Vessel injury to an artery intra-operatively is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY 
CATEGORY. 

 
VASCULAR 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 71 - 
March 31, 2003, Publish Date: August 9, 2006 
Vessel injury-vein  
– Select: 
– Extremity-lower  
– Extremity-upper 
– IVC 
– Jugular 
– Other NOS 
– SVC 
– Viscera 
Vein injury – Select 
Asymptomatic diagnostic 
finding; intervention not 
indicated 
Symptomatic (e.g., 
claudication); not 
interfering with ADL; 
repair or revision not 
indicated  
Symptomatic interfering 
with ADL; repair or 
revision indicated 
Life-threatening; 
disabling; evidence of 
end organ damage  
Death 
NAVIGATION NOTE: Vessel injury to a vein intra-operatively is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY CATEGORY. 
Visceral arterial ischemia 
(non-myocardial) 
Visceral arterial ischemia 
— 
Brief (<24 hrs) episode of 
ischemia managed 
medically and without 
permanent deficit 
Prolonged (≥24 hrs) or 
recurring symptoms 
and/or invasive 
intervention indicated 
Life-threatening; 
disabling; evidence of 
end organ damage  
Death 
ALSO CONSIDER: CNS cerebrovascular ischemia.  
Vascular – Other  
(Specify, __) 
Vascular – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
 

Clinical Trial Protocol:  HGT-SAN-067
Study Title:
An Open-Label Extension of Study HGT-SAN-055 Evaluating 
Long-Term Safety and Clinical Outcomes of Intrathecal Administration 
of rhHNS in Patients with Sanfilippo Syndrome Type A (MPS IIIA)
Study Number:
HGT-SAN-067
Study Phase:
I/II
Product Name:
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Device Names:
SOPH-A-PORT® Mini S, Implantable Access Port, Spinal, Mini 
Unattached, with Guidewire
and
PORT-A-CATH® II Low Profile™Intrathecal Implantable Access 
System (Smiths device)
EudraCT Number:
2010-021348-16
Indication:
Sanfilippo Syndrome A
Investigators:
Multicenter
Sponsor:
Shire Human Genetic Therapies, Inc. 
300 Shire Way
Lexington, MA  02421, United States
Medical Monitor:
 DO,
Date
Original Protocol:
21 June 2010
Amendment 1:
27 January 2011
Amendment 2:
13 January 2012
Amendment 3:
28 August 2012
Amendment 4:
3 May 2013
Amendment 5:
17 January 2014
Amendment 6:
10 July 2014
Amendment 7:
08 February 2016
Confidentiality Statement
This document is the proprietary and confidential property of 
Shire Human Genetic Therapies, Inc.

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
2
TABLE OF CONTENTS
TABLE OF CONTENTS...........................................................................................................2
SYNOPSIS.................................................................................................................................7
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..........................................14
1
INTRODUCTION ...........................................................................................................17
1.1
Disease Background...............................................................................................17
1.2
Nonclinical Overview............................................................................................19
1.2.1
Toxicology in Monkeys ..............................................................................19
1.2.2
Efficacy in Murine and Canine Models of MPS IIIA.................................20
1.3
HGT-SAN-067 Study Rationale............................................................................20
2
STUDY OBJECTIVES....................................................................................................22
2.1
Primary Objective..................................................................................................22
2.2
Secondary Objectives.............................................................................................22
2.3
Exploratory Objective............................................................................................22
3
STUDY ENDPOINTS.....................................................................................................23
3.1
Primary Endpoint...................................................................................................23
3.2
Secondary Endpoints .............................................................................................23
3.3
SOPH-A-PORT Mini S Assessments....................................................................23
4
INVESTIGATIONAL PLAN..........................................................................................24
4.1
Overall Study Design and Plan..............................................................................24
4.2
Rationale for Study Design and Control Group.....................................................26
4.3
Study Duration and Dates......................................................................................27
5
STUDY POPULATION SELECTION ...........................................................................28
5.1
Study Population....................................................................................................28
5.2
Inclusion Criteria ...................................................................................................28
5.3
Exclusion Criteria ..................................................................................................28
6
STUDY TREATMENT(S)..............................................................................................30
6.1
Description of Treatment(s)...................................................................................30
6.1.1
Study Drug ..................................................................................................30
6.1.2
Intrathecal Drug Delivery Device...............................................................30
6.1.3
Placebo or Control.......................................................................................30
6.2
Treatment Administered ........................................................................................30
6.3
Selection and Timing of Dose for Each Patient.....................................................31
6.3.1
Cerebral Spinal Fluid Sample Procedure....................................................31
6.3.2
Administration of HGT-1410 via Lumbar Puncture Guidance 
Concerning Performance of Lumbar Puncture for Study Drug 
Administration and Cerebrospinal Fluid Sample Collection ......................32
6.4
Method of Assigning Patients to Treatment Groups..............................................33
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 2 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
3
6.5
Blinding..................................................................................................................33
6.6
Concomitant Therapy.............................................................................................33
6.7
Restrictions ............................................................................................................33
6.7.1
Prior Therapy ..............................................................................................33
6.7.2
Fluid and Food Intake .................................................................................34
6.7.3
Patient Activity Restrictions .......................................................................34
6.8
Treatment Compliance...........................................................................................34
6.9
Packaging and Labeling.........................................................................................34
6.9.1
Drug Product...............................................................................................34
6.9.2
SOPH-A-PORT Mini S Access Port...........................................................34
6.10
Storage and Accountability....................................................................................35
6.10.1
Investigational Product................................................................................35
6.10.2
Intrathecal Drug Delivery Device...............................................................35
6.10.2.1
PORT-A-CATH IDDD.......................................................................35
6.10.2.2
SOPH-A-PORT Mini S IDDD ...........................................................35
6.11
Investigational Product Retention at Study Site ....................................................35
7
STUDY PROCEDURES .................................................................................................36
7.1
Informed Consent...................................................................................................36
7.2
Physical Examination.............................................................................................36
7.3
Height and Weight .................................................................................................36
7.4
Head Circumference ..............................................................................................37
7.5
Vital Signs..............................................................................................................37
7.6
Electrocardiography...............................................................................................37
7.6.1
Electrocardiograms .....................................................................................37
7.7
Clinical Laboratory Tests.......................................................................................37
7.7.1
Hematology.................................................................................................37
7.7.2
Serum Chemistry.........................................................................................38
7.7.3
Pregnancy Test............................................................................................38
7.7.4
Serum Anti-rhHNS Antibody and Sample Storage ....................................38
7.7.5
Urinalysis ....................................................................................................38
7.7.5.1
Standard Urinalysis.............................................................................39
7.7.5.2
Urine Glycosaminoglycans.................................................................39
7.7.6
Cerebrospinal Fluid Assessments ...............................................................39
7.7.6.1
Cerebrospinal Fluid Cell Counts ........................................................39
7.7.6.2
Cerebrospinal Fluid Heparan Sulfate Levels and Heparan Sulfate 
Derivatives..........................................................................................39
7.7.6.3
Anti-rhHNS Antibodies......................................................................39
7.7.6.4
Cerebrospinal Fluid Biomarkers.........................................................39
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 3 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
4
7.7.7
Sample Collection, Storage, and Shipping..................................................39
7.8
Anesthesia..............................................................................................................40
7.9
Audiometry and Auditory Brainstem Response ....................................................40
7.10
Magnetic Resonance Imaging of the Head ............................................................40
7.11
Device Data............................................................................................................40
7.12
Surgical Re-implantation of the IDDD..................................................................41
7.12.1
Restrictions on the Number of Revision and/or re-implantation of the 
IDDD...........................................................................................................41
7.13
Device Related Study Procedures..........................................................................41
7.13.1
IDDD Implantation or Revision Procedures...............................................41
7.13.2
X-ray Verification of Intrathecal Drug Delivery Device Placement ..........42
7.13.3
CSF Sampling Procedure............................................................................42
7.13.4
Device Removal..........................................................................................42
7.14
Cerebrospinal Fluid Opening Pressure Measurement............................................42
7.15
Dispensing Study Drug..........................................................................................43
7.16
Pharmacokinetic Assessments ...............................................................................43
7.17
Neurological Examination .....................................................................................43
7.18
Neurocognitive and Developmental Assessments.................................................43
7.19
Sleep Questionnaire:  Children’s Sleep Habits Rating Scale.................................45
7.20
Age-Dependent, Health-Related Quality of Life in Children................................45
7.20.1
Quality of Life Indicator:  CHQ-50 ............................................................45
7.20.2
Quality of Life Indicator:  CHQ-87 ............................................................45
7.20.3
Quality of Life Indicator:  ITQOL ..............................................................45
7.21
Concomitant Medications, Therapies and Medical/Surgical Procedures ..............45
7.22
Adverse Events ......................................................................................................46
7.22.1
Definitions of Adverse Events and Serious Adverse Events ......................46
7.22.1.1
Adverse Event.....................................................................................46
7.22.1.2
Potential Adverse Events:  Intrathecal recombinant human heparan 
N-sulfatase ..........................................................................................47
7.22.1.3
Infusion/Hypersensitivity Reactions and Management......................47
7.22.1.4
IDDD-related Adverse Events............................................................48
7.22.1.5
Serious Adverse Event........................................................................49
7.22.2
Device-Associated Definitions....................................................................49
7.22.2.1
Device Revision (Partial and Full) .....................................................49
7.22.2.2
Device Malfunction ............................................................................50
7.22.2.3
Device Failure.....................................................................................50
7.22.2.4
Device Adjustment .............................................................................50
7.22.3
Classification of Adverse Events and Serious Adverse Events ..................50
7.22.4
Relatedness of Adverse Events and Serious Adverse Events.....................50
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 4 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
5
7.22.5
Procedures for Recording and Reporting Adverse Events..........................51
7.22.5.1
Reporting Serious Adverse Events Related to Study Procedures.......51
7.22.5.2
Eliciting Adverse Events ....................................................................52
7.22.5.3
Protocol Deviations for Medical Emergency or Adverse Event ........53
7.23
Abuse, Overdose and Medication Errors...............................................................53
7.24
Safety-related Study Stopping Rules .....................................................................54
7.25
Pregnancy...............................................................................................................54
7.26
Removal of Patients from the Trial or Study Drug................................................54
7.27
Other Study Procedures .........................................................................................56
7.28
Appropriateness of Measurements.........................................................................56
8
STUDY ACTIVITIES .....................................................................................................57
8.1
Screening Visit/Study Start Visit – Main Site .......................................................57
8.2
Treatment:  Drug Administration and Weekly Assessments – Main or Local 
Site......................................................................................................................58
8.2.1
Week 1 ........................................................................................................58
8.2.1.1
Day 1 (Pre-treatment) Assessments Performed Prior to Each Dose...58
8.2.1.2
Day 2 (±2 days) Assessments and Administration of HGT-1410 ......59
8.3
End of Study/Early Termination Procedures:  Month 103 – Main Site.................60
8.4
Safety Follow-up (by Telephone or Visit) Month 104 ..........................................61
9
QUALITY CONTROL AND ASSURANCE .................................................................62
10
PLANNED STATISTICAL METHODS ........................................................................63
10.1
General Statistical Methodology............................................................................63
10.2
Determination of Sample Size ...............................................................................63
10.3
Analysis Populations..............................................................................................63
10.4
Demographics and Baseline Characteristics..........................................................63
10.5
Statistical Analysis of Pharmacokinetic Variables ................................................64
10.6
Efficacy, Safety, and Pharmacodynamic Evaluations ...........................................64
10.6.1
Primary Analyses ........................................................................................64
10.6.1.1
Safety Analysis ...................................................................................64
10.6.2
Other Observations Related to Safety.........................................................65
10.6.2.1
IDDD Performance.............................................................................65
10.6.3
Secondary Analysis.....................................................................................66
10.6.3.1
Clinical Assessments ..........................................................................66
10.6.3.2
Pharmacodynamic Analyses...............................................................66
10.6.4
Interim Analysis..........................................................................................66
11
ADMINISTRATIVE CONSIDERATIONS....................................................................67
11.1
Investigators and Study Administrative Structure.................................................67
11.2
Institutional Review Board or Independent Ethics Committee Approval .............67
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 5 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
6
11.3
Ethical Conduct of the Study.................................................................................67
11.4
Patient Information and Consent ...........................................................................67
11.5
Patient Confidentiality...........................................................................................68
11.6
Study Monitoring...................................................................................................68
11.7
Case Report Forms and Study Records .................................................................69
11.7.1
Critical Documents......................................................................................69
11.8
Device Failure Review Process .............................................................................69
11.9
Protocol Violations/Deviations..............................................................................70
11.10 Access to Source Documentation ..........................................................................70
11.11 Data Generation and Analysis ...............................................................................70
11.12 Premature Closure of the Study.............................................................................71
11.12.1
Study Termination.......................................................................................71
11.12.2
Site Termination..........................................................................................71
11.13 Retention of Data...................................................................................................71
11.14 Financial Disclosure...............................................................................................71
11.15 Publication and Disclosure Policy .........................................................................71
12
LIST OF REFERENCES.................................................................................................73
7.22.1.3
Infusion/Hypersensitivity Reactions and Management......................87
7.22.2.4      Device Adjustment..............................................................................89
LIST OF IN-TEXT TABLES
Table 7-1
Neurodevelopmental Assessments Tests...................................................44
Table 7-2
Sanfilippo-Specific Disability Assessment And Behavior Rating 
Scales .........................................................................................................44
Table 7-3
Adverse Event Severity..............................................................................50
Table 7-4
Adverse Event Relatedness........................................................................50
Table A1-1
HGT-SAN-067 Study Assessments for Patients Who Have Received 
6 Months of HGT-1410 Treatment in Study HGT-SAN-055....................75
Table A2-1
Summary of Neurodevelopmental Outcome Measures .............................79
Table A2-2
Summary of Sanfilippo-specific Assessments...........................................79
LIST OF APPENDICES
Appendix 1
Schedule of Events.....................................................................................75
Appendix 2
Neurodevelopmental and Behavioural Assessments .................................79
Appendix 3
Expected Adverse Device Effects..............................................................83
Appendix 4
Protocol Amendment 7 Summary of Changes...........................................85
Appendix 5
Protocol Signature Page.............................................................................92
Appendix 6
The National Cancer Institute Common Terminology Criteria version 
3.0...............................................................................................................93
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 6 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
7
SYNOPSIS
Sponsor:
Shire Human Genetic Therapies, Inc. 
300 Shire Way
Lexington, MA  02421, United States
Name of Finished Product:
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Name of Active Ingredient:
rhHNS, HGT-1410
Name of Inactive Ingredient:
N/A
Names of Devices:  
SOPH-A-PORTMini S, Implantable Access Port, Spinal, Mini Unattached, with 
Guidewire (SOPH-A-PORT Mini S)
and
PORT-A-CATHII Low ProfileIntrathecal Implantable Access System 
(PORT-A-CATH)
Study Title:
An Open-Label Extension of Study HGT-SAN-055 Evaluating Long-Term Safety and 
Clinical Outcomes of Intrathecal Administration of rhHNS in Patients with Sanfilippo 
Syndrome Type A (MPS IIIA) 
Study Number:
HGT-SAN-067
Study Phase:  I/II
Device, Intended Use
The SOPH-A-PORT Mini S is a system intended for implantation by physicians. The 
SOPH-A-PORT Mini S, once implanted, allows healthcare personnel to administer 
HGT-1410 indicated for intrathecal delivery intermittently over a long period of time.
Prior to approval of Amendment 4, patients were implanted with a PORT-A-CATH 
(Smith’s device). After approval of Amendment 4 all PORT-A-CATH IDDDs requiring 
revision or replacement will be replaced with a SOPH-A-PORT at a time judged 
appropriate by the investigator.
Study Objectives:
Primary Objective: 
The primary objective of this study is:

To collect long-term safety and tolerability data in patients with Sanfilippo Syndrome 
Type A (MPS IIIA) who received HGT-1410 via a surgically implanted intrathecal 
drug delivery device (IDDD) in study HGT-SAN-055 and elected to continue therapy 
in study HGT-SAN-067.
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 7 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
8
Secondary Objectives:
The secondary objectives of this study are:

To collect as measures of drug efficacy, over an extended treatment period (as change 
from baseline), the following:  clinical, neurological, cognitive, behavioral, 
functional, and quality of life (QoL) assessments, together with potential imaging and 
biochemical biomarkers.
Study Endpoints: 
Primary Endpoints:
The primary endpoints of this study are related to the long-term safety of intrathecal 
HGT-1410 administration. The safety endpoints are:

adverse events (type and severity)

changes in clinical laboratory testing (serum chemistry including  liver function tests, 
hematology, and urinalysis)

electrocardiograms (ECG)

cerebrospinal fluid (CSF) chemistries (including cell counts and inflammatory 
markers)

anti-rhHNS antibodies (in CSF and serum).
Secondary Endpoints:
The secondary endpoints of this study are to collect over an extended treatment period (as 
change from baseline) clinical and potential surrogate biomarker efficacy data:

Standardized neurocognitive and behavioral assessments, Sanfilippo-specific 
behavioral rating scales, gross and fine motor assessments, functional adaptive rating 
scales, quality of life questionnaires, and Children’s Sleep Habits Rating Scale.

Concentration of safety and potential surrogate efficacy biomarkers in CSF, urine, 
and serum.

Concentration of heparan sulfate and heparan sulfate derivatives in CSF and 
glycosaminoglycans (GAG), including heparan sulfate and heparan sulfate 
derivatives, in urine.

Brain magnetic resonance imaging (MRI) and auditory brainstem response (ABR), 
Brainstem Auditory Evoked Potentials).
Study Design:
This study, HGT-SAN-067, is an open-label, long term, multicenter, extension of 
Study HGT-SAN-055.  The study is designed to evaluate the long-term safety, clinical 
activity, and biomarker outcomes of intrathecal (IT) administration of 3 dose levels 
(10 mg, 45 mg, and 90 mg once per month [Q4W]) of HGT-1410 via an IDDD in patients 
with MPS IIIA who successfully complete the Phase I/II study HGT-SAN-055 (including 
end of study [EOS] assessments) and elect to continue to receive HGT-1410 treatment.  
Initially, patients will continue in the same treatment group they were assigned to in the 
HGT-SAN-055 study. Following approval of protocol Amendment 4, patients in the 
10 mg group had their dose increased to 45 mg per month.
For nomenclature of chronology purposes, the Baseline Visit for this extension study will 
be considered to be the first day the patient received his/her IT dose of HGT-1410 in 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 8 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
9
Study HGT-SAN-055.  The HGT-SAN-055 EOS assessment information will provide the 
screening/start of study information for patients who continue into the HGT-SAN-067 
extension study.  Note:  HGT-SAN-055 EOS data must be recorded in the context of the 
HGT-SAN-055 trial, and a copy of those data can be used for HGT-SAN-067 screening.  
Once eligibility is confirmed, informed consent must be obtained prior to performing any 
study-related procedures that are specific to HGT-SAN-067.  
Informed consent will be provided by the patient’s parent(s)/legally authorized 
representative(s) prior to the start of the extension study procedures.  Informed consent
may be obtained anytime from week 20 in HGT-SAN-055.  This would allow a patient to 
have a nonfunctional IDDD replaced or revised prior to the first HGT-1410 dose in 
HGT-SAN-067.
Enrolled patients will check in to the study center 1 day before each of the scheduled 
HGT-1410 dosing days for safety assessments (designated Day 1). If no safety concerns 
exist, the patient will subsequently receive IT administration of HGT-1410 on Day 2 
(±2 days). However, if feasible and there are no safety concerns in the opinion of the 
investigator, the Day 1 and Day 2 assessments may be combined and performed on 
Day 2; if this is done the results will be recorded as Day 2. Patients will remain in the 
study center for at least 4 hours following dosing with HGT-1410 and will be discharged 
from the unit when deemed clinically stable by the investigator.
All patients will have received a series of standardized neurodevelopment assessments in 
the HGT-SAN-055 study.  These assessments will have occurred at Baseline and either 
prior to or at the 6-month time point. Patients will continue in HGT-SAN-067 with 
whichever age specific assessment they began with in HGT-SAN-055. If, however, a 
patient’s capability improves and they become capable of completing assessments at a 
higher level, such additional assessments may be added. Any additional assessments 
would be performed after the original assessments (those previously used in study 
HGT-SAN-055) have been carried out. An MRI of the head will be performed at Months 
12, 24, 36, 54, 60, 72, 84, 96, and 102 and ABR testing will be performed at Months 12, 
24, and 36 (note that assessment time point nomenclature includes the 6 months in the 
HGT-SAN-055 study). Note: X-rays may be performed to investigate device malfunction, 
and to verify correct catheter and port placement following surgical implantation or 
revision. In addition, fluoroscopy should be employed intraoperatively to guide catheter 
placement. Thus, patients may undergo 3 X-ray examinations in association with each 
episode of IDDD malfunction and subsequent IDDD revision or replacement. Since the 
number of IDDD revisions/replacements is limited to 2 in any 6-month period (including 
the time in the HGT-SAN-055 study), the number of protocol-associated X-ray 
evaluations is limited to 6 exposures in any 6-month period (including time in the 
HGT-SAN-055). Patients will also have X-ray examinations of the device performed at 
the EOS visit if the patient is to continue to receive intrathecal HGT-1410 beyond the end 
of the study.
Patients will be evaluated for safety throughout the study.  Adverse events that occur in 
HGT-SAN-055 and that are ongoing at enrollment in HGT-SAN-067 will be captured in 
the case report forms (CRFs) for study HGT-SAN-067.  Specific safety stopping criteria 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 9 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
10
will be applied and will be based on the types and severity of adverse events (AEs) 
reported while on-study.  These data will be reviewed to inform the decision to 
discontinue a patient, a dose group, or the study as a whole. 
All patients will have an EOS visit 30 (±7) days following their last administration of 
HGT-1410 (ie, Month 102).  The EOS procedures will include standard clinical 
laboratory tests (serum chemistry, hematology, and urinalysis) in CSF and blood, 
protocol specific laboratory testing (eg, anti-rhHNS antibody testing), 
neurodevelopmental testing, child health questionnaires, and MRI.  
Use of concomitant medications, therapies, and procedures will be recorded and AEs will 
be monitored. 
All patients will be contacted by telephone or will have a visit for a Final Safety 
Follow-up, to be conducted at 30 (±7) days after the EOS visit (ie, Month 103) to collect
updated information on AEs and concomitant medications, therapies, and procedures. 
It is anticipated that the IDDD will be used to obtain CSF samples and to deliver 
administrations of HGT-1410.  However, if a patient’s IDDD appears nonfunctional or if 
its use is precluded on a scheduled day of dosing, site personnel will refer to the 
operations manual (for PORT-A-CATH) or the IDDD Manual (for SOPH-A-PORT), 
which describes the investigation and management of IDDD-related issues.  This will 
include possible partial revision or complete replacement of the IDDD.  As noted above, 
a maximum of 2 partial revisions and/or complete replacements can occur in any 6 month 
period.  If revision or replacement of the IDDD cannot be scheduled in time to avoid a 
delay of the next scheduled dose of HGT-1410, or if the patient experiences more than 
2 IDDD malfunctions in a 6 month period (including participation in study 
HGT-SAN-055), HGT-1410 will be administered via lumbar puncture (LP).  
If there are medical contra-indications to the re-implantation of a new device, or if the 
patient so desires, repeat monthly lumbar punctures may be considered as an alternative 
way of delivering the study drug and obtaining CSF samples under limited circumstances. 
If no safety risks are identified by the investigator, up to 12 consecutive lumbar punctures 
may be performed across the studies HGT-SAN-055 and HGT-SAN-067. Once a patient 
has reached the maximum of 12 consecutive lumbar punctures, a new IDDD may be 
re-implanted for subsequent dosing, unless, in the opinion of the investigator and medical 
monitor, assessment of risk/benefit favors continued dosing via lumbar puncture.
Continued treatment via lumbar puncture beyond the stipulated 12 consecutive monthly 
doses can be considered only in individual cases where this treatment is very well 
tolerated and the investigator has not identified any safety concerns associated with repeat 
lumbar puncture and repeat sedation/anesthesia. 
If there is no significant safety risk in the opinion of the investigator, a non-functional 
IDDD may be left in situ for up to 3 months.
In light of the higher than expected complications experienced with the PORT-A-CATH 
IDDD, the SOPH-A-PORT Mini S device will be introduced for those patients requiring 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 10 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
11
replacement or revision.  This new device has design features anticipated to reduce 
complications encountered with the PORT-A-CATH IDDD device.  Specific device 
assessments are included in the protocol to collect information with respect to 
information specific to SOPH-A-PORT Mini S device safety and function.  
Patients who discontinue or are withdrawn before receiving 3 monthly IT injections will 
not have to undergo the EOS evaluations but will have their IDDD removed.  
Patients will have the IDDD removed when they discontinue from the study, unless the 
patient is continuing to receive treatment through another mechanism (eg, extension 
study, expanded access, commercially available).
An overview of the study appears in the Schedule of Events.
Study Population: 
A maximum of 12 patients are planned for this study.  To be eligible for participation 
patients will have completed all study requirements in Study HGT-SAN-055, including 
the EOS visit, and will have elected to continue treatment with HGT-1410. 
Test Product; Dose; and Mode of Administration: Recombinant human heparan 
N-sulfatase (rhHNS, HGT-1410) will be administered via an IDDD according to the same 
dose to which the patient was assigned in HGT-SAN-055 (ie, 10 mg, 45 mg, or 90 mg 
monthly). Patients assigned to the 10 mg monthly dose had their dose increased to 45 mg 
once per month (Q4W) at the first administration of HGT-1410.
Reference Therapy; Dose; and Mode of Administration: 
N/A
Diagnosis and Main Criteria for Inclusion
Inclusion Criteria:
Each patient must meet the following criteria to be enrolled in this study.
1. The patient must have completed Study HGT-SAN-055 and, in the opinion of the 
investigator, have no safety or medical issues that contraindicate participation. 
2. The patient, patient’s parent(s) or legally authorized representative(s) has voluntarily 
signed an Institutional Review Board/Independent Ethics Committee-approved 
informed consent (and assent, if applicable) form after all relevant aspects of the 
study have been explained and discussed with them.  Informed consent/assent must be 
obtained prior to any study specific procedures.
3. The patient received at least 5 of the 6 planned infusions of HGT-1410 in the 
HGT-SAN-055 study. 
4. The patient must be medically stable, in the opinion of the investigator, to 
accommodate the protocol requirements, including travel, assessments, and IDDD 
surgery (if necessary for replacement purposes), without placing an undue burden on 
the patient/patient's family.
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 11 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
12
Exclusion Criteria: 
Patients will be excluded from the study if there is evidence of any of the following:
1. The patient has experienced an adverse reaction to study drug in Study 
HGT-SAN-055 that contraindicates further treatment with HGT-1410.
2. The patient has a known hypersensitivity to the active ingredient or any excipients in 
HGT-1410 drug product.
3. The patient has non-MPS IIIA related central nervous system (CNS) impairment or 
behavioral disturbances that would confound the scientific integrity or interpretation 
of study assessments, as determined by the investigator.
4. The patient has MPS IIIA behavioral-related issues, as determined by the investigator, 
which would preclude performance of study neurocognitive and developmental 
testing procedures.
5. The patient is pregnant, breast feeding, or is a patient of childbearing potential who 
will not or cannot comply with the use of an acceptable method of birth control, such 
as condoms, barrier method, oral contraception, etc.
6. The patient has any known or suspected hypersensitivity to anesthesia or is thought to 
have an unacceptably high risk for anesthesia due to airway compromise or other 
conditions.
7. The patient has a history of a poorly controlled seizure disorder. 
8. The patient is currently receiving psychotropic or other medications, which in the 
investigator’s opinion, would be likely to substantially confound test results and the 
dose and regimen of which cannot be kept constant throughout the study.
9. The patient cannot sustain absence from aspirin, non-steroidal medications, or 
medications that affect blood clotting within 1 week prior to a relevant study-related 
procedure (eg, device re-implantation if applicable), or has ingested such medications 
within 1 week before any procedures in which any change in clotting activity would 
be deleterious.
10. The patient has received treatment with any investigational drug (other than 
HGT-1410) intended as a treatment for MPS IIIA within the 30 days prior to, during 
the study, or is currently enrolled in another study that involves an investigational 
drug or device (screening through safety follow-up contact).
11. The patient has received a hematopoietic stem cell or bone marrow transplant.
For patients to be implanted with the SOPH-A-PORT Mini S IDDD the following 
conditions are contraindicated, as described in the Instructions for Use: 
1. The patient has had, or may have, an allergic reaction to the materials of construction 
of the SOPH-A-PORT Mini S device
2. The patient’s body size is too small to support the size of the SOPH-A-PORT Mini S 
Access Port, as judged by the investigator 
3. The patient has a known or suspected local or general infection
4. The patient is at risk of abnormal bleeding due to a medical condition or therapy
5. The patient has one or more spinal abnormalities that could complicate safe 
implantation or fixation
6. The patient has a functioning CSF shunt device
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 12 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
13
7. The patient has shown an intolerance to an implanted device
Duration of Treatment: 
The study duration allows patients who completed Study HGT-SAN-055 and elected to 
continue treatment with HGT-1410 in Study HGT-SAN-067 to receive treatment with 
HGT-1410 up to 8 years.
Pharmacokinetic Variables:
N/A.
Safety Assessments: 
Safety evaluations will include vital signs, physical examinations, AE assessments, 
electrocardiograms (ECG); serum chemistry, hematology, urine laboratory tests, and 
screening for antibodies to rhHNS (in CSF and serum).  
Statistical Methods: The statistical methodology supporting the trial will focus on 
descriptive rather than inferential approaches, given the early phase and objectives of the 
trial. Data will be plotted and the mean, standard deviation, median, minimum, and 
maximum for each variable will be tabulated by dose group to look for gross trends over 
time, which may be attributed to treatment. For continuous data, 95% confidence interval 
(CI) around the mean will also be estimated and presented.
The analysis population consists of all eligible patients from HGT-SAN-055 who have 
completed Study HGT-SAN-055 and agreed to participate in this extension study.  Safety 
analyses will be performed using the above mentioned population.  The data will be 
presented by dose group.
Date of Original Protocol: 21 June 2010
Date of Amendment 7: 08 February 2016
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 13 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
14
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ABR
auditory brainstem response
AE
adverse event
ALB
albumin
ALK-P
alkaline phosphatase
ALT
alanine aminotransferase (SGPT)
AST
aspartate aminotransferase (SGOT)
βhCG
human chorionic gonadotropin
BSID-III
Bayley Scales of Infant Development, Third Edition
BBB
blood brain barrier
BUN
blood urea nitrogen
Ca
calcium
CE
Conformité Européenne
CFR
Code of Federal Regulations
CHQ-50
Child Health Questionnaire™ Parent Form 50
CHQ-87
Child Health Questionnaire™ Child Form 87
CK
creatine kinase
Cl
chloride
CNS
central nervous system
CO2
carbon dioxide
CTCAE
Common Terminology Criteria for Adverse Events
CRO
contract research organization
CRIM
cross-reacting immunologic material 
CS
clinically significant
CSF
cerebrospinal fluid
ECG
electrocardiogram
eCRF
electronic case report form
EDC
Electronic Data Capture 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 14 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
15
Abbreviation
Definition
ERT
enzyme replacement therapy
EOS
end of study
EOW
every other week
EU
European Union
FDA
Food and Drug Administration
FPSS/TDS
Four-Point Scoring System/Total Disability Score
GAG
glycosaminoglycan
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
Hct
hematocrit
Hgb
hemoglobin
HS
heparan sulfate
ICH
International Conference on Harmonization 
IDDD
intrathecal drug delivery device
IEC
Independent Ethics Committee
IFU
instructions for use
IND
Investigational New Drug 
IRB
Institutional Review Board
IT
intrathecal
ITQOL
Infant Toddler Quality of Life Questionnaire™
IV
intravenous
K
potassium
KABC-II
Kaufman Assessment Battery for Children, Second Edition
LDH
lactic dehydrogenase
LP
lumbar puncture 
LSD
lysosomal storage disease
M6P
mannose-6-phosphate
MABC-2
Movement Assessment Battery for Children, Second Edition
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 15 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
16
Abbreviation
Definition
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MPS
Mucopolysaccharidosis 
MPS IIIA
Mucopolysaccharidosis IIIA or Sanfilippo syndrome Type A
MRI
magnetic resonance imaging
Na
sodium 
NCI
National Cancer Institute
NCS
not clinically significant
PE
pressure-equalization
QoL
quality of life
Q4W
once per month
RBC
red blood cell (count)
rhHNS
recombinant human heparan N-sulfatase
RNA
ribonucleic acid
SAE
serious adverse event
SAP
Statistical Analysis Plan
SBRS
The Sanfilippo Behavior Rating Scale
SGOT
serum glutamic oxaloacetic transaminase (AST)
SGPT
serum glutamic pyruvic transaminase (ALT)
Shire HGT
Shire Human Genetic Therapies, Inc.
TMF
Trial Master File
TX
treatment
UADE
unanticipated adverse device effect
US
United States
VABS-II
Vineland Adaptive Behavior Scales 
WBC
white blood cell (count)
WHO-DD
World Health Organization-Drug Dictionary 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 16 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
17
1
INTRODUCTION
The progressive and irreversible nature of lysosomal storage diseases (LSDs) present a challenge 
in the interpretation of clinical benefit derived from treatment in studies using enzyme 
replacement therapy (ERT).  Any short-term improvement and/or stabilization of clinically 
important manifestations of the disease may be viewed as clinically meaningful.  However, the 
demonstration of the different aspects of a long-term, clinically-meaningful improvement may be 
limited by the short duration of treatment in clinical studies.  Extended access to treatment 
through extension studies provides an opportunity for further evaluation of long-term safety and 
clinical outcomes for treated patients.  In this extension study, patients who completed study 
HGT-SAN-055, a phase I/II safety and dose-escalation trial, and elected to continue to receive 
recombinant human heparan N-sulfatase (rhHNS), will receive treatment through this extension 
protocol.  Initially, the patient’s treatment group and dosing regimen will be the same as that 
employed in study HGT-SAN-055. Following the analysis of data from HGT-SAN-055, patients 
in the lowest dose group had their dose increased to 45 mg, as outlined in Section 1.3, below.
1.1
Disease Background
Sanfilippo syndrome, or Mucopolysaccharidosis (MPS) III, is LSD caused by loss in activity of 
1 of 4 enzymes necessary for degradation of the glycosaminoglycan (GAG) heparan sulfate (HS) 
in lysosomes.  Four different subtypes (A, B, C, and D) have been identified and are each due to 
a specific enzyme deficiency involved in the lysosomal catabolism of HS.  
Mucopolysaccharidosis IIIA or Sanfilippo syndrome Type A (MPS IIIA) results from deficiency 
of the enzyme heparan N-sulfatase (sulfamidase).  In the absence of this enzyme, intermediates 
of the HS degradation process accumulate in the lysosomes of neurons and glial cells, with lesser 
accumulation outside the brain.  
MPS III is the most prevalent of all mucopolysaccharidoses, with subtype A the most common of 
these.1  The birth prevalence of MPS IIIA has been estimated as 1.28 in 100,000 in Australia, 
1.16 in 100,000 in the Netherlands, and 0.88 in 100,000 in Germany.1-3 In summary, MPS IIIA 
is a rare genetic disorder with apparently widespread geographic distribution and an average 
global birth incidence of approximately 1 in 100,000.
In a recent detailed review of all MPS IIIA patients diagnosed in the Netherlands, it was reported 
that among 81 patients in whom information was available, first symptoms arose at a median of 
2.5 years (range 0.5 to 7 years).4  Owing to the rarity of the disease and the non-specific and 
often subtle nature of its initial manifestations, diagnosis is usually delayed until an average age 
of 4 to 4.5 years.4, 5 Patients present a wide spectrum and severity of clinical symptoms.  The 
central nervous system (CNS) is the most severely affected organ system in patients with MPS 
IIIA, evidenced by deficits in language development, motor skills, and intellectual development.5  
In addition, there are abnormal behaviors including, but not limited to, aggression and excess 
motor activity/hyperactivity that contribute to disturbances in sleep.5-7 In contrast with other 
MPS types, the viscera are mildly affected, with transient enlargement of liver and spleen during 
childhood with no evidence of dysfunction.  There are also reports of unexplained, recurrent and 
severe diarrhea.8  Overall, individuals with MPS IIIA have a marked developmental delay and 
significantly reduced lifespan of 15 years of age on average.8  
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 17 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
18
A milder variant has recently been identified with slower progression and survival to later age in 
approximately 10% of German patients with MPS IIIA.9
No effective, disease-modifying therapies are currently approved as treatments for this rare, 
devastating and disabling disease.  
A long-range goal of Shire Human Genetic Therapies, Inc. (Shire HGT) is to develop a 
recombinant human sulfamidase ERT for patients with MPS IIIA.  A particular problem for 
LSDs that damage the brain such as MPS III is how to target ERT to the brain.10  In animal 
studies, ERT was administered into the cerebrospinal fluid (CSF) via an intrathecal (IT) route, 
because when administered intravenously (IV), it was shown to not cross the blood brain barrier 
(BBB) after the immediate postnatal period of life.11, 12  
As the CNS in patients with MPS IIIA is the most severely affected body system, the main focus 
of the HGT-1410 clinical development program has been the development of ERT specifically 
for delivery directly to the CNS.  Recombinant human heparan N-sulfatase has been developed 
specifically for delivery into the CSF via an intrathecal drug delivery device (IDDD) due to the 
acknowledged impermeability of the BBB to macromolecules. 
Heparan N-sulfatase is a highly purified recombinant form of the naturally occurring human 
lysosomal enzyme sulfamidase.  It is expressed from the well characterized continuous human 
HT-1080 cell line as a 482 amino acid peptide, following cleavage of the 20 amino acid 
N-terminal signal peptide.  The mature protein in solution is a homodimeric glycoprotein of 
approximately 122 kDa, which undergoes post-translational modifications by conversion of 
Cys50 to formylglycine, required for enzyme activity, and glycosylation at 4 of the 5 potential 
N-linked glycosylation sites.  The rhHNS glycans contain mannose-6-phosphate (M6P) residues 
which target the protein for cellular uptake and internalization in its lysosomal site of action via 
the membrane-bound M6P receptors.13, 14-16
The first precedent for intraspinal ERT was recently published and has been shown to be both 
safe and effective for spinal cord compression in MPS I.17  In this study, a patient with MPS I 
received 4 IT doses of enzyme (Laronidase [recombinant α-L- Iduronidase]) at 1-month 
intervals.  Safety evaluations included CSF opening pressure, serum chemistry and CSF protein, 
glucose and cell count, in addition to clinical efficacy studies.  No changes in safety evaluations 
were observed.
In another recent study, a patient with MPS VI and spinal cord compression received IT 
injections of enzyme (Galsulfase) monthly, for 4 months.  CSF analysis revealed no 
inflammatory reaction; no other side effects were noted.18
Several MPS I patients have been treated since 2005 with IT Laronidase in 2 ongoing clinical 
trials (clinicaltrials.gov identifiers NCT00215527 and NCT00786968) studying efficacy on 
spinal cord compression. No results of these trials have yet been published. However, in 
June 2009 a study further investigating the effectiveness of IT ERT as a treatment for another 
neurological symptom in MPS I, cognitive decline, was initiated (clinicaltrials.gov identifier 
NCT00852358). 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 18 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
19
This study is a 24-month, open label, prospective, randomized trial in 16 patients with 
MPS I, 6 years of age or older, who have documented evidence of cognitive decline. In this 
study, the clinical safety of the regimen will be assessed by adverse event (AE) monitoring, CSF 
laboratory assessments, and clinical evaluations.  This study is ongoing; no efficacy or safety 
data have yet been published as of October 2011.19 
In addition, there are 4 ongoing Shire-sponsored studies that are evaluating IT administration of 
ERT:  A Phase I/II safety and dose escalation study of monthly idursulfase-IT injection for 
cognitively impaired patients with Hunter syndrome (Study HGT-HIT-045; NCT00920647), the 
open-label extension to this study (HGT-HIT-046); a Phase I/II ascending dose and dose 
frequency study of monthly IT injection of HGT-1410 in patients with Sanfilippo Syndrome 
Type A (Study HGT-SAN-055; NCT01155778), and the open-label extension to this study 
(HGT-SAN-067; NCT 01299727).
In light of the higher than expected complications experienced with the PORT-A-CATH IDDD, 
the SOPH-A-PORT Mini S device will be introduced for those patients requiring replacement or 
revision.  This new device has design features anticipated to reduce complications encountered 
with the PORT-A-CATH IDDD device.  Specific device assessments are included in the protocol 
to collect information with respect to information specific to SOPH-A-PORT Mini S device 
safety and function.  
1.2
Nonclinical Overview
To circumvent the restriction of the BBB, HGT-1410 was administered into the CSF of rats and 
monkeys via an IT route.  The non-clinical data demonstrate that IT administration of HGT-1410 
leads to uptake by target CNS tissues with appropriate efficacy and distribution.  In addition, 
there were no findings noted in the toxicity studies, allowing for a 6.2-fold safety margin from 
the results in the juvenile cynomolgus monkey.  Intermittent bolus injection of HGT-1410 to the 
brain via the IT route of administration is hypothesized to be of benefit in stabilizing, improving, 
or preventing the CNS manifestations of disease. 
The doses tested in the non-clinical studies adequately support the efficacy of the planned doses 
(10, 45 or 90 mg/month, normalized to the brain weight of the human) in the ongoing Phase I/II 
study, HGT-SAN-055.  Specifically, in the San A mouse, the 100 μg dose corresponds to a 
2.2-fold increase (per kg brain weight) from the highest anticipated human dose (90 mg) (human 
brain = 1 kg).  The 20 μg dose given IT every other week (EOW) or monthly, for which efficacy 
was also observed, corresponds to a 40 mg (per kg brain weight) human dose.  In the Huntaway 
(Sanfilippo A) dogs, the 3 mgHGT-1410 given IT weekly (corresponding to a 33 mg/kg of brain 
weight in man), was not only well tolerated but resulted in significant effects on biomarkers of 
disease activity and improved histopathology. 
1.2.1
Toxicology in Monkeys
In the pivotal, 6-month IT toxicity study in juvenile cynomolgus monkeys, and the highest dose 
of HGT-1410 was 8.3 mg given EOW.  This translates into a 138 mg/kg brain-weight dose (ie, 
based on a 60 g juvenile monkey brain).  Since no HGT-1410-related adverse effects were noted, 
the nonclinical study provides for the proposed Phase I/II clinical trial a ~13.8 × safety margin
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 19 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
20
relative to the starting clinical dose (10 mg), and a 1.5× safety margin relative to the highest 
clinical dose (90 mg).    
1.2.2
Efficacy in Murine and Canine Models of MPS IIIA
Non-clinical proof of concept efficacy studies were conducted using mouse and dog models of 
MPS IIIA, both of which contain naturally-occurring mutations in the HNS gene.  
In the MPS IIIA mouse, direct injection into the CNS had a beneficial effect on clinical signs, 
impaired neurobehavioral, and the biochemical and histopathologic markers of disease activity.  
In Huntaway (Sanfilippo A) dogs, HGT-1410 (3 mg) given IT weekly had a significant effect on 
biomarkers of disease activity and improved histopathology.
Efficacy has been demonstrated at a range of doses in nonclinical mouse and canine models.  In 
MPS IIIA mice, a dose-dependent reduction in the level of a heparan sulfate-derived monosulfate 
disaccharide was observed within the brain (up to 62% reduction compared with vehicle-treated 
mice) and spinal cord (up to 71% reduction).  An ultrastructural examination revealed a 
reduction in lysosomal vesicle formation in various cell types and fewer (ubiquitin-positive) 
axonal spheroids in several brain regions after repeated injections (5 to 20 µg) of HGT-1410 into 
the CSF of MPS III mutant mice via the cisterna magna (ie, IT).  The biochemical changes were 
accompanied by improved behavior, particularly in mice treated more frequently.20
In the MPS IIIA mutant mouse model, intracisternal (ie, IT) injection of a single dose of 100 µg 
HGT-1410 resulted in a substantial (and sustained) reduction of biomarkers of disease activity 
(heparan sulfate-derived disaccharides, microgliosis and astrogliosis).21   Equally impressive was 
the improvement in neurobehavioral parameters (learning in the Morris water maze, 
normalization of aggression) in these mice post-dose.21  One-hundred µg HGT-1410 per mouse 
translates into 200 mg/kg brain weight (ie, based on a 0.5 g mutant mouse brain).  Efficacy at 
lower doses of HGT-1410 (eg, 20 µg, given IT, EOW or monthly) has been demonstrated.11  A 
20 µg injection translates into a 40 mg human dose (ie, 40 mg per kilogram of brain weight).  
Thus, this data further suggests that efficacy will be seen at the highest clinical dose (90 mg, per 
month) in the proposed Phase I/II study. 
In the tolerized Huntaway (San A) dogs, 3 mg HGT-1410 was initially given IT on a weekly 
basis, then EOW, and had a significant effect on biomarkers of disease activity.22  The 3 mg dose 
in the dog translates into a 33 mg (per kg brain weight) human dose (based on a 90 g Huntaway 
dog brain). 
1.3
HGT-SAN-067 Study Rationale
This extension study (Study HGT-SAN-067) will evaluate the effects of long-term HGT-1410 
administration on safety, clinical activity, and biomarker outcomes in patients who completed 
Study HGT-SAN-055 and elected to continue therapy with HGT-1410.
Patients who were enrolled in Study HGT-SAN-055 through Week 26 and completed the end of 
study (EOS) evaluations are eligible for enrollment in this open-label extension study. All 
patients enrolled in this study will initially receive HGT-1410 at the same dose and schedule as 
they received in Study HGT-SAN-055. Patients assigned to 10 mg monthly had their dose 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 20 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
21
increased to 45 mg monthly once per month (Q4W) at the first administration of HGT-1410 
following full approval of protocol Amendment 4. Based on analyses performed at the 
completion of Study HGT-SAN-055 a decline in the primary pharmacodynamic parameter, CSF 
heparan sulfate, was observed. This response to therapy was exhibited at all dose levels, 
however, the greatest impact was at the 2 higher dose levels. An effect on CSF heparan sulfate 
demonstrated in vivo activity of HGT-1410 in the target anatomical compartment. This effect is 
thought to have central importance in mediating the potential therapeutic benefit of HGT-1410. 
As no apparent difference in safety profile was observed between the 3 dose groups, it was 
believed that the increase in the potential therapeutic benefit of the higher dose outweighed any 
potential increase in risks for this lowest dose group.  
Please refer to the current edition of the Investigator’s Brochure for further information 
concerning the safety and clinical development of HGT-1410 and PORT-A-CATH IDDD and 
SOPH-A-PORT Mini S device.
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 21 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
22
2
STUDY OBJECTIVES
2.1
Primary Objective
The primary objective of this study is:

To collect long-term safety and tolerability data in patients with Sanfilippo Syndrome 
Type A (MPS IIIA) who received HGT-1410 via a surgically implanted IDDD in study 
HGT-SAN-055 and elect to continue therapy in study HGT-SAN-067.
2.2
Secondary Objectives 
The secondary objectives of this study are:

To collect, as measures of drug efficacy, over an extended treatment period (as change from 
baseline), the following:  clinical, neurological, cognitive, behavioral, functional, and quality 
of life (QoL) assessments, together with potential imaging and biochemical biomarkers.
2.3
Exploratory Objective
An exploratory objective of this study is:

Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 22 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
23
3
STUDY ENDPOINTS
3.1
Primary Endpoint
The primary endpoints of this study are related to the long-term safety of intrathecal HGT-1410 
administration. The safety endpoints are:

adverse events (type and severity)

changes in clinical laboratory testing (serum chemistry including  liver function tests, 
hematology, and urinalysis)

electrocardiograms (ECG)

CSF chemistries (including cell counts and inflammatory markers)

anti-rhHNS antibodies (in CSF and serum).
3.2
Secondary Endpoints 
The secondary endpoints of this study are to collect over an extended treatment period (as the 
change from baseline [defined as the start of the HGT-SAN-055 study]) clinical and potential 
surrogate biomarker efficacy data: 

Measures of standardized neurocognitive and behavioral assessments, Sanfilippo-specific 
behavioral rating scales, gross and fine motor assessments, functional adaptive rating scales, 
QoL questionnaires, and Children’s Sleep Habits Rating Scale.

Concentration of safety and potential surrogate efficacy biomarkers in CSF, urine, and 
serum.

Concentration of heparan sulfate and heparan sulfate derivatives in CSF and GAG, including 
heparan sulfate and heparan sulfate derivatives, in urine.

Brain magnetic resonance imaging (MRI) and auditory brainstem response (ABR), (also 
known as Brainstem Auditory Evoked Potentials).
3.3
SOPH-A-PORT Mini S Assessments
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 23 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
24
4
INVESTIGATIONAL PLAN
4.1
Overall Study Design and Plan
Study HGT-SAN-067, is an open-label, long term, multicenter, extension of Study 
HGT-SAN-055.  This study is designed to evaluate the long-term safety, clinical activity, and 
biomarker outcomes of IT administration of 3 dose levels (10 mg, 45 mg, and 90 mg once per 
month [Q4W]) of HGT-1410 via an IDDD in patients with MPS IIIA who successfully 
completed HGT-SAN-055 (including the EOS assessments) and elect to continue to receive 
uninterrupted HGT-1410 treatment.  Patients will initially continue in the same treatment group 
they were assigned to in the HGT-SAN-055 study: 

Group 1:  HGT-1410 administered by IT injection 10 mg once per month (Q4W) 

Group 2:  HGT-1410 administered by IT injection 45 mg once per month (Q4W)

Group 3:  HGT-1410 administered by IT injection 90 mg once per month (Q4W) 
Patients assigned to Group 1 will initially receive 10 mg monthly but had their dose increased to 
45 mg monthly (Q4W) at the first administration of HGT-1410 following full approval of 
protocol Amendment 4.
Primarily main sites will be utilized; however, the sponsor and investigator will consider the 
feasibility of transitioning the patient’s IT dosing to local sites to reduce the burden imposed by 
travel. At Month 18 (12 months after study start), patients that already received IT dosing at the 
main site may be eligible to transfer to a local site if in the opinion of the investigator there are 
no safety or medical concerns precluding this transition. Subsequent IT injections of HGT-4110 
may be performed at either the main site or the local site. The local sites will be selected and 
approved by the sponsor, and the patient must have no safety or medical issues that would 
preclude transitioning to a local site (Note: the main site may serve as a local site as needed; and 
in this case, the main site will follow the assessments scheduled for a local site). The 
qualification requirements for physicians at local sites will be identical to those for the main 
sites.  Local sites will be trained if inexperienced with IT administration via an IDDD.  Patients 
will be discharged a minimum of 4 hours after dosing and when deemed clinically stable by the 
investigator. Dosing by IT injection may take place at the main site, rather than local site, if 
scheduled study assessments include MRI and cognitive assessments.  Patients must review and 
agree to written informed consent/assent from the local site to participate in study procedures to 
be conducted at the local site prior to the conduct of these procedures.
In order to maintain a nomenclature system based on study chronology across the original 
HGT-SAN-055 study and this extension study, the Baseline Visit for this extension study will be 
considered to be the day the patient received their first IT dose of HGT-1410 in 
Study HGT-SAN-055.  The HGT-SAN-055 EOS assessment information will provide the 
screening/start of study information for patients who continue into the HGT-SAN-067 extension 
study.  Note: HGT-SAN-055 EOS data must be recorded in the context of the HGT-SAN-055 
trial, and a copy of those data can be used for HGT-SAN-067 screening.  Once eligibility is 
confirmed, informed consent (and assent, if applicable), provided by the patient’s 
parent(s)/legally authorized representative(s), must be obtained prior to performing any 
HGT-SAN-067 study-related procedures.  Informed consent may be obtained anytime from 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 24 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
25
Week 20 in HGT-SAN-055.  This would allow a patient to have a nonfunctional IDDD replaced 
or revised prior to the first HGT-1410 dose in HGT-SAN-067.  
Enrolled patients will check in to the study center 1 day before each of the scheduled HGT-1410 
dosing days for safety assessments (designated Day 1).  If no safety concerns exist, the patient 
will subsequently receive IT administration of HGT-1410 on Day 2 (±2 days).  However, if 
feasible and there are no safety concerns in the opinion of the investigator, the Day 1 and Day 2 
assessments may be combined and performed on Day 2; if this is done the results will be 
recorded as Day 2.  Patients will remain in the study center for at least 4 hours following dosing 
with HGT-1410 and will be discharged from the unit when deemed clinically stable by the 
investigator.  
All patients will have received a series of standardized neurodevelopment assessments; in the 
HGT-SAN-055 study, these will have occurred at Baseline and either prior to or at the 6-month 
time point.  Patients will continue in HGT-SAN-067 with whichever age specific assessment 
they began with in HGT-SAN-055.  If, however, a patient’s capability improves and they 
become capable of completing assessments at a higher level, such additional assessments may be 
added.  Any additional assessments are to be performed after the original assessments (those 
used in study HGT-SAN-055) have been carried out.  
An MRI of the head will be performed at Months 12, 24, 36, 54, 60, 72, 84, 96, and 102 and
ABR testing will be performed at Months 12, 24, 36 and 54 (note that assessment time point 
nomenclature includes the 6 months in the HGT-SAN-055 study).
In the event of a device malfunction, X-rays may be performed to investigate, as well as to verify 
correct catheter and port placement following surgical IDDD implantation or revision.  In 
addition, fluoroscopy may be employed intra-operatively to guide catheter placement.  Patients 
may undergo 3 X-ray examinations in association with each episode of IDDD malfunction and 
subsequent IDDD revision or replacement.  The number of IDDD revisions/replacements is 
limited to 2 in any 6-month period (including the time in the HGT-SAN-055 study), and the 
number of protocol-associated X-ray evaluations is limited to 6 exposures in any 6-month period 
(including time in study HGT-SAN-055). If patients are to continue to receive HGT-1410 using 
the IDDD beyond the duration of this study, they will also have X-ray examinations of the 
device performed at the EOS visit, to document correct positioning.
Patients will be evaluated for safety throughout the study.  Adverse events that occur in 
HGT-SAN-055 and are ongoing at enrollment in HGT-SAN-067 will be captured as ongoing in 
the HGT-SAN-055 study and also be reported as a concurrent condition in the HGT-SAN-067 
eCRFs.  Specific safety stopping criteria will be applied and will be based on the types and 
severity of AEs reported while on-study.  These data will be reviewed to inform the decision to 
discontinue a patient, a dose group, or the study as a whole. 
All patients will have an EOS visit 30 (±7) days following their last administration of HGT-1410 
(ie, Month 102).  The EOS procedures will include standard clinical laboratory tests (serum 
chemistry, hematology, and urinalysis) in CSF and blood, protocol specific laboratory testing 
(eg, anti-rhHNS antibody testing), neurodevelopmental testing, child health questionnaires, and 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 25 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
26
MRI.  Use of concomitant medications, therapies, and procedures will be recorded and AEs will 
be monitored. 
All patients will be contacted by telephone or will have a visit for a Final Safety Follow-up, 
conducted at 30 (±7) days after the EOS visit (ie, Month 103) to collect updated information on 
AEs and concomitant medications, therapies, and procedures. 
It is anticipated that the IDDD will be used to obtain CSF samples and to administer HGT-1410. 
However, if a patient’s PORT-A-CATH IDDD appears nonfunctional or if its use is precluded 
on a scheduled day of dosing, site personnel will refer to the PORT-A-CATH Instructions for 
Use (IFU), which describes the investigation and management of IDDD-related issues with this 
device. This will include possible partial revision or complete replacement of the PORT-A-
CATH IDDD with a SOPH-A-PORT IDDD. For malfunctions involving the SOPH-A-PORT 
Mini S, site personnel will refer to the SOPH-A-PORT IFU.  For either IDDD, a maximum of 
2 partial revisions and/or complete replacements are permitted in any 6 month period (including 
participation in study HGT-SAN-055). If a revision or replacement of the IDDD cannot be 
scheduled in time to avoid a delay of the next scheduled dose of HGT-1410, or if the patient 
experiences more than 2 IDDD malfunctions in a 6 month period, HGT-1410 will be 
administered via lumbar puncture (LP). If implantation of a replacement IDDD is not possible, 
investigational drug may be administered by LP for a maximum of 12 successive monthly doses.  
At that point, a safety discussion needs to take place between the investigator and the sponsor to 
determine the risk/benefit of further dosing by LP.
If there is no significant safety risk in the opinion of the investigator, a non-functional IDDD 
may be left in situ for up to 3 months.
Patients who discontinue or are withdrawn before receiving 3 monthly IT injections will not have 
to undergo the EOS evaluations but will have their IDDD removed.  
If a patient discontinues, or withdraws from the study, or the study is stopped by the sponsor, the 
IDDD will be removed as part of the EOS Procedures. 
An overview of the study appears in the Schedule of Events (Appendix 1).
4.2
Rationale for Study Design and Control Group
The original study, Study HGT-SAN-055, is an ongoing Phase I/II safety and ascending dose 
ranging study of IT administration of HGT-1410 via an IDDD, in patients 3 years of age and 
older with MPS IIIA and early cognitive impairment.  This extension study is proposed to 
continue evaluation of the effects of IT HGT-1410 administration on long-term safety and 
clinical outcomes for patients who completed Study HGT-SAN-055 and elected to continue 
treatment with HGT-1410 in the HGT-SAN-067 study. 
In order to traverse the blood-brain barrier, Shire is evaluating HGT-1410 delivered directly to 
the CNS using an IDDD. The advantage of using an IDDD is that it obviates the need for 
multiple lumbar punctures for drug delivery. Drug products will be administered through this 
port or, if the IDDD is non functional, via lumbar puncture.
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 26 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
27
If patients in the study require revision and/or replacement of the PORT-A-CATH IDDD, it will 
be removed and replaced with the SOPH-A-PORT Mini S device at a time judged appropriate by 
the investigator.
SOPH-A-PORT Mini S revision, implantation or explantation will be performed at the main site. 
However, if in the opinion of the investigator, emergency removal is clinically necessary, device 
explantation may be performed at the patient’s local site.
4.3
Study Duration and Dates
The study duration allows patients who completed Study HGT-SAN-055 and elected to continue 
treatment with HGT-1410 in Study HGT-SAN-067 to receive treatment with HGT-1410 up to 
8 years.
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 27 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
28
5
STUDY POPULATION SELECTION
5.1
Study Population
Patients who have completed all study requirements in Study-HGT-SAN-055 and who elected to 
continue HGT-1410 treatment will be eligible to participate; a maximum of 12 patients are 
planned for this study. 
5.2
Inclusion Criteria
Each patient must meet the following criteria to be considered eligible for enrollment in this 
study.
1. The patient must have completed Study HGT-SAN-055 and, in the opinion of the 
investigator, have no safety or medical issues that contraindicate participation. 
2. The patient, patient’s parent(s) or legally authorized representative(s) has voluntarily signed 
an Institutional Review Board/Independent Ethics Committee-approved informed consent 
(and assent, if applicable) form after all relevant aspects of the study have been explained and 
discussed with them.  Informed consent/assent must be obtained prior to any study specific 
procedures.
3. The patient has received at least 5 of the 6 planned infusions of HGT-1410 in the 
HGT-SAN-055 study. 
4. The patient must be medically stable, in the opinion of the investigator, to accommodate the 
protocol requirements, including travel, assessments, and IDDD surgery (if necessary for 
replacement purposes), without placing an undue burden on the patient/patient's family.
5.3
Exclusion Criteria
Patients will be excluded from the study if there is evidence of any of the following: 
1. The patient has experienced an adverse reaction to study drug in Study HGT-SAN-055 that 
contraindicates further treatment with HGT-1410.
2. The patient has a known hypersensitivity to the active ingredient or any excipients in 
HGT-1410 drug product.
3. The patient has significant non-MPS IIIA related central nervous system impairment or 
behavioral disturbances that would confound the scientific integrity or interpretation of study 
assessments, as determined by the investigator.
4. The patient has MPS IIIA behavioral-related issues, as determined by the investigator, which 
would preclude performance of study neurocognitive and developmental testing procedures.
5. The patient is pregnant, breast feeding, or is of childbearing potential who will not or cannot 
comply with the use of an acceptable method of birth control, such as condoms, barrier 
method, oral contraception, etc.
6. The patient has any known or suspected hypersensitivity to anesthesia or is thought to have 
an unacceptably high risk for anesthesia due to airway compromise or other conditions.
7. The patient has a history of a poorly controlled seizure disorder. 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 28 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
29
8. The patient is currently receiving psychotropic or other medications, which in the 
investigator’s opinion, would be likely to substantially confound test results and the dose and 
regimen of which cannot be kept constant throughout the study.
9. The patient cannot sustain absence of aspirin, non-steroidal medications, or medications that 
affect blood clotting within 1 week prior to a relevant study-related procedure (eg, device 
re-implantation if applicable), or has ingested such medications within 1 week before any 
procedures in which any change in clotting activity would be deleterious.
10. The patient has received treatment with any investigational drug (other than HGT-1410) 
intended as a treatment for MPS IIIA within the 30 days prior to, during the study, or is 
currently enrolled in another study that involves an investigational drug or device (screening 
through safety follow-up contact).
11. The patient has received a hematopoietic stem cell or bone marrow transplant.
For patients to be implanted with the SOPH-A-PORT Mini S IDDD the following conditions are 
contraindicated, as described in the Instructions for Use: 
1. The patient has had, or may have, an allergic reaction to the materials of construction of the 
SOPH-A-PORT Mini S device
2. The patient’s body size is too small to support the size of the SOPH-A-PORT Mini S Access 
Port, as judged by the investigator 
3. The patient has a known or suspected local or general infection
4. The patient is at risk of abnormal bleeding due to a medical condition or therapy
5. The patient has one or more spinal abnormalities that could complicate safe implantation or 
fixation
6. The patient has a functioning CSF shunt device
7. The patient has shown an intolerance to an implanted device
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 29 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
30
6
STUDY TREATMENT(S)
6.1
Description of Treatment(s)
6.1.1
Study Drug
Recombinant human heparan N-sulfatase (HGT-1410 drug product) formulation is a sterile 
solution for injection in single-use vials for IT administration.  It is formulated in an aqueous 
isotonic solution containing 15.0 mg/mL HGT-1410 in 145 mM sodium chloride, 0.02% (v/v) 
polysorbate 20, 5 mM sodium phosphate at pH 7.0.
6.1.2
Intrathecal Drug Delivery Device
The PORT-A-CATH will continue to be used for the administration of drug product for each 
patient until such time as an IDDD replacement may be required. Following implementation of 
protocol Amendment 4, any replacements will be performed using the SOPH-A-PORT Mini S.   
After IDDD replacement the drug product will be administered via the SOPH-A-PORT Mini S 
Implantable Access Port.  The SOPH-A-PORT Mini S device is intended for long-term, 
intermittent access to the IT space for the delivery of investigational drug.
The SOPH-A-PORT Mini S is comprised of the following 7 components:

One SOPH-A-PORT Mini S Access Port

One intrathecal port closed-tip catheter

One guidewire

Two suture wings

One 14-gauge Tuohy needle

One 22-gauge non-coring Huber needle

One Luer lock Connector.
Further details are provided in the Instructions for Use.
6.1.3
Placebo or Control
This study will not employ a placebo or control.  
6.2
Treatment Administered
HGT-1410 for IT administration will be provided by Shire.  HGT-1410 will be administered by 
an IDDD.  Following the review and signing of informed consent (and assent, if applicable), 
eligible patients will initially receive the same dose of HGT-1410 they received in Study HGT-
SAN-055:

Group 1:  HGT-1410 administered by IT injection 10 mg once per month (Q4W) 

Group 2:  HGT-1410 administered by IT injection 45 mg once per month (Q4W)

Group 3:  HGT-1410 administered by IT injection 90 mg once per month (Q4W)
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 30 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
31
Patients assigned to Group 1 had their dose increased to 45 mg once per month (Q4W) at the first 
administration of HGT-1410 following full approval of protocol Amendment 4.
The study drug will be administered through an IDDD.
The initial implantation and revision and/or explantation of the PORT-A-CATH IDDD or 
SOPH-A-PORT Mini S will be performed by pediatric or general neurosurgeons or 
anesthesiologists who have experience in port and catheter implant procedures and 
intrathecal-access procedures. Please refer to the relevant IFU for further details.
Drug administration will be performed in a clinical setting by appropriately trained and skilled 
healthcare providers (nurses or physicians) with knowledge of the patient’s drug regimen and 
experienced in accessing vascular or CNS ports or CNS infusion pumps. Patients and patients’ 
families will not be directly using the device to administer drugs and will have limited direct 
interaction with the device as there is minimal care required during the immediate postoperative 
period as the implant site heals, or at times of drug administration.
As previously noted in Section 4.1, under the appropriate conditions, IT HGT-1410 may be 
administered at local sites rather than main sites to reduce the burden of monthly travel.
6.3
Selection and Timing of Dose for Each Patient
Patients will check into the study center 1 day prior to IT HGT-1410 dosing for safety 
assessments, designated Day 1, on each HGT-1410 treatment week, and if no safety concerns 
exist, will receive IT administration of HGT-1410 on Day 2 (±2 days).  However, if feasible and 
there are no safety concerns in the opinion of the investigator, the Day 1 and Day 2 assessments 
and dosing may be combined and performed on Day 2; if this is done the results will be recorded 
as Day 2.  Patients will remain in the study center for at least 4 hours following dosing with 
HGT-1410 and will be discharged from the unit when deemed clinically stable by the 
investigator.  
The IT injections are to be administered every 28 days (±7 days).  If a patient’s IDDD becomes 
nonfunctional, it may be revised (partial or complete) (a maximum of twice in a 6 month period) 
so that the patient can remain on study (see Section 7.12 for details).
6.3.1
Cerebral Spinal Fluid Sample Procedure
CSF samples will be obtained prior to each injection for clinical laboratory evaluation and 
potential biomarker studies.  The IDDD will be used for CSF sampling and a topical anesthetic 
agent may be applied over the skin covering the IDDD reservoir prior to sampling. Site 
personnel should refer to the operations manual for instructions on the use of topical anesthesia 
prior to accessing the IDDD reservoir.
If use of the IDDD is precluded on a scheduled day of dosing, CSF samples may be obtained by 
LP, as described in the IDDD Manual and Section 6.3.2. Intrathecal Administration of 
HGT-1410
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 31 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
32
A visual examination of both the port and catheter track will be performed before each IT 
injection.
HGT-1410 will be administered using an IDDD.  After appropriate pre-procedure assessments 
are completed, anesthesia cream will be applied to the skin over the port.  Patients may receive 
sedation as necessary to alleviate anxiety and/or to facilitate drug delivery.
Patients will receive HGT-1410 via slow push/injection through an appropriately sized syringe 
(see the Pharmacy Manual).  Replacement of fluid, including drug, to the CSF will be an 
approximate equal volume to that removed.  The patient’s vital signs will be continuously 
monitored.  The patient will also be monitored closely during study drug administration and 
through the next 4 hours for any adverse clinical reactions.  The patient will be encouraged to lie 
down comfortably for 1 to 3 hours post injection, although this may be difficult for the most 
hyperactive patients.
For the Soph-A-Port Mini S, a 22-gauge Huber non-coring needle is to be used for access to the 
implanted port; standard hypodermic needles would damage the septum and may cause leakage. 
If no needle-free connector is present, either a stopcock of the Huber needle infusion set’s clamp 
is to be used to prevent CSF backflow and to mitigate the risk of air entering the system. It is 
possible to use other brands of Huber non-coring needles, provided that their specifications are 
identical to that of the Huber needle supplied by Sophysa in the SOPH-A-PORT Mini S (22G).
The injection date, injection start/stop time, planned dose, injection volume, and flush volume 
will be recorded on the patient’s eCRF.  
In the event of IDDD malfunction, CSF collection and study drug administration may be 
performed via LP (see Section 6.3.2).  The investigation and management of a malfunctioning 
IDDD is detailed in the PORT-A-CATH or SOPH-A-PORT IFUs. Partial or complete 
replacement of the IDDD may be necessary (only permitted twice in a 6-month period, including 
the time a patient was in study HGT-SAN-055), and will require scheduling of the appropriate 
procedure.  The definitive diagnosis of the cause of IDDD failure may not be possible until the 
time of exploratory surgery.  Surgery will take place at the earliest convenience, so the patient 
may remain on, or as close as possible to their treatment schedule. 
6.3.2
Administration of HGT-1410 via Lumbar Puncture Guidance Concerning 
Performance of Lumbar Puncture for Study Drug Administration and 
Cerebrospinal Fluid Sample Collection
It is intended that the IDDD will be used to deliver all IT injections of study drug and to obtain 
CSF samples.  If the IDDD appears to be nonfunctional, or if its use is precluded on a scheduled 
day of dosing, site personnel will refer to the IDDD manual (s), which provides details on the 
investigation and management of any IDDD-related issues.  This may include possible partial 
revision or complete replacement of the IDDD as indicated.  If the nonfunctional IDDD is a 
PORT-A-CATH device, then it will be replaced by a SOPH-A-PORT Mini S device. 
If there are medical contra-indication to the re-implantation of a new device, or if the patient so 
desires, repeat monthly lumbar punctures may be considered as an alternative way of delivering 
the study drug and obtaining CSF samples under limited circumstances.  If no safety risks are 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 32 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
33
identified by the investigator, up to 12 consecutive lumbar punctures may be performed across 
studies HGT-SAN-055 and HGT-SAN-067.  Once a patient has reached the maximum of 
12 consecutive lumbar punctures, a new IDDD will be re-implanted for subsequent dosing, 
unless, in the opinion of the investigator and medical monitor, assessment of risk/benefit favors 
continued dosing via lumbar puncture.
Continued treatment via repeat lumbar puncture beyond the stipulated 12 consecutive monthly 
doses can be considered only in individual cases of patients where this treatment is very well 
tolerated and the investigator has not identified any safety concerns associated with repeat 
lumbar puncture and repeat sedation/anesthesia.
6.4
Method of Assigning Patients to Treatment Groups
This is an open-label, non-randomized study; all patients enrolled in this study will be treated 
with HGT-1410. Patients will initially receive the same dose of HGT-1410 they received in 
Study HGT-SAN-055. Patients assigned to Group 1 (10 mg once per month [Q4W]) had their 
dose increased to 45 mg once per month (Q4W) at the first administration of HGT-1410 
following full approval of protocol Amendment 4.
6.5
Blinding
Not applicable; as this trial is not blinded.
6.6
Concomitant Therapy
All non-protocol treatments and procedures that occur from the time of informed consent (and 
assent, if applicable) through the safety follow-up contact are regarded as concomitant and will 
be documented on the appropriate pages of the eCRF.  Concomitant therapy includes 
medications (including Genistein), therapies/interventions administered to patients, and 
medical/surgical procedures performed on the patients. 
Every effort should be made to keep the patient’s symptomatic Sanfilippo syndrome Type A 
treatment constant throughout the study.  However, changes in medications are acceptable if 
necessary according to clinical judgment.  All changes will be recorded on the appropriate eCRF.  
Concomitant medication will be coded using World Health Organization Drug Dictionary 
(WHO-DD).
6.7
Restrictions
6.7.1
Prior Therapy
Prior therapy excluded for this study consists of the following:

Psychotropic or other medications, which in the investigator’s opinion would be likely to 
substantially confound test results, and the dose and regimen of which cannot be kept 
constant throughout the study.

The patient cannot sustain absence from aspirin, non-steroidal medications, or medications 
that affect blood clotting within 1 week prior to a relevant study related procedure (eg, device 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 33 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
34
implantation if applicable) or medications within 1 week before any procedures in which any 
change in clotting activity would be deleterious.

The patient has received any investigational drug or device intended as a treatment for 
MPS IIIA within the 30 days prior to the study other than HGT-1410 or is enrolled in another 
study that involves an investigational drug or device.

Hematopoietic stem cell or bone marrow transplant.
6.7.2
Fluid and Food Intake 
Food and fluid intake are not restricted over the course of the study, with the exception of 
hospital standard pre-anesthesia dietary restrictions.
6.7.3
Patient Activity Restrictions
For patients implanted with the SOPH-A-PORT Mini S please refer to the SOPH-A-PORT Mini 
S IFU for details regarding patient activity restrictions for patients to be implanted with this 
device.
6.8
Treatment Compliance
HGT-1410 is administered under controlled conditions by the investigator; therefore, full patient 
compliance with study treatment is anticipated in this study. 
6.9
Packaging and Labeling
6.9.1
Drug Product
Drug product will be supplied in a 3 mL clear, colorless glass (Type 1) vial. Each vial holds an 
extractable volume of 1 mL of HGT-1410. The closure is a gray, 13 mm stopper composed of 
butyl rubber with a fluoro resin lamination. The overseal is an aluminium seal with a flip-off, 
plastic, tamper evident cap. 
See the Pharmacy Manual for additional details.
6.9.2
SOPH-A-PORT Mini S Access Port
The SOPH-A-PORT Mini S Access Port is available in one size, individually packaged, with 
other SOPH-A-PORT Mini S components in double peel-off, sterile, pyrogen-free packaging, 
sterilized with Ethylene Oxide.  Instructions for use are also included in the packaging. A 
guidewire is provided in separate double pouch, sterile, pyrogen-free packaging.
Labels are provided on the outer carton, and on both the SOPH-A-PORT Mini S box and 
guidewire/cannula package inside.
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 34 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
35
6.10
Storage and Accountability
6.10.1
Investigational Product
Drug product should be stored refrigerated (2°C to 8°C); drug product may not be stored beyond 
the expiration date on the vial.
All HGT-1410 study drug delivered to an investigator will be recorded and accounted for 
throughout the study.  All HGT-1410 study drug must be recorded on a patient-by-patient basis.  
The lot number of the IDDD and the date and time of administration of the study medication will 
be documented on the appropriate eCRF.
All unused study medication and other study materials are to be returned to the sponsor or its 
designee or disposed of after sponsor approval per site policy after study completion.
6.10.2
Intrathecal Drug Delivery Device
6.10.2.1
PORT-A-CATH IDDD
Please refer to the operations manual for return instructions.
6.10.2.2
SOPH-A-PORT Mini S IDDD
The disposition of all SOPH-A-PORT Mini S intrathecal drug delivery devices delivered to a 
principal investigator must be recorded on a patient-by-patient basis by completing the 
Accountability Log.  The date and time of administration of the investigational product and use 
of the SOPH-A-PORT Mini S device must be documented on the patient’s appropriate eCRF.
The principal investigator, clinical research coordinator, or designee (eg, pharmacist) must 
ensure that all documentation regarding receipt, storage, dispensing, loss/damaged 
SOPH-A-PORT Mini S intrathecal drug delivery devices and return of used/unused intrathecal 
drug delivery devices) is complete, accurate, and ready for review at each monitoring visit and/or 
audit.  The sites must ensure that the SOPH-A-PORT Mini S devices are available for the 
monitor to inventory and prepare for return shipment to the sponsor or designee, if required.
The SOPH-A-PORT Mini S and its components are sterile, single-use devices.
Please refer to the relevant IDDD Manual for device return instructions.
6.11
Investigational Product Retention at Study Site
All HGT-1410 study drug delivered to an investigator will be recorded and accounted for 
throughout the study.  All HGT-1410 study drug must be recorded on a patient-by-patient basis.  
The lot number of the IDDD and the date and time of administration of the study medication will 
be documented on the appropriate eCRF.
All unused study medication and other study materials are to be returned to the sponsor or its 
designee or disposed of after sponsor approval per site policy after study completion.
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 35 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
36
7
STUDY PROCEDURES
7.1
Informed Consent
Study procedures will be conducted only after written informed consent for the patient to 
participate in this study is provided by the parent(s) or the patient’s legally authorized 
representative(s) and assent from the patient (if applicable).  Detailed descriptions of patient 
evaluations required for this protocol are described in this section.  These evaluations will be 
performed during the indicated days and weeks of each study month (see Appendix 1 Schedule 
of Events).
All data collected are to be recorded on the appropriate eCRF. Blood, urine and CSF volumes to 
be collected for each clinical laboratory measurement are described in detail in the Laboratory 
Manual.
7.2
Physical Examination
A full physical examination or a symptom-directed physical examination of each patient will be 
performed at time points detailed in Appendix 1 Schedule of Events.
Any changes from the screening physical examination will be captured as AEs in the eCRF.  If 
the patient experiences an AE associated with genitourinary evaluation, the patient may have the 
genitourinary evaluation performed by their primary care provider and a follow-up report will be 
sent to the investigator.  Therefore, the genitourinary evaluation may not need to be performed 
again if the examination occurred within the visit window for that time point.
Note:  if the patient’s hearing cannot be assessed during the physical examination, the patient 
will have an Ears, Nose, and Throat Evaluation performed under anesthesia at the screening/start 
of study visit.  If it is determined that the patient requires pressure-equalization (PE) tubes, they 
may be implanted during that evaluation (see Section 7.9).  Note:  PE tubes may be re-implanted 
if they fall out during this study.
The physical examination findings will be recorded on the eCRF and will include a review of the 
patient’s general appearance as well as the following evaluations:
-
Head and neck
-
Eyes, ears, nose, and throat
-
Chest and lungs
-
Cardiovascular
-
Abdomen
-
Skin
-
Lymphatic
-
Musculoskeletal
-
Neurological (symptom directed and 
at least every 12 months)
-
Endocrine
-
Genitourinary (as per referring 
physician)
7.3
Height and Weight
Height or length (cm), and weight (kg) will be measured once and recorded on the eCRF.
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 36 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
37
7.4
Head Circumference
Head circumference (cm) will be measured and recorded on the eCRF.
7.5
Vital Signs
Vital signs (blood pressure, heart rate, respiratory rate, and temperature measurements) will be 
measured and recorded on the eCRF.
7.6
Electrocardiography
7.6.1
Electrocardiograms
An ECG will be performed.  Each ECG will include an assessment of heart rate, sinus rhythm, 
atrial or ventricular hypertrophy, PR, QRS, QT, and QTc intervals.  The ECGs will be conducted 
in accordance with the clinical site’s standard practice(s), and will be read locally at the clinical 
site.  Identification of any clinically significant findings and/or conduction abnormalities will be 
recorded on the eCRF. 
7.7
Clinical Laboratory Tests
Blood, urine, and CSF samples will be collected as described below for clinical laboratory 
testing. Procedures for collection and handling of samples are included in the Laboratory 
Manual. The conduct of a clinical trial in an extremely rare disease such as MPS IIIA provides a 
unique opportunity to collect samples for potential biomarker research. In the context of this 
study, a biomarker is defined as a characteristic that is objectively measured and evaluated as an 
indicator of the MPS IIIA pathogenic process, or a pharmacologic response to experimental 
therapy with HGT-1410. In addition to exploration of potential biomarkers, as part of the 
assessment of the SOPH-A-PORT Mini S, it may be necessary to determine the levels of 
leachables from the device into the CSF and blood. 
Patients will be in a seated or supine position during blood collection.  Clinical laboratory tests 
will include hematology, serum chemistry, and urinalysis.
Laboratory Parameters 
Clinical laboratory tests will be performed at a central laboratory.  Clinical laboratory tests will 
include the following:
7.7.1
Hematology

Hematocrit (Hct)

Hemoglobin (Hgb)

Mean corpuscular hemoglobin (MCH)

Mean corpuscular hemoglobin 
concentration (MCHC)

Mean corpuscular volume (MCV)

Platelet count

Red blood cell (RBC) count 

White blood cell (WBC) count with 
differential 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 37 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
38
7.7.2
Serum Chemistry

Albumin (ALB)

Alkaline phosphatase (ALK-P)

Alanine aminotransferase (ALT; SGPT)

Aspartate aminotransferase (AST; 
SGOT)

Blood urea nitrogen (BUN)

Calcium (Ca)

Carbon dioxide (CO2)

Chloride (Cl)

Creatinine

Creatine kinase (CK) and subtypes

Gamma-glutamyl transferase (GGT)

Globulin

Glucose

Lactate dehydrogenase (LDH)

Phosphorus

Potassium (K)

Sodium (Na)

Total bilirubin

Direct bilirubin

Total cholesterol

Total protein

Triglycerides

Uric acid

Human Chorionic Gonadotropin 
(βhCG) Pregnancy Test
In addition a leukocyte pellet will be prepared, stored frozen, and will be used for additional 
disease-related laboratory studies, including possible assessment of cross-reactive immunologic 
material (CRIM).
7.7.3
Pregnancy Test
A pregnancy test will be performed on Day 1 of each dosing week.  Pregnancy testing will be 
performed using either a serum or urine sample (at the discretion of the site), and only on 
females who have reached menarche.  All pregnancy testing and the reporting of results will be 
performed locally by the clinical site staff.  Study drug must not be administered in the event of a 
positive or inconclusive pregnancy result. 
7.7.4
Serum Anti-rhHNS Antibody and Sample Storage 
Blood samples will be collected and evaluated at Shire or Shire-designated laboratories for the 
determination of anti-rhHNS antibodies. Samples will be reserved in accordance with local 
regulations for potential future MPS IIIA research that may determine biomarkers of disease 
severity and progression. 
Two blood samples will be collected from each patient at each designated time point. One 
sample will be collected in tubes intended for serum specimens, while the second sample will be 
collected in tubes intended for plasma specimens. Blood sample collection, processing, and 
shipping instructions will be provided in the Laboratory Manual.
7.7.5
Urinalysis 
Patient catheterization may be required for obtaining urine samples (if deemed necessary by the 
investigator).  
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 38 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
39
7.7.5.1
Standard Urinalysis
The following urinalysis parameters will be performed at a central laboratory:  pH, macroscopic 
and microscopic evaluations.
7.7.5.2
Urine Glycosaminoglycans 
A urine sample will be collected for the determination of GAG (including heparan sulfate and 
heparan sulfate derivatives) and the analysis will be performed at Shire, or Shire designated 
laboratories. A urine sample from each visit will be reserved for possible exploratory biomarker 
studies that may provide new indicators or markers of MPS IIIA disease severity or progression.
7.7.6
Cerebrospinal Fluid Assessments
Cerebrospinal fluid sample collection, processing, and shipping instructions will be provided in 
the Laboratory Manual. A CSF sample will be reserved for possible exploratory biomarker 
studies for MPS IIIA disease.
Each CSF sample collected will be assessed for appearance and will be analyzed using the assays
listed in Sections 7.7.6.1, 7.7.6.2, and 7.7.6.4.  In addition, as more is learned about Sanfilippo 
CNS pathology and etiology, future exploratory assays of CSF metabolites, protein or 
ribonucleic acid (RNA) may become used as they become available in the future.
7.7.6.1
Cerebrospinal Fluid Cell Counts
An aliquot of each CSF sample collected will be evaluated for CSF standard chemistries, 
glucose, protein, and cell counts.  These assessments will be performed at the local laboratory.
7.7.6.2
Cerebrospinal Fluid Heparan Sulfate Levels and Heparan Sulfate Derivatives
An aliquot of each CSF sample collected will be quick frozen as per the Laboratory Manual for 
subsequent determination of CSF heparan sulfate and heparan sulfate derivatives at Shire 
designated laboratories.
7.7.6.3
Anti-rhHNS Antibodies
An aliquot of each CSF sample collected will be quick frozen as per the Laboratory Manual for 
subsequent determination of anti-rhHNS antibodies at Shire or Shire designated laboratories.
7.7.6.4
Cerebrospinal Fluid Biomarkers 
An aliquot of each CSF sample collected will be quick frozen as per the Laboratory Manual for 
subsequent determination of MPS exploratory biomarkers at Shire or Shire-designated 
laboratories.
7.7.7
Sample Collection, Storage, and Shipping
Sample collection, processing, and shipping instructions will be provided in the Laboratory 
Manual to be provided by Shire.
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 39 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
40
CSF, urine, and serum samples may be reserved for potential, future, biomarker studies.  
Samples will be stored securely to ensure patient confidentiality.  
7.8
Anesthesia
Administration of anesthesia/sedation will be given prior to obtaining CSF (when the use of the 
IDDD is precluded), prior to performing a MRI of the head, the ABR, the CSF opening pressure, 
and the partial revision or replacement of the IDDD (if applicable).  
See Appendix 1 for the Schedule of Events. When logistically feasible, the MRI, ABR, and 
surgical implantation of the IDDD may be performed together to reduce exposure to 
general anesthesia.
Note:  The neurologic exam and the neurocognitive and developmental assessments must be 
performed prior to the administration of anesthesia.
7.9
Audiometry and Auditory Brainstem Response
The rare attenuated patients with MPS IIIA with high levels of cognitive functioning will have 
hearing tests via clinical audiometry measurement performed using age-appropriate testing 
methods based on the child’s developmental age at the time of the testing.  It is anticipated that 
most of the cognitively-impaired and/or behaviorally-deteriorated patients with Sanfilippo A will 
be unable to cooperate with a (conscious) hearing evaluation.  In these instances, the investigator 
will utilize his best clinical judgment to estimate the extent of hearing loss (if any) during the 
physical examination.  In this situation, a specific evaluation of hearing loss will occur during an 
examination of waveforms in the ABR (see below).  If the patient has a history of multiple 
instances of otitis media or evidence of clinically-significant otitis media on physical 
examination, which the investigator believes causes significant conductive hearing loss and 
impairment of daily living, the investigator will discuss and offer the parent or legally authorized 
representative(s) placement of PE tubes as part of the scheduled anesthesia.  A patient’s PE tubes 
may be replaced if they fall out during the course of this study.
The ABR will be conducted under anesthesia.  The ABR findings will be considered within 
normal limits if, after applying appropriate correction factors, the waveforms reveal normal 
morphology. 
7.10
Magnetic Resonance Imaging of the Head
The regional brain volume will be assessed through a MRI, of the head.  The patient will be 
under general anesthesia for this assessment.  All MRIs will be centrally read by the University 
of Minnesota Medical Center. Refer to the Study Operations Manual for specific procedures and 
precautions.
7.11
Device Data
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 40 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
41
7.12
Surgical Re-implantation of the IDDD
If a patient’s IDDD becomes nonfunctional or infected, it will be replaced or revised so that the 
patient can remain on study. After full approval of protocol Amendment 4, all IDDD 
replacements will be made with the SOPH-A-PORT IDDD. If the IDDD device is a 
PORT-A-CATH IDDD, it will be replaced by a SOPH-A PORT IDDD. Management details for 
the PORT-A- CATH IDDD or for the SOPH-A PORT IDDD are provided in the respective 
device's IFU. Procedures for implantation are detailed in the relevant device’s Instructions for 
Use Manual and in the training materials provided by Shire. The patient will be under general 
anesthesia for this procedure. Standard hospital procedure for surgery will be followed and will 
include an X-ray to confirm that the device has been (1) surgically implanted correctly, and (2) 
positioned so that the intrathecal catheter tip is at the mid-thoracic level (a check list is provided 
in the IDDD Manual). 
A post-operative check of the IDDD and incision will be performed on Day 4 following surgery.  
X-rays may be performed to check placement of the device, as needed, throughout the study (see 
Section 7.12.1 for limits on the number of x-rays and IDDD revisions and or replacement).
7.12.1
Restrictions on the Number of Revision and/or re-implantation of the IDDD
A non-functional IDDD can be replaced or revised twice in a 6-month period, including the time 
a patient was in study HGT-SAN-055.  Similarly, 6 X-rays may be taken in a 6-month period 
(including the time in HGT-SAN-055).
7.13
Device Related Study Procedures
7.13.1
IDDD Implantation or Revision Procedures
The IDDD will be surgically implanted or revised at the clinical site. Procedures for implantation 
and revision are detailed in the device’s IFU. Standard hospital procedures for surgery will be 
followed; the patient will be under general anesthesia for this procedure.  It is planned that 
device explantation will occur at the main site unless urgent device removal is medically 
indicated requiring the procedure to be performed locally or patient travel to the main site is 
medically inadvisable. 
An additional medical device, the catheter passer, is necessary for the implantation procedure, 
for patients receiving the SOPH-A-PORT Mini S.  The catheter passer is a sterile, single use 
device that will be used in the subcutaneous placement of the catheter.  The Phoenix Neuro 
Disposable Catheter Passer, manufactured by Sophysa is CE marked in the European Union 
(EU) and cleared under K853370 in the United States (US). Other catheter passers that are 
compatible with the SOPH-A-PORT Mini S may be used.
Details of the implantation/revision and malfunctions/failure for the SOPH-A-PORT will be 
documented on the patient’s eCRF.
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 41 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
42
7.13.2
X-ray Verification of Intrathecal Drug Delivery Device Placement 
A postoperative x-ray check of the IDDD will be performed following surgery to verify proper 
installation and confirmation of IDDD placement at the mid-thoracic level. The x-rays may be 
performed to check placement of the device, as needed, throughout the study. If the patient is to 
receive intrathecal HGT-1410 beyond the end of the study, an X-ray will be performed at the end 
of the study to verify that the IDDD is in the correct position. At a minimum, the date of the 
x-ray verifying correct IDDD placement will be documented on the patient’s eCRF. If the device 
requires revision or replacement during the study, additional x-rays will be taken to document 
proper positioning of the device. If an IDDD malfunctions, an X-ray may be performed to assess 
the potential cause of malfunction. Fluoroscopy may be used during device implant or revision 
procedures.
7.13.3
CSF Sampling Procedure
Cerebrospinal fluid will be sampled via the device. If this is not possible, and if CSF sampling is 
necessary, either for adherence to the protocol, or to investigate clinical concerns, an LP may be 
performed to sample CSF, either with or without administration of drug afterwards. 
7.13.4
Device Removal
If at the time of a scheduled dosing it is not possible to administer a full medication dosage as 
per the standard administration steps detailed in the device’s IFU due to a device-related issue, 
the IDDD will be declared a device malfunction. If the device malfunction is irreversible and 
cannot be corrected without a device surgical intervention, the IDDD will be declared a device 
failure, starting from the date of the initial malfunction. 
The IDDD will then be surgically removed or revised and a new device and/or device 
components will be re-implanted at the earliest possible opportunity, preferably at the same time. 
Patients who have a PORT-A-CATH IDDD device failure will have this device replaced by a 
SOPH-A-PORT Mini S.
Details of the device removal will be recorded in the patient’s eCRF. Refer to the relevant IFU 
for further details.
If the IT space is not accessible via the IDDD, study drug may be administered by LP up to 
5 times.
Patients will have the IDDD removed when they discontinue from the study, unless the patient is 
continuing to receive treatment through another mechanism (eg, extension study, expanded 
access, commercially available).
7.14
Cerebrospinal Fluid Opening Pressure Measurement
A CSF opening pressure measurement (cm of H2O) will be conducted as per standard hospital 
practice.  The measurement will be obtained whenever a LP is performed and an IDDD revision 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 42 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
43
or replacement is done. Following implementation of Amendment 6 the CSF opening pressure 
measurement will not be required with the LP.
7.15
Dispensing Study Drug
A visual examination of both the port and catheter track will be performed before each IT 
injection.
HGT-1410 will be administered IT by means of an IDDD (or via LP if necessary) to patients on 
Day 2 (±2 days) of Week 1 of each treatment month. 
The patient may be sedated for this procedure.  HGT-1410 will be administered through an 
appropriately sized syringe (see the Pharmacy Manual).  If the IT space is not accessible via the 
IDDD, HGT-1410 may be administered via LP.  See Section 6.3.2 for details.
For the Soph-A-Port Mini S, a 22-gauge Huber non-coring needle is to be used for access to the 
implanted port; standard hypodermic needles would damage the septum and may cause leakage. 
If no needle-free connector is present, either a stopcock or the Huber needle infusion set’s clamp 
is to be used to prevent CSF backflow and to mitigate the risk of air entering the system. It is 
possible to use other brands of Huber non-coring needles, provided that their specifications are 
identical to that of the Huber needle supplied by Sophysa in the SOPH-A-PORT Mini S (22G).
7.16
Pharmacokinetic Assessments
Pharmacokinetic assessments are not included in this study.
7.17
Neurological Examination
A neurological examination to monitor CNS changes in a patient’s neurological status will be 
conducted during this study.  See Appendix 2 for a complete list of the neurological 
examinations.
The neurological exam should not occur sooner than 4 hours after study drug administration or 
before the patient has fully recovered from any anesthesia administered for the dosing, 
whichever occurs later.
7.18
Neurocognitive and Developmental Assessments
Patients will undergo neurocognitive and neurobehavioral development testing.  The assessments 
are estimated to last between 2 and 4 hours and must be conducted prior to sedation or 
anesthesia. 
A full neurodevelopmental assessment, including global development, cognition, adaptive 
behavior, receptive and expressive language, and gross motor function, will be evaluated using 
standardized developmental and behavioral tests to provide a surrogate and quantifiable measure 
of global CNS neurodevelopmental/neurobehavioral function. 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 43 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
44
All patients will have received a series of standardized neurodevelopment assessments; in the 
HGT-SAN-055 study, patients in HGT-SAN-067 will continue with the age specific assessment 
they began with in HGT-SAN-055.  If, however, a patient’s capability improves and they 
become capable of completing assessments at a higher level, any such additional assessments 
may be added.  Any additional assessments would be performed after the original assessments 
have been carried out.  
For this study, outcome measures will be computed for each patient enrolled.  The psychometric 
instruments and Sanfilippo-specific assessments are summarized below in Table 7-1 and 
Table 7-2, respectively.  See Appendix 2 for details on these assessments.
Table 7-1
Neurodevelopmental Assessments Tests 
Developmental or Cognitive 
Domain(s)
Patient Age:  Representative Cognitive Test or 
Scale
COGNITIVE DEVELOPMENT ASSESSMENT
Summary score and sub-domains:
- Cognitive
- Motor
- Social/emotional
0 to 42 months:  Bayley Scales of Infant Development-III 
Bayley Scales of Infant Development, Third Edition 
(BSID-III)23
- Cognitive 
- Processing skills
3 to 18 years:  Kaufman Assessment Battery for Children, 
Second Edition (KABC-II)24
GROSS AND FINE MOTOR SKILLS ASSESSMENT AND VOLUNTARY MOVEMENT
Motor
3.0 to 16:11 years:  Movement Assessment Battery for 
Children II (MABC-2)25
- Cognitive
- Motor
0 to 5 ½ years:  Bayley Scales of Infant Development III 
(BSID-III)23
ADAPTIVE BEHAVIOR
Communication
Daily Living
Socialization
Motor Skills
0 to 90 years:  Vineland Adaptive Behavior Scales (VABS-II)  
Second Edition26
Table 7-2
Sanfilippo-Specific Disability Assessment And Behavior Rating Scales
DEVELOPMENTAL OR COGNITIVE 
DOMAIN(S)
SANFILIPPO SPECIFIC ASSESSMENTS
Parent-scored behavioral inventory
- communication:  understanding
- communication:  expression
- tantrums
- specific behaviors inventory
- mood & emotions inventory
Sanfilippo Behavior Rating Scale (SBRS)
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 44 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
45
Table 7-2
Sanfilippo-Specific Disability Assessment And Behavior Rating Scales
DEVELOPMENTAL OR COGNITIVE 
DOMAIN(S)
SANFILIPPO SPECIFIC ASSESSMENTS
MPS-specific disability score 
- cognitive functioning
- expressive language
- motor score
Four-Point Scoring System/Total Disability Score 
(FPSS/TDS)5  
7.19
Sleep Questionnaire:  Children’s Sleep Habits Rating Scale 
A sleep questionnaire, Children’s Sleep Habits Rating Scale, will be administered to the patient's 
parent(s)/legally authorized representative(s).
7.20
Age-Dependent, Health-Related Quality of Life in Children
The Quality of Life questionnaires will be administered as outlined in Sections 7.20.1, 7.20.2, 
and 7.20.3.
7.20.1
Quality of Life Indicator:  CHQ-50
The Child Health Questionnaire™ Parent Form 50 Questions (CHQ-50) will be administered 
during the study.  The questionnaire is a generic quality of life instrument, measuring 14 unique 
physical and psychosocial concepts, which was developed for children from 5 to 18 years of age.
7.20.2
Quality of Life Indicator:  CHQ-87
The Child Health Questionnaire™ Child Form 87 (CHQ-87) will be administered during the 
study.  The CHQ-87 is a child and adolescent self-report, developed for ages 10 and older, which 
assesses the child’s self-perceived physical and psychosocial well-being.
7.20.3
Quality of Life Indicator:  ITQOL
The Infant Toddler Quality of Life Questionnaire™ (ITQOL) will be administered during the 
study.  The ITQOL was developed for children at least 2 months of age up to 5 years and 
assesses the physical, mental, and social well being of the child and assesses the quality of the 
parent/legally authorized representative(s) life.  
7.21
Concomitant Medications, Therapies and Medical/Surgical Procedures
All non-protocol treatments that occur from the time of informed consent (and assent, if 
applicable) through the safety follow-up contact are regarded as concomitant and will be 
documented on the appropriate pages of the eCRF.  Concomitant therapy includes medication 
(including Genistein), therapies/interventions administered to patients, and medical/surgical 
procedures performed on the patients.
Every effort should be made to keep symptomatic Sanfilippo syndrome Type A treatment 
constant throughout the study.  However, changes in medications are acceptable if necessary 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 45 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
46
according to clinical judgment.  All changes will be recorded on the appropriate eCRF.  
Concomitant medication will be coded using WHO-DD.
7.22
Adverse Events
7.22.1
Definitions of Adverse Events and Serious Adverse Events
7.22.1.1
Adverse Event
An AE is any noxious, pathologic, or unintended change in anatomical, physiologic, or 
metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in 
any phase of a clinical study, whether or not considered study drug-related.  This includes an 
exacerbation of a pre-existing condition.  Once the informed consent is signed and dated, any 
adverse event prior to the start of study drug must be reported. 
AEs include:

Worsening (change in nature, severity, or frequency) of conditions present at the onset of the 
study

Intercurrent illnesses

Drug interactions

Events related to or possibly related to concomitant medications

Abnormal laboratory values (this includes significant shifts from baseline  within the range 
of normal that the investigator considers to be clinically important)

Clinically significant abnormalities in physical examination, vital signs, and weight
Throughout the study, the investigator must record all AEs on the AE eCRF, regardless of the 
severity or relationship to study drug.  The investigator should treat patients with AEs 
appropriately and observe them at suitable intervals until the events stabilize or resolve.  AEs 
may be discovered through observation or examination of the patient, questioning of the patient, 
complaint by the patient, or by abnormal clinical laboratory values.
In addition, AEs may also include laboratory values that become significantly out of range.  In 
the event of an out-of-range value, the laboratory test should be repeated until it returns to 
normal or can be explained and the patient’s safety is not at risk.  
All AEs should be recorded with causality assessment.
The information presented below is intended to provide issues to consider for AEs associated 
with intrathecal injections of HGT-1410.  In general, these AEs can be classified as follows: 

Adverse events due to systemic exposure to HGT-1410 caused by the drug diffusion from the 
CSF to the peripheral circulation; 

Adverse events related to the direct delivery of HGT-1410 to the intrathecal CSF space and 
meninges, and subsequent diffusion into brain parenchyma, via an intrathecal route 

IDDD–related AEs  
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 46 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
47
Note:  the classification of potential AEs and the examples presented below are based on purely 
theoretical considerations and/or published literature as there is limited human experience with 
intrathecal HGT-1410 therapy to date.
7.22.1.2
Potential Adverse Events:  Intrathecal recombinant human heparan 
N-sulfatase 
ADVERSE EVENTS RELATED TO THE DIRECT DELIVERY OF HGT-1410 TO THE CNS THROUGH 
INTRATHECAL ADMINISTRATION
Examples of AEs observed in other published clinical trials with intrathecally-administered 
peptides or proteins, include, but are not limited to the following:  headache, fever, feeling of 
warmth, sensory paresthesias (including feelings of warmth, tingling, or pain) or autonomic 
symptoms such as dry mouth or gustatory abnormalities (including loss of smell and metallic 
taste).  Changes in mental cognitive status or level of consciousness that are not caused by 
pre-medication may either occur acutely or develop post-injection, over time
ADVERSE EVENTS DUE TO SYSTEMIC EXPOSURE TO HGT-1410
Although HGT-1410 is given intrathecally only, some proportion of the drug will diffuse from 
the CSF into the peripheral circulation.  The resulting systemic exposure may cause events that 
are typically seen in patients receiving ERT via an intravenous administration, known as 
infusion-related reactions.  An infusion-related reaction is defined as an adverse event that 
(1) begins either during or within 24 hours after the start of the infusion, and (2) is judged as 
possibly or probably related to study drug.  Other AEs that occur prior to the infusion, along with 
AEs associated with protocol-defined testing and assessments (laboratory testing and physical 
examinations) that were performed prior to the infusion will not be defined as infusion-related 
reactions.
7.22.1.3
Infusion/Hypersensitivity Reactions and Management
Infusions of proteins can be associated with reactions to the infusion that may or may not be 
immune-mediated (hypersensitivity reactions).  Thus, potential reactions to the infusion of 
investigational drug are unpredictable.  It is often difficult to clinically distinguish infusion 
reactions from hypersensitivity reactions.  Symptoms may include headache, fever, sensory 
paresthesias (including feeling of warmth, tingling, or pain), rash, pruritus, or autonomic 
symptoms, such as dry mouth or gustatory abnormalities (including loss of smell and metallic 
taste).  Changes in mental status or level of consciousness that are not caused by pre-medication 
may either occur acutely or develop post-injection over time.
The management of infusion reactions and hypersensitivity reactions is similar.  The following 
steps may be taken, at the discretion of the investigator, in the event of a suspected infusion 
related/hypersensitivity reaction and the management of such reactions should be based on the 
severity of the reaction:

Treatment with medications such as antihistamines, antipyretics, and/or corticosteroids

Stopping and resuming treatment
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 47 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
48

Pretreatment with antihistamines and/or corticosteroids may prevent subsequent reactions in 
those cases where symptomatic treatment was required
7.22.1.4
IDDD-related Adverse Events 
IDDD ADVERSE EVENTS
Examples of AEs related to use of the IDDD include, but are not limited to, the following: device 
failure, device malfunction, incorrect connection of IDDD components, erosion of the 
portal/catheter through the skin, fibrin sheath formation around the catheter tip, hematoma, 
implant rejection, migration of the portal/catheter, occlusion of the portal/catheter, portal site, or 
subcutaneous tract infection. The device may also need to be replaced or repaired as needed. A 
malfunction of the device (defined in Section 7.22.2.2) should not be entered as an AE unless it 
has physiological consequences.  In the event of a device failure (defined in Section 7.22.2.3), 
the device may need to be replaced or repaired. Hospitalization for such a procedure will be 
reported as a serious adverse event (SAE).  Details of the cause of IDDD malfunction or failure 
will be recorded on the Device Malfunction/Failure CRF.  A list of the more common IDDD
AEs is included in Appendix 3.
DEVICE SURGICAL PROCEDURE-RELATED ADVERSE EVENTS
Examples of AEs related to device surgical procedures include, but are not limited to, the 
following: events that occur during or following IDDD implant/explant, IDDD adjustment, full 
revision, partial revision, IDDD removal, and delayed re-implantation after previous IDDD 
removal (such as complications of anesthesia, excessive bleeding, wound hematoma) and post 
operative complications (such as post-operative infection).
IT ADMINISTRATION PROCESS ADVERSE EVENTS 
Intrathecal administration process AEs include those caused by anesthesia during drug 
administration, drug administration issues (eg, extravasation during infusion or hematoma due to 
Huber needle) or complications of lumbar puncture.
RISKS ASSOCIATED WITH ANESTHESIA REQUIRED FOR STUDY ASSESSMENTS
The use of an IDDD has been chosen to minimize the risks inherent in utilizing novel delivery 
systems and to alleviate the need for multiple administrations of anesthesia required for drug 
injection via repeated LP. The risks from anesthesia include respiratory depression, aspiration, 
cardiac events, hypoxia, hypotension and hypertension, difficult intubations and extubations, 
stroke, rapid changes in body temperature, laryngospasm or laryngeal edema, allergic reaction, 
and death. Patients will be closely monitored for changes in vital signs and related events.
RISKS ASSOCIATED WITH LUMBAR PUNCTURE
Risks associated with LP include pain at the injection site, infection, meningitis, encephalitis, 
cerebritis, failed procedure, bleeding, dural tears, spinal headache, spinal fluid leakage, nerve 
damage, and focal and non-focal neurological injury (including paralysis). Patients may require 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 48 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
49
anesthesia prior to an LP. Risks from anesthesia are discussed separately in this section 
(Section 7.22.1.4).  
7.22.1.5
Serious Adverse Event
1. An SAE is any AE occurring at any dose of investigational drug or at any procedure that 
results in any of the following outcomes:

Death

Is life-threatening

Requires inpatient hospitalization

Requires prolongation of existing hospitalization

A persistent or significant disability or incapacity 

A congenital anomaly or birth defect
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization. Hospitalizations, which are the 
result of elective or previously scheduled surgery for pre-existing conditions, which have not 
worsened after initiation of treatment, should not be classified as SAEs. For example, an 
admission for a previously scheduled ventral hernia repair would not be classified as an SAE; 
however, complication(s) resulting from a hospitalization for an elective or previously scheduled 
surgery that meet(s) serious criteria must be reported as SAE(s). Furthermore, this does not 
apply to device failures resulting in scheduled surgical revisions, which should be reported as 
SAEs.”
2.  Unanticipated Adverse Device Effect (UADE) - Any serious adverse effect on health or 
safety or any life-threatening problem or death caused by, or associated with, a device, if that 
effect, problem, or death was not previously identified in nature, severity, or degree of incidence 
in the investigational plan or application (including a supplementary plan or application), or any 
other unanticipated serious problem associated with a device that relates to the rights, safety, or 
welfare of patients. (21CFR812.3[s] or other regulatory requirements, as applicable).
7.22.2
Device-Associated Definitions
7.22.2.1
Device Revision (Partial and Full)
Partial device revision: surgical revision/replacement of one or more component(s) of the device; 
other component(s) of the original device remain implanted and are not affected (eg, port 
revision).
Full device revision: the device is removed (explanted) in its entirety and a completely new 
device is implanted.
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 49 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
50
7.22.2.2
Device Malfunction
The device does not perform as intended, based on the description in the device’s IFU, but does 
not require either a partial or full device revision.
7.22.2.3
Device Failure
The device irreversibly fails to perform as intended and requires either a partial or full device 
revision or removal.
7.22.2.4
Device Adjustment
Surgery of the device which does not result in partial or complete device revision or removal (eg, 
surgical exploration only or placement of additional sutures, tissue glue, and/or fascial repair).  
7.22.3
Classification of Adverse Events and Serious Adverse Events
The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
version 3.0 grading scale should be referenced when assessing the severity of an AE (see 
Appendix 6).  If an AE is not described in the NCI CTC, the severity should be recorded based 
on the scale provided in Table 7-3. The severity of all AEs/SAEs should be recorded on the 
appropriate eCRF page. Adverse events are graded as Grade 1, 2, 3, 4, or 5 corresponding, 
respectively, to a severity of mild, moderate, severe, life-threatening, or death. 
Table 7-3
Adverse Event Severity
Severity
Definition
Grade 1 (Mild)
No limitation of usual activities.
Grade 2 (Moderate)
Some limitation of usual activities.
Grade 3 (Severe)
Inability to carry out usual activities.
Grade 4 (Life-threatening)
Immediate risk of death.
Grade 5 (Death related to an AE)
Death
7.22.4
Relatedness of Adverse Events and Serious Adverse Events
Relationship of an AE or SAE to investigational product, device, device surgical procedure, or 
IT administration process is to be determined by the investigator based on the definitions in 
Table 7-4:
Table 7-4
Adverse Event Relatedness
Relationship to Product(s)
Definition
Not Related
Unrelated to study drug, device, device surgical procedure, or IT 
administration process. 
Possibly Related
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of study drug, device, device surgical 
procedure, or IT administration process but which could also be 
explained by concurrent disease or other drugs or chemicals.
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 50 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
51
Table 7-4
Adverse Event Relatedness
Relationship to Product(s)
Definition
Probably Related
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of study drug, device, device surgical 
procedure, or IT administration process unlikely to be attributable to 
concurrent disease or other drugs and chemicals and which follows a 
clinically reasonable response on de-challenge.  The association of the 
clinical event or laboratory abnormality must also have some biologic 
plausibility, at least on theoretical grounds.
Definitely Related
The event follows a reasonable temporal sequence from administration 
of the medication,  device, device surgical procedure, or IT 
administration process follows a known or suspected response pattern 
to the medication, is confirmed by improvement upon stopping the 
medication (dechallenge) and reappears upon repeated exposure 
(rechallenge).  
Note that this is not to be construed as requiring re-exposure of the 
patient to study drug; however, the determination of definitely related 
can only be used when recurrence of event is observed.
7.22.5
Procedures for Recording and Reporting Adverse Events
7.22.5.1
Reporting Serious Adverse Events Related to Study Procedures
Any SAE regardless of relationship to investigational product, device, device surgical procedure, 
or IT administration process that occurs in a patient after informed consent (and assent if 
applicable) should be recorded by the clinical site on an SAE form that is to be transmitted to the 
Shire Medical Monitor and to the Shire Pharmacovigilance and Risk Management Department at 
the contact number provided below.  The SAE must be completely described on the patient’s 
eCRF, including the judgment of the investigator as to the relationship of the SAE to the 
investigational product and or device.  The investigator will promptly supply all information 
identified and requested by the sponsor (and/or contract research organization [CRO]) regarding 
the SAE as to the relationship of the SAE to study drug, device, or procedure. 
The investigator must report the SAE to the Shire Pharmacovigilance and Risk Management 
Department AND to the Shire Medical Monitor on an SAE form.  The SAE form must be 
completed and FAXED or scanned and EMAILED (PDF sent by e-mail) within 24 hours of the 
investigator’s learning of the event to: 
Shire Pharmacovigilance and Risk Management Department:
International FAX: 
United Kingdom OR 
United States FAX:  
Email:  
AND
Shire HGT Medical Monitor:
FAX: 
(United States)
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 51 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
52
Any follow-up information must also be completed on an SAE form and faxed or scanned to the 
same numbers or e-mail address listed above.
In the event of a severe and unexpected, fatal, or life-threatening SAE, the clinical site must 
contact the Shire Medical Monitor by telephone; this is in addition to completing and 
transmitting the SAE form as stated above.  The following provides contact information for the 
Shire Medical Monitor.
If an SAE is assessed as severe and unexpected, or life-threatening, contact:
, DO
Shire Human Genetic Therapies, Inc.
300 Shire Way
Lexington, MA  02421,  United States
Telephone: 
Fax: 
(United States)
Mobile: 
(24-hour access)
The investigator must promptly report all required information to the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC).  It is the responsibility of the sponsor to ensure that 
each investigator receives a copy of any CIOMS I/MedWatch report that has been submitted to 
the appropriate regulatory agencies notifying them of an unexpected related SAE.  The 
investigator or sponsor must ensure that the IRB/IEC receives a copy of the report and that a 
copy is also filed within their study files.  In addition, the sponsor will also notify the 
investigators and IRBs/IECs of all deaths that occur during the study, irrespective of relationship 
to study medication
7.22.5.2
Eliciting Adverse Events
Patients should be asked non-leading questions (eg, “How do you feel?”) and further questions 
should be posed if there is indication of an AE.  The questioning should be conducted with due 
The investigator may also call the medical monitor directly (optional):
Shire HGT Medical Monitor: 
, DO
Shire HGT
Work:
Cell:
(24 hour access)
Email: 
AND
Clinical Project Manager CC’d: 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 52 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
53
regard for objectivity and, in particular, the questioner should gather information regarding AEs 
from questioning the patient, the patient’s parent/guardian, spontaneous report by the patient or 
parent/guardian, laboratory reports, and any health care provider’s observations.
The onset date, resolution date, treatment administered, and outcome of each AE must be 
recorded on the appropriate eCRF. The relationship of each AE to study medication must be 
recorded. In addition AEs may be considered to be related to the IDDD, the IDDD surgical 
procedure, or the IT administration process. Since the AE may be deemed to be related to more 
than one of these factors, as many of these IDDD-related options as apply should be indicated on 
the eCRF.
7.22.5.3
Protocol Deviations for Medical Emergency or Adverse Event
During and following a patient’s participation in the study, the investigator should ensure that 
adequate medical care is provided to a patient for any AEs, including clinically significant 
laboratory test results.  
The investigator should inform the patient, the patient’s parent(s), or the patient’s legally 
authorized representative when medical care is needed for intercurrent illness(es) of which the 
investigator becomes aware.  In an emergency situation, the investigator should contact the Shire 
Medical Monitor (see Section 7.22.5.1).
Only when an emergency occurs that requires an immediate deviation from the protocol for the 
safety of a patient, will there be such a deviation and this will be only for that patient.  
The investigator or other physician in attendance in such an emergency must contact the Shire 
Medical Monitor as soon as possible.  
The investigator, along with the Shire Medical Monitor, will make a decision as to whether or 
not the patient should continue in the study prior to the next scheduled dose.  The departure from 
the protocol and the grounds for it should be stated in the eCRF.
7.23
Abuse, Overdose and Medication Errors
Abuse, misuse, overdose or medication error must be reported to the sponsor according to the 
SAE reporting procedure whether or not they result in an AE/SAE as described in Section 7.22.

Abuse – Persistent or sporadic intentional intake of investigational medicinal product at a 
dose higher than prescribed per protocol (but below the dose defined for overdose) or when 
used for non-medical purpose (eg, altering one’s state of consciousness)

Misuse – Intentional or unintentional use of investigational medicinal product other than as 
directed or indicated at any dose, which is at or below the dose defined for overdose (Note: 
This includes a situation where the test article is not used as directed at the dose prescribed 
by the protocol)

Overdose – Overdosage with adverse clinical consequences is not anticipated with the use of 
HGT-1410. Additionally, HGT-1410 will be given in a clinical setting by a health care 
provider. 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 53 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
54

Medication Error – A mistake made in prescribing, dispensing, administration and/or use of 
the investigational medicinal product.
7.24
Safety-related Study Stopping Rules
If any patient experiences a life-threatening (Grade 4) adverse event or death which is considered 
by the sponsor to be possibly, probably, or definitely related to study drug or the IDDD, or if 
2 or more patients experience a Grade 3 adverse event during the trial that is considered by the 
sponsor to be possibly, probably, or definitely related to the study drug or the IDDD, then the 
site will be instructed to halt further HGT-1410 administration to all patients and the safety data 
reviewed. Following a review of safety data, the study will be either:

Resumed unchanged

Resumed with modifications to the protocol or

Terminated
Patient safety will be monitored on a continuous basis during this study until the last patient 
completes his or her last scheduled study visit/assessment.  
7.25
Pregnancy
Pregnancy and breast feeding are exclusion criteria.  Only female patients who have 
reached menarche will be tested for pregnancy in HGT-SAN-067.  If applicable, this will occur 
at study start and before each dose of HGT-1410 throughout the study.  Pregnancy testing will be 
performed on a blood or urine sample.  Patients with a positive or inconclusive result will not be 
eligible for this study.
At study start, a pregnancy test will be performed if more than 30 days have passed since the 
initial screening sample.  Throughout the study pregnancy testing will occur prior to each dose of 
HGT-1410.  The clinical site’s local laboratory will analyze and report all pregnancy testing 
results.  If a pregnancy test is positive the patient will be discontinued from the study, and the 
investigator must contact the Shire Medical Monitor. 
Pregnancy is not to be reported as an AE; the Pregnancy Reporting Form, found in the Study 
Operations Manual along with instructions for completion, should be used to report the 
pregnancy.  The pregnancy will be followed up through delivery or final outcome.
7.26
Removal of Patients from the Trial or Study Drug
The patient's parent or legally authorized representative acting on behalf of the patient is free to 
withdraw consent and discontinue participation in the study at any time without prejudice to 
further treatment.  Since this is an extension trial, there will be no replacement of patients who 
discontinue the study for any reason.
A patient’s participation in the study may be discontinued at any time at the discretion of the 
investigator, sponsor, or medical monitor.  The following may be justifiable reasons for the 
investigator, sponsor, or medical monitor to remove a patient from the study:
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 54 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
55

Adverse Event:  If a patient experiences an AE which, in the judgment of the investigator, the 
sponsor, or the medical monitor, presents an unacceptable consequence or risk to the patient.

Adverse Laboratory Experience:  If a patient has an adverse laboratory experience which, in 
the judgment of the investigator, the sponsor, or the medical monitor, presents an 
unacceptable consequence or risk to the patient, the patient may be withdrawn from the 
study.

Comorbidity:  If a patient develops comorbidity during the course of the study that is 
independent of the study indication, and treatment is required that is not consistent with 
protocol requirements. 

Intercurrent Illness:  If a patient develops an illness during the course of the study that is not 
associated with the condition under study, and which requires treatment that is not consistent 
with protocol requirements.

Refusal of Treatment:  If the patient, the patient’s parent(s) or legally authorized 
representative(s) discontinues participation in the study, or the patient is discontinued by the 
investigator, reasonable efforts will be made to follow the patient through the end of study 
assessments.  The reason for refusal will be documented on the eCRF.  

Withdrawal of Informed Consent:  A patient’s parent or legally authorized representative 
may withdraw his informed consent to participate in the study at any time.

Cerebrospinal fluid leukocyte count >100 cells per cubic millimeter for 2 consecutive 
months.

New onset seizure.

Anaphylactic reaction beyond reasonable management as described in the Investigator’s 
Brochure.

Clinically problematic intubations or extubations, which may preclude safe airway 
management and anesthesia.

Development of refractory spinal fluid leakage. 

Clinically significant prolonged (eg, greater than 24 to 48 hours) worsening in mental status, 
including development of new focal or non-focal neurological symptoms, or recurrence of a 
previously stable prior medical problem judged due to study drug or participation that is 
exclusive of effects from anesthesia.

Non-compliance, including failure to appear at 1 or more study visits.

The patient was erroneously included in the study.

The patient develops an exclusion criterion.

The study is terminated by the sponsor.

The patient becomes pregnant during the trial.
If a patient discontinues the study the Patient Completion/Discontinuation eCRF describing the 
reason for discontinuation must be completed.  Any AE’s experienced up to the point of
discontinuation must be documented on the AE eCRF.  
If AEs are present when the patient withdraws from the study, the patient will be re-evaluated 
within 30 days of withdrawal.  All ongoing SAEs at the time of withdrawal will be followed until 
resolution.
At the time of discontinuation or withdrawal, patients will be asked to participate in all safety 
and efficacy evaluations required for the end of study visit and for the safety follow-up visit.  
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 55 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
56
Participation in these EOS procedures will be strongly encouraged, but is voluntary for those 
patients electing to discontinue from the study.  The patient will be scheduled for the removal of 
the IDDD. 
7.27
Other Study Procedures
This section is not applicable.
7.28
Appropriateness of Measurements
The neurocognitive and developmental assessments are intended to gauge which domains can be 
accurately measured, with which specific tools, despite the considerable behavioral and cognitive 
challenges in Sanfilippo syndrome.  The evaluation of these domains and the analysis of CSF, 
serum, and urine biomarkers may provide the pivotal data necessary to inform the clinical 
assessments and biomarkers used in possible future Sanfilippo syndrome ERT trials.
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 56 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
57
8
STUDY ACTIVITIES
Patients who participated in Study HGT-SAN-055 through Week 26 and completed the EOS 
evaluations may be eligible for enrollment in this open-label extension study.  Informed consent 
(and assent, if applicable) must be obtained prior to performing any study related procedures that 
are specific to HGT-SAN-067.  Informed consent may be obtained anytime from Week 20 in 
HGT-SAN-055.  This would allow a patient to have a nonfunctional IDDD replaced or revised 
prior to the first HGT-1410 dose in HGT-SAN-067.
8.1
Screening Visit/Study Start Visit – Main Site
All Screening assessments for this study are to have been performed during the Week 26 EOS 
procedures in HGT-SAN-055 (ie, 30 [±7] days after the last HGT-1410 administration).  If less 
than 60 days have elapsed since completion of the EOS assessments for HGT-SAN-055, and the 
start of HGT-SAN-067, the assessments detailed in this Screening visit do not need to be 
repeated.  The Baseline visit for this study will be the first day the patient received their first 
dose of HGT-1410 in the HGT-SAN-055 Study.  
If more than 60 days have elapsed following the HGT-SAN-055 EOS procedures, patients will 
be evaluated for enrollment in HGT-SAN-067 on a case-by-case basis by the investigator.  A 
decision about enrollment will be made following discussion with the medical monitor.  If the 
patient is enrolled, the following assessments are to be repeated within 30 days prior to the first 
scheduled intrathecal HGT-1410 dose:

Physical examination

Height and weight

Head circumference

ECG

Vital signs

Hematology 

Leukocyte pellet preparation to be used for additional disease-related laboratory studies, 
including possible assessment of cross-reactive immunologic material (if this is not collected 
at baseline, it can be collected at any subsequent pre-dosing time point)

Serum chemistry 

Pregnancy testing (for post menarche premenopausal females only)

Urinalysis 

Urine GAG, including heparan sulfate and heparan sulfate derivatives

Plasma collection for biomarkers

Anti-rhHNS antibody testing (serum and CSF)

General anesthesia:  administration of anesthesia will be given prior to the following 
assessments:

ABR

MRI of the head

Neurological examination (performed prior to the administration of anesthesia)
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 57 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
58

Full Neurodevelopmental assessments, including Vineland Adaptive Behavior Scales, 
Second Edition (VABS-II; all assessments performed prior to the administration of 
anesthesia)

CSF sample collection (chemistry, cell count, heparan sulfate and heparan sulfate derivatives, 
and other MPS exploratory biomarkers) via the IDDD

Children’s Sleep Habits Rating Scale 

CHQ-50

CHQ-87

ITQOL

Concomitant medications, therapies, and procedures

AE assessments
8.2
Treatment:  Drug Administration and Weekly Assessments – Main or Local Site
Patients will receive HGT-1410 IDDD monthly (Q4W), on Day 2 (±2 days), Week 1.  
Patient assessments for safety, biochemical, and neurological baseline measures (Day 1, Week 1) 
will occur on the day before the first IT injection.  Note:  Day 1 assessments may be performed 
on the same day as the administration of study drug (Day 2).  This can occur if it is feasible for 
the patient to arrive at the study site early in the day, and if it is deemed clinically appropriate by 
the investigator.  If the procedures on Day 1 and Day 2 are combined in this way, the 
assessments will be recorded as occurring on Day 2.
CSF samples will be obtained from these patients on Day 2, immediately prior to the first IT 
study drug injection.  
8.2.1
Week 1 
8.2.1.1
Day 1 (Pre-treatment) Assessments Performed Prior to Each Dose

Physical examination

Height and weight

Vital signs (may be performed on Day 2 if feasible for the patient to arrive at the study site 
early in the day and if deemed clinically appropriate by the investigator)

Hematology (after Month 54 frequency reduced to Q3 Months)

Serum chemistry (after Month 54 frequency reduced to Q3 Months)

Urinalysis (after Month 54 frequency reduced to Q3 Months)

Pregnancy testing (applicable females only)

Neurological examination (to be performed if symptom directed prior to the administration of 
anesthesia and the HGT-1410 IT injection and at a minimum of every 12 months)

Concomitant medications, therapies, and procedures

AE assessments
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 58 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
59
Note: If the HGT-SAN-055 EOS (or HGT-SAN-067 Screening) assessments were performed 
within 7 days of first intrathecal HGT-1410 treatment in this study, the pre-treatment 
assessments described in this section do not need to be completed prior to the first treatment in 
study HGT-SAN-067.
DAY 1 (PRE-TREATMENT) ADDITIONAL ASSESSMENTS PERFORMED AT MONTHS 12, 24, 36, 54,
60, 72, 84, 96, AND 102

Head circumference

Visual and hearing assessments 

Urine GAG, including heparan sulfate and heparan sulfate derivatives (performed at Months
60, 66, 72, 78, 84, 90, and 96, ie, Q6 Months following Month 54)

Plasma collection for biomarkers

Anti-rhHNS antibody testing (performed at Months 60, 66, 72, 78, 84, 90, and 96, ie, Q6 
Months following Month 54)

ABR (not performed after Month 54, ie not on Months 60, 66, 72, 84, 96, or 102)

MRI of the head 

Full neurodevelopmental testing, including VABS-II (performed prior to the administration 
of anesthesia and the HGT-1410 IT injection)

Children’s Sleep Habits Rating Scale 

Child health questionnaire-50 

Child health questionnaire-87 

Infant toddler QoL Questionnaire 
8.2.1.2
Day 2 (±2 days) Assessments and Administration of HGT-1410
Patients may be discharged from the clinical site 4 hours after dosing, if deemed stable by the 
investigator.

Physical examination (after Month 54 the full physical examination will be performed on an 
annual basis at Months 66, 78, 90, and 102. The remainder of the physical examinations will 
be symptom-directed.)

ECG (performed following IT study drug injection)(after Month 54 performed Q3 months)

Vital signs (to be performed at the discretion of the investigator)

CSF sample collection (obtained prior to IT study drug injection)

HGT-1410 IT injection (Day 2 ±2 days)

Neurological examination (to be performed if symptom directed and at a minimum of every 
12 months)

Concomitant medications, therapies, and procedures

AE assessments
The neurological exam should not occur sooner than 4 hours after study drug administration or 
before the patient has fully recovered from any anesthesia administered for the dosing, 
whichever occurs later.
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 59 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
60
8.3
End of Study/Early Termination Procedures:  Month 103 – Main Site
Patients who complete the study or who discontinue prior to the end of the study, will have EOS 
assessments performed 30 (±7 days) after their last dose of HGT-1410.  
Patients who discontinue or are withdrawn prior to study completion will be asked to participate 
in the EOS procedures at the time of discontinuation.  Participation in these EOS procedures will 
be strongly encouraged, but is voluntary for those patients electing to discontinue from the study.  
Note:  Patients will have the IDDD removed when they discontinue from the study, unless the 
patient is continuing to receive treatment through another mechanism (eg, expanded access, 
commercially available).

Physical examination

Height and weight

Head circumference

Visual and hearing assessment

ECG

Vital signs

Hematology

Serum chemistries

Urinalysis

Pregnancy testing (applicable females only)

Urine GAG, including heparan sulfate and heparan sulfate derivatives 

Plasma collection for biomarkers

Anti-rhHNS antibody testing (serum and CSF)

MRI of the head (unless performed at Month 102)

CSF sample collection (unless performed at Month 102)

Neurological examination

Full neurodevelopmental testing, including VABS-II 

Children’s Sleep Habits Rating Scale 

CHQ-50 

CHQ-87 

Infant toddler QoL Questionnaire 

Concomitant medications, therapies, and procedures

AE assessments
All patients who discontinue the study early will have their IDDD removed.  
Patients who withdraw or discontinue after having received fewer than 3 IT injections will not 
need to complete the EOS visit.  
Patients who withdraw or discontinue from the study after having received 3 or more IT 
injections, will be asked to complete the EOS visit and undergo all the scheduled assessments.
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 60 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
61
8.4
Safety Follow-up (by Telephone or Visit) Month 104
Patients who complete the study or withdraw early will have a safety follow-up telephone call or 
visit 30 Days (±7 days) after the last study visit.  This will assess:

Concomitant medications, therapies, and procedures

AE assessments
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 61 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
62
9
QUALITY CONTROL AND ASSURANCE
Training will occur at an investigator meeting or at the site initiation visit or both, and instruction 
manuals (eg, laboratory manuals and pharmacy manuals) will be provided to aid consistency in 
data collection and reporting across sites.
Clinical sites will be monitored by Shire or its designee to ensure the accuracy of data against 
source documents.  The required data will be captured in a validated clinical data management 
system that is compliant with the Food and Drug Administration (FDA) 21 Code of Federal 
Regulations (CFR) Part 11 Guidance.  The clinical trial database will include an audit trail to 
document any evidence of data processing or activity on each data field by each user.  Users will 
be trained and given restricted access, based on their role in the study, through a password 
protected environment.  
Data entered in the system will be reviewed manually for validity and completeness against the 
source documents by a clinical monitor from Shire or its designee.  If necessary, the study site 
will be contacted for corrections or clarifications; all missing data will be accounted for.
SAE information captured in the clinical trial database will be reconciled with the information 
captured in the Pharmacovigilance database.
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 62 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
63
10
PLANNED STATISTICAL METHODS
10.1
General Statistical Methodology
This is an open-label extension of study HGT-SAN-055 to evaluate the long-term safety and 
clinical outcomes of intrathecal administration of HGT-1410 in patients with MPS IIIA.  The 
statistical methodology supporting the trial will focus on descriptive rather than inferential 
approaches, given the early phase and objectives of this trial. 
Data will be summarized by dose group (10 mg, 45 mg, and 90 mg) with respect to demographic 
and baseline characteristics, efficacy variables, and safety variables. Summary statistics for 
continuous variables will include the n, mean, standard deviation, median, minimum and 
maximum. Categorical variables will be summarized in a contingency table by the frequency and 
percentage of patients in each category. Data will be plotted to assess trends across time as 
appropriate.
No a priori hypotheses will be tested.  Exploratory hypotheses may emerge from the data 
analysis, in which case, appropriate testing methods will be applied and specified in the 
statistical analysis plan.
There are no formal hypotheses associated with the evaluation of the safety and performance of 
the IDDD device (SOPH-A-PORT Mini S). All analyses of device safety and performance will 
be descriptive and no statistical testing will be performed. Device related analyses will be based 
on patients for whom the device implant procedure was performed and are described in the 
sections below.
10.2
Determination of Sample Size
Since this is an extension study, sample size is determined by the number of patients who 
completed HGT-SAN-055 (maximum of 12 patients) and elected to continue treatment with 
HGT-1410 in this study. Hence no statistical estimation of the sample size was performed.
10.3
Analysis Populations
The primary analysis population consists of all eligible patients from HGT-SAN-055 who have 
agreed to participate in the extension study. This population will be used to perform both safety 
and efficacy analyses. The collection of detailed data pertaining to the SOPH-A-PORT mini S 
will permit device-related analyses to be conducted in the subset of patients in the primary 
analysis population who had the SOPH-A-PORT Mini S implant procedure performed.
10.4
Demographics and Baseline Characteristics
Patient disposition for those enrolled will be presented in a summary table using number and 
percentage of patients enrolled, completed or discontinued/withdrew. The reasons for 
discontinuation/withdrawal will also be presented.
Demographic and baseline characteristics (eg, age, race, ethnicity, medical history, and surgical 
history) will be reported in summary tables.
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 63 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
64
10.5
Statistical Analysis of Pharmacokinetic Variables
Not applicable.
10.6
Efficacy, Safety, and Pharmacodynamic Evaluations    
10.6.1
Primary Analyses
10.6.1.1
Safety Analysis
In general, safety assessments will be based on all assessments post-baseline.  The assessment of 
safety will be based primarily on the frequency of AEs, and on the frequency of clinically 
notable abnormal vital sign and laboratory values.  Changes from baseline will be calculated by 
subtracting the baseline value from the post-baseline value.
All enrolled patients who had an IDDD surgical procedure and/or received administration of 
HGT-1410 will be included in the safety analysis.  
Adverse events will be recorded throughout the study and at early termination.  Adverse events 
and medical conditions will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). 
Adverse events will be summarized by presenting, for each dose group, the number and 
percentage of patients having any AE, having an AE in system organ class, and having each 
individual AE. In addition, those events which resulted in death or were otherwise classified as 
serious will be presented in a separate listing. The incidence of treatment-emergent adverse 
events , defined as all AEs from the time of the surgery for IDDD implantation to the last follow 
up contact, ie, 30 days after the last HGT-1410 administration, (new or worsened from baseline) 
will be summarized by system organ class, severity, type of adverse event and relationship to 
trial medication/procedure. 
Treatment-emergent AEs deemed related to HGT-1410 administration will be summarized 
separately.
IDDD and procedure-related AEs will be summarized within system organ class by preferred 
term. IDDD and procedure-related AEs will be tabulated by severity (mild, moderate, severe) 
and degree of relatedness.  Separate tabulations will be provided for adverse events related to the 
IDDD, device surgical procedure (including post-implant infections) and IT administration 
process.  These summaries will be presented by device and overall, as appropriate. 
Descriptive summaries of clinical laboratory evaluations (hematology, serum chemistry, 
urinalysis and CSF) results will be presented in summary tables by evaluation visit.  Changes 
from baseline will be summarized for each post-baseline visit.  Each laboratory result will be 
categorized as a patient having had (1) an Abnormal and Clinically Significant (CS) value at any 
time, (2) no CS values at any time but had at least one Abnormal and not CS (NCS) value, and 
(3) no CS or NCS values at any time; the number and percentage in each category will be 
presented.  For any patient who experiences a CS laboratory result at any time that was not CS at 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 64 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
65
baseline (or the most recent non-missing value prior to the start of the treatment), their entire 
profile for that particular laboratory parameter will be presented as a listing.
The observed values and changes from baseline for vital sign data will be summarized for each 
dose group.  Shift tables may be presented, utilizing reference ranges.  Patients with notably 
abnormal values will be identified and listed separately along with their values.
The observed values and changes from baseline for ECG data will be summarized for each dose 
group.  Patients with any clinically significant findings and/or conduction abnormalities will be 
listed separately along with their values. 
Anti-rhHNS antibody formation will be monitored throughout the study.  Results will be 
presented in summary tables by number and percentage of positive and negative specimens by 
evaluation visit, and number and percentage of positive and negative specimens overall.  The 
effect of antibodies on other safety parameters will be assessed by presenting summary tables by 
antibody status.  
For those patients who fail to complete the study, the reason for discontinuation will be listed by 
patient and dose group. 
Listings of all study safety data will be presented.
10.6.2
Other Observations Related to Safety
10.6.2.1
IDDD Performance
IDDD safety and performance will be summarized in detail for patients implanted with the 
SOPH-A-PORT Mini S. Difficulties associated with the implant procedure (e.g. excessive 
bleeding, CSF leakage, etc.) will be summarized.  A summary of abnormal findings from the 
IDDD radiological assessments will also be presented.  
The proportion of patients with at least one IDDD failure and/or malfunction, as well as the 
number of and reasons for IDDD failures/malfunctions will be summarized.  The rate of IDDD 
failures/malfunctions and 95% confidence interval will also be estimated.  The time from initial 
implant surgery to first IDDD failure and/or malfunction will be summarized.  Patients without 
an IDDD failure/malfunction will be censored at their last study drug injection date.  A by-
patient listing of the device failure/malfunction data will be displayed.
The proportion of patients for whom a successful first injection of study drug occurred will be 
reported among those for whom a first injection was attempted (i.e. those who had an apparently 
successful implantation and did not suffer a device removal or revision prior to first scheduled 
injection). The proportion of patients who had no failed injection attempts during the study will 
also be summarized. The corresponding 95% confidence intervals of the proportion of interest 
will be estimated, where appropriate. Injections not given for patient reasons (e.g. patient 
uncooperative, competing medical issue, etc) will not be included in the determination of these 
success proportions.
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 65 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
66
10.6.3
Secondary Analysis
10.6.3.1
Clinical Assessments
The change from baseline in neurocognitive assessment based scores will be examined by dose 
group.  Furthermore, the effect of HGT-1410 administration on QoL measures will be examined 
by presenting mean change from baseline by dose groups.  Other relevant assessments which 
might help in the understanding of clinical activity will also be analyzed.
10.6.3.2
Pharmacodynamic Analyses
To determine the effects of HGT-1410 administration on biomarkers, mean change from baseline 
will be assessed at selected time points.  The heparan sulfate reduction (in CSF) will be 
examined using mean change and the corresponding 95% confidence interval.  Other exploratory 
biomarkers in CSF, serum, and urine may also be examined.
The effect of anti- rhHNS antibodies on the changes in CSF biomarkers may also be examined 
by presenting summary tables by antibody status.
10.6.4
Interim Analysis
No formal analysis or interim statistical testing for early stopping of the trial is planned.  
Descriptive analyses of the data before trial completion may be performed for safety monitoring, 
regulatory reporting, publication, or general planning purposes.
The planned final analyses and presentations will be defined in the Statistical Analysis Plan 
(SAP).
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 66 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
67
11
ADMINISTRATIVE CONSIDERATIONS
11.1
Investigators and Study Administrative Structure
Before initiation of the study, the investigators must provide the sponsor with a completed Form 
FDA 1572 or Investigator Agreement.  Study medications may be administered only under the 
supervision of the investigators listed on this form.  Curriculum vitae must be provided for the 
investigators and sub-investigators listed on Form FDA 1572 or Investigator Agreement.
The investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, any amendments to the protocol, the study treatments, and their study related 
duties and functions.  The investigator must maintain a list of sub-investigators and other 
appropriately qualified persons to whom he or she has delegated significant study related duties.
11.2
Institutional Review Board or Independent Ethics Committee Approval
Before initiation of the study, the investigator must provide the sponsor with a copy of the 
written IRB or IEC approval of the protocol and the informed consent form.  This approval must 
refer to the informed consent form and to the study title, study number, and version and date of 
issue of the study protocol, as given by the sponsor on the cover page of the protocol.  
Status reports must be submitted to the IRB/IEC at least once per year.  The IRB/IEC must be 
notified of completion of the study.  Within 3 months of study completion or termination, a final 
report must be provided to the IRB/IEC.  A copy of these reports will be sent to the study clinical 
monitor.  The investigators must maintain an accurate and complete record of all submissions 
made to the IRB/IEC, including a list of all reports and documents submitted.  AEs which are 
reported to the US FDA or other Regulatory agencies (Investigational New Drug [IND] Safety 
Reports) must be submitted promptly to the IRB/IEC.
11.3
Ethical Conduct of the Study
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and investigators abide by 
good clinical practice (GCP) as described in the 21 CFR Parts 50, 56, and 312 and the 
International Conference on Harmonization (ICH) GCP Guidelines. 
11.4
Patient Information and Consent
Before enrolling in the clinical study, the patient’s parent(s), or the patient’s legally authorized 
representative(s) must consent to participate after the nature, scope, and possible consequences 
of the clinical study have been explained in a form understandable to him or her.  An informed 
consent form that includes information about the study will be prepared and given to the 
patient’s parent(s), or the patient’s legally authorized representative(s).  This document will 
contain all FDA and ICH-required elements.  
The informed consent form must be in a language understandable to the patient’s parent(s), or 
the patient’s legally authorized representative(s) and must specify who informed the patient’s 
parent(s) or the patient’s legally authorized representative.
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 67 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
68
After reading the informed consent document, the patient, patient’s parent(s), or the patient’s 
legally authorized representative(s) must give consent in writing.  The patient’s consent must be 
confirmed at the time of consent by the personally dated signature of the patient, patient’s 
parent(s) or the patient’s legally authorized representative(s) and by the personally dated 
signature of the person conducting the informed consent discussions.  If the patient, patient’s 
parent(s), or the patient’s legally authorized representative(s) is unable to read, oral presentation 
and explanation of the written informed consent form and information to be supplied must take 
place in the presence of an impartial witness.  Consent (or assent) must be confirmed at the time 
of consent orally and by the personally dated signature of the patient, patient’s parent(s) or by the 
patient’s legally authorized representative(s).  The witness and the person conducting the 
informed consent discussions must also sign and personally date the informed consent document.  
It should also be recorded and dated in the source document that consent was given.
A copy of the signed and dated consent document(s) must be given to the patient’s parent(s), or 
the patient’s legally authorized representative(s).  The original signed and dated consent 
document will be retained by the investigator.
The investigator will not undertake any measures specifically required solely for the clinical 
study until valid consent has been obtained.
A model of the informed consent form to be used in this study will be provided to the sites 
separately from this protocol.  
Where applicable, signed assent(s) to participate in the study must be obtained.
11.5
Patient Confidentiality
Patient names will not be supplied to the sponsor.  Only the patient number and patient initials 
will be recorded in the eCRF, and if the patient name appears on any other document, it must be 
obliterated before a copy of the document is supplied to the sponsor.  Study findings stored on a 
computer will be stored in accordance with local data protection laws.  The patients will be told 
that representatives of the sponsor, a designated CRO, the IRB/IEC, or regulatory authorities 
may inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws.  The investigator will maintain a personal patient 
identification list (patient numbers with the corresponding patient names) to enable records to be 
identified.
11.6
Study Monitoring
Monitoring procedures that comply with current GCP guidelines will be followed.  On-site 
review of the eCRFs for completeness and clarity, cross-checking with source documents, and 
clarification of administrative matters will be performed.
The study will be monitored by the sponsor or its designee.  On site monitoring will be 
performed by a representative of the sponsor (clinical study monitor) who will review the CRFs 
and source documents.  The site monitor will ensure that the investigation is conducted 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 68 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
69
according to protocol design and regulatory requirements by frequent site visits and 
communications (letter, telephone, and facsimile).
11.7
Case Report Forms and Study Records
Case report forms are provided for each patient in electronic format.  Electronic Data Capture 
(EDC) will be used for this study.  The study data will be recorded from the source documents 
into the eCRF.  The electronic files will be considered as the CRFs. 
All forms must be filled out by authorized study personnel.  All corrections to the original eCRF 
entry must indicate the reason for change.  The investigator is required to sign the eCRF after all 
data have been captured for each patient.  If corrections are made after review and signature by 
the investigator, he or she must be made aware of the changes, and his or her awareness 
documented by re-signing the eCRF.   
11.7.1
Critical Documents
Before Shire initiates the trial (ie, obtains informed consent [assent if applicable] from the first 
patient), it is the responsibility of the investigator to ensure that the following documents are 
available to Shire or their designee:

Curricula vitae of investigator and sub-investigator(s) (current, dated and signed or supported 
by an official regulatory document)

Current medical license of investigator and sub-investigator(s)

Signed and dated agreement of the final protocol

Signed and dated agreement of any amendment(s), if applicable

Approval/favorable opinion from the IRB/IEC clearly identifying the documents reviewed:  
protocol, any amendments, Patient Information/Informed Consent Form (Assent form if 
applicable), and any other written information to be provided regarding patients recruitment 
procedures

Copy of IRB/IEC approved Patient Information/Informed Consent Form (Assent Form if 
applicable)/any other written information/advertisement

Any additional regulatory approvals, ie national regulatory approvals

List of IRB/IEC Committee members/constitution

Financial agreement(s)

Documentation from central or local laboratory as applicable
•
Reference ranges
•
Certification/QA scheme/other documentation
Regulatory approval and notification as required must also be available; these are the 
responsibility of Shire.  All trial documents will be available in a Trial Master File (TMF) at the 
investigator/trial site and at Shire.     
11.8
Device Failure Review Process
The final cause for device failures will be reviewed by a Shire team by examining the clinical
database, safety database, and manufacturer investigation of returned devices.
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 69 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
70
11.9
Protocol Violations/Deviations
The investigator will conduct the study in compliance with the protocol.  The protocol will not 
be initiated until the IRB/IEC and the appropriate regulatory authorities have given 
approval/favorable opinion.  Modifications to the protocol will not be made without agreement 
of the sponsor.  Changes to the protocol will require written IRB/IEC approval/favorable opinion 
prior to implementation, except when the modification is needed to eliminate an immediate 
hazard(s) to patients.  The IRB/IEC may provide, if applicable regulatory authorities permit, 
expedited review and approval/favorable opinion for minor change(s) in ongoing studies that 
have the approval/favorable opinion of the IRB/IEC.  The sponsor will submit all protocol 
modifications to the regulatory authorities in accordance with the governing regulations.  A 
record of patients screened, but not entered into the study, is also to be maintained.  There will be 
no protocol exemptions granted for this study.
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
patients, the investigator will contact the sponsor or its designee, if circumstances permit, to 
discuss the planned course of action.  Any departures from the protocol must be fully 
documented as a protocol deviation.  Protocol deviations will need to be reviewed by the medical 
monitor and may also be required to be submitted to the IRB/IEC.
Protocol modifications will only be initiated by the sponsor and must be approved by the 
IRB/IEC and submitted to the FDA or other applicable international regulatory authority before 
initiation.
11.10 Access to Source Documentation
Regulatory authorities, the IEC/IRB, or the sponsor may request access to all source documents, 
CRFs, and other study documentation for on-site audit or inspection.  Direct access to these 
documents must be guaranteed by the investigator, who must provide support at all times for 
these activities.  Monitoring and auditing procedures that comply with current GCP guidelines 
will be followed.  On-site review of the CRFs for completeness and clarity, crosschecking with 
source documents, and clarification of administrative matters will be performed.
11.11 Data Generation and Analysis
The clinical database will be developed and maintained by a contract research organization or an 
electronic data capture technology provider as designated by Shire.  Shire or its designee will be 
responsible for performing study data management activities. 
Adverse events will be coded using MedDRA.  Concomitant medication will be coded using 
WHO-DD.  Centralized laboratories will be employed as described in the study manual to aid in 
consistent measurement of efficacy and safety parameters.
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 70 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
71
11.12 Premature Closure of the Study
11.12.1
Study Termination
If the sponsor or an investigator discovers conditions arising during the study which indicate that 
the clinical investigation should be halted due to an unacceptable patient risk, the study may be 
terminated after appropriate consultation between Shire and the investigators.  In addition, a 
decision on the part of Shire to suspend or discontinue development of the study material may be 
made at any time.
11.12.2
Site Termination
A specific site may be terminated separate from the general study for, but not limited to, the 
following conditions:

The discovery of an unexpected, significant, or unacceptable risk to the patients enrolled at 
the site.

Failure of the investigator to enter patients at an acceptable rate.

Insufficient adherence by the investigator to protocol requirements.
11.13 Retention of Data
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application and until there are no pending or contemplated marketing applications or 
at least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product.  The sponsor will notify the investigator if these documents must be 
retained for a longer period of time.  It is the responsibility of the sponsor to inform the 
investigator or institution as to when these documents no longer need to be retained. 
Biological samples may be reserved for potential, future, biomarker studies (see Section 7.7.7).  
11.14 Financial Disclosure
The investigator should disclose any financial interests in the sponsor as described in 21 CFR 
Part 54 prior to beginning this study.  The appropriate form will be provided to the investigator 
by the sponsor, which will be signed and dated by the investigator, prior to the start of the study. 
11.15 Publication and Disclosure Policy
All information concerning the study material, such as patent applications, manufacturing 
processes, basic scientific data, and formulation information supplied by the sponsor and not 
previously published are considered confidential and will remain the sole property of the 
sponsor.  The investigator agrees to use this information only in accomplishing this study and 
will not use it for other purposes.
It is understood by the investigator that the information developed in the clinical study may be 
disclosed as required to the authorized regulatory authorities and governmental agencies.  
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 71 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
72
In order to allow for the use of the information derived from the clinical studies, it is understood 
that there is an obligation to provide the sponsor with complete test results and all data developed 
in the study in a timely manner.
The investigator and any other clinical personnel associated with this study will not publish the 
results of the study, in whole or in part, at any time, unless they have consulted with Shire, 
provided Shire a copy of the draft document intended for publication, and obtained Shire’s 
written consent for such publication.  All information obtained during the conduct of this study 
will be regarded as confidential.  Shire will use the information for registration purposes and for 
the general development of the drug.
Shire may perform analyses of interim and/or final locked study data for the purpose of 
publication.
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 72 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
73
12
LIST OF REFERENCES
1. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. 
JAMA : the journal of the American Medical Association 1999;281:249-54.
2. Poorthuis BJ, Wevers RA, Kleijer WJ, et al. The frequency of lysosomal storage diseases in 
The Netherlands. Human genetics 1999;105:151-6.
3. Baehner F, Schmiedeskamp C, Krummenauer F, et al. Cumulative incidence rates of the 
mucopolysaccharidoses in Germany. J Inherit Metab Dis 2005;28:1011-7.
4. Valstar MJ, Bruggenwirth HT, Olmer R, et al. Mucopolysaccharidosis type IIIB may 
predominantly present with an attenuated clinical phenotype. Journal of inherited metabolic 
disease 2010;33:759-67.
5. Meyer A, Kossow K, Gal A, et al. Scoring evaluation of the natural course of 
mucopolysaccharidosis type IIIA (Sanfilippo syndrome type A). Pediatrics 
2007;120:e1255-61.
6. Cleary MA, Wraith JE. Management of mucopolysaccharidosis type III. Arch Dis Child 
1993;69:403-6.
7. Fraser J, Wraith JE, Delatycki MB. Sleep disturbance in mucopolysaccharidosis type III 
(Sanfilippo syndrome): a survey of managing clinicians. Clin Genet 2002;62:418-21.
8. Neufeld E, Muenzer J. The Mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, 
Valle D, eds. The metabolic and molecular bases of inherited disease. 8th ed. New York: 
McGraw-Hill; 2001:4 v. (xivii, 6338, I-104 p.).
9. Meyer A, Kossow K, Gal A, et al. The mutation p.Ser298Pro in the sulphamidase gene 
(SGSH) is associated with a slowly progressive clinical phenotype in mucopolysaccharidosis 
type IIIA (Sanfilippo A syndrome). Hum Mutat 2008;29:770.
10. Vellodi A. Lysosomal storage disorders. Br J Haematol 2005;128:413-31.
11. Hemsley KM, Beard H, King BM, Hopwood JJ. Effect of high dose, repeated intra-CSF 
injection of sulphamidase on neuropathology in MPS IIIA mice. Genes Brain Behav 2008.
12. Urayama A, Grubb JH, Sly WS, Banks WA. Mannose 6-phosphate receptor-mediated 
transport of sulfamidase across the blood-brain barrier in the newborn mouse. Mol Ther 
2008;16:1261-6.
13. Bielicki J, Hopwood JJ, Melville EL, Anson DS. Recombinant human sulphamidase: 
expression, amplification, purification and characterization. Biochem J 1998;329 ( Pt 
1):145-50.
14. Di Natale P, Vanacore B, Daniele A, Esposito S. Heparan N-sulfatase: in vitro mutagenesis 
of potential N-glycosylation sites. Biochem Biophys Res Commun 2001;280:1251-7.
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 73 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
74
15. Daniele A, Di Natale P. Heparan N-sulfatase: cysteine 70 plays a role in the enzyme catalysis 
and processing. FEBS Lett 2001;505:445-8.
16. Perkins KJ, Byers S, Yogalingam G, Weber B, Hopwood JJ. Expression and characterization 
of wild type and mutant recombinant human sulfamidase. Implications for Sanfilippo 
(Mucopolysaccharidosis IIIA) syndrome. J Biol Chem 1999;274:37193-9.
17. Munoz-Rojas MV, Vieira T, Costa R, et al. Intrathecal enzyme replacement therapy in a 
patient with mucopolysaccharidosis type I and symptomatic spinal cord compression. Am J 
Med Genet A 2008;146A:2538-44.
18. Muñoz-Rojas M, Dain D, Horovitz G, et al. Intrathecal administration of recombinant human 
N-acetylgalactosamine 4-sulfatase to a MPS VI patient with pachymeningitis cervicalis. 
Molecular Genetics and Metabolism 2010;99:346-50.
19. Chen A, Dickson P, Shapiro E, Lyons B, Kan S, Guillaume D. A study of intrathecal enzyme 
replacement for cognitivedecline in mucopolysaccharidosis. Mol Genet Metab 
2010;99:S13-S4.
20. Hemsley K, King B, Hopwood J. Injection of recombinant human sulfamidase into the CSF 
via the cerebellomedullary cistern in MPS IIIA mice. Mol Genet Metab 2007;90:313-28.
21. Hemsley KM, Luck AJ, Crawley AC, et al. Examination of intravenous and intra-CSF 
protein delivery for treatment of neurological disease. Eur J Neurosci 2009;29:1197-214.
22. Hemsley KM, Norman EJ, Crawley AC, et al. Effect of cisternal sulfamidase delivery in 
MPS IIIA Huntaway dogs-A proof of principle study. Mol Genet Metab 2009.
23. Bayley N. Bayley Scales of Infant and Toddler Development: Third Edition. San Antonio, 
TX The Psychological Corporation; 2005.
24. Kaufman S, Kaufman N. Kaufman Assessment Battery for Children (KABC-II). 2nd ed.
25. Henderson S, Sugden D, Barnett A. Movement Assessment Battery for Children (second 
ed.). London: Harcourt Assessment; 2007.
26. Sparrow S, Balla D, Cicchetti D. Vineland Adaptive Behavior Scales (Second Edition). 4201 
Woodland Road Circle Pines, MN 55014-1796: American Guidance Service, Inc; 2005.
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 74 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
Confidential
75
Appendix 1
Schedule of Events 
Table A1-1
HGT-SAN-067 Study Assessments for Patients Who Have Received 6 Months of HGT-1410 Treatment in Study 
HGT-SAN-055
Assessment
Month 7 through Month 104 (from the start of HGT-SAN-055)
Dosed every 28 (±7) days 
(ie, Q4W)
Screening/or 
HGT-SAN-
055 EOS 
Visitj
(Month 6 
from the 
start of 
HGT-SAN-
055)
Pre-Tx
Day 1a
IT dosing
Day 2 (±2)
Months 12, 
24, 36, 54, 
60, 72, 84, 96 
and 102 
(from the 
start of 
HGT-SAN-
055)
Additional 
Assessments 
at Months 
66, 78, and 
90 (from the 
start of 
HGT-SAN-
055)
Months 9, 
15, 18, 21, 
27, 30, 33, 
39, 42, 45, 
48, and 51 
(from the 
start of 
HGT-SAN-
055)
EOSe
Month 103 
(from the 
start of 
HGT-SAN-
055)
Month 104 
Safety 
Follow-upf
Main Site 
only
Main or 
Local Site
Main or 
Local Site
Main Site 
only
Main Site 
only
Main Site 
only
Main Site 
only
Informed Consent/Enrollment
●
Physical Examination 
●
●p
●p
●p
Symptom-Directed Physical Examination
●p
●p
●
Neurological Examinationh
●
●s
●s
●
Height and Weight
●
●
●
Head Circumference
●
●
●
Visual and Hearing Assessment
●
●
ECG
●
●b 
●
Vital Signs
●
●s
●s
●
Hematology
●
●
●
Serum Chemistry
●
●
●
anti-rhHNS antibody testing (serum)k
●
●t
●t
●
Plasma storage for biomarkers
●
●
●
●
Pregnancy Testingl
●
●
●
Urinalysis
●
●
●
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 75 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
Confidential
76
Table A1-1
HGT-SAN-067 Study Assessments for Patients Who Have Received 6 Months of HGT-1410 Treatment in Study 
HGT-SAN-055
Assessment
Month 7 through Month 104 (from the start of HGT-SAN-055)
Dosed every 28 (±7) days 
(ie, Q4W)
Screening/or 
HGT-SAN-
055 EOS 
Visitj
(Month 6 
from the 
start of 
HGT-SAN-
055)
Pre-Tx
Day 1a
IT dosing
Day 2 (±2)
Months 12, 
24, 36, 54, 
60, 72, 84, 96 
and 102 
(from the 
start of 
HGT-SAN-
055)
Additional 
Assessments 
at Months 
66, 78, and 
90 (from the 
start of 
HGT-SAN-
055)
Months 9, 
15, 18, 21, 
27, 30, 33, 
39, 42, 45, 
48, and 51 
(from the 
start of 
HGT-SAN-
055)
EOSe
Month 103 
(from the 
start of 
HGT-SAN-
055)
Month 104 
Safety 
Follow-upf
Main Site 
only
Main or 
Local Site
Main or 
Local Site
Main Site 
only
Main Site 
only
Main Site 
only
Main Site 
only
Urine GAGs
●
●t
●t
●
Leukocyte pellet preparationm
●
CSF chemistry and cell countsc
●
●
●
CSF sample storagec,o
●
●
●
CSF Heparan Sulfate and Heparan 
Sulfate Derivativesc
●
●t
●t
●
Anti-rhHNS antibody testing (CSF)c
●
●t
●t
●
Auditory Brainstem Response (ABR)q
●
●
MRI of the Head
●
●
●n
HGT-1410 dosing: every 28 (7) daysd,g
●
Full Neurodevelopmental Testingi
●
●
●
Children’s Sleep Habits Rating Scale
●
●
●
Child Health Questionnaire-50
●
●
●
Child Health Questionnaire-87
●
●
●
Infant Toddler QOL Questionnaire
●
●
●
Concomitant Medications, Therapies, 
and Procedures
●
●
●
●
●
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 76 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
Confidential
77
Table A1-1
HGT-SAN-067 Study Assessments for Patients Who Have Received 6 Months of HGT-1410 Treatment in Study 
HGT-SAN-055
Assessment
Month 7 through Month 104 (from the start of HGT-SAN-055)
Dosed every 28 (±7) days 
(ie, Q4W)
Screening/or 
HGT-SAN-
055 EOS 
Visitj
(Month 6 
from the 
start of 
HGT-SAN-
055)
Pre-Tx
Day 1a
IT dosing
Day 2 (±2)
Months 12, 
24, 36, 54, 
60, 72, 84, 96 
and 102 
(from the 
start of 
HGT-SAN-
055)
Additional 
Assessments 
at Months 
66, 78, and 
90 (from the 
start of 
HGT-SAN-
055)
Months 9, 
15, 18, 21, 
27, 30, 33, 
39, 42, 45, 
48, and 51 
(from the 
start of 
HGT-SAN-
055)
EOSe
Month 103 
(from the 
start of 
HGT-SAN-
055)
Month 104 
Safety 
Follow-upf
Main Site 
only
Main or 
Local Site
Main or 
Local Site
Main Site 
only
Main Site 
only
Main Site 
only
Main Site 
only
Adverse Event Monitoring
●
●
●
●
●
Abbreviations:ABR = Auditory brainstem response; CSF = cerebrospinal fluid; EOS  = end of study ; ECG = electrocardiogram; IT = intrathecal; 
MRI = Magnetic resonance imaging; TX = treatment
Note:
The timing of assessments is calculated from the start of HGT-SAN-055. Therefore, for example, the end-of-study visit, as presented here at Month 102, corresponds to 
Month 102 in HGT-SAN-067, but represents a total of 102 months of study treatment (102 months in HGT-SAN-067 + 6 months in HGT-SAN-055).
a
Week 1 only, and only performed if >7 days have elapsed since HGT-SAN-055 EOS visit assessments.
b
ECG to be performed following administration of study drug, after Month 54 it is to be performed every 3 months.
c
CSF samples will be obtained according to the process within the study laboratory manual. An attempt will be made to obtain a CSF sample via the IDDD prior to each 
administration of HGT-1410 and at the End of Study visit. If it is not possible to obtain a CSF using the IDDD, the IDDD may be replaced (up to twice in a 6 month period 
[including the time in the HGT-SAN-055 study]) or an LP may be performed.
d
Patients may be discharged as early as 4 hours post HGT-1410 infusion (ie, on Day 2) when deemed clinically stable by the investigator. 
e
All patients who complete the study will have end of study assessments performed 30 (±7 days) after their last dose of study drug.
f
A safety follow up telephone call will be made 30 (±7 days) after End of Study Procedures.
g
If a patient’s IDDD becomes nonfunctional or infected; it will be replaced (up to 2 times in a 6 month period; including the time in Study HGT-SAN-055).
h
The neurological exam should not occur sooner than 4 hours after administration of study drug or before the patient has fully recovered from any anesthesia administered for 
the dosing, whichever occurs later.  
i
Full neurodevelopmental testing includes an assessment with the Vineland Adaptive Behavior Scales, Second Edition (VABS-II).
j
Assessments will be required only if more than 60 days have elapsed following the HGT-SAN-055 procedures.  These assessments would be repeated within 30 days prior to 
the first scheduled HGT-1410 IT dose.
k
Blood sample drawn before IT injection of HGT-1410.
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 77 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
Confidential
78
Table A1-1
HGT-SAN-067 Study Assessments for Patients Who Have Received 6 Months of HGT-1410 Treatment in Study 
HGT-SAN-055
Assessment
Month 7 through Month 104 (from the start of HGT-SAN-055)
Dosed every 28 (±7) days 
(ie, Q4W)
Screening/or 
HGT-SAN-
055 EOS 
Visitj
(Month 6 
from the 
start of 
HGT-SAN-
055)
Pre-Tx
Day 1a
IT dosing
Day 2 (±2)
Months 12, 
24, 36, 54, 
60, 72, 84, 96 
and 102 
(from the 
start of 
HGT-SAN-
055)
Additional 
Assessments 
at Months 
66, 78, and 
90 (from the 
start of 
HGT-SAN-
055)
Months 9, 
15, 18, 21, 
27, 30, 33, 
39, 42, 45, 
48, and 51 
(from the 
start of 
HGT-SAN-
055)
EOSe
Month 103 
(from the 
start of 
HGT-SAN-
055)
Month 104 
Safety 
Follow-upf
Main Site 
only
Main or 
Local Site
Main or 
Local Site
Main Site 
only
Main Site 
only
Main Site 
only
Main Site 
only
l
A pregnancy test will be carried out on pre-treatment Day 1 in females who are postmenarche to premenopause (childbearing).  The results must be negative before study drug 
can be administered.
m
A blood sample for leukocyte pellet preparation is to be taken at baseline, before dosing.  This pellet should be stored frozen, and will be used for additional disease-related 
laboratory studies, including possible assessment of cross-reactive immunologic material.  If this is not drawn at baseline, it can be drawn at any subsequent visit, but it must 
be taken before dosing.  This only needs to be taken once during the study.
n
These assessments are not to be performed at an EOS visit conducted at Month 103 if they were performed at the Month 102 visit.
o
CSF samples will be tested for MPS exploratory biomarkers, and possibly extractables and leachables.
p
After Month 54 the Symptom-Directed PE is to be done monthly. Full PE is done monthly to Month 54 and then at least yearly (ie, Months 66, 78, 90, and 102), or more 
frequently at the investigator’s discretion.  Genitourinary AEs may be evaluated by the patient's primary care physician and a follow-up report will be sent to the study site.
q
ABR will not be performed after Month 54.
r
Informed consent will be obtained at Screening and Month 54.
s
These Day 1 assessments may be performed on the same day as the administration of study drug (Day 2).  This can occur if it is feasible for the patient to arrive at the study 
site early in the day, and if it is deemed clinically appropriate by the investigator.  If the procedures on Day 1 and Day 2 are combined in this way, the assessments will be 
recorded as occurring on Day 2.
t
Urine GAG, including heparan sulfate and heparan sulfate derivatives, and anti-rhHNS antibody testing will be performed at Months 60, 66, 72, 78, 84, 90, and 96, ie, Q6 
Months following Month 54); these assessments must be performed at the main site.
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 78 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
79
Appendix 2
Neurodevelopmental and Behavioural Assessments 
Tables A2-1 and A2-2 detail the specific psychometric instruments that will be used to provide 
measures of each of relevant neurobehavioral or developmental domain assessed.  The tables 
also summarize the rules used to select a test for a patient, the subtests included in each test, and 
the subscales generated by the test battery.
Table A2-1
Summary of Neurodevelopmental Outcome Measures
Domain
Age
Test
Summary score and 
subdomains:
- Cognitive
- Motor
- Social/Emotional
0 to 42 months
Bayley Scales of Infant Development, Third Edition (BSID-
III)23
- Cognitive 
- Processing skills
3 to 18 years
Kaufman Assessment Battery for Children, Second Edition 
(KABC-II)24  
Motor
3.0 to 16:11 years
Movement Assessment Battery for Children, Second Edition 
(MABC-2)25  
Communication
Daily Living
Socialization
Motor Skills
0 to 90 years
Vineland Adaptive Behavior Scales, Second Edition 
(VABS-II)26
Table A2-2
Summary of Sanfilippo-specific Assessments
Domain
Assessment
Parent-scored behavioral inventory
- communication:  understanding
- communication:  expression
- tantrums
- specific behaviors inventory
- mood & emotions inventory
Sanfilippo Behavior Rating Scale
MPS-specific four-point scoring system/total 
disability score
- cognition
- expressive language
- motor score
Four-Point Scoring System/Total Disability Score 
(FPSS/TDS)5
The term “neurodevelopmental” refers to the process by which the neurological system matures 
and changes over time.  Assessing these changes in a population of children whose neurological 
system is progressively more affected can be very challenging.  
Typically, neurodevelopmental progress is reflected by the child’s abilities to perform certain 
skills (sitting, walking, and talking).  
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 79 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
80
However, a child with a neurological disorder may be able to perform age appropriate skills, but 
with atypical patterns.  For example, the child may be able to walk, but his gait is not normal.  
Most assessments will therefore measure the skills, but are not designed to capture the 
abnormalities in pattern or quality of the skill.  
These qualitative differences will be evident to the skilled test administrator/clinician who is 
familiar with the disorder.  However, only longitudinal tracking and repeated measures will 
reveal the significance of these abnormalities in overall function to the less experienced clinician.   
The rate at which different skills develop or regress over time will give insight into the disease 
process.  The next step is to determine how the learned skills are used for daily functional 
activities so that as the children grow up they become independent from caregivers.  These 
functional skills can be tracked to reflect quality of life issues for both parents and children. 
Neurodevelopmental assessments described below will be scheduled for administration in the 
morning and estimated to last between 2 and 4 hours.
The list of assessments and algorithm is discussed in detail in the Study Operations Manual and 
includes:
Bayley Scales of Infant Development, Third Edition (BSID-III)23
The Bayley Scales of Infant Development is a standard series of measurements used primarily to 
assess the motor (fine and gross), language (receptive and expressive), and cognitive 
development of infants and toddlers, ages 0 to 42 months.  This measure consists of a series of 
developmental play tasks and takes between 45 and 60 minutes to administer.  Raw scores of 
successfully completed items are converted to scale scores and to composite scores.  These 
scores are used to determine the child's performance compared with norms taken from typically 
developing children of their age (in months).  The assessment is often used in conjunction with 
the Social-Emotional Adaptive Behavior Questionnaire. Completed by the parent or caregiver, 
this questionnaire establishes the range of adaptive behaviors that the child can currently achieve 
and enables comparison with age norms.
Kaufman Assessment Battery for Children, Second Edition (KABC-II)24
Purpose:
The KABC-II measures a child’s cognitive ability and processing skills and was designed to 
minimize verbal instructions and responses.  In addition, the assessment contains little cultural 
content to provide a more accurate assessment of children from diverse backgrounds.  Thus 
language difficulties or cultural differences are minimized in the test battery’s results.
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 80 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
81
Description:
Investigators may choose either the Cattell-Horn-Carroll or the Luria model for a patient’s 
assessment.  
The Cattell-Horn-Carroll model is used with children from a mainstream cultural and language 
background and the Luria model is used for children with significantly limited verbal ability.  
Subtests are administered on four or five ability scales and interpreted using the chosen model. 
Movement Assessment Battery for Children, Second Edition (MABC-2)25
Purpose:
The Movement Assessment Battery for Children, Second Edition identifies, describes and guides 
treatment of motor impairment in children from 3.0 to 16:11 years of age.
Description:
The MABC-2 checklist is administered individually over approximately 30 minutes.  It yields 
both normative and qualitative measures of movement competence, manual dexterity, ball skills, 
static and dynamic balance.
Vineland Adaptive Behavior Scales, Second Edition (VABS-II)26
Purpose:
The test measures adaptive behaviors, including the ability to cope with environmental changes, 
to learn new everyday skills and to demonstrate independence.  It is an instrument that supports 
the diagnosis of intellectual and developmental disabilities.  It encompasses ages from birth to 
90 years. 
Description:
Adaptive behavior is a composite of various dimensions.  This test measures 5 domains:  
communication, daily living skills, socialization, motor skills, and maladaptive behavior 
(optional) and is administered in a semi-structured interview in through a questionnaire.  The
scales of the VABS-II were organized within a 3-domain structure:  Communication, Daily 
Living, and Socialization.  This structure corresponds to the 3 broad domains of adaptive 
functioning by the American Association of Intellectual and Developmental Disabilities:  
Conceptual, Practical, and Social.  In addition, VABS-II offers a Motor Skills Domain and an 
optional Maladaptive Behavior Index.  The scores are interpreted by means of score equivalents 
for the raw scores in each domain, percentile ranks, age equivalents, adaptive levels, and 
maladaptive levels.
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 81 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
82
Sanfilippo Behavior Rating Scale (SBRS)
The Sanfilippo Behavior Rating Scale (SBRS) is a newly-developed scale designed by Drs. Elsa 
Shapiro and Michael Potegal to measure a cluster of behaviors known to occur in Sanfilippo 
syndrome.  The SBRS is a parent-scored behavioral inventory measuring (1) comprehensive 
language skills, (2) expressive language skills, (3) tantrums, (4) mood and emotions, and 
(5) other behaviors not otherwise classified.
Four-Point Scoring System/Total Disability Score (FPSS/TDS)5
The FPSS assesses motor function, expressive language, and cognitive function on a 0 to 3 point 
scale and can be used for individuals of all ages.  The total disability score is the average of the 
motor function, speech, and cognitive function scores.
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 82 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
83
Appendix 3
Expected Adverse Device Effects
Procedure-Related Complications

Components handled improperly before, during, or after implantation 

Access port implanted incorrectly

Catheter positioned improperly

Injection through septum performed incorrectly

Injection of incorrect medication through access port

Injection outside the access port into pocket or subcutaneous tissue or extravasation

Pocket seroma, hematoma, erosion, or infection
Intrathecal Access Complications

Surgical complications such as hemorrhage or hematoma

Infection of the implant site or catheter track

Radiculitis or arachnoiditis

Intrathecal space infection resulting in meningitis or encephalitis

Bleeding 

Spinal cord damage or trauma to the spinal cord or nerve roots

Post-lumbar puncture, cerebrospinal fluid (CSF) leak, leading to headache, or  subcutaneous 
CSF collection

Epidural instead of intrathecal placement of catheter

Inflammatory mass resulting in neurological impairment, including paralysis

Pain on injection

Complications of anesthesia

Pseudomeningocele
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 83 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
84
System-Related Complications

Improperly positioned access port

Erosion of the skin because of the underlying access port or the catheter

Wound dehiscence

Access port migration, fracture, breakage or occlusion

Catheter damage, dislodgement, migration, disconnection, kinking or occlusion, fibrosis, or 
hygroma, resulting in tissue damage or a loss of or change in therapy, or other potentially 
serious adverse health consequences

Catheter breakage and migration of residual catheter fragments, potentially resulting in 
serious adverse health consequences and the need for surgical removal 

Local immunological or fibrous reaction to the presence of a foreign body (the device)

End of device service life or component failure, requiring surgical replacement

Component failure, resulting in loss of therapy

Access port inversion (“flipping”), rotation, or extrusion

Access port or catheter rejection 

Fibrin sheath formation around catheter tip
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 84 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
85
Appendix 4
Protocol Amendment 7 Summary of Changes 
AMENDMENT SUMMARY AND RATIONALE
Clinical protocol HGT-SAN-067 has been amended to extend the study and provide treatment 
with HGT-1410 for an additional 24 months (to Month 103 from start of study HGT-SAN-055),
and to include the addition of local (satellite) sites to reduce the burden imposed by monthly 
travel.
replaced 
in the role of Medical Monitor. Language 
regarding infusion related reactions and risk language for anesthesia and lumbar puncture was 
added. Other clarifications related to the IDDD use were added, including the allowance of 
device explanation at local sites. Language clarifying some of the assessment language, 
including neurocognitive and vital sign assessment performance on the same day as drug 
administration, and genitourinary assessment may be performed by primary care provider (with 
follow-up report to investigator) if an AE associated with genitourinary evaluation occurs.  
Language was also added to allow for interim and final locked study data publications.  
Previous Amendment:  Amendment 6; 10 July 2014
DETAILED SUMMARY OF CHANGES FOR THE AMENDMENT 
This is a section that has been updated to describe the changes from the previous protocol 
version.  Significant changes and additions to the protocol text are captured below.  Bold text 
indicates new text.  Strikethrough text indicates deleted text.
Change:  Replacement of
by
as Medical Monitor
Section impacted by this change: Title page
Other sections impacted by this change: Section 7.22.5.1, Appendix 5 Signature Page
Change:  Removal of informed consent at Month 54
Section impacted by this change: Synopsis
Informed consent will be provided by the patient’s parent(s)/legally authorized 
representative(s) prior to the start of the extension study procedures and again at Month 
54.  
Other sections impacted by this change: None
Change:  Addition of language to allow for local (satellite) sites
Section impacted by this change: Section 4.1
Primarily main sites will be utilized; however, the sponsor and investigator will 
consider the feasibility of transitioning the patient’s IT dosing to local sites to reduce 
the burden imposed by travel. At Month 18 (12 months after study start), patients 
that already received IT dosing at the main site may be eligible to transfer to a local 
site if in the opinion of the investigator there are no safety or medical concerns 
precluding this transition. Subsequent IT injections of HGT-4110 may be performed 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 85 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
86
at either the main site or the local site. The local sites will be selected and approved 
by the sponsor, and the patient must have no safety or medical issues that would 
preclude transitioning to a local site (Note: the main site may serve as a local site as 
needed; and in this case, the main site will follow the assessments scheduled for a 
local site). The qualification requirements for physicians at local sites will be 
identical to those for the main sites.  Local sites will be trained if inexperienced with 
IT administration via an IDDD.  Patients will be discharged a minimum of 4 hours 
after dosing and when deemed clinically stable by the investigator. Dosing by IT 
injection may take place at the main site, rather than local site, if scheduled study 
assessments include MRI and cognitive assessments.  Patients must review and agree 
to written informed consent/assent from the local site to participate in study 
procedures to be conducted at the local site prior to the conduct of these procedures.
Other sections impacted by this change: Section 6.2, Section 8.1, Section 8.2, Appendix 1 
Table A1-1  Schedule of Events
Change:  Last planned administration of HGT-1410 designated as Month 102, EOS study 
procedures designated as Month 103, Safety Follow-up designated as Month 104
Section impacted by this change: Section 4.1
All patients will have an EOS visit 30 (±7) days following their last administration of 
HGT-1410 (ie, Month 78102).
All patients will be contacted by telephone or will have a visit for a Final Safety 
Follow-up, to be conducted at 30 (±7) days after the EOS visit (ie, Month 79103) to 
collect updated information on AEs and concomitant medications, therapies, and 
procedures. 
Other sections impacted by this change: Synopsis; Section 8.2, Section 8.3, Section 8.4, 
Appendix 1 Table A1-1 Schedule of Events
Change:  Study duration changed from 6 years to 8 years
Section impacted by this change: Section 4.3
The study duration will be 6 allows patients who completed Study HGT-SAN-055 and 
elected to continue treatment with HGT-1410 in Study HGT-SAN-067 to receive 
treatment with HGT-1410 up to 8 years.
Other sections impacted by this change: Synopsis; Appendix 1 Table A1-1 Schedule of 
Events
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 86 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
87
Change:  Allowance of genitourinary evaluation by primary care physician if AE 
associated with genitourinary evaluation 
Section impacted by this change: Section 7.2
Any changes from the screening physical examination will be captured as AEs in the 
eCRF. If the patient experiences an AE associated with genitourinary evaluation, the 
patient may have the genitourinary evaluation performed by their primary care 
provider and a follow-up report will be sent to the investigator.  Therefore, the 
genitourinary evaluation may not need to be performed again if the examination 
occurred within the visit window for that time point.
Other sections impacted by this change: Appendix 1 Table A1-1  Schedule of Events
Change:  Additional of language to allow device explanation to be performed at local 
sites
Section impacted by this change: Section 7.13.1
The IDDD will be surgically implanted or revised at the clinical site. Procedures for 
implantation and revision are detailed in the device’s IFU. Standard hospital procedures 
for surgery will be followed; the patient will be under general anesthesia for this 
procedure.  It is planned that device explantation will occur at the main site unless 
urgent device removal is medically indicated requiring the procedure to be 
performed locally or patient travel to the main site is medically inadvisable.
Other sections impacted by this change: Section 4.2
Change:  Addition of language regarding infusion/hypersensitivity reactions and 
management
Section impacted by this change: Section 7.22.1.3
7.22.1.3
Infusion/Hypersensitivity Reactions and Management
Infusions of proteins can be associated with reactions to the infusion that may or 
may not be immune-mediated (hypersensitivity reactions).  Thus, potential reactions 
to the infusion of investigational drug are unpredictable.  It is often difficult to 
clinically distinguish infusion reactions from hypersensitivity reactions.  Symptoms 
may include headache, fever, sensory paresthesias (including feeling of warmth, 
tingling, or pain), rash, pruritus, or autonomic symptoms, such as dry mouth or 
gustatory abnormalities (including loss of smell and metallic taste).  Changes in 
mental status or level of consciousness that are not caused by pre-medication may 
either occur acutely or develop post-injection over time.
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 87 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
88
The management of infusion reactions and hypersensitivity reactions is similar.  
The following steps may be taken, at the discretion of the investigator, in the event 
of a suspected infusion related/hypersensitivity reaction and the management of 
such reactions should be based on the severity of the reaction:

Treatment with medications such as antihistamines, antipyretics, and/or 
corticosteroids

Stopping and resuming treatment

Pretreatment with antihistamines and/or corticosteroids may prevent 
subsequent reactions in those cases where symptomatic treatment was required
Other sections impacted by this change: None
Change:  Addition of risk language for anesthesia and lumbar puncture
Section impacted by this change: Section 7.22.1.4
RISKS ASSOCIATED WITH ANESTHESIA REQUIRED FOR STUDY
ASSESSMENTS
The use of an IDDD has been chosen to minimize the risks inherent in utilizing 
novel delivery systems and to alleviate the need for multiple administrations of 
anesthesia required for drug injection via repeated LP. The risks from anesthesia 
include respiratory depression, aspiration, cardiac events, hypoxia, hypotension and 
hypertension, difficult intubations and extubations, stroke, rapid changes in body 
temperature, laryngospasm or laryngeal edema, allergic reaction, and death.
Patients will be closely monitored for changes in vital signs and related events.
RISKS ASSOCIATED WITH LUMBAR PUNCTURE
Risks associated with LP include pain at the injection site, infection, meningitis, 
encephalitis, cerebritis, failed procedure, bleeding, dural tears, spinal headache, 
spinal fluid leakage, nerve damage, and focal and non-focal neurological injury 
(including paralysis). Patients may require anesthesia prior to an LP. Risks from 
anesthesia are discussed separately in this section (Section 7.22.1.4).  
Other sections impacted by this change: None
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 88 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
89
Change:  Addition of definition for device adjustment
Section impacted by this change: Section 7.22.2.4
7.22.2.4      Device Adjustment
Surgery of the device which does not result in partial or complete device revision or 
removal (eg, surgical exploration only or placement of additional sutures, tissue 
glue, and/or fascial repair).  
Other sections impacted by this change: None
Change:  Clarification regarding study assessments, including vital signs, neurological 
examination, MRI of the head, and physical examination; and a change in timing to the 
ECG (to Q12)
Section impacted by this change: Section 8.2.1
8.2.1.1   Day 1 (Pre-treatment) Assessments Performed Prior to Each Dose

Physical examination

Height and weight

Vital signs (may be performed on Day 2 if feasible for the patient to arrive at the 
study site early in the day and if deemed clinically appropriate by the 
investigator)

Hematology (after Month 54 frequency reduced to Q3 Months)

Serum chemistry (after Month 54 frequency reduced to Q3 Months)

Urinalysis (after Month 54 frequency reduced to Q3 Months)

Pregnancy testing (applicable females only)

Neurological examination (to be performed if symptom directed prior to the 
administration of anesthesia and the HGT-1410 IT injection and at a minimum of 
every 12 months)
…
DAY 1 (PRE-TREATMENT) ADDITIONAL ASSESSMENTS PERFORMED AT MONTHS 12, 24,
36, 54, 66, 60, 72, 84, 96, AND 78102

Head circumference

Visual and hearing assessments 

Urine GAG, including heparan sulfate and heparan sulfate derivatives (alsoperformed 
at Months 60, 66 and ,Month 72, 78, 84, 90, Month and 96, ie, Q6 Months following 
Month 54)

Plasma collection for biomarkers

Anti-rhHNS antibody testing (alsoperformed at Months 60, 66,78 and Month 72, 78, 
84, 90, and 96, ie, Q6 Months following Month 54)

ABR (not performed after Month 54, ie not on Months 60, 66, 72, 84, 96, or 78102)

MRI of the head
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 89 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
90
…
8.2.1.2   Day 2 (±2 days) Assessments and Administration of HGT-1410
Patients may be discharged from the clinical site 4 hours after dosing, if deemed stable 
by the investigator.

Physical examination (after Month 54 the full physical examination will be 
performed on an annual basis at Months 54, 66, and 78, 90, and 102. The remainder 
of the physical examinations will be symptom-directed.)

ECG (performed following IT study drug injection)(after Month 54 performed Q3
months)

Vital signs (to be performed at the discretion of the investigator)

CSF sample collection (obtained prior to IT study drug injection)

HGT-1410 IT injection (Day 2 ±2 days)

Neurological examination (to be performed if symptom directed and at a 
minimum of every 12 months)
…
Other sections impacted by this change: Synopsis; Section 4.1; Appendix 1 Table A1-1  
Schedule of Events
Change:  Clarification regarding the inclusion of ECG, plasma storage for biomarkers, 
and pregnancy testing as EOS assessments
Section impacted by this change: Section 8.3
Other sections impacted by this change: Appendix 1 Table A1-1  Schedule of Events
Change:  Addition of language to allow for analyses of interim/final data for purpose of 
publication
Section impacted by this change: Section 11.15
Shire may perform analyses of interim and/or final locked study data for the 
purpose of publication.
Other sections impacted by this change: Section 10.6.4
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 90 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
91
Change:  Clarification in schedule regarding Day 1/Day 2 neurocognitive and vital sign 
assessments, and additional assessments at Months 66, 78, and 90 for urine GAG, 
including heparin sulfate and heparin sulfate derivatives, and anti-rhHNS antibody 
testing
Section impacted by this change: Appendix 1 Table A1-1  Schedule of Events
Addition of footnotes:
s   These Day 1 assessments may be performed on the same day as the administration of study drug 
(Day 2).  This can occur if it is feasible for the patient to arrive at the study site early in the day, and 
if it is deemed clinically appropriate by the investigator.  If the procedures on Day 1 and Day 2 are 
combined in this way, the assessments will be recorded as occurring on Day 2. 
t   Urine GAG, including heparan sulfate and heparan sulfate derivatives, and anti-rhHNS antibody 
testing will be performed at Months 60, 66, 72, 78, 84, 90, and 96, ie, Q6 Months following 
Month 54); these assessments must be performed at the main site.
Other sections impacted by this change: None
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 91 of 165

Recombinant human hepnran N-sull'atase (rhHNS, HGT-1410) 
Clinical Trial Protocol: IIGT-SAN-067 Amendment 7 
08 February 2016 
Appendix 5 
Protocol Signature Page 
Study Title: 
An Open-Label Extension of Study HGT-SAN-055 Evaluating 
Long-Term Safety and Clinical Outcomes ofintratheco.l 
Administration of rhl-INS in Patients with Sanfilippo Syndrome 
Type A (MPS IliA) 
Study Number: 
HGT-SAN-067 Amendment 7 
Final Date: 
Amendment 1 Date: 
Amendment 2 Date: 
Amendment 3 Date: 
Amendment 4 Date: 
Amendment 5 Date: 
Amendment 6 Date: 
Amendment 7 Date: 
21 J1me 2010 
22 January 2011 
13 January 2012 
28 Augnst 2012 
3 May2013 
17 January 2014 
10 July 2014 
08 February 2016 
I have read the protocol described above. I agree to comply witl1 all applicable regulations and 
to conduct tl1e study as described in the protocol. 
Signatory: 
Investigator 
Signature 
Printed Name 
I have read and approve the protocol described above. 
Signatory: 
Shire Medical 
Monitor 
Shire 
 DO 
Printed Name 
Confidential 
Date 
Date 
94 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 92 of 165

Recombinant human heparan N-
Clinical Trial Protocol: HGT-SAN-067 Amendment 7
08 February 2016
Shire
93
Appendix 6
The National Cancer Institute Common Terminology Criteria version 3.0
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 93 of 165

Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, Version 3.0, DCTD, NCI, NIH, DHHS 
 
March 31, 2003 (http://ctep.cancer.gov), Publish Date: August 9, 2006 
Common Terminology Criteria for Adverse Events v3.0 (CTCAE) 
Publish Date: August 9, 2006 
Quick Reference 
The NCI Common Terminology Criteria for Adverse Events 
v3.0 is a descriptive terminology which can be utilized for 
Adverse Event (AE) reporting. A grading (severity) scale is 
provided for each AE term. 
Components and Organization  
CATEGORY 
A CATEGORY is a broad classification of AEs based on 
anatomy and/or pathophysiology. Within each CATEGORY, 
AEs are listed accompanied by their descriptions of severity 
(Grade). 
Adverse Event Terms 
An AE is any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medical treatment or procedure 
that may or may not be considered related to the medical 
treatment or procedure. An AE is a term that is a unique 
representation of a specific event used for medical 
documentation and scientific analyses. Each AE term is 
mapped to a MedDRA term and code. AEs are listed 
alphabetically within CATEGORIES. 
Short AE Name 
The ‘SHORT NAME’ column is new and it is used to simplify 
documentation of AE names on Case Report Forms.   
Supra-ordinate Terms  
A supra-ordinate term is located within a CATEGORY and is a 
grouping term based on disease process, signs, symptoms, 
or diagnosis. A supra-ordinate term is followed by the word 
‘Select’ and is accompanied by specific AEs that are all 
related to the supra-ordinate term. Supra-ordinate terms 
provide clustering and consistent representation of Grade for 
related AEs. Supra-ordinate terms are not AEs, are not 
mapped to a MedDRA term and code, cannot be graded and 
cannot be used for reporting. 
REMARK 
A ‘REMARK’ is a clarification of an AE. 
ALSO CONSIDER 
An ‘ALSO CONSIDER’ indicates additional AEs that are to be 
graded if they are clinically significant. 
NAVIGATION NOTE 
A ‘NAVIGATION NOTE’ indicates the location of an AE term 
within the CTCAE document. It lists signs/symptoms 
alphabetically and the CTCAE term will appear in the same 
CATEGORY unless the ‘NAVIGATION NOTE’ states differently. 
Grades 
Grade refers to the severity of the AE. The CTCAE v3.0 
displays Grades 1 through 5 with unique clinical descriptions 
of severity for each AE based on this general guideline: 
Grade 1 
Mild AE  
Grade 2 
Moderate AE 
Grade 3 
Severe AE 
Grade 4 
Life-threatening or disabling AE 
Grade 5 
Death related to AE 
A Semi-colon indicates ‘or’ within the description of the grade. 
An ‘Em dash’ (—) indicates a grade not available. 
Not all Grades are appropriate for all AEs. Therefore, some 
AEs are listed with fewer than five options for Grade 
selection. 
Grade 5 
Grade 5 (Death) is not appropriate for some AEs and 
therefore is not an option. 
The DEATH CATEGORY is new. Only one Supra-ordinate 
term is listed in this CATEGORY: ‘Death not associated with 
CTCAE term – Select’ with 4 AE options: Death NOS; 
Disease progression NOS; Multi-organ failure; Sudden death. 
Important: 
• 
Grade 5 is the only appropriate Grade 
• 
This AE is to be used in the situation where 
a death  
1. cannot be reported using a CTCAE v3.0 
term associated with Grade 5, or 
2. cannot be reported within a CTCAE 
CATEGORY as ‘Other (Specify)’ 
 
 
 
 
 
Contents 
ALLERGY/IMMUNOLOGY ............................................1 
AUDITORY/EAR............................................................2 
BLOOD/BONE MARROW .............................................4 
CARDIAC ARRHYTHMIA..............................................5 
CARDIAC GENERAL ....................................................7 
COAGULATION ..........................................................10 
CONSTITUTIONAL SYMPTOMS................................11 
DEATH ........................................................................13 
DERMATOLOGY/SKIN ...............................................14 
ENDOCRINE...............................................................17 
GASTROINTESTINAL.................................................19 
GROWTH AND DEVELOPMENT................................29 
HEMORRHAGE/BLEEDING ....................................... 30 
HEPATOBILIARY/PANCREAS ................................... 34 
INFECTION................................................................. 35 
LYMPHATICS ............................................................. 38 
METABOLIC/LABORATORY ...................................... 40 
MUSCULOSKELETAL/SOFT TISSUE........................ 43 
NEUROLOGY ............................................................. 47 
OCULAR/VISUAL........................................................ 52 
PAIN............................................................................ 55 
PULMONARY/UPPER RESPIRATORY...................... 56 
RENAL/GENITOURINARY.......................................... 60 
SECONDARY MALIGNANCY..................................... 63 
SEXUAL/REPRODUCTIVE FUNCTION ..................... 64 
SURGERY/INTRA-OPERATIVE INJURY ................... 66 
SYNDROMES............................................................. 68 
VASCULAR................................................................. 70 
 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 94 of 165

 
ALLERGY/IMMUNOLOGY 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 1 - 
March 31, 2003, Publish Date: August 9, 2006 
Allergic reaction/ 
hypersensitivity  
(including drug fever) 
Allergic reaction 
Transient flushing or 
rash; drug fever <38°C 
(<100.4°F) 
Rash; flushing; urticaria; 
dyspnea; drug fever 
≥38°C (≥100.4°F) 
Symptomatic 
bronchospasm, with or 
without urticaria; 
parenteral medication(s) 
indicated; allergy-related 
edema/angioedema; 
hypotension 
Anaphylaxis 
Death 
REMARK: Urticaria with manifestations of allergic or hypersensitivity reaction is graded as Allergic reaction/hypersensitivity (including drug fever). 
ALSO CONSIDER: Cytokine release syndrome/acute infusion reaction. 
Allergic rhinitis  
(including sneezing, 
nasal stuffiness, 
postnasal drip) 
Rhinitis 
Mild, intervention not 
indicated  
Moderate, intervention 
indicated 
— 
— 
— 
REMARK: Rhinitis associated with obstruction or stenosis is graded as Obstruction/stenosis of airway – Select in the PULMONARY/UPPER RESPIRATORY CATEGORY. 
Autoimmune reaction 
Autoimmune reaction 
Asymptomatic and 
serologic or other 
evidence of autoimmune 
reaction, with normal 
organ function and 
intervention not indicated 
Evidence of autoimmune 
reaction involving a non-
essential organ or 
function (e.g., 
hypothyroidism) 
Reversible autoimmune 
reaction involving function 
of a major organ or other 
adverse event (e.g., 
transient colitis or 
anemia)  
Autoimmune reaction with 
life-threatening 
consequences 
Death 
ALSO CONSIDER: Colitis; Hemoglobin; Hemolysis (e.g., immune hemolytic anemia, drug-related hemolysis); Thyroid function, low (hypothyroidism). 
Serum sickness 
Serum sickness 
— 
— 
Present 
— 
Death 
NAVIGATION NOTE: Splenic function is graded in the BLOOD/BONE MARROW CATEGORY. 
NAVIGATION NOTE: Urticaria as an isolated symptom is graded as Urticaria (hives, welts, wheals) in the DERMATOLOGY/SKIN CATEGORY. 
Vasculitis 
Vasculitis 
Mild, intervention not 
indicated 
Symptomatic, non-
steroidal medical 
intervention indicated 
Steroids indicated 
Ischemic changes; 
amputation indicated 
Death 
Allergy/Immunology – 
Other (Specify, __) 
Allergy – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 95 of 165

 
AUDITORY/EAR 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 2 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Earache (otalgia) is graded as Pain – Select in the PAIN CATEGORY. 
Hearing:  
patients with/without 
baseline audiogram and 
enrolled in a monitoring 
program1 
Hearing (monitoring 
program) 
Threshold shift or loss of 
15 – 25 dB relative to 
baseline, averaged at 2 
or more contiguous test 
frequencies in at least 
one ear; or subjective 
change in the absence of 
a Grade 1 threshold shift 
Threshold shift or loss of 
>25 – 90 dB, averaged at 
2 contiguous test 
frequencies in at least 
one ear 
Adult only: Threshold shift 
of >25 – 90 dB, averaged 
at 3 contiguous test 
frequencies in at least 
one ear  
Pediatric:  
Hearing loss sufficient to 
indicate therapeutic 
intervention, including 
hearing aids (e.g., ≥20 dB 
bilateral HL in the speech 
frequencies; ≥30 dB 
unilateral HL; and 
requiring additional 
speech-language related 
services) 
Adult only: Profound 
bilateral hearing loss 
(>90 dB) 
Pediatric:  
Audiologic indication for 
cochlear implant and 
requiring additional 
speech-language related 
services  
— 
REMARK: Pediatric recommendations are identical to those for adults, unless specified. For children and adolescents (≤18 years of age) without a baseline test, pre-exposure/pre-
treatment hearing should be considered to be <5 dB loss. 
Hearing: 
patients without baseline 
audiogram and not 
enrolled in a monitoring 
program1  
Hearing (without 
monitoring program) 
— 
Hearing loss not requiring 
hearing aid or 
intervention (i.e., not 
interfering with ADL) 
Hearing loss requiring 
hearing aid or 
intervention (i.e., 
interfering with ADL) 
Profound bilateral hearing 
loss (>90 dB) 
— 
REMARK: Pediatric recommendations are identical to those for adults, unless specified. For children and adolescents (≤18 years of age) without a baseline test, pre-exposure/pre-
treatment hearing should be considered to be <5 dB loss. 
Otitis, external ear 
(non-infectious) 
Otitis, external  
External otitis with 
erythema or dry 
desquamation  
External otitis with moist 
desquamation, edema, 
enhanced cerumen or 
discharge; tympanic 
membrane perforation; 
tympanostomy 
External otitis with 
mastoiditis; stenosis or 
osteomyelitis 
Necrosis of soft tissue or 
bone 
Death 
ALSO CONSIDER: Hearing: patients with/without baseline audiogram and enrolled in a monitoring program1; Hearing: patients without baseline audiogram and not enrolled in a 
monitoring program1.  
Otitis, middle ear  
(non-infectious) 
Otitis, middle 
Serous otitis  
Serous otitis, medical 
intervention indicated 
Otitis with discharge; 
mastoiditis  
Necrosis of the canal soft 
tissue or bone 
Death 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 96 of 165

 
AUDITORY/EAR 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 3 - 
March 31, 2003, Publish Date: August 9, 2006 
Tinnitus 
Tinnitus 
— 
Tinnitus not interfering 
with ADL 
Tinnitus interfering with 
ADL 
Disabling 
— 
ALSO CONSIDER: Hearing: patients with/without baseline audiogram and enrolled in a monitoring program1; Hearing: patients without baseline audiogram and not enrolled in a 
monitoring program1. 
Auditory/Ear – Other 
(Specify, __) 
Auditory/Ear – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
 
 
 
 
 
 
                                            
1 Drug-induced ototoxicity should be distinguished from age-related threshold decrements or unrelated cochlear insult. When considering whether an adverse event has occurred, it is 
first necessary to classify the patient into one of two groups. (1) The patient is under standard treatment/enrolled in a clinical trial <2.5 years, and has a 15 dB or greater threshold 
shift averaged across two contiguous frequencies; or (2) The patient is under standard treatment/enrolled in a clinical trial >2.5 years, and the difference between the expected age-
related and the observed threshold shifts is 15 dB or greater averaged across two contiguous frequencies. Consult standard references for appropriate age- and gender-specific 
hearing norms, e.g., Morrell, et al. Age- and gender-specific reference ranges for hearing level and longitudinal changes in hearing level. Journal of the Acoustical Society of America 
100:1949-1967, 1996; or Shotland, et al. Recommendations for cancer prevention trials using potentially ototoxic test agents. Journal of Clinical Oncology 19:1658-1663, 2001.  
In the absence of a baseline prior to initial treatment, subsequent audiograms should be referenced to an appropriate database of normals. ANSI. (1996) 
American National Standard: Determination of occupational noise exposure and estimation of noise-induced hearing impairment, ANSI S 3.44-1996. (Standard S 3.44). New York: 
American National Standards Institute. The recommended ANSI S3.44 database is Annex B. 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 97 of 165

 
BLOOD/BONE MARROW 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 4 - 
March 31, 2003, Publish Date: August 9, 2006 
Bone marrow cellularity 
Bone marrow cellularity 
Mildly hypocellular or  
≤25% reduction from 
normal cellularity for age 
Moderately hypocellular 
or >25 – ≤50% reduction 
from normal cellularity for 
age  
Severely hypocellular or 
>50 – ≤75% reduction 
cellularity from normal for 
age  
— 
Death 
CD4 count  
CD4 count 
<LLN – 500/mm3 
<LLN – 0.5 x 109 /L 
<500 – 200/mm3  
<0.5 – 0.2 x 109 /L 
<200 – 50/mm3  
<0.2 x 0.05 – 109 /L 
<50/mm3  
<0.05 x 109 /L 
Death 
Haptoglobin  
Haptoglobin 
<LLN  
— 
Absent 
— 
Death 
Hemoglobin  
Hemoglobin 
<LLN – 10.0 g/dL  
<LLN – 6.2 mmol/L  
<LLN – 100 g/L 
<10.0 – 8.0 g/dL 
<6.2 – 4.9 mmol/L  
<100 – 80g/L 
<8.0 – 6.5 g/dL 
<4.9 – 4.0 mmol/L 
<80 – 65 g/L 
<6.5 g/dL 
<4.0 mmol/L  
<65 g/L 
Death 
Hemolysis (e.g., immune 
hemolytic anemia, drug-
related hemolysis) 
Hemolysis 
Laboratory evidence of 
hemolysis only (e.g., 
direct antiglobulin test 
[DAT, Coombs’] 
schistocytes) 
Evidence of red cell 
destruction and ≥2 gm 
decrease in hemoglobin, 
no transfusion 
Transfusion or medical 
intervention (e.g., 
steroids) indicated 
Catastrophic 
consequences of 
hemolysis (e.g., renal 
failure, hypotension, 
bronchospasm, 
emergency splenectomy) 
Death 
ALSO CONSIDER: Haptoglobin; Hemoglobin. 
Iron overload 
Iron overload 
— 
Asymptomatic iron 
overload, intervention not 
indicated  
Iron overload, 
intervention indicated  
Organ impairment (e.g., 
endocrinopathy, 
cardiopathy) 
Death 
Leukocytes (total WBC) 
Leukocytes 
<LLN – 3000/mm3 
<LLN – 3.0 x 109 /L  
<3000 – 2000/mm3 
<3.0 – 2.0 x 109 /L 
<2000 – 1000/mm3 
<2.0 – 1.0 x 109 /L 
<1000/mm3  
<1.0 x 109 /L 
Death 
Lymphopenia  
Lymphopenia 
<LLN – 800/mm3 
<LLN x 0.8 – 109 /L 
<800 – 500/mm3 
<0.8 – 0.5 x 109 /L 
<500 – 200 mm3 
<0.5 – 0.2 x 109 /L 
<200/mm3 
<0.2 x 109 /L 
Death 
Myelodysplasia 
Myelodysplasia 
— 
— 
Abnormal marrow 
cytogenetics (marrow 
blasts ≤5%)  
RAEB or RAEB-T 
(marrow blasts >5%) 
Death 
Neutrophils/granulocytes 
(ANC/AGC) 
Neutrophils 
<LLN – 1500/mm3  
<LLN – 1.5 x 109 /L 
<1500 – 1000/mm3 
<1.5 – 1.0 x 109 /L  
<1000 – 500/mm3 
<1.0 – 0.5 x 109 /L 
<500/mm3 
<0.5 x 109 /L 
Death 
Platelets 
Platelets 
<LLN – 75,000/mm3 
<LLN – 75.0 x 109 /L 
<75,000 – 50,000/mm3 
<75.0 – 50.0 x 109 /L 
<50,000 – 25,000/mm3  
<50.0 – 25.0 x 109 /L 
<25,000/mm3  
<25.0 x 109 /L 
Death 
Splenic function 
Splenic function 
Incidental findings (e.g., 
Howell-Jolly bodies) 
Prophylactic antibiotics 
indicated 
—  
Life-threatening 
consequences 
Death 
Blood/Bone Marrow – 
Other (Specify, __) 
Blood – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 98 of 165

 
CARDIAC ARRHYTHMIA 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 5 - 
March 31, 2003, Publish Date: August 9, 2006 
Conduction abnormality/ 
atrioventricular heart 
block  
– Select:  
Conduction abnormality 
– Select 
Asymptomatic, 
intervention not indicated 
– Asystole 
– AV Block-First degree 
– AV Block-Second degree Mobitz Type I (Wenckebach)  
– AV Block-Second degree Mobitz Type II 
– AV Block-Third degree (Complete AV block) 
– Conduction abnormality NOS 
– Sick Sinus Syndrome  
– Stokes-Adams Syndrome 
– Wolff-Parkinson-White Syndrome 
Non-urgent medical 
intervention indicated 
Incompletely controlled 
medically or controlled  
with device (e.g., 
pacemaker) 
Life-threatening (e.g., 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
Death 
Palpitations 
Palpitations 
Present 
Present with associated 
symptoms (e.g., 
lightheadedness, 
shortness of breath) 
— 
— 
— 
REMARK: Grade palpitations only in the absence of a documented arrhythmia. 
Prolonged QTc interval 
Prolonged QTc 
QTc >0.45 – 0.47 second 
 QTc >0.47 – 0.50 
second; ≥0.06 second 
above baseline 
QTc >0.50 second 
QTc >0.50 second; life-
threatening signs or 
symptoms (e.g., 
arrhythmia, CHF, 
hypotension, shock 
syncope); Torsade de 
pointes 
Death 
Supraventricular and 
nodal arrhythmia  
– Select: 
Supraventricular 
arrhythmia – Select 
Asymptomatic, 
intervention not indicated 
Non-urgent medical 
intervention indicated 
– Atrial fibrillation 
– Atrial flutter  
– Atrial tachycardia/Paroxysmal Atrial Tachycardia 
– Nodal/Junctional 
– Sinus arrhythmia  
– Sinus bradycardia 
– Sinus tachycardia  
– Supraventricular arrhythmia NOS 
– Supraventricular extrasystoles (Premature Atrial Contractions; Premature Nodal/Junctional Contractions) 
– Supraventricular tachycardia 
Symptomatic and 
incompletely controlled 
medically, or controlled 
with device (e.g., 
pacemaker) 
Life-threatening (e.g., 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
Death 
NAVIGATION NOTE: Syncope is graded as Syncope (fainting) in the NEUROLOGY CATEGORY. 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 99 of 165

 
CARDIAC ARRHYTHMIA 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 6 - 
March 31, 2003, Publish Date: August 9, 2006 
Vasovagal episode 
Vasovagal episode 
— 
Present without loss of 
consciousness 
Present with loss of 
consciousness 
Life-threatening 
consequences  
Death 
Ventricular arrhythmia 
– Select: 
Ventricular arrhythmia 
– Select 
– Bigeminy 
– Idioventricular rhythm 
– PVCs 
– Torsade de pointes 
– Trigeminy 
– Ventricular arrhythmia NOS 
– Ventricular fibrillation  
– Ventricular flutter 
– Ventricular tachycardia 
Asymptomatic, no 
intervention indicated 
Non-urgent medical 
intervention indicated 
Symptomatic and 
incompletely controlled 
medically or controlled 
with device (e.g., 
defibrillator) 
Life-threatening (e.g., 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
Death 
Cardiac Arrhythmia  
– Other (Specify, __) 
Cardiac Arrhythmia – 
Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling  
Death 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 100 of 165

 
CARDIAC GENERAL 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 7 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Angina is graded as Cardiac ischemia/infarction in the CARDIAC GENERAL CATEGORY. 
Cardiac 
ischemia/infarction 
Cardiac 
ischemia/infarction 
Asymptomatic arterial 
narrowing without 
ischemia 
Asymptomatic and testing 
suggesting ischemia; 
stable angina  
Symptomatic and testing 
consistent with ischemia; 
unstable angina; 
intervention indicated 
Acute myocardial 
infarction 
Death 
Cardiac troponin I (cTnI) 
cTnI 
— 
— 
Levels consistent with 
unstable angina as 
defined by the 
manufacturer 
Levels consistent with 
myocardial infarction as 
defined by the 
manufacturer 
Death 
Cardiac troponin T (cTnT) 
cTnT 
0.03 – <0.05 ng/mL 
0.05 – <0.1 ng/mL 
0.1 – <0.2 ng/mL 
0.2 ng/mL 
Death 
Cardiopulmonary arrest, 
cause unknown 
(non-fatal) 
Cardiopulmonary arrest 
— 
— 
— 
Life-threatening  
— 
REMARK: Grade 4 (non-fatal) is the only appropriate grade. CTCAE provides three alternatives for reporting Death: 
1. A CTCAE term associated with Grade 5.  
2. A CTCAE 'Other (Specify, __)’ within any CATEGORY. 
3. Death not associated with CTCAE term – Select in the DEATH CATEGORY. 
NAVIGATION NOTE: Chest pain (non-cardiac and non-pleuritic) is graded as Pain – Select in the PAIN CATEGORY. 
NAVIGATION NOTE: CNS ischemia is graded as CNS cerebrovascular ischemia in the NEUROLOGY CATEGORY. 
Hypertension 
Hypertension 
Asymptomatic, transient 
(<24 hrs) increase by >20 
mmHg (diastolic) or to 
>150/100 if previously 
WNL; intervention not 
indicated  
Pediatric: 
Asymptomatic, transient 
(<24 hrs) BP increase 
>ULN; intervention not 
indicated 
Recurrent or persistent 
(≥24 hrs) or symptomatic 
increase by >20 mmHg 
(diastolic) or to >150/100 
if previously WNL; 
monotherapy may be 
indicated  
Pediatric: 
Recurrent or persistent 
(≥24 hrs) BP >ULN; 
monotherapy may be 
indicated 
Requiring more than one 
drug or more intensive 
therapy than previously 
Pediatric: 
Same as adult 
Life-threatening 
consequences (e.g., 
hypertensive crisis) 
Pediatric: 
Same as adult 
Death 
REMARK: Use age and gender-appropriate normal values >95th percentile ULN for pediatric patients. 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 101 of 165

 
CARDIAC GENERAL 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 8 - 
March 31, 2003, Publish Date: August 9, 2006 
Hypotension 
Hypotension 
Changes, intervention not 
indicated 
Brief (<24 hrs) fluid 
replacement or other 
therapy; no physiologic 
consequences 
Sustained (≥24 hrs) 
therapy, resolves without 
persisting physiologic 
consequences 
Shock (e.g., acidemia; 
impairment of vital organ 
function)  
Death 
ALSO CONSIDER: Syncope (fainting). 
Left ventricular diastolic 
dysfunction 
Left ventricular diastolic 
dysfunction 
Asymptomatic diagnostic 
finding; intervention not 
indicated 
Asymptomatic, 
intervention indicated 
Symptomatic CHF 
responsive to intervention 
Refractory CHF, poorly 
controlled; intervention 
such as ventricular assist 
device or heart transplant 
indicated  
Death 
Left ventricular systolic 
dysfunction 
Left ventricular systolic 
dysfunction 
Asymptomatic, resting 
ejection fraction (EF)  
<60 – 50%; shortening 
fraction (SF) <30 – 24% 
Asymptomatic, resting  
EF <50 – 40%; 
SF <24 – 15% 
Symptomatic CHF 
responsive to 
intervention; 
EF <40 – 20% 
SF <15% 
Refractory CHF or poorly 
controlled; EF <20%; 
intervention such as 
ventricular assist device, 
ventricular reduction 
surgery, or heart 
transplant indicated 
Death 
NAVIGATION NOTE: Myocardial infarction is graded as Cardiac ischemia/infarction in the CARDIAC GENERAL CATEGORY. 
Myocarditis 
Myocarditis 
— 
— 
CHF responsive to 
intervention 
Severe or refractory CHF 
Death 
Pericardial effusion 
(non-malignant) 
Pericardial effusion 
Asymptomatic effusion  
—  
Effusion with physiologic 
consequences 
Life-threatening 
consequences (e.g., 
tamponade); emergency 
intervention indicated 
Death 
Pericarditis 
Pericarditis 
Asymptomatic, ECG or 
physical exam (rub) 
changes consistent with 
pericarditis 
Symptomatic pericarditis 
(e.g., chest pain) 
Pericarditis with 
physiologic 
consequences (e.g., 
pericardial constriction) 
Life-threatening 
consequences; 
emergency intervention 
indicated 
Death 
NAVIGATION NOTE: Pleuritic pain is graded as Pain – Select in the PAIN CATEGORY. 
Pulmonary hypertension 
Pulmonary hypertension 
Asymptomatic without 
therapy 
Asymptomatic, therapy 
indicated 
Symptomatic 
hypertension, responsive 
to therapy 
Symptomatic 
hypertension, poorly 
controlled 
Death 
Restrictive 
cardiomyopathy  
Restrictive 
cardiomyopathy  
Asymptomatic, therapy 
not indicated 
Asymptomatic, therapy 
indicated 
Symptomatic CHF 
responsive to intervention 
Refractory CHF, poorly 
controlled; intervention 
such as ventricular assist 
device, or heart 
transplant indicated  
Death 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 102 of 165

 
CARDIAC GENERAL 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 9 - 
March 31, 2003, Publish Date: August 9, 2006 
Right ventricular 
dysfunction 
(cor pulmonale) 
Right ventricular 
dysfunction 
Asymptomatic without 
therapy 
Asymptomatic, therapy 
indicated 
Symptomatic cor 
pulmonale, responsive to 
intervention 
Symptomatic cor 
pulmonale poorly 
controlled; intervention 
such as ventricular assist 
device, or heart 
transplant indicated  
Death 
Valvular heart disease 
Valvular heart disease 
Asymptomatic valvular 
thickening with or without 
mild valvular regurgitation 
or stenosis; treatment 
other than endocarditis 
prophylaxis not indicated 
Asymptomatic; moderate 
regurgitation or stenosis 
by imaging 
Symptomatic; severe 
regurgitation or stenosis; 
symptoms controlled with 
medical therapy 
Life-threatening; 
disabling; intervention 
(e.g., valve replacement, 
valvuloplasty) indicated 
Death 
Cardiac General – Other 
(Specify, __) 
Cardiac General – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 103 of 165

 
COAGULATION 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 10 - 
March 31, 2003, Publish Date: August 9, 2006 
DIC (disseminated 
intravascular coagulation) 
DIC 
— 
Laboratory findings with 
no bleeding 
Laboratory findings and 
bleeding 
Laboratory findings, life-
threatening or disabling 
consequences (e.g., CNS 
hemorrhage, organ 
damage, or 
hemodynamically 
significant blood loss) 
Death 
REMARK: DIC (disseminated intravascular coagulation) must have increased fibrin split products or D-dimer.  
ALSO CONSIDER: Platelets. 
 
Fibrinogen  
Fibrinogen 
<1.0 – 0.75 x LLN 
or <25% decrease from 
baseline 
<0.75 – 0.5 x LLN 
or 25 – <50% decrease 
from baseline 
<0.5 – 0.25 x LLN 
or 50 – <75% decrease 
from baseline 
<0.25 x LLN  
or 75% decrease from 
baseline or absolute 
value <50 mg/dL  
Death 
REMARK: Use % decrease only when baseline is <LLN (local laboratory value). 
INR (International 
Normalized Ratio of 
prothrombin time) 
INR 
 
>1 – 1.5 x ULN 
>1.5 – 2 x ULN 
>2 x ULN 
— 
— 
ALSO CONSIDER: Hemorrhage, CNS; Hemorrhage, GI – Select; Hemorrhage, GU – Select; Hemorrhage, pulmonary/upper respiratory – Select. 
PTT (Partial 
Thromboplastin Time)  
PTT 
>1 – 1.5 x ULN 
>1.5 – 2 x ULN 
>2 x ULN 
— 
— 
ALSO CONSIDER: Hemorrhage, CNS; Hemorrhage, GI – Select; Hemorrhage, GU – Select; Hemorrhage, pulmonary/upper respiratory – Select. 
Thrombotic 
microangiopathy (e.g., 
thrombotic 
thrombocytopenic 
purpura [TTP] or 
hemolytic uremic 
syndrome [HUS]) 
Thrombotic 
microangiopathy 
Evidence of RBC 
destruction 
(schistocytosis) without 
clinical consequences 
— 
Laboratory findings 
present with clinical 
consequences (e.g., renal 
insufficiency, petechiae) 
Laboratory findings and 
life-threatening or 
disabling consequences, 
(e.g., CNS hemorrhage/ 
bleeding or thrombosis/ 
embolism or renal failure) 
Death 
REMARK: Must have microangiopathic changes on blood smear (e.g., schistocytes, helmet cells, red cell fragments). 
ALSO CONSIDER: Creatinine; Hemoglobin; Platelets. 
Coagulation – Other 
(Specify, __) 
Coagulation – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 104 of 165

 
CONSTITUTIONAL SYMPTOMS 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 11 - 
March 31, 2003, Publish Date: August 9, 2006 
Fatigue  
(asthenia, lethargy, 
malaise) 
Fatigue 
Mild fatigue over baseline 
Moderate or causing 
difficulty performing some 
ADL 
Severe fatigue interfering 
with ADL 
Disabling 
— 
Fever  
(in the absence of 
neutropenia, where 
neutropenia is defined as 
ANC <1.0 x 109/L) 
Fever 
38.0 – 39.0°C  
(100.4 – 102.2°F) 
>39.0 – 40.0°C 
(102.3 – 104.0°F)  
>40.0°C 
(>104.0°F) for ≤24 hrs  
>40.0°C 
(>104.0°F) for >24 hrs 
Death 
REMARK: The temperature measurements listed are oral or tympanic. 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever).  
NAVIGATION NOTE: Hot flashes are graded as Hot flashes/flushes in the ENDOCRINE CATEGORY. 
Hypothermia 
Hypothermia 
— 
35 – >32°C 
95 – >89.6°F 
32 – >28°C  
89.6 – >82.4° F 
≤28 °C  
82.4°F or life-threatening 
consequences (e.g., 
coma, hypotension, 
pulmonary edema, 
acidemia, ventricular 
fibrillation) 
Death 
Insomnia 
Insomnia 
Occasional difficulty 
sleeping, not interfering 
with function 
Difficulty sleeping, 
interfering with function 
but not interfering with 
ADL 
Frequent difficulty 
sleeping, interfering with 
ADL 
Disabling 
— 
REMARK: If pain or other symptoms interfere with sleep, do NOT grade as insomnia. Grade primary event(s) causing insomnia. 
Obesity2 
Obesity 
— 
BMI 25 – 29.9 kg/m2 
BMI 30 – 39.99 kg/m2 
BMI ≥40 kg/m2 
— 
REMARK: BMI = (weight [kg]) / (height [m])2 
Odor  
(patient odor) 
Patient odor 
Mild odor 
Pronounced odor 
— 
— 
— 
Rigors/chills 
Rigors/chills 
Mild 
Moderate, narcotics 
indicated 
Severe or prolonged, not 
responsive to narcotics 
— 
— 
                                            
2 NHLBI Obesity Task Force. "Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults," The Evidence Report, Obes Res 6:51S-
209S, 1998.  
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 105 of 165

 
CONSTITUTIONAL SYMPTOMS 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 12 - 
March 31, 2003, Publish Date: August 9, 2006 
Sweating  
(diaphoresis) 
Sweating  
Mild and occasional 
Frequent or drenching 
— 
— 
— 
ALSO CONSIDER: Hot flashes/flushes.  
Weight gain  
Weight gain 
5 – <10% of baseline 
10 – <20% of baseline 
≥20% of baseline 
— 
— 
REMARK: Edema, depending on etiology, is graded in the CARDIAC GENERAL or LYMPHATICS CATEGORIES. 
ALSO CONSIDER: Ascites (non-malignant); Pleural effusion (non-malignant). 
Weight loss 
Weight loss 
5 to <10% from baseline; 
intervention not indicated 
10 – <20% from baseline; 
nutritional support 
indicated 
≥20% from baseline; tube 
feeding or TPN indicated 
— 
— 
Constitutional Symptoms 
– Other (Specify, __) 
Constitutional Symptoms 
– Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 106 of 165

 
DEATH 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 13 - 
March 31, 2003, Publish Date: August 9, 2006 
Death not associated with 
CTCAE term  
– Select: 
Death not associated with 
CTCAE term – Select 
– Death NOS 
– Disease progression NOS 
– Multi-organ failure 
– Sudden death 
— 
— 
— 
— 
Death 
REMARK: Grade 5 is the only appropriate grade. 'Death not associated with CTCAE term – Select' is to be used where a death: 
1. Cannot be attributed to a CTCAE term associated with Grade 5. 
2. Cannot be reported within any CATEGORY using a CTCAE 'Other (Specify, __)’.  
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 107 of 165

 
DERMATOLOGY/SKIN 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 14 - 
March 31, 2003, Publish Date: August 9, 2006 
Atrophy, skin 
Atrophy, skin 
Detectable 
Marked 
— 
— 
— 
Atrophy, subcutaneous 
fat 
Atrophy, subcutaneous 
fat 
Detectable 
Marked 
— 
— 
— 
ALSO CONSIDER: Induration/fibrosis (skin and subcutaneous tissue). 
Bruising  
(in absence of Grade 3 or 
4 thrombocytopenia) 
Bruising  
Localized or in a 
dependent area 
Generalized 
— 
— 
— 
Burn 
Burn 
Minimal symptoms; 
intervention not indicated  
Medical intervention; 
minimal debridement 
indicated  
Moderate to major 
debridement or 
reconstruction indicated  
Life-threatening 
consequences 
Death 
REMARK: Burn refers to all burns including radiation, chemical, etc. 
Cheilitis 
Cheilitis 
Asymptomatic 
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
— 
— 
Dry skin 
Dry skin 
Asymptomatic 
Symptomatic, not 
interfering with ADL 
Interfering with ADL 
— 
— 
Flushing 
Flushing 
Asymptomatic 
Symptomatic 
— 
— 
— 
Hair loss/alopecia 
(scalp or body) 
Alopecia 
Thinning or patchy 
Complete 
— 
— 
— 
Hyperpigmentation 
Hyperpigmentation 
Slight or localized 
Marked or generalized 
— 
— 
— 
Hypopigmentation 
Hypopigmentation 
Slight or localized 
Marked or generalized 
— 
— 
— 
Induration/fibrosis 
(skin and subcutaneous 
tissue) 
Induration  
Increased density on 
palpation 
Moderate impairment of 
function not interfering 
with ADL; marked 
increase in density and 
firmness on palpation 
with or without minimal 
retraction 
Dysfunction interfering 
with ADL; very marked 
density, retraction or 
fixation 
— 
— 
ALSO CONSIDER: Fibrosis-cosmesis; Fibrosis-deep connective tissue.  
Injection site reaction/ 
extravasation changes 
Injection site reaction 
Pain; itching; erythema 
Pain or swelling, with 
inflammation or phlebitis 
Ulceration or necrosis 
that is severe; operative 
intervention indicated  
— 
— 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever); Ulceration. 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 108 of 165

 
DERMATOLOGY/SKIN 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 15 - 
March 31, 2003, Publish Date: August 9, 2006 
Nail changes 
Nail changes 
Discoloration; ridging 
(koilonychias); pitting 
Partial or complete loss of 
nail(s); pain in nailbed(s) 
Interfering with ADL  
— 
— 
NAVIGATION NOTE: Petechiae is graded as Petechiae/purpura (hemorrhage/bleeding into skin or mucosa) in the HEMORRHAGE/BLEEDING CATEGORY. 
Photosensitivity 
Photosensitivity 
Painless erythema 
Painful erythema 
Erythema with 
desquamation 
Life-threatening; disabling 
Death 
Pruritus/itching 
Pruritus 
Mild or localized 
Intense or widespread 
Intense or widespread 
and interfering with ADL  
— 
— 
ALSO CONSIDER: Rash/desquamation. 
Rash/desquamation  
Rash 
Macular or papular 
eruption or erythema 
without associated 
symptoms 
Macular or papular 
eruption or erythema with 
pruritus or other 
associated symptoms; 
localized desquamation 
or other lesions covering 
<50% of body surface 
area (BSA) 
Severe, generalized 
erythroderma or macular, 
papular or vesicular 
eruption; desquamation 
covering ≥50% BSA 
Generalized exfoliative, 
ulcerative, or bullous 
dermatitis 
Death 
REMARK: Rash/desquamation may be used for GVHD. 
Rash:  
acne/acneiform 
Acne 
Intervention not indicated  
Intervention indicated 
Associated with pain, 
disfigurement, ulceration, 
or desquamation 
— 
Death 
Rash:  
dermatitis associated with 
radiation  
– Select: 
– Chemoradiation 
– Radiation 
Dermatitis – Select  
Faint erythema or dry 
desquamation 
Moderate to brisk 
erythema; patchy moist 
desquamation, mostly 
confined to skin folds and 
creases; moderate 
edema 
Moist desquamation other 
than skin folds and 
creases; bleeding 
induced by minor trauma 
or abrasion 
Skin necrosis or 
ulceration of full thickness 
dermis; spontaneous 
bleeding from involved 
site  
Death 
Rash:  
erythema multiforme 
(e.g., Stevens-Johnson 
syndrome, toxic 
epidermal necrolysis) 
Erythema multiforme 
— 
Scattered, but not 
generalized eruption 
Severe (e.g., generalized 
rash or painful stomatitis); 
IV fluids, tube feedings, 
or TPN indicated 
Life-threatening; disabling 
Death 
Rash:  
hand-foot skin reaction 
Hand-foot 
Minimal skin changes or 
dermatitis (e.g., 
erythema) without pain  
Skin changes (e.g., 
peeling, blisters, 
bleeding, edema) or pain, 
not interfering with 
function  
Ulcerative dermatitis or 
skin changes with pain 
interfering with function  
— 
— 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 109 of 165

 
DERMATOLOGY/SKIN 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 16 - 
March 31, 2003, Publish Date: August 9, 2006 
Skin breakdown/ 
decubitus ulcer 
Decubitus  
— 
Local wound care; 
medical intervention 
indicated 
Operative debridement or 
other invasive 
intervention indicated 
(e.g., hyperbaric oxygen)  
Life-threatening 
consequences; major 
invasive intervention 
indicated (e.g., tissue 
reconstruction, flap, or 
grafting) 
Death 
REMARK: Skin breakdown/decubitus ulcer is to be used for loss of skin integrity or decubitus ulcer from pressure or as the result of operative or medical intervention. 
Striae 
Striae 
Mild 
Cosmetically significant 
— 
— 
— 
Telangiectasia 
Telangiectasia 
Few 
Moderate number 
Many and confluent 
— 
— 
Ulceration 
Ulceration 
— 
Superficial ulceration  
<2 cm size; local wound 
care; medical intervention 
indicated 
Ulceration ≥2 cm size; 
operative debridement, 
primary closure or other 
invasive intervention 
indicated (e.g., hyperbaric 
oxygen)  
Life-threatening 
consequences; major 
invasive intervention 
indicated (e.g., complete 
resection, tissue 
reconstruction, flap, or 
grafting) 
Death 
Urticaria  
(hives, welts, wheals) 
Urticaria 
Intervention not indicated 
Intervention indicated for 
<24 hrs 
Intervention indicated for 
≥24 hrs 
— 
— 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever). 
Wound complication, 
non-infectious  
Wound complication, 
non-infectious 
Incisional separation of  
≤25% of wound, no 
deeper than superficial 
fascia 
Incisional separation 
>25% of wound with local 
care; asymptomatic 
hernia 
Symptomatic hernia 
without evidence of 
strangulation; fascial 
disruption/dehiscence 
without evisceration; 
primary wound closure or 
revision by operative 
intervention indicated; 
hospitalization or 
hyperbaric oxygen 
indicated 
Symptomatic hernia with 
evidence of strangulation; 
fascial disruption with 
evisceration; major 
reconstruction flap, 
grafting, resection, or 
amputation indicated 
Death 
REMARK: Wound complication, non-infectious is to be used for separation of incision, hernia, dehiscence, evisceration, or second surgery for wound revision. 
Dermatology/Skin – Other 
(Specify, __) 
Dermatology – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 110 of 165

 
ENDOCRINE 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 17 - 
March 31, 2003, Publish Date: August 9, 2006 
Adrenal insufficiency 
Adrenal insufficiency 
Asymptomatic, 
intervention not indicated 
Symptomatic, intervention 
indicated 
Hospitalization  
Life-threatening; disabling 
Death 
REMARK: Adrenal insufficiency includes any of the following signs and symptoms: abdominal pain, anorexia, constipation, diarrhea, hypotension, pigmentation of mucous membranes, 
pigmentation of skin, salt craving, syncope (fainting), vitiligo, vomiting, weakness, weight loss. Adrenal insufficiency must be confirmed by laboratory studies (low cortisol frequently 
accompanied by low aldosterone). 
ALSO CONSIDER: Potassium, serum-high (hyperkalemia); Thyroid function, low (hypothyroidism). 
Cushingoid appearance 
(e.g., moon face, buffalo 
hump, centripetal obesity, 
cutaneous striae) 
Cushingoid  
— 
Present 
— 
— 
— 
ALSO CONSIDER: Glucose, serum-high (hyperglycemia); Potassium, serum-low (hypokalemia). 
Feminization of male 
Feminization of male 
— 
— 
Present 
— 
— 
NAVIGATION NOTE: Gynecomastia is graded in the SEXUAL/REPRODUCTIVE FUNCTION CATEGORY. 
Hot flashes/flushes3 
Hot flashes 
Mild  
Moderate  
Interfering with ADL 
— 
— 
Masculinization of female 
Masculinization of female 
— 
— 
Present 
— 
— 
Neuroendocrine: 
ACTH deficiency 
ACTH  
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL; hospitalization 
indicated 
Life-threatening 
consequences (e.g., 
severe hypotension) 
Death 
Neuroendocrine: 
ADH secretion 
abnormality (e.g., SIADH 
or low ADH) 
ADH 
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL 
Life-threatening 
consequences 
Death 
Neuroendocrine: 
gonadotropin secretion 
abnormality 
Gonadotropin 
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL; osteopenia; 
fracture; infertility 
— 
— 
Neuroendocrine:  
growth hormone 
secretion abnormality 
Growth hormone  
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
— 
— 
— 
Neuroendocrine:  
prolactin hormone 
secretion abnormality 
Prolactin  
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL; amenorrhea; 
galactorrhea 
— 
Death 
                                            
3 Sloan JA, Loprinzi CL, Novotny PJ, Barton DL, Lavasseur BI, Windschitl HJ, "Methodologic Lessons Learned from Hot Flash Studies," J Clin Oncol 2001 Dec 1;19(23):4280-90 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 111 of 165

 
ENDOCRINE 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 18 - 
March 31, 2003, Publish Date: August 9, 2006 
Pancreatic endocrine:  
glucose intolerance 
Diabetes 
Asymptomatic, 
intervention not indicated 
Symptomatic; dietary 
modification or oral agent 
indicated 
Symptoms interfering with 
ADL; insulin indicated 
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar non-ketotic 
coma)  
Death 
Parathyroid function, low 
(hypoparathyroidism) 
Hypoparathyroidism 
Asymptomatic, 
intervention not indicated 
Symptomatic; intervention 
indicated 
— 
— 
— 
Thyroid function, high 
(hyperthyroidism, 
thyrotoxicosis) 
Hyperthyroidism  
Asymptomatic, 
intervention not indicated 
Symptomatic, not 
interfering with ADL; 
thyroid suppression 
therapy indicated 
Symptoms interfering with 
ADL; hospitalization 
indicated  
Life-threatening 
consequences (e.g., 
thyroid storm) 
Death 
Thyroid function, low 
(hypothyroidism) 
Hypothyroidism 
Asymptomatic, 
intervention not indicated 
Symptomatic, not 
interfering with ADL; 
thyroid replacement 
indicated 
Symptoms interfering with 
ADL; hospitalization 
indicated  
Life-threatening 
myxedema coma 
Death 
Endocrine – Other  
(Specify, __) 
Endocrine – Other  
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 112 of 165

 
GASTROINTESTINAL 
Page 1 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 19 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Abdominal pain or cramping is graded as Pain – Select in the PAIN CATEGORY. 
Anorexia 
Anorexia 
Loss of appetite without 
alteration in eating habits 
Oral intake altered 
without significant weight 
loss or malnutrition; oral 
nutritional supplements 
indicated 
Associated with 
significant weight loss or 
malnutrition (e.g., 
inadequate oral caloric 
and/or fluid intake); IV 
fluids, tube feedings or 
TPN indicated 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Weight loss. 
Ascites (non-malignant) 
Ascites 
Asymptomatic 
Symptomatic, medical 
intervention indicated 
Symptomatic, invasive 
procedure indicated 
Life-threatening 
consequences 
Death 
REMARK: Ascites (non-malignant) refers to documented non-malignant ascites or unknown etiology, but unlikely malignant, and includes chylous ascites. 
Colitis 
Colitis 
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain; mucus 
or blood in stool 
Abdominal pain, fever, 
change in bowel habits 
with ileus; peritoneal 
signs 
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis, toxic 
megacolon) 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select.  
Constipation 
Constipation 
Occasional or intermittent 
symptoms; occasional 
use of stool softeners, 
laxatives, dietary 
modification, or enema 
Persistent symptoms with 
regular use of laxatives 
or enemas indicated 
Symptoms interfering 
with ADL; obstipation 
with manual evacuation 
indicated  
Life-threatening 
consequences (e.g., 
obstruction, toxic 
megacolon) 
Death 
ALSO CONSIDER: Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation); Obstruction, GI – Select. 
Dehydration 
Dehydration 
Increased oral fluids 
indicated; dry mucous 
membranes; diminished 
skin turgor 
IV fluids indicated <24 
hrs 
IV fluids indicated ≥24 hrs 
Life-threatening 
consequences (e.g., 
hemodynamic collapse) 
Death 
ALSO CONSIDER: Diarrhea; Hypotension; Vomiting. 
Dental:  
dentures or prosthesis 
Dentures  
Minimal discomfort, no 
restriction in activities  
Discomfort preventing 
use in some activities 
(e.g., eating), but not 
others (e.g., speaking) 
Unable to use dentures 
or prosthesis at any time 
— 
— 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 113 of 165

 
GASTROINTESTINAL 
Page 2 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 20 - 
March 31, 2003, Publish Date: August 9, 2006 
Dental:  
periodontal disease  
Periodontal  
Gingival recession or 
gingivitis; limited bleeding 
on probing; mild local 
bone loss 
Moderate gingival 
recession or gingivitis; 
multiple sites of bleeding 
on probing; moderate 
bone loss 
Spontaneous bleeding; 
severe bone loss with or 
without tooth loss; 
osteonecrosis of maxilla 
or mandible  
— 
— 
REMARK: Severe periodontal disease leading to osteonecrosis is graded as Osteonecrosis (avascular necrosis) in the MUSCULOSKELETAL CATEGORY. 
Dental: 
teeth  
Teeth 
Surface stains; dental 
caries; restorable, without 
extractions 
Less than full mouth 
extractions; tooth fracture 
or crown amputation or 
repair indicated 
Full mouth extractions 
indicated 
— 
— 
Dental:  
teeth development 
Teeth development 
Hypoplasia of tooth or 
enamel not interfering 
with function 
Functional impairment 
correctable with oral 
surgery 
Maldevelopment with 
functional impairment not 
surgically correctable 
— 
— 
Diarrhea 
Diarrhea 
Increase of <4 stools per 
day over baseline; mild 
increase in ostomy output 
compared to baseline 
Increase of 4 – 6 stools 
per day over baseline; IV 
fluids indicated <24hrs; 
moderate increase in 
ostomy output compared 
to baseline; not 
interfering with ADL 
Increase of ≥7 stools per 
day over baseline; 
incontinence; IV fluids 
≥24 hrs; hospitalization; 
severe increase in 
ostomy output compared 
to baseline; interfering 
with ADL 
Life-threatening 
consequences (e.g., 
hemodynamic collapse) 
Death 
REMARK: Diarrhea includes diarrhea of small bowel or colonic origin, and/or ostomy diarrhea. 
ALSO CONSIDER: Dehydration; Hypotension. 
Distension/bloating, 
abdominal 
Distension 
Asymptomatic  
Symptomatic, but not 
interfering with GI 
function 
Symptomatic, interfering 
with GI function 
— 
— 
ALSO CONSIDER: Ascites (non-malignant); Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation); Obstruction, GI – Select.  
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 114 of 165

 
GASTROINTESTINAL 
Page 3 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 21 - 
March 31, 2003, Publish Date: August 9, 2006 
Dry mouth/salivary gland 
(xerostomia) 
Dry mouth 
Symptomatic (dry or thick 
saliva) without significant 
dietary alteration; 
unstimulated saliva flow 
>0.2 ml/min 
Symptomatic and 
significant oral intake 
alteration (e.g., copious 
water, other lubricants, 
diet limited to purees 
and/or soft, moist foods); 
unstimulated saliva 
0.1 to 0.2 ml/min 
Symptoms leading to 
inability to adequately 
aliment orally; IV fluids, 
tube feedings, or TPN 
indicated; unstimulated 
saliva <0.1 ml/min 
— 
— 
REMARK: Dry mouth/salivary gland (xerostomia) includes descriptions of grade using both subjective and objective assessment parameters. Record this event consistently throughout 
a patient’s participation on study. If salivary flow measurements are used for initial assessment, subsequent assessments must use salivary flow. 
ALSO CONSIDER: Salivary gland changes/saliva.  
Dysphagia 
(difficulty swallowing) 
Dysphagia 
Symptomatic, able to eat 
regular diet  
Symptomatic and altered 
eating/swallowing (e.g., 
altered dietary habits, 
oral supplements); IV 
fluids indicated <24 hrs 
Symptomatic and 
severely altered 
eating/swallowing (e.g., 
inadequate oral caloric or 
fluid intake); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences (e.g., 
obstruction, perforation) 
 
Death 
REMARK: Dysphagia (difficulty swallowing) is to be used for swallowing difficulty from oral, pharyngeal, esophageal, or neurologic origin. Dysphagia requiring dilation is graded as 
Stricture/stenosis (including anastomotic), GI – Select. 
ALSO CONSIDER: Dehydration; Esophagitis. 
Enteritis  
(inflammation of the small 
bowel) 
Enteritis 
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain; mucus 
or blood in stool 
Abdominal pain, fever, 
change in bowel habits 
with ileus; peritoneal 
signs 
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis) 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select; Typhlitis (cecal inflammation).  
Esophagitis 
Esophagitis 
Asymptomatic pathologic, 
radiographic, or 
endoscopic findings only 
Symptomatic; altered 
eating/swallowing (e.g., 
altered dietary habits, 
oral supplements); IV 
fluids indicated <24 hrs 
Symptomatic and 
severely altered 
eating/swallowing (e.g., 
inadequate oral caloric or 
fluid intake); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences 
Death 
REMARK: Esophagitis includes reflux esophagitis.  
ALSO CONSIDER: Dysphagia (difficulty swallowing). 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 115 of 165

 
GASTROINTESTINAL 
Page 4 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 22 - 
March 31, 2003, Publish Date: August 9, 2006 
Fistula, GI 
– Select: 
Fistula, GI – Select  
– Abdomen NOS 
– Anus 
– Biliary tree  
– Colon/cecum/appendix 
– Duodenum 
– Esophagus 
– Gallbladder  
– Ileum 
– Jejunum 
– Oral cavity 
– Pancreas 
– Pharynx 
– Rectum 
– Salivary gland  
– Small bowel NOS 
– Stomach 
Asymptomatic, 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, diarrhea, 
or GI fluid loss); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered GI 
function (e.g., altered 
dietary habits, diarrhea, 
or GI fluid loss); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences  
Death 
REMARK: A fistula is defined as an abnormal communication between two body cavities, potential spaces, and/or the skin. The site indicated for a fistula should be the site from which 
the abnormal process is believed to have originated. For example, a tracheo-esophageal fistula arising in the context of a resected or irradiated esophageal cancer is graded as 
Fistula, GI – esophagus. 
Flatulence 
Flatulence 
Mild 
Moderate 
— 
— 
— 
Gastritis (including bile 
reflux gastritis) 
Gastritis 
Asymptomatic 
radiographic or 
endoscopic findings only 
Symptomatic; altered 
gastric function (e.g., 
inadequate oral caloric or 
fluid intake); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered gastric 
function (e.g., inadequate 
oral caloric or fluid 
intake); IV fluids, tube 
feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., gastrectomy)  
Death 
ALSO CONSIDER: Hemorrhage, GI – Select; Ulcer, GI – Select. 
NAVIGATION NOTE: Head and neck soft tissue necrosis is graded as Soft tissue necrosis – Select in the MUSCULOSKELETAL/SOFT TISSUE CATEGORY. 
Heartburn/dyspepsia 
Heartburn 
Mild 
Moderate 
Severe 
— 
— 
Hemorrhoids 
Hemorrhoids 
Asymptomatic 
Symptomatic; banding or 
medical intervention 
indicated 
Interfering with ADL; 
interventional radiology, 
endoscopic, or operative 
intervention indicated 
Life-threatening 
consequences 
Death 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 116 of 165

 
GASTROINTESTINAL 
Page 5 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 23 - 
March 31, 2003, Publish Date: August 9, 2006 
Ileus, GI (functional 
obstruction of bowel, i.e., 
neuroconstipation) 
Ileus 
Asymptomatic, 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered GI 
function; IV fluids, tube 
feeding, or TPN indicated 
≥24 hrs 
Life-threatening 
consequences 
Death 
REMARK: Ileus, GI is to be used for altered upper or lower GI function (e.g., delayed gastric or colonic emptying). 
ALSO CONSIDER: Constipation; Nausea; Obstruction, GI – Select; Vomiting. 
Incontinence, anal 
Incontinence, anal 
Occasional use of pads 
required 
Daily use of pads 
required 
Interfering with ADL; 
operative intervention 
indicated 
Permanent bowel 
diversion indicated 
Death 
REMARK: Incontinence, anal is to be used for loss of sphincter control as sequelae of operative or therapeutic intervention. 
Leak (including 
anastomotic), GI 
– Select: 
– Biliary tree 
– Esophagus 
– Large bowel 
– Leak NOS 
– Pancreas 
– Pharynx 
– Rectum 
– Small bowel  
– Stoma 
– Stomach 
Leak, GI – Select  
Asymptomatic 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and 
interfering with GI 
function; invasive or 
endoscopic intervention 
indicated  
Life-threatening 
consequences 
Death 
REMARK: Leak (including anasomotic), GI – Select is to be used for clinical signs/symptoms or radiographic confirmation of anastomotic or conduit leak (e.g., biliary, esophageal, 
intestinal, pancreatic, pharyngeal, rectal), but without development of fistula. 
Malabsorption  
Malabsorption 
— 
Altered diet; oral 
therapies indicated (e.g., 
enzymes, medications, 
dietary supplements)  
Inability to aliment 
adequately via GI tract 
(i.e., TPN indicated) 
Life-threatening 
consequences 
Death 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 117 of 165

 
GASTROINTESTINAL 
Page 6 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 24 - 
March 31, 2003, Publish Date: August 9, 2006 
Mucositis/stomatitis 
(clinical exam)  
– Select: 
– Anus 
– Esophagus 
– Large bowel 
– Larynx 
– Oral cavity 
– Pharynx 
– Rectum 
– Small bowel 
– Stomach 
– Trachea 
Mucositis (clinical exam) 
– Select  
Erythema of the mucosa 
Patchy ulcerations or 
pseudomembranes  
Confluent ulcerations or 
pseudomembranes; 
bleeding with minor 
trauma 
Tissue necrosis; 
significant spontaneous 
bleeding; life-threatening 
consequences 
Death 
REMARK: Mucositis/stomatitis (functional/symptomatic) may be used for mucositis of the upper aero-digestive tract caused by radiation, agents, or GVHD.  
Mucositis/stomatitis 
(functional/symptomatic)  
– Select: 
– Anus 
– Esophagus 
– Large bowel 
– Larynx 
– Oral cavity 
– Pharynx 
– Rectum 
– Small bowel 
– Stomach 
– Trachea 
Mucositis (functional/ 
symptomatic) – Select  
Upper aerodigestive tract 
sites: Minimal symptoms, 
normal diet; minimal 
respiratory symptoms but 
not interfering with 
function 
Lower GI sites: 
Minimal discomfort, 
intervention not indicated 
Upper aerodigestive tract 
sites: Symptomatic but 
can eat and swallow 
modified diet; respiratory 
symptoms interfering with 
function but not 
interfering with ADL 
Lower GI sites:  
Symptomatic, medical 
intervention indicated but 
not interfering with ADL 
Upper aerodigestive tract 
sites: Symptomatic and 
unable to adequately 
aliment or hydrate orally; 
respiratory symptoms 
interfering with ADL 
Lower GI sites: 
Stool incontinence or 
other symptoms 
interfering with ADL 
Symptoms associated 
with life-threatening 
consequences  
Death 
Nausea 
Nausea 
Loss of appetite without 
alteration in eating habits 
Oral intake decreased 
without significant weight 
loss, dehydration or 
malnutrition; IV fluids 
indicated <24 hrs 
Inadequate oral caloric or 
fluid intake; IV fluids, tube 
feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Anorexia; Vomiting. 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 118 of 165

 
GASTROINTESTINAL 
Page 7 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 25 - 
March 31, 2003, Publish Date: August 9, 2006 
Necrosis, GI 
– Select:  
Necrosis, GI – Select  
– Anus 
– Colon/cecum/appendix 
– Duodenum 
– Esophagus 
– Gallbladder 
– Hepatic 
– Ileum 
– Jejunum 
– Oral 
– Pancreas 
– Peritoneal cavity 
– Pharynx  
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
— 
— 
Inability to aliment 
adequately by GI tract 
(e.g., requiring enteral or 
parenteral nutrition); 
interventional radiology, 
endoscopic, or operative 
intervention indicated  
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., total colectomy)  
Death 
ALSO CONSIDER: Visceral arterial ischemia (non-myocardial). 
Obstruction, GI 
– Select: 
– Cecum 
– Colon 
– Duodenum 
– Esophagus 
– Gallbladder 
– Ileum 
– Jejunum 
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
Obstruction, GI – Select 
Asymptomatic 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, vomiting, 
diarrhea, or GI fluid loss); 
IV fluids indicated <24 
hrs 
Symptomatic and 
severely altered GI 
function (e.g., altered 
dietary habits, vomiting, 
diarrhea, or GI fluid loss); 
IV fluids, tube feedings, 
or TPN indicated ≥24 hrs; 
operative intervention 
indicated 
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., total colectomy)  
Death 
NAVIGATION NOTE: Operative injury is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY CATEGORY. 
NAVIGATION NOTE: Pelvic pain is graded as Pain – Select in the PAIN CATEGORY. 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 119 of 165

 
GASTROINTESTINAL 
Page 8 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 26 - 
March 31, 2003, Publish Date: August 9, 2006 
Perforation, GI 
– Select: 
– Appendix 
– Biliary tree 
– Cecum 
– Colon 
– Duodenum 
– Esophagus 
– Gallbladder 
– Ileum 
– Jejunum 
– Rectum 
– Small bowel NOS 
– Stomach 
Perforation, GI – Select 
Asymptomatic 
radiographic findings only 
Medical intervention 
indicated; IV fluids 
indicated <24 hrs 
IV fluids, tube feedings, 
or TPN indicated ≥24 hrs; 
operative intervention 
indicated 
Life-threatening 
consequences 
Death 
Proctitis  
Proctitis 
Rectal discomfort, 
intervention not indicated 
Symptoms not interfering 
with ADL; medical 
intervention indicated  
Stool incontinence or 
other symptoms 
interfering with ADL; 
operative intervention 
indicated 
Life-threatening 
consequences (e.g., 
perforation) 
Death 
Prolapse of stoma, GI 
Prolapse of stoma, GI 
Asymptomatic  
Extraordinary local care 
or maintenance; minor 
revision indicated 
Dysfunctional stoma; 
major revision indicated  
Life-threatening 
consequences 
Death 
REMARK: Other stoma complications may be graded as Fistula, GI – Select; Leak (including anastomotic), GI – Select; Obstruction, GI – Select; Perforation, GI – Select; 
Stricture/stenosis (including anastomotic), GI – Select. 
NAVIGATION NOTE: Rectal or perirectal pain (proctalgia) is graded as Pain – Select in the PAIN CATEGORY.  
Salivary gland 
changes/saliva 
Salivary gland changes 
Slightly thickened saliva; 
slightly altered taste (e.g., 
metallic) 
Thick, ropy, sticky saliva; 
markedly altered taste; 
alteration in diet 
indicated; secretion-
induced symptoms not 
interfering with ADL 
Acute salivary gland 
necrosis; severe 
secretion-induced 
symptoms interfering with 
ADL  
Disabling 
— 
ALSO CONSIDER: Dry mouth/salivary gland (xerostomia); Mucositis/stomatitis (clinical exam) – Select; Mucositis/stomatitis (functional/symptomatic) – Select; Taste alteration 
(dysgeusia). 
NAVIGATION NOTE: Splenic function is graded in the BLOOD/BONE MARROW CATEGORY. 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 120 of 165

 
GASTROINTESTINAL 
Page 9 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 27 - 
March 31, 2003, Publish Date: August 9, 2006 
Stricture/stenosis 
(including anastomotic), 
GI 
– Select:  
Stricture, GI – Select  
– Anus 
– Biliary tree 
– Cecum 
– Colon  
– Duodenum  
– Esophagus 
– Ileum 
– Jejunum 
– Pancreas/pancreatic duct 
– Pharynx 
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
Asymptomatic 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, vomiting, 
bleeding, diarrhea); IV 
fluids indicated <24 hrs 
Symptomatic and 
severely altered GI 
function (e.g., altered 
dietary habits, diarrhea, 
or GI fluid loss); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs; 
operative intervention 
indicated 
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., total colectomy)  
Death 
Taste alteration 
(dysgeusia) 
Taste alteration 
Altered taste but no 
change in diet 
Altered taste with change 
in diet (e.g., oral 
supplements); noxious or 
unpleasant taste; loss of 
taste 
— 
— 
— 
Typhlitis 
(cecal inflammation) 
Typhlitis 
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain; mucus 
or blood in stool 
Abdominal pain, fever, 
change in bowel habits 
with ileus; peritoneal 
signs 
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis); 
operative intervention 
indicated 
Death 
ALSO CONSIDER: Colitis; Hemorrhage, GI – Select ; Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation).  
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 121 of 165

 
GASTROINTESTINAL 
Page 10 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 28 - 
March 31, 2003, Publish Date: August 9, 2006 
Ulcer, GI 
– Select: 
– Anus 
– Cecum 
– Colon 
– Duodenum 
– Esophagus 
– Ileum 
– Jejunum 
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
Ulcer, GI – Select 
Asymptomatic, 
radiographic or 
endoscopic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, oral 
supplements); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered GI 
function (e.g., inadequate 
oral caloric or fluid 
intake); IV fluids, tube 
feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select. 
Vomiting 
Vomiting 
1 episode in 24 hrs 
2 – 5 episodes in 24 hrs; 
IV fluids indicated  
<24 hrs 
≥6 episodes in 24 hrs; IV 
fluids, or TPN indicated 
≥24 hrs 
Life-threatening 
consequences  
Death 
ALSO CONSIDER: Dehydration. 
Gastrointestinal – Other 
(Specify, __) 
GI – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling 
Death 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 122 of 165

 
GROWTH AND DEVELOPMENT 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 29 - 
March 31, 2003, Publish Date: August 9, 2006 
Bone age 
(alteration in bone age) 
Bone age 
— 
+2 SD (standard 
deviation) from normal 
— 
— 
— 
Bone growth: 
femoral head; slipped 
capital femoral epiphysis 
Femoral head growth 
Mild valgus/varus 
deformity 
Moderate valgus/varus 
deformity, symptomatic, 
interfering with function 
but not interfering with 
ADL 
Mild slipped capital 
femoral epiphysis; 
operative intervention 
(e.g., fixation) indicated; 
interfering with ADL 
Disabling; severe slipped 
capital femoral epiphysis 
>60%; avascular necrosis 
— 
Bone growth: 
limb length discrepancy 
Limb length  
Mild length discrepancy 
<2 cm 
Moderate length 
discrepancy 2 – 5 cm; 
shoe lift indicated 
Severe length 
discrepancy >5 cm; 
operative intervention 
indicated; interfering with 
ADL 
Disabling; epiphysiodesis 
— 
Bone growth: 
spine kyphosis/lordosis 
Kyphosis/lordosis 
Mild radiographic 
changes  
Moderate accentuation; 
interfering with function 
but not interfering with 
ADL 
Severe accentuation; 
operative intervention 
indicated; interfering with 
ADL 
Disabling (e.g., cannot lift 
head) 
— 
Growth velocity 
(reduction in growth 
velocity) 
Reduction in growth 
velocity 
10 – 29% reduction in 
growth from the baseline 
growth curve 
30 – 49% reduction in 
growth from the baseline 
growth curve 
≥50% reduction in growth 
from the baseline growth 
curve  
— 
— 
Puberty (delayed) 
Delayed puberty 
— 
No breast development 
by age 13 yrs for females; 
no Tanner Stage 2 
development by age 14.5 
yrs for males 
No sexual development 
by age 14 yrs for girls, 
age 16 yrs for boys; 
hormone replacement 
indicated 
— 
— 
REMARK: Do not use testicular size for Tanner Stage in male cancer survivors. 
Puberty (precocious)  
Precocious puberty 
— 
Physical signs of puberty 
<7 years for females,  
<9 years for males 
— 
— 
— 
Short stature 
Short stature 
Beyond two standard 
deviations of age and 
gender mean height 
Altered ADL 
— 
— 
— 
REMARK: Short stature is secondary to growth hormone deficiency. 
ALSO CONSIDER: Neuroendocrine: growth hormone secretion abnormality. 
Growth and Development 
– Other (Specify, __) 
Growth and Development 
– Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 123 of 165

 
HEMORRHAGE/BLEEDING 
Page 1 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 30 - 
March 31, 2003, Publish Date: August 9, 2006 
Hematoma  
Hematoma 
Minimal symptoms, 
invasive intervention not 
indicated  
Minimally invasive 
evacuation or aspiration 
indicated 
Transfusion, 
interventional radiology, 
or operative intervention 
indicated 
Life-threatening 
consequences; major 
urgent intervention 
indicated 
Death 
REMARK: Hematoma refers to extravasation at wound or operative site or secondary to other intervention. Transfusion implies pRBC.  
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Hemorrhage/bleeding 
associated with surgery, 
intra-operative or 
postoperative 
Hemorrhage with surgery 
— 
— 
Requiring transfusion of  
2 units non-autologous 
(10 cc/kg for pediatrics) 
pRBCs beyond protocol 
specification; 
postoperative 
interventional radiology, 
endoscopic, or operative 
intervention indicated 
Life-threatening 
consequences  
Death 
REMARK: Postoperative period is defined as ≤72 hours after surgery. Verify protocol-specific acceptable guidelines regarding pRBC transfusion. 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Hemorrhage, CNS 
CNS hemorrhage 
Asymptomatic, 
radiographic findings only 
Medical intervention 
indicated  
Ventriculostomy, ICP 
monitoring, 
intraventricular 
thrombolysis, or operative 
intervention indicated 
Life-threatening 
consequences; 
neurologic deficit or 
disability 
Death 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 124 of 165

 
HEMORRHAGE/BLEEDING 
Page 2 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 31 - 
March 31, 2003, Publish Date: August 9, 2006 
Hemorrhage, GI  
– Select: 
– Abdomen NOS 
– Anus 
– Biliary tree  
– Cecum/appendix  
– Colon 
– Duodenum 
– Esophagus 
– Ileum 
– Jejunum 
– Liver 
– Lower GI NOS 
– Oral cavity 
– Pancreas 
– Peritoneal cavity 
– Rectum 
– Stoma 
– Stomach 
– Upper GI NOS 
– Varices (esophageal) 
– Varices (rectal) 
Hemorrhage, GI – Select 
Mild, intervention (other 
than iron supplements) 
not indicated 
Symptomatic and medical 
intervention or minor 
cauterization indicated 
Transfusion, 
interventional radiology, 
endoscopic, or operative 
intervention indicated; 
radiation therapy (i.e., 
hemostasis of bleeding 
site) 
Life-threatening 
consequences; major 
urgent intervention 
indicated  
Death 
REMARK: Transfusion implies pRBC. 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 125 of 165

 
HEMORRHAGE/BLEEDING 
Page 3 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 32 - 
March 31, 2003, Publish Date: August 9, 2006 
Hemorrhage, GU  
– Select:  
– Bladder 
– Fallopian tube 
– Kidney 
– Ovary 
– Prostate  
– Retroperitoneum  
– Spermatic cord 
– Stoma 
– Testes 
– Ureter 
– Urethra 
– Urinary NOS 
– Uterus 
– Vagina 
– Vas deferens 
Hemorrhage, GU – Select 
Minimal or microscopic 
bleeding; intervention not 
indicated 
Gross bleeding, medical 
intervention, or urinary 
tract irrigation indicated 
Transfusion, 
interventional radiology, 
endoscopic, or operative 
intervention indicated; 
radiation therapy (i.e., 
hemostasis of bleeding 
site) 
Life-threatening 
consequences; major 
urgent intervention 
indicated 
Death 
REMARK: Transfusion implies pRBC. 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Hemorrhage, pulmonary/ 
upper respiratory  
– Select: 
Hemorrhage pulmonary  
– Select 
– Bronchopulmonary NOS 
– Bronchus  
– Larynx  
– Lung  
– Mediastinum 
– Nose 
– Pharynx 
– Pleura 
– Respiratory tract NOS 
– Stoma 
– Trachea 
Mild, intervention not 
indicated 
Symptomatic and 
medical intervention 
indicated 
Transfusion, 
interventional radiology, 
endoscopic, or operative 
intervention indicated; 
radiation therapy (i.e., 
hemostasis of bleeding 
site) 
Life-threatening 
consequences; major 
urgent intervention 
indicated 
Death 
REMARK: Transfusion implies pRBC.  
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Petechiae/purpura 
(hemorrhage/bleeding 
into skin or mucosa) 
Petechiae 
Few petechiae 
Moderate petechiae; 
purpura 
Generalized petechiae or 
purpura 
— 
— 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 126 of 165

 
HEMORRHAGE/BLEEDING 
Page 4 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 33 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Vitreous hemorrhage is graded in the OCULAR/VISUAL CATEGORY. 
Hemorrhage/Bleeding – 
Other (Specify, __) 
Hemorrhage – Other 
(Specify) 
Mild without transfusion 
— 
Transfusion indicated 
Catastrophic bleeding, 
requiring major non-
elective intervention 
Death 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 127 of 165

 
HEPATOBILIARY/PANCREAS 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 34 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Biliary tree damage is graded as Fistula, GI – Select; Leak (including anastomotic), GI – Select; Necrosis, GI – Select; Obstruction, GI – Select; Perforation, GI – 
Select; Stricture/stenosis (including anastomotic), GI – Select in the GASTROINTESTINAL CATEGORY. 
Cholecystitis 
Cholecystitis 
Asymptomatic, 
radiographic findings only 
Symptomatic, medical 
intervention indicated 
Interventional radiology, 
endoscopic, or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
sepsis or perforation)  
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection 
with unknown ANC – Select.  
Liver dysfunction/failure 
(clinical)  
Liver dysfunction  
— 
Jaundice  
Asterixis 
Encephalopathy or coma 
Death 
REMARK: Jaundice is not an AE, but occurs when the liver is not working properly or when a bile duct is blocked. It is graded as a result of liver dysfunction/failure or elevated bilirubin. 
ALSO CONSIDER: Bilirubin (hyperbilirubinemia). 
Pancreas, exocrine 
enzyme deficiency 
Pancreas, exocrine 
enzyme deficiency 
— 
Increase in stool 
frequency, bulk, or odor; 
steatorrhea 
Sequelae of absorption 
deficiency (e.g., weight 
loss)  
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Diarrhea. 
Pancreatitis  
Pancreatitis 
Asymptomatic, enzyme 
elevation and/or 
radiographic findings  
Symptomatic, medical 
intervention indicated 
Interventional radiology or 
operative intervention 
indicated 
Life-threatening 
consequences 
(e.g., circulatory failure, 
hemorrhage, sepsis) 
Death 
ALSO CONSIDER: Amylase. 
NAVIGATION NOTE: Stricture (biliary tree, hepatic or pancreatic) is graded as Stricture/stenosis (including anastomotic), GI – Select in the GASTROINTESTINAL CATEGORY. 
Hepatobiliary/Pancreas – 
Other (Specify, __) 
Hepatobiliary – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 128 of 165

 
INFECTION 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 35 - 
March 31, 2003, Publish Date: August 9, 2006 
Colitis, infectious 
(e.g., Clostridium difficile) 
Colitis, infectious  
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain with 
mucus and/or blood in 
stool 
IV antibiotics or TPN 
indicated  
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis or 
toxic megacolon); 
operative resection or 
diversion indicated 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select; Typhlitis (cecal inflammation).  
Febrile neutropenia 
(fever of unknown origin 
without clinically or 
microbiologically 
documented infection) 
(ANC <1.0 x 109/L, fever 
≥38.5°C) 
Febrile neutropenia 
— 
— 
Present 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
ALSO CONSIDER: Neutrophils/granulocytes (ANC/AGC). 
Infection  
(documented clinically or 
microbiologically) with 
Grade 3 or 4 neutrophils  
(ANC <1.0 x 109/L) 
– Select  
‘Select’ AEs appear at the 
end of the CATEGORY. 
Infection (documented 
clinically) with Grade 3 or 
4 ANC – Select 
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
REMARK: Fever with Grade 3 or 4 neutrophils in the absence of documented infection is graded as Febrile neutropenia (fever of unknown origin without clinically or microbiologically 
documented infection). 
ALSO CONSIDER: Neutrophils/granulocytes (ANC/AGC). 
Infection with normal 
ANC or Grade 1 or 2 
neutrophils  
– Select  
‘Select’ AEs appear at the 
end of the CATEGORY. 
Infection with normal 
ANC – Select 
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 129 of 165

 
INFECTION 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 36 - 
March 31, 2003, Publish Date: August 9, 2006 
Infection with unknown 
ANC 
– Select  
‘Select’ AEs appear at the 
end of the CATEGORY. 
Infection with unknown 
ANC – Select 
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
REMARK: Infection with unknown ANC – Select is to be used in the rare case when ANC is unknown. 
Opportunistic infection 
associated with ≥Grade 2 
Lymphopenia 
Opportunistic infection  
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
ALSO CONSIDER: Lymphopenia. 
Viral hepatitis 
Viral hepatitis 
Present; transaminases 
and liver function normal 
Transaminases 
abnormal, liver function 
normal  
Symptomatic liver 
dysfunction; fibrosis by 
biopsy; compensated 
cirrhosis 
Decompensated liver 
function (e.g., ascites, 
coagulopathy, 
encephalopathy, coma) 
Death 
REMARK: Non-viral hepatitis is graded as Infection – Select. 
ALSO CONSIDER: Albumin, serum-low (hypoalbuminemia); ALT, SGPT (serum glutamic pyruvic transaminase); AST, SGOT (serum glutamic oxaloacetic transaminase); Bilirubin 
(hyperbilirubinemia); Encephalopathy. 
Infection – Other 
(Specify, __) 
Infection – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 130 of 165

 
INFECTION – SELECT 
Page 3 of 3 
CTCAE v3.0  
- 37 - 
March 31, 2003, Publish Date: August 9, 2006 
AUDITORY/EAR 
– External ear (otitis externa) 
– Middle ear (otitis media) 
CARDIOVASCULAR 
– Artery 
– Heart (endocarditis) 
– Spleen 
– Vein 
DERMATOLOGY/SKIN  
– Lip/perioral 
– Peristomal 
– Skin (cellulitis) 
– Ungual (nails) 
GASTROINTESTINAL  
– Abdomen NOS 
– Anal/perianal 
– Appendix 
– Cecum 
– Colon 
– Dental-tooth 
– Duodenum 
– Esophagus 
– Ileum 
– Jejunum 
– Oral cavity-gums (gingivitis) 
– Peritoneal cavity 
– Rectum 
– Salivary gland 
– Small bowel NOS 
– Stomach 
GENERAL 
– Blood 
– Catheter-related 
– Foreign body (e.g., graft, implant,  
prosthesis, stent) 
– Wound  
HEPATOBILIARY/PANCREAS 
– Biliary tree 
– Gallbladder (cholecystitis) 
– Liver 
– Pancreas 
LYMPHATIC 
– Lymphatic 
MUSCULOSKELETAL 
– Bone (osteomyelitis) 
– Joint 
– Muscle (infection myositis) 
– Soft tissue NOS 
NEUROLOGY 
– Brain (encephalitis, infectious) 
– Brain + Spinal cord (encephalomyelitis) 
– Meninges (meningitis) 
– Nerve-cranial 
– Nerve-peripheral 
– Spinal cord (myelitis) 
OCULAR 
– Conjunctiva 
– Cornea 
– Eye NOS 
– Lens 
PULMONARY/UPPER RESPIRATORY 
– Bronchus 
– Larynx 
– Lung (pneumonia) 
– Mediastinum NOS 
– Mucosa 
– Neck NOS 
– Nose 
– Paranasal 
– Pharynx 
– Pleura (empyema) 
– Sinus 
– Trachea 
– Upper aerodigestive NOS 
– Upper airway NOS  
RENAL/GENITOURINARY  
– Bladder (urinary) 
– Kidney 
– Prostate 
– Ureter 
– Urethra 
– Urinary tract NOS 
SEXUAL/REPRODUCTIVE FUNCTION 
– Cervix 
– Fallopian tube 
– Pelvis NOS 
– Penis 
– Scrotum 
– Uterus 
– Vagina 
– Vulva 
 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 131 of 165

 
LYMPHATICS 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 38 - 
March 31, 2003, Publish Date: August 9, 2006 
Chyle or lymph leakage  
Chyle or lymph leakage 
Asymptomatic, clinical or 
radiographic findings 
Symptomatic, medical 
intervention indicated  
Interventional radiology 
or operative intervention 
indicated 
Life-threatening 
complications 
Death 
ALSO CONSIDER: Chylothorax. 
Dermal change 
lymphedema, 
phlebolymphedema  
Dermal change 
Trace thickening or faint 
discoloration 
Marked discoloration; 
leathery skin texture; 
papillary formation 
— 
— 
— 
REMARK: Dermal change lymphedema, phlebolymphedema refers to changes due to venous stasis. 
ALSO CONSIDER: Ulceration.  
Edema: 
head and neck 
Edema: head and neck 
Localized to dependent 
areas, no disability or 
functional impairment 
Localized facial or neck 
edema with functional 
impairment 
Generalized facial or 
neck edema with 
functional impairment 
(e.g., difficulty in turning 
neck or opening mouth 
compared to baseline) 
Severe with ulceration or 
cerebral edema; 
tracheotomy or feeding 
tube indicated 
Death 
Edema: 
limb 
Edema: limb 
5 – 10% inter-limb 
discrepancy in volume or 
circumference at point of 
greatest visible 
difference; swelling or 
obscuration of anatomic 
architecture on close 
inspection; pitting edema 
>10 – 30% inter-limb 
discrepancy in volume or 
circumference at point of 
greatest visible 
difference; readily 
apparent obscuration of 
anatomic architecture; 
obliteration of skin folds; 
readily apparent 
deviation from normal 
anatomic contour  
>30% inter-limb 
discrepancy in volume; 
lymphorrhea; gross 
deviation from normal 
anatomic contour; 
interfering with ADL 
Progression to 
malignancy (i.e., 
lymphangiosarcoma); 
amputation indicated; 
disabling 
Death 
Edema: 
trunk/genital 
Edema: trunk/genital 
Swelling or obscuration 
of anatomic architecture 
on close inspection; 
pitting edema 
Readily apparent 
obscuration of anatomic 
architecture; obliteration 
of skin folds; readily 
apparent deviation from 
normal anatomic contour 
Lymphorrhea; interfering 
with ADL; gross deviation 
from normal anatomic 
contour 
Progression to 
malignancy (i.e., 
lymphangiosarcoma); 
disabling  
Death 
Edema: 
viscera 
Edema: viscera 
Asymptomatic; clinical or 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and unable 
to aliment adequately 
orally; interventional 
radiology or operative 
intervention indicated  
Life-threatening 
consequences 
Death 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 132 of 165

 
LYMPHATICS 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 39 - 
March 31, 2003, Publish Date: August 9, 2006 
Lymphedema-related 
fibrosis 
Lymphedema-related 
fibrosis 
Minimal to moderate 
redundant soft tissue, 
unresponsive to elevation 
or compression, with 
moderately firm texture or 
spongy feel 
Marked increase in 
density and firmness, 
with or without tethering 
Very marked density and 
firmness with tethering 
affecting ≥40% of the 
edematous area 
— 
— 
Lymphocele 
Lymphocele 
Asymptomatic, clinical or 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and 
interventional radiology 
or operative intervention 
indicated 
— 
— 
Phlebolymphatic cording  
Phlebolymphatic cording 
Asymptomatic, clinical 
findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and leading 
to contracture or reduced 
range of motion 
— 
— 
Lymphatics – Other  
(Specify, __) 
Lymphatics – Other  
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling 
Death 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 133 of 165

 
METABOLIC/LABORATORY 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 40 - 
March 31, 2003, Publish Date: August 9, 2006 
Acidosis  
(metabolic or respiratory) 
Acidosis  
pH <normal, but ≥7.3 
— 
pH <7.3 
pH <7.3 with life-
threatening 
consequences 
Death 
Albumin, serum-low 
(hypoalbuminemia)  
Hypoalbuminemia 
<LLN – 3 g/dL  
<LLN – 30 g/L 
<3 – 2 g/dL 
<30 – 20 g/L  
<2 g/dL  
<20 g/L 
— 
Death 
Alkaline phosphatase 
Alkaline phosphatase 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Alkalosis  
(metabolic or respiratory) 
Alkalosis 
pH >normal, but ≤7.5 
— 
pH >7.5 
pH >7.5 with life-
threatening 
consequences 
Death 
ALT, SGPT  
(serum glutamic pyruvic 
transaminase) 
ALT 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Amylase 
Amylase 
>ULN – 1.5 x ULN 
>1.5 – 2.0 x ULN 
>2.0 – 5.0 x ULN 
>5.0 x ULN 
— 
AST, SGOT 
(serum glutamic 
oxaloacetic 
transaminase) 
AST 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Bicarbonate, serum-low  
Bicarbonate, serum-low 
<LLN – 16 mmol/L 
<16 – 11 mmol/L 
<11 – 8 mmol/L 
<8 mmol/L 
Death 
Bilirubin 
(hyperbilirubinemia) 
Bilirubin 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x ULN 
>3.0 – 10.0 x ULN 
>10.0 x ULN 
— 
REMARK: Jaundice is not an AE, but may be a manifestation of liver dysfunction/failure or elevated bilirubin. If jaundice is associated with elevated bilirubin, grade bilirubin. 
Calcium, serum-low 
(hypocalcemia) 
Hypocalcemia 
<LLN – 8.0 mg/dL 
<LLN – 2.0 mmol/L 
Ionized calcium: 
<LLN – 1.0 mmol/L 
<8.0 – 7.0 mg/dL 
<2.0 – 1.75 mmol/L 
Ionized calcium: 
<1.0 – 0.9 mmol/L 
<7.0 – 6.0 mg/dL 
<1.75 – 1.5 mmol/L 
Ionized calcium: 
<0.9 – 0.8 mmol/L 
<6.0 mg/dL 
<1.5 mmol/L 
Ionized calcium: 
<0.8 mmol/L 
Death 
REMARK: Calcium can be falsely low if hypoalbuminemia is present. Serum albumin is <4.0 g/dL, hypocalcemia is reported after the following corrective calculation has been 
performed: Corrected Calcium (mg/dL) = Total Calcium (mg/dL) – 0.8 [Albumin (g/dL) – 4] 4. Alternatively, direct measurement of ionized calcium is the definitive method to diagnose 
metabolically relevant alterations in serum calcium. 
                                            
4Crit Rev Clin Lab Sci 1984;21(1):51-97 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 134 of 165

 
METABOLIC/LABORATORY 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 41 - 
March 31, 2003, Publish Date: August 9, 2006 
Calcium, serum-high 
(hypercalcemia) 
Hypercalcemia 
>ULN – 11.5 mg/dL 
>ULN – 2.9 mmol/L 
Ionized calcium: 
>ULN – 1.5 mmol/L 
>11.5 – 12.5 mg/dL 
>2.9 – 3.1 mmol/L 
Ionized calcium: 
>1.5 – 1.6 mmol/L 
>12.5 – 13.5 mg/dL 
>3.1 – 3.4 mmol/L 
Ionized calcium: 
>1.6 – 1.8 mmol/L 
>13.5 mg/dL 
>3.4 mmol/L 
Ionized calcium: 
>1.8 mmol/L 
Death 
Cholesterol, serum-high 
(hypercholesteremia) 
Cholesterol 
>ULN – 300 mg/dL 
>ULN – 7.75 mmol/L 
>300 – 400 mg/dL 
>7.75 – 10.34 mmol/L 
>400 – 500 mg/dL 
>10.34 – 12.92 mmol/L 
>500 mg/dL 
>12.92 mmol/L 
Death 
CPK (creatine 
phosphokinase) 
CPK 
>ULN – 2.5 x ULN 
>2.5 x ULN – 5 x ULN 
>5 x ULN – 10 x ULN 
>10 x ULN 
Death 
Creatinine 
Creatinine 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x ULN 
>3.0 – 6.0 x ULN 
>6.0 x ULN 
Death 
REMARK: Adjust to age-appropriate levels for pediatric patients.  
ALSO CONSIDER: Glomerular filtration rate. 
GGT (γ-Glutamyl 
transpeptidase) 
GGT 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Glomerular filtration rate  
GFR 
<75 – 50% LLN 
<50 – 25% LLN 
<25% LLN, chronic 
dialysis not indicated 
Chronic dialysis or renal 
transplant indicated 
Death 
ALSO CONSIDER: Creatinine. 
Glucose, serum-high 
(hyperglycemia)  
Hyperglycemia 
>ULN – 160 mg/dL 
>ULN – 8.9 mmol/L 
>160 – 250 mg/dL 
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL 
>13.9 – 27.8 mmol/L 
>500 mg/dL 
>27.8 mmol/L or acidosis 
Death 
REMARK: Hyperglycemia, in general, is defined as fasting unless otherwise specified in protocol. 
Glucose, serum-low 
(hypoglycemia) 
Hypoglycemia 
<LLN – 55 mg/dL 
<LLN – 3.0 mmol/L 
<55 – 40 mg/dL 
<3.0 – 2.2 mmol/L 
<40 – 30 mg/dL 
<2.2 – 1.7 mmol/L 
<30 mg/dL 
<1.7 mmol/L 
Death 
Hemoglobinuria 
Hemoglobinuria 
Present 
— 
— 
— 
Death 
Lipase 
Lipase 
>ULN – 1.5 x ULN 
>1.5 – 2.0 x ULN 
>2.0 – 5.0 x ULN 
>5.0 x ULN 
— 
Magnesium, serum-high 
(hypermagnesemia) 
Hypermagnesemia 
>ULN – 3.0 mg/dL 
>ULN – 1.23 mmol/L 
— 
>3.0 – 8.0 mg/dL 
>1.23 – 3.30 mmol/L 
>8.0 mg/dL 
>3.30 mmol/L 
Death 
Magnesium, serum-low 
(hypomagnesemia)  
Hypomagnesemia 
<LLN – 1.2 mg/dL 
<LLN – 0.5 mmol/L 
<1.2 – 0.9 mg/dL 
<0.5 – 0.4 mmol/L 
<0.9 – 0.7 mg/dL 
<0.4 – 0.3 mmol/L 
<0.7 mg/dL 
<0.3 mmol/L 
Death 
Phosphate, serum-low 
(hypophosphatemia)  
Hypophosphatemia 
<LLN – 2.5 mg/dL 
<LLN – 0.8 mmol/L 
<2.5 – 2.0 mg/dL  
<0.8 – 0.6 mmol/L 
<2.0 – 1.0 mg/dL 
<0.6 – 0.3 mmol/L 
<1.0 mg/dL 
<0.3 mmol/L 
Death 
Potassium, serum-high 
(hyperkalemia) 
Hyperkalemia 
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L 
>6.0 – 7.0 mmol/L 
>7.0 mmol/L 
Death 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 135 of 165

 
METABOLIC/LABORATORY 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 42 - 
March 31, 2003, Publish Date: August 9, 2006 
Potassium, serum-low 
(hypokalemia)  
Hypokalemia 
<LLN – 3.0 mmol/L 
— 
<3.0 – 2.5 mmol/L 
<2.5 mmol/L 
Death 
Proteinuria 
Proteinuria 
1+ or 
0.15 – 1.0 g/24 hrs 
2+ to 3+ or 
>1.0 – 3.5 g/24 hrs  
4+ or 
>3.5 g/24 hrs 
Nephrotic syndrome 
Death 
Sodium, serum-high 
(hypernatremia) 
Hypernatremia 
>ULN – 150 mmol/L 
>150 – 155 mmol/L 
>155 – 160 mmol/L 
>160 mmol/L 
Death 
Sodium, serum-low 
(hyponatremia) 
Hyponatremia 
<LLN – 130 mmol/L 
— 
<130 – 120 mmol/L 
<120 mmol/L 
Death 
Triglyceride, serum-high 
(hypertriglyceridemia) 
Hypertriglyceridemia 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 10 x ULN 
>10 x ULN 
Death 
Uric acid, serum-high 
(hyperuricemia) 
Hyperuricemia 
>ULN – 10 mg/dL 
≤0.59 mmol/L without 
physiologic 
consequences 
— 
>ULN – 10 mg/dL 
≤0.59 mmol/L with 
physiologic 
consequences 
>10 mg/dL 
>0.59 mmol/L 
Death 
ALSO CONSIDER: Creatinine; Potassium, serum-high (hyperkalemia); Renal failure; Tumor lysis syndrome. 
Metabolic/Laboratory – 
Other (Specify, __) 
Metabolic/Lab – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 136 of 165

 
MUSCULOSKELETAL/SOFT TISSUE 
Page 1 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 43 - 
March 31, 2003, Publish Date: August 9, 2006 
Arthritis (non-septic) 
Arthritis 
Mild pain with 
inflammation, erythema, 
or joint swelling, but not 
interfering with function 
Moderate pain with 
inflammation, erythema, 
or joint swelling 
interfering with function, 
but not interfering with 
ADL 
Severe pain with 
inflammation, erythema, 
or joint swelling and 
interfering with ADL 
Disabling 
Death 
REMARK: Report only when the diagnosis of arthritis (e.g., inflammation of a joint or a state characterized by inflammation of joints) is made. Arthralgia (sign or symptom of pain in a 
joint, especially non-inflammatory in character) is graded as Pain – Select in the PAIN CATEGORY.  
Bone: 
spine-scoliosis 
Scoliosis  
≤20 degrees; clinically 
undetectable 
>20 – 45 degrees; visible 
by forward flexion; 
interfering with function 
but not interfering with 
ADL 
>45 degrees; scapular 
prominence in forward 
flexion; operative 
intervention indicated; 
interfering with ADL 
Disabling (e.g., interfering 
with cardiopulmonary 
function) 
Death 
Cervical spine-range of 
motion 
Cervical spine ROM 
Mild restriction of rotation 
or flexion between  
60 – 70 degrees 
Rotation <60 degrees to 
right or left; <60 degrees 
of flexion 
Ankylosed/fused over 
multiple segments with 
no C-spine rotation 
— 
— 
REMARK: 60 – 65 degrees of rotation is required for reversing a car; 60 – 65 degrees of flexion is required to tie shoes. 
Exostosis 
Exostosis 
Asymptomatic 
Involving multiple sites; 
pain or interfering with 
function  
Excision indicated 
Progression to 
malignancy (i.e., 
chondrosarcoma) 
Death 
Extremity-lower 
(gait/walking) 
Gait/walking 
Limp evident only to 
trained observer and able 
to walk ≥1 kilometer; 
cane indicated for 
walking 
Noticeable limp, or 
limitation of limb function, 
but able to walk ≥0.1 
kilometer (1 city block); 
quad cane indicated for 
walking 
Severe limp with stride 
modified to maintain 
balance (widened base of 
support, marked 
reduction in step length); 
ambulation limited to 
walker; crutches 
indicated 
Unable to walk 
— 
ALSO CONSIDER: Ataxia (incoordination); Muscle weakness, generalized or specific area (not due to neuropathy) – Select.  
Extremity-upper 
(function)  
Extremity-upper 
(function) 
Able to perform most 
household or work 
activities with affected 
limb 
Able to perform most 
household or work 
activities with 
compensation from 
unaffected limb 
Interfering with ADL  
Disabling; no function of 
affected limb 
— 
Fibrosis-cosmesis 
Fibrosis-cosmesis 
Visible only on close 
examination 
Readily apparent but not 
disfiguring 
Significant disfigurement; 
operative intervention 
indicated if patient 
chooses 
— 
— 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 137 of 165

 
MUSCULOSKELETAL/SOFT TISSUE 
Page 2 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 44 - 
March 31, 2003, Publish Date: August 9, 2006 
Fibrosis-deep connective 
tissue 
Fibrosis-deep connective 
tissue  
Increased density, 
“spongy” feel 
Increased density with 
firmness or tethering 
Increased density with 
fixation of tissue; 
operative intervention 
indicated; interfering with 
ADL 
Life-threatening; 
disabling; loss of limb; 
interfering with vital organ 
function 
Death 
ALSO CONSIDER: Induration/fibrosis (skin and subcutaneous tissue); Muscle weakness, generalized or specific area (not due to neuropathy) – Select; Neuropathy: motor; Neuropathy: 
sensory. 
Fracture 
Fracture 
Asymptomatic, 
radiographic findings only 
(e.g., asymptomatic rib 
fracture on plain x-ray, 
pelvic insufficiency 
fracture on MRI, etc.) 
Symptomatic but non-
displaced; immobilization 
indicated 
Symptomatic and 
displaced or open wound 
with bone exposure; 
operative intervention 
indicated 
Disabling; amputation 
indicated 
Death 
Joint-effusion 
Joint-effusion 
Asymptomatic, clinical or 
radiographic findings only 
Symptomatic; interfering 
with function but not 
interfering with ADL 
Symptomatic and 
interfering with ADL 
Disabling 
Death 
ALSO CONSIDER: Arthritis (non-septic). 
Joint-function5 
Joint-function 
Stiffness interfering with 
athletic activity; ≤25% 
loss of range of motion 
(ROM) 
Stiffness interfering with 
function but not 
interfering with ADL;  
>25 – 50% decrease in 
ROM 
Stiffness interfering with 
ADL; >50 – 75% 
decrease in ROM  
Fixed or non-functional 
joint (arthrodesis); 
>75% decrease in ROM 
— 
ALSO CONSIDER: Arthritis (non-septic). 
Local complication –
device/prosthesis-related 
Device/prosthesis 
Asymptomatic  
Symptomatic, but not 
interfering with ADL; local 
wound care; medical 
intervention indicated 
Symptomatic, interfering 
with ADL; operative 
intervention indicated 
(e.g., hardware/device 
replacement or removal, 
reconstruction)  
Life-threatening; 
disabling; loss of limb or 
organ 
Death 
Lumbar spine-range of 
motion 
Lumbar spine ROM 
Stiffness and difficulty 
bending to the floor to 
pick up a very light object 
but able to do activity 
Some lumbar spine 
flexion but requires a 
reaching aid to pick up a 
very light object from the 
floor 
Ankylosed/fused over 
multiple segments with 
no L-spine flexion (i.e., 
unable to reach to floor to 
pick up a very light 
— 
— 
                                            
5 Adapted from the International SFTR Method of Measuring and Recording Joint Motion, International Standard Orthopedic Measurements (ISOM), Jon J. Gerhardt and Otto A. 
Russee, Bern, Switzerland, Han Huber 9 Publisher), 1975. 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 138 of 165

 
MUSCULOSKELETAL/SOFT TISSUE 
Page 3 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 45 - 
March 31, 2003, Publish Date: August 9, 2006 
object) 
Muscle weakness, 
generalized or specific 
area (not due to 
neuropathy)  
– Select: 
Muscle weakness  
– Select  
– Extraocular 
– Extremity-lower  
– Extremity-upper 
– Facial 
– Left-sided 
– Ocular 
– Pelvic 
– Right-sided 
– Trunk 
– Whole body/generalized  
Asymptomatic, weakness 
on physical exam 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Life-threatening; disabling 
Death 
ALSO CONSIDER: Fatigue (asthenia, lethargy, malaise). 
Muscular/skeletal 
hypoplasia 
Muscular/skeletal 
hypoplasia 
Cosmetically and 
functionally insignificant 
hypoplasia  
Deformity, hypoplasia, or 
asymmetry able to be 
remediated by prosthesis 
(e.g., shoe insert) or 
covered by clothing  
Functionally significant 
deformity, hypoplasia, or 
asymmetry, unable to be 
remediated by prosthesis 
or covered by clothing  
Disabling 
— 
Myositis 
(inflammation/damage of 
muscle) 
Myositis 
Mild pain, not interfering 
with function 
Pain interfering with 
function, but not 
interfering with ADL 
Pain interfering with ADL 
Disabling 
Death 
REMARK: Myositis implies muscle damage (i.e., elevated CPK). 
ALSO CONSIDER: CPK (creatine phosphokinase); Pain – Select. 
Osteonecrosis  
(avascular necrosis) 
Osteonecrosis 
Asymptomatic, 
radiographic findings only 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL; minimal bone 
removal indicated (i.e., 
minor sequestrectomy)  
Symptomatic and 
interfering with ADL; 
operative intervention or 
hyperbaric oxygen 
indicated 
Disabling  
Death 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 139 of 165

 
MUSCULOSKELETAL/SOFT TISSUE 
Page 4 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 46 - 
March 31, 2003, Publish Date: August 9, 2006 
Osteoporosis6 
Osteoporosis 
Radiographic evidence of 
osteoporosis or Bone 
Mineral Density (BMD) 
t-score –1 to –2.5 
(osteopenia) and no loss 
of height or therapy 
indicated 
BMD t-score < –2.5; loss 
of height <2 cm; anti-
osteoporotic therapy 
indicated 
Fractures; loss of height 
≥2 cm 
Disabling 
Death 
Seroma 
Seroma 
Asymptomatic 
Symptomatic; medical 
intervention or simple 
aspiration indicated 
Symptomatic, 
interventional radiology 
or operative intervention 
indicated 
— 
— 
Soft tissue necrosis 
– Select: 
– Abdomen 
– Extremity-lower 
– Extremity-upper  
– Head 
– Neck 
– Pelvic 
– Thorax 
Soft tissue necrosis 
– Select 
— 
Local wound care; 
medical intervention 
indicated 
Operative debridement or 
other invasive 
intervention indicated 
(e.g., hyperbaric oxygen)  
Life-threatening 
consequences; major 
invasive intervention 
indicated (e.g., tissue 
reconstruction, flap, or 
grafting) 
Death 
Trismus (difficulty, 
restriction or pain when 
opening mouth) 
Trismus 
Decreased range of 
motion without impaired 
eating  
Decreased range of 
motion requiring small 
bites, soft foods or 
purees 
Decreased range of 
motion with inability to 
adequately aliment or 
hydrate orally 
— 
— 
NAVIGATION NOTE: Wound-infectious is graded as Infection – Select in the INFECTION CATEGORY. 
NAVIGATION NOTE: Wound non-infectious is graded as Wound complication, non-infectious in the DERMATOLOGY/SKIN CATEGORY.  
Musculoskeletal/Soft 
Tissue – Other 
(Specify, __) 
Musculoskeletal – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
                                            
6 "Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis," Report of a WHO Study Group Technical Report Series, No. 843, 1994, v + 129 
pages [C*, E, F, R, S], ISBN 92 4 120843 0, Sw.fr. 22.-/US $19.80; in developing countries: Sw.fr. 15.40, Order no. 1100843 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 140 of 165

 
NEUROLOGY 
Page 1 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 47 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: ADD (Attention Deficit Disorder) is graded as Cognitive disturbance. 
NAVIGATION NOTE: Aphasia, receptive and/or expressive, is graded as Speech impairment (e.g., dysphasia or aphasia). 
Apnea 
Apnea 
— 
— 
Present 
Intubation indicated  
Death 
Arachnoiditis/ 
meningismus/radiculitis 
Arachnoiditis 
Symptomatic, not 
interfering with function; 
medical intervention 
indicated 
Symptomatic (e.g., 
photophobia, nausea) 
interfering with function 
but not interfering with 
ADL  
Symptomatic, interfering 
with ADL 
Life-threatening; disabling 
(e.g., paraplegia) 
Death 
ALSO CONSIDER: Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 109/L); Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select; Pain – Select; Vomiting. 
Ataxia (incoordination) 
Ataxia 
Asymptomatic  
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL; mechanical 
assistance indicated  
Disabling 
Death 
REMARK: Ataxia (incoordination) refers to the consequence of medical or operative intervention. 
Brachial plexopathy 
Brachial plexopathy 
Asymptomatic 
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
Disabling 
Death 
CNS cerebrovascular 
ischemia 
CNS ischemia 
— 
Asymptomatic, 
radiographic findings only 
Transient ischemic event 
or attack (TIA) ≤24 hrs 
duration 
Cerebral vascular 
accident (CVA, stroke), 
neurologic deficit 
>24 hrs  
Death 
NAVIGATION NOTE: CNS hemorrhage/bleeding is graded as Hemorrhage, CNS in the HEMORRHAGE/BLEEDING CATEGORY.  
CNS necrosis/cystic 
progression 
CNS necrosis 
Asymptomatic, 
radiographic findings only 
Symptomatic, not 
interfering with ADL; 
medical intervention 
indicated 
Symptomatic and 
interfering with ADL; 
hyperbaric oxygen 
indicated 
Life-threatening; 
disabling; operative 
intervention indicated to 
prevent or treat CNS 
necrosis/cystic 
progression 
Death 
Cognitive disturbance 
Cognitive disturbance 
Mild cognitive disability; 
not interfering with 
work/school/life 
performance; specialized 
educational 
services/devices not 
indicated 
Moderate cognitive 
disability; interfering with 
work/school/life 
performance but capable 
of independent living; 
specialized resources on 
part-time basis indicated 
Severe cognitive 
disability; significant 
impairment of 
work/school/life 
performance 
Unable to perform ADL; 
full-time specialized 
resources or 
institutionalization 
indicated 
Death 
REMARK: Cognitive disturbance may be used for Attention Deficit Disorder (ADD). 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 141 of 165

 
NEUROLOGY 
Page 2 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 48 - 
March 31, 2003, Publish Date: August 9, 2006 
Confusion 
Confusion 
Transient confusion, 
disorientation, or attention 
deficit 
Confusion, disorientation, 
or attention deficit 
interfering with function, 
but not interfering with 
ADL 
Confusion or delirium 
interfering with ADL 
Harmful to others or self; 
hospitalization indicated 
Death 
REMARK: Attention Deficit Disorder (ADD) is graded as Cognitive disturbance. 
NAVIGATION NOTE: Cranial neuropathy is graded as Neuropathy-cranial – Select. 
Dizziness  
Dizziness 
With head movements or 
nystagmus only; not 
interfering with function 
Interfering with function, 
but not interfering with 
ADL 
Interfering with ADL 
Disabling 
— 
REMARK: Dizziness includes disequilibrium, lightheadedness, and vertigo. 
ALSO CONSIDER: Neuropathy: cranial – Select; Syncope (fainting). 
NAVIGATION NOTE: Dysphasia, receptive and/or expressive, is graded as Speech impairment (e.g., dysphasia or aphasia). 
Encephalopathy 
Encephalopathy 
— 
Mild signs or symptoms; 
not interfering with ADL 
Signs or symptoms 
interfering with ADL; 
hospitalization indicated 
Life-threatening; disabling 
Death 
ALSO CONSIDER: Cognitive disturbance; Confusion; Dizziness; Memory impairment; Mental status; Mood alteration – Select; Psychosis (hallucinations/delusions); 
Somnolence/depressed level of consciousness. 
Extrapyramidal/ 
involuntary movement/ 
restlessness 
Involuntary movement 
Mild involuntary 
movements not 
interfering with function 
Moderate involuntary 
movements interfering 
with function, but not 
interfering with ADL 
Severe involuntary 
movements or torticollis 
interfering with ADL 
Disabling 
 
Death 
NAVIGATION NOTE: Headache/neuropathic pain (e.g., jaw pain, neurologic pain, phantom limb pain, post-infectious neuralgia, or painful neuropathies) is graded as Pain – Select in the 
PAIN CATEGORY. 
Hydrocephalus 
Hydrocephalus 
Asymptomatic, 
radiographic findings only 
Mild to moderate 
symptoms not interfering 
with ADL 
Severe symptoms or 
neurological deficit 
interfering with ADL 
Disabling  
Death 
Irritability (children <3 
years of age) 
Irritability 
Mild; easily consolable 
Moderate; requiring 
increased attention 
Severe; inconsolable 
— 
— 
Laryngeal nerve 
dysfunction  
Laryngeal nerve 
Asymptomatic, weakness 
on clinical 
examination/testing only 
Symptomatic, but not 
interfering with ADL; 
intervention not indicated 
Symptomatic, interfering 
with ADL; intervention 
indicated (e.g., 
thyroplasty, vocal cord 
injection) 
Life-threatening; 
tracheostomy indicated 
 
Death 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 142 of 165

 
NEUROLOGY 
Page 3 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 49 - 
March 31, 2003, Publish Date: August 9, 2006 
Leak, cerebrospinal fluid 
(CSF) 
CSF leak 
Transient headache; 
postural care indicated 
Symptomatic, not 
interfering with ADL; 
blood patch indicated 
Symptomatic, interfering 
with ADL; operative 
intervention indicated 
Life-threatening; disabling 
Death 
REMARK: Leak, cerebrospinal fluid (CSF) may be used for CSF leak associated with operation and persisting >72 hours. 
Leukoencephalopathy 
(radiographic findings) 
Leukoencephalopathy  
Mild increase in 
subarachnoid space 
(SAS); mild 
ventriculomegaly; small 
(+/- multiple) focal T2 
hyperintensities, involving 
periventricular white 
matter or <1/3 of 
susceptible areas of 
cerebrum 
Moderate increase in 
SAS; moderate 
ventriculomegaly; focal 
T2 hyperintensities 
extending into centrum 
ovale or involving 1/3 to 
2/3 of susceptible areas 
of cerebrum 
Severe increase in SAS; 
severe ventriculomegaly; 
near total white matter T2 
hyperintensities or diffuse 
low attenuation (CT) 
— 
— 
REMARK: Leukoencephalopathy is a diffuse white matter process, specifically NOT associated with necrosis. Leukoencephalopathy (radiographic findings) does not include lacunas, 
which are areas that become void of neural tissue.  
Memory impairment 
Memory impairment 
Memory impairment not 
interfering with function 
Memory impairment 
interfering with function, 
but not interfering with 
ADL 
Memory impairment 
interfering with ADL 
Amnesia 
— 
Mental status7 
Mental status 
— 
1 – 3 point below age  
and educational norm in 
Folstein Mini-Mental 
Status Exam (MMSE) 
>3 point below age and 
educational norm in 
Folstein MMSE  
— 
— 
Mood alteration  
– Select: 
– Agitation 
– Anxiety 
– Depression 
– Euphoria 
Mood alteration – Select 
Mild mood alteration not 
interfering with function 
Moderate mood alteration 
interfering with function, 
but not interfering with 
ADL; medication 
indicated 
Severe mood alteration 
interfering with ADL 
Suicidal ideation; danger 
to self or others 
Death 
Myelitis 
Myelitis 
Asymptomatic, mild signs 
(e.g., Babinski’s or 
Lhermitte’s sign) 
Weakness or sensory 
loss not interfering with 
ADL 
Weakness or sensory 
loss interfering with ADL 
Disabling 
Death 
                                            
7 Folstein MF, Folstein, SE and McHugh PR (1975) "Mini-Mental State: A Practical Method for Grading the State of Patients for the Clinician," Journal of Psychiatric Research, 12: 
189-198 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 143 of 165

 
NEUROLOGY 
Page 4 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 50 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Neuropathic pain is graded as Pain – Select in the PAIN CATEGORY.  
Neuropathy: 
cranial  
– Select: 
Neuropathy: cranial  
– Select 
Asymptomatic, detected 
on exam/testing only 
– CN I  
Smell 
– CN II  Vision 
– CN III  Pupil, upper eyelid, extra ocular movements 
– CN IV  Downward, inward movement of eye 
– CN V  Motor-jaw muscles; Sensory-facial 
– CN VI  Lateral deviation of eye 
– CN VII Motor-face; Sensory-taste 
– CN VIII Hearing and balance 
– CN IX Motor-pharynx; Sensory-ear, pharynx, tongue 
– CN X 
Motor-palate; pharynx, larynx 
– CN XI Motor-sternomastoid and trapezius 
– CN XII Motor-tongue 
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
Life-threatening; disabling 
Death 
Neuropathy: 
motor  
Neuropathy-motor 
Asymptomatic, weakness 
on exam/testing only 
Symptomatic weakness 
interfering with function, 
but not interfering with 
ADL 
Weakness interfering with 
ADL; bracing or 
assistance to walk (e.g., 
cane or walker) indicated 
Life-threatening; disabling 
(e.g., paralysis)  
Death 
REMARK: Cranial nerve motor neuropathy is graded as Neuropathy: cranial – Select. 
ALSO CONSIDER: Laryngeal nerve dysfunction; Phrenic nerve dysfunction.  
Neuropathy: 
sensory 
Neuropathy-sensory 
Asymptomatic; loss of 
deep tendon reflexes or 
paresthesia (including 
tingling) but not 
interfering with function 
Sensory alteration or 
paresthesia (including 
tingling), interfering with 
function, but not 
interfering with ADL 
Sensory alteration or 
paresthesia interfering 
with ADL  
Disabling  
Death 
REMARK: Cranial nerve sensory neuropathy is graded as Neuropathy: cranial – Select. 
Personality/behavioral 
Personality 
Change, but not 
adversely affecting 
patient or family 
Change, adversely 
affecting patient or family  
Mental health intervention 
indicated 
Change harmful to others 
or self; hospitalization 
indicated 
Death 
Phrenic nerve dysfunction  Phrenic nerve 
Asymptomatic weakness 
on exam/testing only 
Symptomatic but not 
interfering with ADL; 
intervention not indicated 
Significant dysfunction; 
intervention indicated 
(e.g., diaphragmatic 
plication) 
Life-threatening 
respiratory compromise; 
mechanical ventilation 
indicated 
Death 
Psychosis (hallucinations/ 
delusions) 
Psychosis 
— 
Transient episode 
Interfering with ADL; 
medication, supervision 
Harmful to others or self; 
life-threatening 
Death 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 144 of 165

 
NEUROLOGY 
Page 5 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 51 - 
March 31, 2003, Publish Date: August 9, 2006 
or restraints indicated  
consequences 
Pyramidal tract 
dysfunction (e.g., ↑ tone, 
hyperreflexia, positive 
Babinski, ↓ fine motor 
coordination) 
Pyramidal tract 
dysfunction 
Asymptomatic, 
abnormality on exam or 
testing only  
Symptomatic; interfering 
with function but not 
interfering with ADL 
Interfering with ADL 
Disabling; paralysis 
Death 
Seizure 
Seizure 
— 
One brief generalized 
seizure; seizure(s) well 
controlled by 
anticonvulsants or 
infrequent focal motor 
seizures not interfering 
with ADL 
Seizures in which 
consciousness is altered; 
poorly controlled seizure 
disorder, with 
breakthrough generalized 
seizures despite medical 
intervention 
Seizures of any kind 
which are prolonged, 
repetitive, or difficult to 
control (e.g., status 
epilepticus, intractable 
epilepsy) 
Death 
Somnolence/depressed 
level of consciousness 
Somnolence 
— 
Somnolence or sedation 
interfering with function, 
but not interfering with 
ADL 
Obtundation or stupor; 
difficult to arouse; 
interfering with ADL 
Coma 
Death 
Speech impairment  
(e.g., dysphasia or 
aphasia)  
Speech impairment 
— 
Awareness of receptive 
or expressive dysphasia, 
not impairing ability to 
communicate 
Receptive or expressive 
dysphasia, impairing 
ability to communicate 
Inability to communicate 
— 
REMARK: Speech impairment refers to a primary CNS process, not neuropathy or end organ dysfunction. 
ALSO CONSIDER: Laryngeal nerve dysfunction; Voice changes/dysarthria (e.g., hoarseness, loss, or alteration in voice, laryngitis). 
Syncope (fainting) 
Syncope (fainting) 
— 
— 
Present 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: CNS cerebrovascular ischemia; Conduction abnormality/atrioventricular heart block – Select; Dizziness; Supraventricular and nodal arrhythmia – Select; Vasovagal 
episode; Ventricular arrhythmia – Select. 
NAVIGATION NOTE: Taste alteration (CN VII, IX) is graded as Taste alteration (dysgeusia) in the GASTROINTESTINAL CATEGORY. 
Tremor 
Tremor 
Mild and brief or 
intermittent but not 
interfering with function 
Moderate tremor 
interfering with function, 
but not interfering with 
ADL 
Severe tremor interfering 
with ADL 
Disabling 
— 
Neurology – Other 
(Specify, __) 
Neurology – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 145 of 165

 
OCULAR/VISUAL 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 52 - 
March 31, 2003, Publish Date: August 9, 2006 
Cataract 
Cataract 
Asymptomatic, detected 
on exam only  
Symptomatic, with 
moderate decrease in 
visual acuity  
(20/40 or better); 
decreased visual function 
correctable with glasses  
Symptomatic with marked 
decrease in visual acuity 
(worse than 20/40); 
operative intervention 
indicated (e.g., cataract 
surgery) 
— 
— 
Dry eye syndrome  
Dry eye 
Mild, intervention not 
indicated 
Symptomatic, interfering 
with function but not 
interfering with ADL; 
medical intervention 
indicated  
Symptomatic or decrease 
in visual acuity interfering 
with ADL; operative 
intervention indicated 
— 
— 
Eyelid dysfunction  
Eyelid dysfunction 
Asymptomatic  
Symptomatic, interfering 
with function but not ADL; 
requiring topical agents or 
epilation 
Symptomatic; interfering 
with ADL; surgical 
intervention indicated 
— 
— 
REMARK: Eyelid dysfunction includes canalicular stenosis, ectropion, entropion, erythema, madarosis, symblepharon, telangiectasis, thickening, and trichiasis. 
ALSO CONSIDER: Neuropathy: cranial – Select. 
Glaucoma  
Glaucoma 
Elevated intraocular 
pressure (EIOP) with 
single topical agent for 
intervention; no visual 
field deficit 
EIOP causing early visual 
field deficit (i.e., nasal 
step or arcuate deficit); 
multiple topical or oral 
agents indicated 
EIOP causing marked 
visual field deficits (i.e., 
involving both superior 
and inferior visual fields); 
operative intervention 
indicated 
EIOP resulting in 
blindness (20/200 or 
worse); enucleation 
indicated 
— 
Keratitis (corneal 
inflammation/corneal 
ulceration) 
Keratitis 
Abnormal ophthalmologic 
changes only; 
intervention not indicated 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL; 
operative intervention 
indicated 
Perforation or blindness 
(20/200 or worse)  
— 
NAVIGATION NOTE: Ocular muscle weakness is graded as Muscle weakness, generalized or specific area (not due to neuropathy) – Select in the MUSCULOSKELETAL/SOFT TISSUE 
CATEGORY.  
Night blindness 
(nyctalopia) 
Nyctalopia 
Symptomatic, not 
interfering with function 
Symptomatic and 
interfering with function 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL  
Disabling 
— 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 146 of 165

 
OCULAR/VISUAL 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 53 - 
March 31, 2003, Publish Date: August 9, 2006 
Nystagmus 
Nystagmus 
Asymptomatic 
Symptomatic and 
interfering with function 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
ALSO CONSIDER: Neuropathy: cranial – Select; Ophthalmoplegia/diplopia (double vision). 
Ocular surface disease  
Ocular surface disease  
Asymptomatic or 
minimally symptomatic 
but not interfering with 
function 
Symptomatic, interfering 
with function but not 
interfering with ADL; 
topical antibiotics or other 
topical intervention 
indicated 
Symptomatic, interfering 
with ADL; operative 
intervention indicated 
— 
— 
REMARK: Ocular surface disease includes conjunctivitis, keratoconjunctivitis sicca, chemosis, keratinization, and palpebral conjunctival epithelial metaplasia. 
Ophthalmoplegia/ 
diplopia (double vision) 
Diplopia 
Intermittently 
symptomatic, intervention 
not indicated 
Symptomatic and 
interfering with function 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL; 
surgical intervention 
indicated 
Disabling 
— 
ALSO CONSIDER: Neuropathy: cranial – Select. 
Optic disc edema 
Optic disc edema 
Asymptomatic 
Decreased visual acuity 
(20/40 or better); visual 
field defect present 
Decreased visual acuity 
(worse than 20/40); 
marked visual field defect 
but sparing the central 20 
degrees 
Blindness  
(20/200 or worse) 
— 
ALSO CONSIDER: Neuropathy: cranial – Select.  
Proptosis/enophthalmos 
Proptosis/enophthalmos 
Asymptomatic, 
intervention not indicated 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
— 
— 
Retinal detachment 
Retinal detachment 
Exudative; no central 
vision loss; intervention 
not indicated 
Exudative and visual 
acuity 20/40 or better but 
intervention not indicated 
Rhegmatogenous or 
exudative detachment; 
operative intervention 
indicated 
Blindness 
(20/200 or worse) 
— 
Retinopathy  
Retinopathy 
Asymptomatic  
Symptomatic with 
moderate decrease in 
visual acuity 
(20/40 or better) 
Symptomatic with marked 
decrease in visual acuity 
(worse than 20/40) 
Blindness 
(20/200 or worse) 
— 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 147 of 165

 
OCULAR/VISUAL 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 54 - 
March 31, 2003, Publish Date: August 9, 2006 
Scleral necrosis/melt 
Scleral necrosis 
Asymptomatic or 
symptomatic but not 
interfering with function 
Symptomatic, interfering 
with function but not 
interfering with ADL; 
moderate decrease in 
visual acuity (20/40 or 
better); medical 
intervention indicated 
Symptomatic, interfering 
with ADL; marked 
decrease in visual acuity 
(worse than 20/40); 
operative intervention 
indicated 
Blindness (20/200 or 
worse); painful eye with 
enucleation indicated 
— 
Uveitis  
Uveitis 
Asymptomatic 
Anterior uveitis; medical 
intervention indicated 
Posterior or pan-uveitis; 
operative intervention 
indicated 
Blindness 
(20/200 or worse) 
— 
Vision-blurred vision 
Blurred vision 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
Vision-flashing 
lights/floaters 
Flashing lights 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
Vision-photophobia 
Photophobia 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
Vitreous hemorrhage 
Vitreous hemorrhage 
Asymptomatic, clinical 
findings only 
Symptomatic, interfering 
with function, but not 
interfering with ADL; 
intervention not indicated 
Symptomatic, interfering 
with ADL; vitrectomy 
indicated  
— 
— 
Watery eye (epiphora, 
tearing) 
Watery eye 
Symptomatic, intervention 
not indicated 
Symptomatic, interfering 
with function but not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
— 
— 
Ocular/Visual – Other  
(Specify, __) 
Ocular – Other  
(Specify) 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Blindness 
(20/200 or worse) 
Death 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 148 of 165

 
PAIN 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 55 - 
March 31, 2003, Publish Date: August 9, 2006 
Pain  
– Select: 
‘Select’ AEs appear at the 
end of the CATEGORY. 
Pain – Select  
Mild pain not interfering 
with function 
Moderate pain; pain or 
analgesics interfering with 
function, but not 
interfering with ADL 
Severe pain; pain or 
analgesics severely 
interfering with ADL 
Disabling 
— 
Pain – Other 
(Specify, __) 
Pain – Other (Specify) 
Mild pain not interfering 
with function 
Moderate pain; pain or 
analgesics interfering with 
function, but not 
interfering with ADL 
Severe pain; pain or 
analgesics severely 
interfering with ADL 
Disabling 
— 
PAIN – SELECT 
AUDITORY/EAR 
– External ear 
– Middle ear 
CARDIOVASCULAR 
– Cardiac/heart  
– Pericardium 
DERMATOLOGY/SKIN 
– Face 
– Lip 
– Oral-gums 
– Scalp 
– Skin 
GASTROINTESTINAL 
– Abdomen NOS 
– Anus 
– Dental/teeth/peridontal 
– Esophagus 
– Oral cavity 
– Peritoneum 
– Rectum 
– Stomach 
GENERAL 
– Pain NOS 
– Tumor pain  
HEPATOBILIARY/PANCREAS 
– Gallbladder 
– Liver  
LYMPHATIC 
– Lymph node 
MUSCULOSKELETAL 
– Back 
– Bone 
– Buttock 
– Extremity-limb 
– Intestine 
– Joint 
– Muscle 
– Neck 
– Phantom (pain associated with missing limb) 
NEUROLOGY 
– Head/headache 
– Neuralgia/peripheral nerve 
OCULAR 
– Eye 
PULMONARY/UPPER RESPIRATORY 
– Chest wall 
– Chest/thorax NOS 
PULMONARY/UPPER RESPIRATORY (continued) 
– Larynx 
– Pleura 
– Sinus 
– Throat/pharynx/larynx 
RENAL/GENITOURINARY 
– Bladder 
– Kidney 
SEXUAL/REPRODUCTIVE FUNCTION 
– Breast 
– Ovulatory 
– Pelvis 
– Penis 
– Perineum 
– Prostate 
– Scrotum 
– Testicle 
– Urethra 
– Uterus 
– Vagina 
 
 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 149 of 165

 
PULMONARY/UPPER RESPIRATORY 
Page 1 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 56 - 
March 31, 2003, Publish Date: August 9, 2006 
Adult Respiratory 
Distress Syndrome 
(ARDS) 
ARDS 
— 
— 
Present, intubation not 
indicated  
Present, intubation 
indicated 
Death 
ALSO CONSIDER: Dyspnea (shortness of breath); Hypoxia; Pneumonitis/pulmonary infiltrates. 
Aspiration 
Aspiration 
Asymptomatic (“silent 
aspiration”); endoscopy 
or radiographic (e.g., 
barium swallow) findings  
Symptomatic (e.g., 
altered eating habits, 
coughing or choking 
episodes consistent with 
aspiration); medical 
intervention indicated 
(e.g., antibiotics, suction 
or oxygen) 
Clinical or radiographic 
signs of pneumonia or 
pneumonitis; unable to 
aliment orally 
Life-threatening (e.g., 
aspiration pneumonia or 
pneumonitis)  
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils 
– Select; Infection with unknown ANC – Select; Laryngeal nerve dysfunction; Neuropathy: cranial – Select; Pneumonitis/pulmonary infiltrates. 
Atelectasis  
Atelectasis  
Asymptomatic  
Symptomatic (e.g., 
dyspnea, cough), medical 
intervention indicated 
(e.g., bronchoscopic 
suctioning, chest 
physiotherapy, 
suctioning)  
Operative (e.g., stent, 
laser) intervention 
indicated  
Life-threatening 
respiratory compromise 
Death 
ALSO CONSIDER: Adult Respiratory Distress Syndrome (ARDS); Cough; Dyspnea (shortness of breath); Hypoxia; Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select; Obstruction/stenosis of airway – 
Select; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes). 
Bronchospasm, 
wheezing  
Bronchospasm 
Asymptomatic  
Symptomatic not 
interfering with function 
Symptomatic interfering 
with function 
Life-threatening 
Death 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever); Dyspnea (shortness of breath).  
Carbon monoxide 
diffusion capacity (DLCO) 
DLCO 
90 – 75% of predicted 
value 
<75 – 50% of predicted 
value 
<50 – 25% of predicted 
value 
<25% of predicted value 
Death 
ALSO CONSIDER: Hypoxia; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes). 
Chylothorax  
Chylothorax 
Asymptomatic 
Symptomatic; 
thoracentesis or tube 
drainage indicated  
Operative intervention 
indicated 
Life-threatening (e.g., 
hemodynamic instability 
or ventilatory support 
indicated) 
Death 
Cough 
Cough 
Symptomatic, non-
narcotic medication only 
indicated  
Symptomatic and 
narcotic medication 
indicated  
Symptomatic and 
significantly interfering 
with sleep or ADL 
— 
— 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 150 of 165

 
PULMONARY/UPPER RESPIRATORY 
Page 2 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 57 - 
March 31, 2003, Publish Date: August 9, 2006 
Dyspnea (shortness of 
breath)  
Dyspnea  
Dyspnea on exertion, but 
can walk 1 flight of stairs 
without stopping 
Dyspnea on exertion but 
unable to walk 1 flight of 
stairs or 1 city block 
(0.1km) without stopping 
Dyspnea with ADL 
Dyspnea at rest; 
intubation/ventilator 
indicated  
Death 
ALSO CONSIDER: Hypoxia; Neuropathy: motor; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes). 
Edema, larynx  
Edema, larynx 
Asymptomatic edema by 
exam only 
Symptomatic edema, no 
respiratory distress  
Stridor; respiratory 
distress; interfering with 
ADL 
Life-threatening airway 
compromise; 
tracheotomy, intubation, 
or laryngectomy indicated 
Death 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever). 
FEV1  
FEV1 
90 – 75% of predicted 
value 
<75 – 50% of predicted 
value 
<50 – 25% of predicted 
value 
<25% of predicted 
Death 
Fistula, pulmonary/upper 
respiratory  
– Select: 
– Bronchus 
– Larynx 
– Lung 
– Oral cavity 
– Pharynx  
– Pleura 
– Trachea 
Fistula, pulmonary  
– Select  
Asymptomatic, 
radiographic findings only 
Symptomatic, tube 
thoracostomy or medical 
management indicated; 
associated with altered 
respiratory function but 
not interfering with ADL 
Symptomatic and 
associated with altered 
respiratory function 
interfering with ADL; or 
endoscopic (e.g., stent) 
or primary closure by 
operative intervention 
indicated 
Life-threatening 
consequences; operative 
intervention with 
thoracoplasty, chronic 
open drainage or multiple 
thoracotomies indicated 
Death 
REMARK: A fistula is defined as an abnormal communication between two body cavities, potential spaces, and/or the skin. The site indicated for a fistula should be the site from which 
the abnormal process is believed to have arisen. For example, a tracheo-esophageal fistula arising in the context of a resected or irradiated esophageal cancer should be graded as 
Fistula, GI – esophagus in the GASTROINTESTINAL CATEGORY. 
NAVIGATION NOTE: Hemoptysis is graded as Hemorrhage, pulmonary/upper respiratory – Select in the HEMORRHAGE/BLEEDING CATEGORY.  
Hiccoughs (hiccups, 
singultus) 
Hiccoughs 
Symptomatic, 
intervention not indicated 
Symptomatic, 
intervention indicated  
Symptomatic, 
significantly interfering 
with sleep or ADL 
— 
— 
Hypoxia 
Hypoxia 
— 
Decreased O2 saturation 
with exercise (e.g., pulse 
oximeter <88%); 
intermittent supplemental 
oxygen  
Decreased O2 saturation 
at rest; continuous 
oxygen indicated 
Life-threatening; 
intubation or ventilation 
indicated  
Death 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 151 of 165

 
PULMONARY/UPPER RESPIRATORY 
Page 3 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 58 - 
March 31, 2003, Publish Date: August 9, 2006 
Nasal cavity/paranasal 
sinus reactions 
Nasal/paranasal 
reactions 
Asymptomatic mucosal 
crusting, blood-tinged 
secretions 
Symptomatic stenosis or 
edema/narrowing 
interfering with airflow 
Stenosis with significant 
nasal obstruction; 
interfering with ADL 
Necrosis of soft tissue or 
bone 
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils 
– Select; Infection with unknown ANC – Select. 
Obstruction/stenosis of 
airway 
– Select: 
– Bronchus 
– Larynx 
– Pharynx 
– Trachea 
Airway obstruction  
– Select  
Asymptomatic obstruction 
or stenosis on exam, 
endoscopy, or radiograph 
Symptomatic (e.g., noisy 
airway breathing), but 
causing no respiratory 
distress; medical 
management indicated 
(e.g., steroids)  
Interfering with ADL; 
stridor or endoscopic 
intervention indicated 
(e.g., stent, laser)  
Life-threatening airway 
compromise; tracheotomy 
or intubation indicated 
Death 
Pleural effusion 
(non-malignant)  
Pleural effusion 
Asymptomatic 
Symptomatic, 
intervention such as 
diuretics or up to 2 
therapeutic 
thoracenteses indicated 
Symptomatic and 
supplemental oxygen,  
>2 therapeutic 
thoracenteses, tube 
drainage, or pleurodesis 
indicated 
Life-threatening (e.g., 
causing hemodynamic 
instability or ventilatory 
support indicated)  
Death 
ALSO CONSIDER: Atelectasis; Cough; Dyspnea (shortness of breath); Hypoxia; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes).  
NAVIGATION NOTE: Pleuritic pain is graded as Pain – Select in the PAIN CATEGORY. 
Pneumonitis/pulmonary 
infiltrates  
Pneumonitis 
Asymptomatic, 
radiographic findings only 
Symptomatic, not 
interfering with ADL  
Symptomatic, interfering 
with ADL; O2 indicated  
Life-threatening; 
ventilatory support 
indicated 
Death 
ALSO CONSIDER: Adult Respiratory Distress Syndrome (ARDS); Cough; Dyspnea (shortness of breath); Hypoxia; Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select; Pneumonitis/pulmonary infiltrates; 
Pulmonary fibrosis (radiographic changes). 
Pneumothorax  
Pneumothorax  
Asymptomatic, 
radiographic findings only 
Symptomatic; 
intervention indicated 
(e.g., hospitalization for 
observation, tube 
placement without 
sclerosis) 
Sclerosis and/or 
operative intervention 
indicated 
Life-threatening, causing 
hemodynamic instability 
(e.g., tension 
pneumothorax); 
ventilatory support 
indicated 
Death 
Prolonged chest tube 
drainage or air leak after 
pulmonary resection 
Chest tube drainage or 
leak 
— 
Sclerosis or additional 
tube thoracostomy 
indicated 
Operative intervention 
indicated (e.g., 
thoracotomy with stapling 
or sealant application) 
Life-threatening; 
debilitating; organ 
resection indicated 
Death 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 152 of 165

 
PULMONARY/UPPER RESPIRATORY 
Page 4 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 59 - 
March 31, 2003, Publish Date: August 9, 2006 
Prolonged intubation 
after pulmonary resection 
(>24 hrs after surgery)  
Prolonged intubation 
— 
Extubated within  
24 – 72 hrs 
postoperatively 
Extubated >72 hrs 
postoperatively, but 
before tracheostomy 
indicated 
Tracheostomy indicated 
Death 
NAVIGATION NOTE: Pulmonary embolism is graded as Grade 4 either as Thrombosis/embolism (vascular access-related) or Thrombosis/thrombus/embolism in the VASCULAR 
CATEGORY.  
Pulmonary fibrosis 
(radiographic changes)  
Pulmonary fibrosis 
Minimal radiographic 
findings (or patchy or bi-
basilar changes) with 
estimated radiographic 
proportion of total lung 
volume that is fibrotic of 
<25% 
Patchy or bi-basilar 
changes with estimated 
radiographic proportion of 
total lung volume that is 
fibrotic of 25 – <50% 
Dense or widespread 
infiltrates/consolidation 
with estimated 
radiographic proportion of 
total lung volume that is 
fibrotic of 50 – <75% 
Estimated radiographic 
proportion of total lung 
volume that is fibrotic is 
≥75%; honeycombing 
Death 
REMARK: Fibrosis is usually a “late effect” seen >3 months after radiation or combined modality therapy (including surgery). It is thought to represent scar/fibrotic lung tissue. It may be 
difficult to distinguish from pneumonitis that is generally seen within 3 months of radiation or combined modality therapy.  
ALSO CONSIDER: Adult Respiratory Distress Syndrome (ARDS); Cough; Dyspnea (shortness of breath); Hypoxia; Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select. 
NAVIGATION NOTE: Recurrent laryngeal nerve dysfunction is graded as Laryngeal nerve dysfunction in the NEUROLOGY CATEGORY. 
Vital capacity  
Vital capacity 
90 – 75% of predicted 
value 
<75 – 50% of predicted 
value 
<50 – 25% of predicted 
value 
<25% of predicted value 
Death 
Voice changes/dysarthria 
(e.g., hoarseness, loss or 
alteration in voice, 
laryngitis)  
Voice changes  
Mild or intermittent 
hoarseness or voice 
change, but fully 
understandable 
Moderate or persistent 
voice changes, may 
require occasional 
repetition but 
understandable on 
telephone 
Severe voice changes 
including predominantly 
whispered speech; may 
require frequent repetition 
or face-to-face contact for 
understandability; 
requires voice aid (e.g., 
electrolarynx) for ≤50% of 
communication 
Disabling; 
non-understandable voice 
or aphonic; requires voice 
aid (e.g., electrolarynx) 
for >50% of 
communication or 
requires >50% written 
communication 
Death 
ALSO CONSIDER: Laryngeal nerve dysfunction; Speech impairment (e.g., dysphasia or aphasia). 
Pulmonary/Upper 
Respiratory – Other 
(Specify, __) 
Pulmonary – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling 
Death 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 153 of 165

 
RENAL/GENITOURINARY 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 60 - 
March 31, 2003, Publish Date: August 9, 2006 
Bladder spasms 
Bladder spasms 
Symptomatic, intervention 
not indicated 
Symptomatic, 
antispasmodics indicated 
Narcotics indicated 
Major surgical 
intervention indicated 
(e.g., cystectomy) 
— 
Cystitis 
Cystitis 
Asymptomatic 
Frequency with dysuria; 
macroscopic hematuria 
Transfusion; IV pain 
medications; bladder 
irrigation indicated 
Catastrophic bleeding; 
major non-elective 
intervention indicated 
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils 
– Select; Infection with unknown ANC – Select; Pain – Select. 
Fistula, GU 
– Select:  
– Bladder 
– Genital tract-female 
– Kidney 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
Fistula, GU – Select  
Asymptomatic, 
radiographic findings only 
Symptomatic; 
noninvasive intervention 
indicated  
Symptomatic interfering 
with ADL; invasive 
intervention indicated  
Life-threatening 
consequences; operative 
intervention requiring 
partial or full organ 
resection; permanent 
urinary diversion  
Death 
REMARK: A fistula is defined as an abnormal communication between two body cavities, potential spaces, and/or the skin. The site indicated for a fistula should be the site from which 
the abnormal process is believed to have originated. 
Incontinence, urinary  
Incontinence, urinary 
Occasional (e.g., with 
coughing, sneezing, etc.), 
pads not indicated 
Spontaneous, pads 
indicated  
Interfering with ADL; 
intervention indicated 
(e.g., clamp, collagen 
injections) 
Operative intervention 
indicated (e.g., 
cystectomy or permanent 
urinary diversion) 
— 
Leak (including 
anastomotic), GU 
– Select: 
– Bladder 
– Fallopian tube  
– Kidney 
– Spermatic cord 
– Stoma 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Leak, GU – Select  
Asymptomatic, 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic, interfering 
with GU function; invasive 
or endoscopic 
intervention indicated 
Life-threatening 
Death 
REMARK: Leak (including anastomotic), GU – Select refers to clinical signs and symptoms or radiographic confirmation of anastomotic leak but without development of fistula. 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 154 of 165

 
RENAL/GENITOURINARY 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 61 - 
March 31, 2003, Publish Date: August 9, 2006 
Obstruction, GU  
– Select: 
– Bladder 
– Fallopian tube 
– Prostate 
– Spermatic cord 
– Stoma 
– Testes 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Obstruction, GU – Select  
Asymptomatic, 
radiographic or 
endoscopic findings only 
Symptomatic but no 
hydronephrosis, sepsis or 
renal dysfunction; dilation 
or endoscopic repair or 
stent placement indicated 
Symptomatic and altered 
organ function (e.g., 
sepsis or hydronephrosis, 
or renal dysfunction); 
operative intervention 
indicated  
Life-threatening 
consequences; organ 
failure or operative 
intervention requiring 
complete organ resection 
indicated  
Death 
NAVIGATION NOTE: Operative injury is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY CATEGORY.  
Perforation, GU  
– Select: 
– Bladder 
– Fallopian tube 
– Kidney  
– Ovary 
– Prostate 
– Spermatic cord 
– Stoma 
– Testes 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Perforation, GU – Select 
Asymptomatic 
radiographic findings only 
Symptomatic, associated 
with altered renal/GU 
function 
Symptomatic, operative 
intervention indicated 
Life-threatening 
consequences or organ 
failure; operative 
intervention requiring 
organ resection indicated 
Death 
Prolapse of stoma, GU 
Prolapse stoma, GU 
Asymptomatic; special 
intervention, 
extraordinary care not 
indicated 
Extraordinary local care 
or maintenance; minor 
revision under local 
anesthesia indicated 
Dysfunctional stoma; 
operative intervention or 
major stomal revision 
indicated 
Life-threatening 
consequences 
Death 
REMARK: Other stoma complications may be graded as Fistula, GU – Select; Leak (including anastomotic), GU – Select; Obstruction, GU – Select; Perforation, GU – Select; 
Stricture/stenosis (including anastomotic), GU – Select. 
Renal failure  
Renal failure 
— 
— 
Chronic dialysis not 
indicated 
Chronic dialysis or renal 
transplant indicated 
Death 
ALSO CONSIDER: Glomerular filtration rate. 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 155 of 165

 
RENAL/GENITOURINARY 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 62 - 
March 31, 2003, Publish Date: August 9, 2006 
Stricture/stenosis 
(including anastomotic), 
GU 
– Select: 
– Bladder 
– Fallopian tube 
– Prostate 
– Spermatic cord 
– Stoma 
– Testes 
– Ureter  
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Stricture, anastomotic, 
GU – Select  
Asymptomatic, 
radiographic or 
endoscopic findings only 
Symptomatic but no 
hydronephrosis, sepsis or 
renal dysfunction; dilation 
or endoscopic repair or 
stent placement indicated 
Symptomatic and altered 
organ function (e.g., 
sepsis or hydronephrosis, 
or renal dysfunction); 
operative intervention 
indicated  
Life-threatening 
consequences; organ 
failure or operative 
intervention requiring 
organ resection indicated  
Death 
ALSO CONSIDER: Obstruction, GU – Select. 
Urinary electrolyte 
wasting (e.g., Fanconi’s 
syndrome, renal tubular 
acidosis) 
Urinary electrolyte 
wasting 
Asymptomatic, 
intervention not indicated 
Mild, reversible and 
manageable with 
replacement 
Irreversible, requiring 
continued replacement  
— 
— 
ALSO CONSIDER: Acidosis (metabolic or respiratory); Bicarbonate, serum-low; Calcium, serum-low (hypocalcemia); Phosphate, serum-low (hypophosphatemia). 
Urinary 
frequency/urgency 
Urinary frequency 
Increase in frequency or 
nocturia up to 2 x normal; 
enuresis 
Increase >2 x normal but 
<hourly 
≥1 x/hr; urgency; catheter 
indicated 
— 
— 
Urinary retention 
(including neurogenic 
bladder)  
Urinary retention 
Hesitancy or dribbling, no 
significant residual urine; 
retention occurring during 
the immediate 
postoperative period 
Hesitancy requiring 
medication; or operative 
bladder atony requiring 
indwelling catheter 
beyond immediate 
postoperative period but 
for <6 weeks 
More than daily 
catheterization indicated; 
urological intervention 
indicated (e.g., TURP, 
suprapubic tube, 
urethrotomy) 
Life-threatening 
consequences; organ 
failure (e.g., bladder 
rupture); operative 
intervention requiring 
organ resection indicated 
Death 
REMARK: The etiology of retention (if known) is graded as Obstruction, GU – Select; Stricture/stenosis (including anastomotic), GU – Select. 
ALSO CONSIDER: Obstruction, GU – Select; Stricture/stenosis (including anastomotic), GU – Select. 
Urine color change  
Urine color change 
Present 
— 
— 
— 
— 
REMARK: Urine color refers to change that is not related to other dietary or physiologic cause (e.g., bilirubin, concentrated urine, and hematuria). 
Renal/Genitourinary – 
Other (Specify, __) 
Renal – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 156 of 165

 
SECONDARY MALIGNANCY 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 63 - 
March 31, 2003, Publish Date: August 9, 2006 
Secondary Malignancy – 
possibly related to cancer 
treatment (Specify, __)  
Secondary Malignancy 
(possibly related to 
cancer treatment) 
— 
— 
Non-life-threatening basal 
or squamous cell 
carcinoma of the skin 
Solid tumor, leukemia or 
lymphoma  
Death 
REMARK: Secondary malignancy excludes metastasis from initial primary. Any malignancy possibly related to cancer treatment (including AML/MDS) should be reported via the routine 
reporting mechanisms outlined in each protocol. Important: Secondary Malignancy is an exception to NCI Expedited Adverse Event Reporting Guidelines. Secondary Malignancy is 
“Grade 4, present” but NCI does not require AdEERS Expedited Reporting for any (related or unrelated to treatment) Secondary Malignancy. A diagnosis of AML/MDS following 
treatment with an NCI-sponsored investigational agent is to be reported using the form available from the CTEP Web site at http://ctep.cancer.gov. Cancers not suspected of being 
treatment-related are not to be reported here. 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 157 of 165

 
SEXUAL/REPRODUCTIVE FUNCTION 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 64 - 
March 31, 2003, Publish Date: August 9, 2006 
Breast function/lactation 
Breast function 
Mammary abnormality, 
not functionally significant 
Mammary abnormality, 
functionally significant 
— 
— 
— 
Breast nipple/areolar 
deformity  
Nipple/areolar 
Limited areolar 
asymmetry with no 
change in nipple/areolar 
projection 
Asymmetry of nipple 
areolar complex with 
slight deviation in nipple 
projection 
Marked deviation of 
nipple projection  
— 
— 
Breast volume/hypoplasia 
Breast 
Minimal asymmetry; 
minimal hypoplasia 
Asymmetry exists, ≤1/3 of 
the breast volume; 
moderate hypoplasia  
Asymmetry exists, >1/3 of 
the breast volume; severe 
hypoplasia 
— 
— 
REMARK: Breast volume is referenced with both arms straight overhead. 
NAVIGATION NOTE: Dysmenorrhea is graded as Pain – Select in the PAIN CATEGORY.  
NAVIGATION NOTE: Dyspareunia is graded as Pain – Select in the PAIN CATEGORY.  
NAVIGATION NOTE: Dysuria (painful urination) is graded as Pain – Select in the PAIN CATEGORY.  
Erectile dysfunction 
Erectile dysfunction 
Decrease in erectile 
function 
(frequency/rigidity of 
erections) but erectile 
aids not indicated 
Decrease in erectile 
function 
(frequency/rigidity of 
erections), erectile aids 
indicated 
Decrease in erectile 
function 
(frequency/rigidity of 
erections) but erectile 
aids not helpful; penile 
prosthesis indicated 
— 
— 
Ejaculatory dysfunction 
Ejaculatory dysfunction 
Diminished ejaculation 
Anejaculation or 
retrograde ejaculation 
— 
— 
— 
NAVIGATION NOTE: Feminization of male is graded in the ENDOCRINE CATEGORY. 
Gynecomastia 
Gynecomastia 
— 
Asymptomatic breast 
enlargement 
Symptomatic breast 
enlargement; intervention 
indicated 
— 
— 
ALSO CONSIDER: Pain – Select.  
Infertility/sterility 
Infertility/sterility 
— 
Male: oligospermia/low 
sperm count 
Female: diminished 
fertility/ovulation 
Male: sterile/azoospermia 
Female: infertile/ 
anovulatory 
— 
— 
Irregular menses  
(change from baseline) 
Irregular menses 
1 – 3 months without 
menses 
>3 – 6 months without 
menses but continuing 
menstrual cycles 
Persistent amenorrhea 
for >6 months 
— 
— 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 158 of 165

 
SEXUAL/REPRODUCTIVE FUNCTION 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 65 - 
March 31, 2003, Publish Date: August 9, 2006 
Libido 
Libido 
Decrease in interest but 
not affecting relationship; 
intervention not indicated 
Decrease in interest and 
adversely affecting 
relationship; intervention 
indicated 
— 
— 
— 
NAVIGATION NOTE: Masculinization of female is graded in the ENDOCRINE CATEGORY. 
Orgasmic dysfunction 
Orgasmic function 
Transient decrease 
Decrease in orgasmic 
response requiring 
intervention 
Complete inability of 
orgasmic response; not 
responding to intervention 
— 
— 
NAVIGATION NOTE: Pelvic pain is graded as Pain – Select in the PAIN CATEGORY. 
NAVIGATION NOTE: Ulcers of the labia or perineum are graded as Ulceration in DERMATOLOGY/SKIN CATEGORY. 
Vaginal discharge  
(non-infectious) 
Vaginal discharge 
Mild 
Moderate to heavy; pad 
use indicated 
— 
— 
— 
Vaginal dryness 
Vaginal dryness 
Mild 
Interfering with sexual 
function; dyspareunia; 
intervention indicated 
— 
— 
— 
ALSO CONSIDER: Pain – Select. 
Vaginal mucositis 
Vaginal mucositis 
Erythema of the mucosa; 
minimal symptoms 
Patchy ulcerations; 
moderate symptoms or 
dyspareunia 
Confluent ulcerations; 
bleeding with trauma; 
unable to tolerate vaginal 
exam, sexual intercourse 
or tampon placement  
Tissue necrosis; 
significant spontaneous 
bleeding; life-threatening 
consequences 
— 
Vaginal stenosis/length 
Vaginal stenosis 
Vaginal narrowing and/or 
shortening not interfering 
with function  
Vaginal narrowing and/or 
shortening interfering with 
function  
Complete obliteration; not 
surgically correctable 
— 
— 
Vaginitis (not due to 
infection) 
Vaginitis 
Mild, intervention not 
indicated 
Moderate, intervention 
indicated 
Severe, not relieved with 
treatment; ulceration, but 
operative intervention not 
indicated 
Ulceration and operative 
intervention indicated 
— 
Sexual/Reproductive 
Function – Other 
(Specify, __) 
Sexual – Other (Specify) 
Mild 
Moderate 
Severe 
Disabling 
Death 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 159 of 165

 
SURGERY/INTRA-OPERATIVE INJURY 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 66 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Intra-operative hemorrhage is graded as Hemorrhage/bleeding associated with surgery, intra-operative or postoperative in the HEMORRHAGE/BLEEDING 
CATEGORY.  
Intra-operative injury  
– Select Organ or 
Structure 
‘Select’ AEs appear at the 
end of the CATEGORY. 
Intraop injury – Select  
Primary repair of injured 
organ/structure indicated  
Partial resection of 
injured organ/structure 
indicated 
Complete resection or 
reconstruction of injured 
organ/structure indicated 
Life threatening 
consequences; disabling 
— 
REMARK: The ‘Select’ AEs are defined as significant, unanticipated injuries that are recognized at the time of surgery. These AEs do not refer to additional surgical procedures that 
must be performed because of a change in the operative plan based on intra-operative findings. Any sequelae resulting from the intra-operative injury that result in an adverse 
outcome for the patient must also be recorded and graded under the relevant CTCAE Term. 
Intra-operative Injury – 
Other (Specify, __) 
Intraop Injury – Other 
(Specify) 
Primary repair of injured 
organ/structure indicated  
Partial resection of 
injured organ/structure 
indicated 
Complete resection or 
reconstruction of injured 
organ/structure indicated 
Life threatening 
consequences; disabling 
— 
REMARK: Intra-operative Injury – Other (Specify, __) is to be used only to report an organ/structure not included in the ‘Select’ AEs found at the end of the CATEGORY. Any sequelae 
resulting from the intra-operative injury that result in an adverse outcome for the patient must also be recorded and graded under the relevant CTCAE Term. 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 160 of 165

 
SURGERY/INTRA-OPERATIVE INJURY – SELECT  
Page 2 of 2 
CTCAE v3.0  
- 67 - 
March 31, 2003, Publish Date: August 9, 2006 
AUDITORY/EAR 
– Inner ear  
– Middle ear  
– Outer ear NOS  
– Outer ear-Pinna  
CARDIOVASCULAR 
– Artery-aorta  
– Artery-carotid  
– Artery-cerebral  
– Artery-extremity (lower)  
– Artery-extremity (upper)  
– Artery-hepatic  
– Artery-major visceral artery  
– Artery-pulmonary  
– Artery NOS 
– Heart  
– Spleen 
– Vein-extremity (lower)  
– Vein-extremity (upper)  
– Vein-hepatic  
– Vein-inferior vena cava  
– Vein-jugular  
– Vein-major visceral vein  
– Vein-portal vein  
– Vein-pulmonary  
– Vein-superior vena cava  
– Vein NOS 
DERMATOLOGY/SKIN 
– Breast  
– Nails  
– Skin 
ENDOCRINE 
– Adrenal gland 
– Parathyroid 
– Pituitary  
ENDOCRINE (continued) 
– Thyroid 
HEAD AND NECK 
– Gingiva  
– Larynx  
– Lip/perioral area  
– Face NOS  
– Nasal cavity  
– Nasopharynx  
– Neck NOS 
– Nose  
– Oral cavity NOS  
– Parotid gland  
– Pharynx  
– Salivary duct  
– Salivary gland  
– Sinus  
– Teeth  
– Tongue  
– Upper aerodigestive NOS 
GASTROINTESTINAL 
– Abdomen NOS  
– Anal sphincter  
– Anus 
– Appendix  
– Cecum  
– Colon  
– Duodenum  
– Esophagus  
– Ileum  
– Jejunum  
– Oral  
– Peritoneal cavity  
– Rectum 
– Small bowel NOS 
GASTROINTESTINAL (continued) 
– Stoma (GI)  
– Stomach  
HEPATOBILIARY/ PANCREAS 
– Biliary tree-common bile  
duct  
– Biliary tree-common hepatic 
duct  
– Biliary tree-left hepatic duct  
– Biliary tree-right hepatic duct  
– Biliary tree NOS  
– Gallbladder  
– Liver 
– Pancreas 
– Pancreatic duct 
MUSCULOSKELETAL 
– Bone  
– Cartilage  
– Extremity-lower 
– Extremity-upper 
– Joint  
– Ligament  
– Muscle  
– Soft tissue NOS 
– Tendon 
NEUROLOGY  
– Brain  
– Meninges  
– Spinal cord 
NERVES: 
– Brachial plexus 
– CN I (olfactory) 
– CN II (optic) 
– CN III (oculomotor) 
– CN IV (trochlear)  
NEUROLOGY (continued) 
NERVES: 
– CN V (trigeminal) motor  
– CN V (trigeminal) sensory  
– CN VI (abducens)  
– CN VII (facial) motor-face  
– CN VII (facial) sensory-
taste  
– CN VIII (vestibulocochlear)  
– CN IX (glossopharyngeal) 
motor pharynx  
– CN IX (glossopharyngeal) 
sensory ear-pharynx-
tongue  
– CN X (vagus)  
– CN XI (spinal accessory)  
– CN XII (hypoglossal)  
– Cranial nerve or branch 
NOS  
– Lingual  
– Lung thoracic  
– Peripheral motor NOS 
– Peripheral sensory NOS 
– Recurrent laryngeal  
– Sacral plexus  
– Sciatic 
– Thoracodorsal 
OCULAR 
– Conjunctiva  
– Cornea  
– Eye NOS 
– Lens 
– Retina 
PULMONARY/UPPER 
RESPIRATORY 
– Bronchus  
– Lung  
– Mediastinum  
– Pleura  
– Thoracic duct  
– Trachea 
– Upper airway NOS 
RENAL/GENITOURINARY 
– Bladder  
– Cervix  
– Fallopian tube  
– Kidney  
– Ovary  
– Pelvis NOS  
– Penis  
– Prostate  
– Scrotum  
– Testis  
– Ureter  
– Urethra  
– Urinary conduit  
– Urinary tract NOS  
– Uterus  
– Vagina  
– Vulva 
 
 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 161 of 165

 
SYNDROMES 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 68 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Acute vascular leak syndrome is graded in the VASCULAR CATEGORY. 
NAVIGATION NOTE: Adrenal insufficiency is graded in the ENDOCRINE CATEGORY. 
NAVIGATION NOTE: Adult Respiratory Distress Syndrome (ARDS) is graded in the PULMONARY/UPPER RESPIRATORY CATEGORY. 
Alcohol intolerance 
syndrome (antabuse-like 
syndrome) 
Alcohol intolerance 
syndrome 
— 
— 
Present 
— 
Death 
REMARK: An antabuse-like syndrome occurs with some new anti-androgens (e.g., nilutamide) when patient also consumes alcohol. 
NAVIGATION NOTE: Autoimmune reaction is graded as Autoimmune reaction/hypersensitivity (including drug fever) in the ALLERGY/IMMUNOLOGY CATEGORY. 
Cytokine release 
syndrome/acute infusion 
reaction 
Cytokine release 
syndrome 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDS, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption of 
infusion); recurrence of 
symptoms following initial 
improvement; 
hospitalization indicated 
for other clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates) 
Life-threatening; pressor 
or ventilatory support 
indicated 
Death 
REMARK: Cytokine release syndromes/acute infusion reactions are different from Allergic/hypersensitive reactions, although some of the manifestations are common to both AEs. An 
acute infusion reaction may occur with an agent that causes cytokine release (e.g., monoclonal antibodies or other biological agents). Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hrs of completion of infusion. Signs/symptoms may include: Allergic reaction/hypersensitivity (including drug 
fever); Arthralgia (joint pain); Bronchospasm; Cough; Dizziness; Dyspnea (shortness of breath); Fatigue (asthenia, lethargy, malaise); Headache; Hypertension; Hypotension; Myalgia 
(muscle pain); Nausea; Pruritis/itching; Rash/desquamation; Rigors/chills; Sweating (diaphoresis); Tachycardia; Tumor pain (onset or exacerbation of tumor pain due to treatment); 
Urticaria (hives, welts, wheals); Vomiting.  
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever); Bronchospasm, wheezing; Dyspnea (shortness of breath); Hypertension; Hypotension; Hypoxia; Prolonged 
QTc interval; Supraventricular and nodal arrhythmia – Select; Ventricular arrhythmia – Select.  
NAVIGATION NOTE: Disseminated intravascular coagulation (DIC) is graded in the COAGULATION CATEGORY. 
NAVIGATION NOTE: Fanconi’s syndrome is graded as Urinary electrolyte wasting (e.g., Fanconi’s syndrome, renal tubular acidosis) in the RENAL/GENITOURINARY CATEGORY. 
Flu-like syndrome 
Flu-like syndrome 
Symptoms present but 
not interfering with 
function 
Moderate or causing 
difficulty performing some 
ADL 
Severe symptoms 
interfering with ADL 
Disabling 
Death 
REMARK: Flu-like syndrome represents a constellation of symptoms which may include cough with catarrhal symptoms, fever, headache, malaise, myalgia, prostration, and is to be 
used when the symptoms occur in a cluster consistent with one single pathophysiological process. 
NAVIGATION NOTE: Renal tubular acidosis is graded as Urinary electrolyte wasting (e.g., Fanconi’s syndrome, renal tubular acidosis) in the RENAL/GENITOURINARY CATEGORY. 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 162 of 165

 
SYNDROMES 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 69 - 
March 31, 2003, Publish Date: August 9, 2006 
“Retinoic acid syndrome”  
“Retinoic acid syndrome” 
Fluid retention; less than 
3 kg of weight gain; 
intervention with fluid 
restriction and/or diuretics 
indicated 
Mild to moderate signs/ 
symptoms; steroids 
indicated 
Severe signs/symptoms; 
hospitalization indicated 
Life-threatening; 
ventilatory support 
indicated 
Death 
REMARK: Patients with acute promyelocytic leukemia may experience a syndrome similar to “retinoic acid syndrome” in association with other agents such as arsenic trioxide. The 
syndrome is usually manifested by otherwise unexplained fever, weight gain, respiratory distress, pulmonary infiltrates and/or pleural effusion, with or without leukocytosis.  
ALSO CONSIDER: Acute vascular leak syndrome; Pleural effusion (non-malignant); Pneumonitis/pulmonary infiltrates. 
NAVIGATION NOTE: SIADH is graded as Neuroendocrine: ADH secretion abnormality (e.g., SIADH or low ADH) in the ENDOCRINE CATEGORY.  
NAVIGATION NOTE: Stevens-Johnson syndrome is graded as Rash: erythema multiforme (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis) in the DERMATOLOGY/SKIN 
CATEGORY. 
NAVIGATION NOTE: Thrombotic microangiopathy is graded as Thrombotic microangiopathy (e.g., thrombotic thrombocytopenic purpura [TTP] or hemolytic uremic syndrome [HUS]) in 
the COAGULATION CATEGORY. 
Tumor flare 
Tumor flare 
Mild pain not interfering 
with function 
Moderate pain; pain or 
analgesics interfering with 
function, but not 
interfering with ADL 
Severe pain; pain or 
analgesics interfering with 
function and interfering 
with ADL 
Disabling 
Death 
REMARK: Tumor flare is characterized by a constellation of signs and symptoms in direct relation to initiation of therapy (e.g., anti-estrogens/androgens or additional hormones). The 
symptoms/signs include tumor pain, inflammation of visible tumor, hypercalcemia, diffuse bone pain, and other electrolyte disturbances.  
ALSO CONSIDER: Calcium, serum-high (hypercalcemia). 
Tumor lysis syndrome 
Tumor lysis syndrome 
— 
— 
Present 
— 
Death 
ALSO CONSIDER: Creatinine; Potassium, serum-high (hyperkalemia). 
Syndromes – Other 
(Specify, __) 
Syndromes – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 163 of 165

 
VASCULAR 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 70 - 
March 31, 2003, Publish Date: August 9, 2006 
Acute vascular leak 
syndrome 
Acute vascular leak 
syndrome 
— 
Symptomatic, fluid 
support not indicated 
Respiratory compromise 
or fluids indicated 
Life-threatening; pressor 
support or ventilatory 
support indicated  
Death 
Peripheral arterial 
ischemia 
Peripheral arterial 
ischemia 
— 
Brief (<24 hrs) episode of 
ischemia managed non-
surgically and without 
permanent deficit 
Recurring or prolonged 
(≥24 hrs) and/or invasive 
intervention indicated 
Life-threatening, disabling 
and/or associated with 
end organ damage 
(e.g., limb loss) 
Death 
Phlebitis (including 
superficial thrombosis) 
Phlebitis 
— 
Present 
— 
— 
— 
ALSO CONSIDER: Injection site reaction/extravasation changes. 
Portal vein flow 
Portal flow 
— 
Decreased portal vein 
flow 
Reversal/retrograde 
portal vein flow 
— 
— 
Thrombosis/embolism 
(vascular access-related) 
Thrombosis/embolism 
(vascular access) 
— 
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
not indicated 
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
indicated 
Embolic event including 
pulmonary embolism or 
life-threatening thrombus 
Death 
Thrombosis/thrombus/ 
embolism 
Thrombosis/thrombus/ 
embolism 
— 
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
not indicated  
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
indicated  
Embolic event including 
pulmonary embolism or 
life-threatening thrombus 
Death 
Vessel injury-artery  
– Select:  
– Aorta 
– Carotid 
– Extremity-lower 
– Extremity-upper  
– Other NOS 
– Visceral 
Artery injury – Select 
Asymptomatic diagnostic 
finding; intervention not 
indicated 
Symptomatic (e.g., 
claudication); not 
interfering with ADL; 
repair or revision not 
indicated 
Symptomatic interfering 
with ADL; repair or 
revision indicated 
Life-threatening; 
disabling; evidence of 
end organ damage (e.g., 
stroke, MI, organ or limb 
loss) 
Death 
NAVIGATION NOTE: Vessel injury to an artery intra-operatively is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY 
CATEGORY. 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 164 of 165

 
VASCULAR 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 71 - 
March 31, 2003, Publish Date: August 9, 2006 
Vessel injury-vein  
– Select: 
– Extremity-lower  
– Extremity-upper 
– IVC 
– Jugular 
– Other NOS 
– SVC 
– Viscera 
Vein injury – Select 
Asymptomatic diagnostic 
finding; intervention not 
indicated 
Symptomatic (e.g., 
claudication); not 
interfering with ADL; 
repair or revision not 
indicated  
Symptomatic interfering 
with ADL; repair or 
revision indicated 
Life-threatening; 
disabling; evidence of 
end organ damage  
Death 
NAVIGATION NOTE: Vessel injury to a vein intra-operatively is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY CATEGORY. 
Visceral arterial ischemia 
(non-myocardial) 
Visceral arterial ischemia 
— 
Brief (<24 hrs) episode of 
ischemia managed 
medically and without 
permanent deficit 
Prolonged (≥24 hrs) or 
recurring symptoms 
and/or invasive 
intervention indicated 
Life-threatening; 
disabling; evidence of 
end organ damage  
Death 
ALSO CONSIDER: CNS cerebrovascular ischemia.  
Vascular – Other  
(Specify, __) 
Vascular – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
 
Shire 
HGT-SAN-067 Protocol Amendment 7
CONFIDENTIAL 
Version 1.0,  Final
08 February 2016 
Page 165 of 165

Clinical Trial Protocol:  HGT-SAN-067
Study Title:
An Open-Label Extension of Study HGT-SAN-055 Evaluating 
Long-Term Safety and Clinical Outcomes of Intrathecal Administration 
of rhHNS in Patients with Sanfilippo Syndrome Type A (MPS IIIA)
Study Number:
HGT-SAN-067
Study Phase:
I/II
Product Name:
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Device Names:
SOPH-A-PORT® Mini S, Implantable Access Port, Spinal, Mini 
Unattached, with Guidewire
and
PORT-A-CATH® II Low Profile™Intrathecal Implantable Access 
System (Smiths device)
EudraCT Number:
2010-021348-16
Indication:
Sanfilippo Syndrome A
Investigators:
Multicenter
Sponsor:
Shire Human Genetic Therapies, Inc. 
300 Shire Way
Lexington, MA  02421, United States
Medical Monitor:
, DO,
Date
Original Protocol:
21 June 2010
Amendment 1:
27 January 2011
Amendment 2:
13 January 2012
Amendment 3:
28 August 2012
Amendment 4:
3 May 2013
Amendment 5:
17 January 2014
Amendment 6:
10 July 2014
Amendment 7:
08 February 2016
Amendment 8: 
01 February 2017
Confidentiality Statement
This document is the proprietary and confidential property of 
Shire Human Genetic Therapies, Inc.

Shire
CONFIDENTIAL
Page 2
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
TABLE OF CONTENTS
TABLE OF CONTENTS.................................................................................................................2
SYNOPSIS.......................................................................................................................................8
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS................................................16
1
INTRODUCTION..................................................................................................................19
1.1
Disease Background.................................................................................................19
1.2
Nonclinical Overview ..............................................................................................21
1.2.1
Toxicology in Monkeys........................................................................................21
1.2.2
Efficacy in Murine and Canine Models of MPS IIIA ..........................................22
1.3
HGT-SAN-067 Study Rationale ..............................................................................22
2
STUDY OBJECTIVES ..........................................................................................................24
2.1
Primary Objective ....................................................................................................24
2.2
Secondary Objectives...............................................................................................24
2.3
Exploratory Objective ..............................................................................................24
3
STUDY ENDPOINTS............................................................................................................25
3.1
Primary Endpoint .....................................................................................................25
3.2
Secondary Endpoints................................................................................................25
3.3
SOPH-A-PORT Mini S Assessments ......................................................................25
4
INVESTIGATIONAL PLAN.................................................................................................26
4.1
Overall Study Design and Plan ................................................................................26
4.2
Rationale for Study Design and Control Group.......................................................29
4.3
Study Duration and Dates ........................................................................................29
5
STUDY POPULATION SELECTION ..................................................................................30
5.1
Study Population ......................................................................................................30
5.2
Inclusion Criteria......................................................................................................30
5.3
Exclusion Criteria.....................................................................................................30
6
STUDY TREATMENT(S).....................................................................................................32
6.1
Description of Treatment(s) .....................................................................................32
6.1.1
Study Drug ...........................................................................................................32
6.1.2
Intrathecal Drug Delivery Device ........................................................................32
6.1.3
Placebo or Control................................................................................................32
6.2
Treatment Administered...........................................................................................32
6.3
Selection and Timing of Dose for Each Patient .......................................................33
6.3.1
Cerebral Spinal Fluid Sample Procedure .............................................................33
6.3.2
Administration of HGT-1410 via Lumbar Puncture Guidance Concerning 
Performance of Lumbar Puncture for Study Drug Administration and 
Cerebrospinal Fluid Sample Collection ...............................................................34

Shire
CONFIDENTIAL
Page 3
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
6.4
Method of Assigning Patients to Treatment Groups................................................35
6.5
Blinding....................................................................................................................35
6.6
Concomitant Therapy...............................................................................................35
6.7
Restrictions...............................................................................................................35
6.7.1
Prior Therapy........................................................................................................35
6.7.2
Fluid and Food Intake...........................................................................................36
6.7.3
Patient Activity Restrictions.................................................................................36
6.8
Treatment Compliance .............................................................................................36
6.9
Packaging and Labeling ...........................................................................................36
6.9.1
Drug Product ........................................................................................................36
6.9.2
SOPH-A-PORT Mini S Access Port....................................................................36
6.10
Storage and Accountability......................................................................................37
6.10.1
Investigational Product.........................................................................................37
6.10.2
Intrathecal Drug Delivery Device ........................................................................37
6.10.2.1
PORT-A-CATH IDDD ..........................................................................37
6.10.2.2
SOPH-A-PORT Mini S IDDD...............................................................37
6.11
Investigational Product Retention at Study Site.......................................................37
7
STUDY PROCEDURES........................................................................................................38
7.1
Informed Consent.....................................................................................................38
7.2
Physical Examination...............................................................................................38
7.3
Height and Weight ...................................................................................................39
7.4
Head Circumference.................................................................................................39
7.5
Vital Signs................................................................................................................39
7.6
Electrocardiography .................................................................................................39
7.6.1
Electrocardiograms...............................................................................................39
7.7
Clinical Laboratory Tests.........................................................................................39
7.7.1
Hematology ..........................................................................................................40
7.7.2
Serum Chemistry..................................................................................................40
7.7.3
Pregnancy Test .....................................................................................................40
7.7.4
Serum Anti-rhHNS Antibody and Sample Storage..............................................41
7.7.5
Urinalysis..............................................................................................................41
7.7.5.1
Standard Urinalysis ................................................................................41
7.7.5.2
Urine Glycosaminoglycans ....................................................................41
7.7.6
Cerebrospinal Fluid Assessments.........................................................................41
7.7.6.1
Cerebrospinal Fluid Cell Counts............................................................41
7.7.6.2
Cerebrospinal Fluid Heparan Sulfate Levels and Heparan Sulfate 
Derivatives .............................................................................................41
7.7.6.3
Anti-rhHNS Antibodies..........................................................................42

Shire
CONFIDENTIAL
Page 4
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
7.7.6.4
Cerebrospinal Fluid Biomarkers ............................................................42
7.7.7
Sample Collection, Storage, and Shipping...........................................................42
7.8
Anesthesia ................................................................................................................42
7.9
Audiometry and Auditory Brainstem Response.......................................................42
7.10
Magnetic Resonance Imaging of the Head...............................................................43
7.11
Device Data..............................................................................................................43
7.12
Surgical Re-implantation of the IDDD ....................................................................43
7.12.1
Restrictions on the Number of Revision and/or re-implantation of the 
IDDD
................................................................................................................43
7.13
Device Related Study Procedures ............................................................................44
7.13.1
IDDD Implantation or Revision Procedures ........................................................44
7.13.2
X-ray Verification of Intrathecal Drug Delivery Device Placement....................44
7.13.3
CSF Sampling Procedure .....................................................................................44
7.13.4
Device Removal ...................................................................................................44
7.14
Cerebrospinal Fluid Opening Pressure Measurement..............................................45
7.15
Dispensing Study Drug ............................................................................................45
7.16
Pharmacokinetic Assessments..................................................................................45
7.17
Neurological Examination........................................................................................46
7.18
Neurocognitive and Developmental Assessments ...................................................46
7.19
Sleep Questionnaire:  Children’s Sleep Habits Rating Scale...................................47
7.20
Age-Dependent, Health-Related Quality of Life in Children ..................................47
7.20.1
Quality of Life Indicator:  CHQ-50......................................................................48
7.20.2
Quality of Life Indicator:  CHQ-87......................................................................48
7.20.3
Quality of Life Indicator:  ITQOL .......................................................................48
7.21
Concomitant Medications, Therapies and Medical/Surgical Procedures.................48
7.22
Adverse Events.........................................................................................................48
7.22.1
Definitions of Adverse Events and Serious Adverse Events ...............................48
7.22.1.1
Adverse Event ........................................................................................48
7.22.1.2
Potential Adverse Events:  Intrathecal recombinant human heparan 
N-sulfatase..............................................................................................49
7.22.1.3
Infusion/Hypersensitivity Reactions and Management..........................50
7.22.1.4
IDDD-related Adverse Events ...............................................................50
7.22.1.5
Serious Adverse Event ...........................................................................51
7.22.2
Device-Associated Definitions.............................................................................52
7.22.2.1
Device Revision (Partial and Full).........................................................52
7.22.2.2
Device Malfunction................................................................................52
7.22.2.3
Device Failure ........................................................................................52
7.22.2.4
Device Adjustment.................................................................................52

Shire
CONFIDENTIAL
Page 5
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
7.22.3
Classification of Adverse Events and Serious Adverse Events ...........................52
7.22.4
Relatedness of Adverse Events and Serious Adverse Events ..............................53
7.22.5
Procedures for Recording and Reporting Adverse Events...................................54
7.22.5.1
Reporting Serious Adverse Events Related to Study Procedures ..........54
7.22.5.2
Eliciting Adverse Events........................................................................55
7.22.5.3
Protocol Deviations for Medical Emergency or Adverse Event............55
7.23
Abuse, Overdose and Medication Errors .................................................................56
7.24
Safety-related Study Stopping Rules........................................................................56
7.25
Pregnancy.................................................................................................................57
7.26
Removal of Patients from the Trial or Study Drug ..................................................57
7.27
Study Discontinuation Process.................................................................................58
7.28
Other Study Procedures............................................................................................59
7.29
Appropriateness of Measurements...........................................................................59
8
STUDY ACTIVITIES............................................................................................................60
8.1
Screening Visit/Study Start Visit – Main Site..........................................................60
8.2
Treatment:  Drug Administration and Weekly Assessments – Main or Local 
Site............................................................................................................................61
8.2.1
Week 1..................................................................................................................61
8.2.1.1
Day 1 (Pre-treatment) Assessments Performed Prior to Each Dose ......61
8.2.1.2
Day 2 (±2 days) Assessments and Administration of HGT-1410..........62
8.3
End of Study/Early Termination Procedures for Treatment Period:  Month 
103 – Main Site ........................................................................................................63
8.4
Safety Follow-up (by Telephone or Visit) Month 104.............................................64
8.5
Safety Follow-up Period if Device Not Removed ...................................................64
9
QUALITY CONTROL AND ASSURANCE ........................................................................65
10 PLANNED STATISTICAL METHODS...............................................................................66
10.1
General Statistical Methodology..............................................................................66
10.2
Determination of Sample Size..................................................................................66
10.3
Analysis Populations................................................................................................66
10.4
Demographics and Baseline Characteristics ............................................................66
10.5
Statistical Analysis of Pharmacokinetic Variables...................................................67
10.6
Efficacy, Safety, and Pharmacodynamic Evaluations..............................................67
10.6.1
Primary Analyses .................................................................................................67
10.6.1.1
Safety Analysis.......................................................................................67
10.6.2
Other Observations Related to Safety ..................................................................68
10.6.2.1
IDDD Performance ................................................................................68
10.6.3
Secondary Analysis ..............................................................................................69
10.6.3.1
Clinical Assessments..............................................................................69

Shire
CONFIDENTIAL
Page 6
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
10.6.3.2
Pharmacodynamic Analyses ..................................................................69
10.6.4
Interim Analysis ...................................................................................................69
11 ADMINISTRATIVE CONSIDERATIONS ..........................................................................70
11.1
Investigators and Study Administrative Structure ...................................................70
11.2
Institutional Review Board or Independent Ethics Committee Approval................70
11.3
Ethical Conduct of the Study ...................................................................................70
11.4
Patient Information and Consent..............................................................................70
11.5
Patient Confidentiality..............................................................................................71
11.6
Study Monitoring .....................................................................................................71
11.7
Case Report Forms and Study Records....................................................................72
11.7.1
Critical Documents...............................................................................................72
11.8
Device Failure Review Process................................................................................73
11.9
Protocol Violations/Deviations ................................................................................73
11.10
Access to Source Documentation.............................................................................73
11.11
Data Generation and Analysis..................................................................................73
11.12
Premature Closure of the Study ...............................................................................74
11.12.1 Study Termination................................................................................................74
11.12.2 Site Termination...................................................................................................74
11.13
Retention of Data .....................................................................................................74
11.14
Financial Disclosure.................................................................................................74
11.15
Publication and Disclosure Policy............................................................................74
12 LIST OF REFERENCES........................................................................................................76
LIST OF IN-TEXT TABLES
Table 7-1
Neurodevelopmental Assessments Tests.......................................................46
Table 7-2
Sanfilippo-Specific Disability Assessment And Behavior Rating 
Scales.............................................................................................................47
Table 7-3
Adverse Event Severity.................................................................................53
Table 7-4
Adverse Event Relatedness ...........................................................................53
Table A1-1
HGT-SAN-067 Study Assessments for Patients Who Have Received 6 
Months of HGT-1410 Treatment in Study HGT-SAN-055 ..........................78
Table A1-2
HGT-SAN-067 Study Assessments for the Safety Follow-up Period 
for Patients with Implanted Partial or Full Device After Treatment 
Completion ....................................................................................................82
Table A2-1
Summary of Neurodevelopmental Outcome Measures.................................83
Table A2-2
Summary of Sanfilippo-specific Assessments ..............................................83

Shire
CONFIDENTIAL
Page 7
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
LIST OF APPENDICES
Appendix 1
Schedule of Events ........................................................................................78
Appendix 2
Neurodevelopmental and Behavioural Assessments.....................................83
Appendix 3
Expected Adverse Device Effects .................................................................87
Appendix 4
Protocol Amendment 8 Summary of Changes ..............................................89
Appendix 5
Protocol Signature Page ................................................................................97
Appendix 6
The National Cancer Institute Common Terminology Criteria version 
3.0 ..................................................................................................................98

Shire
CONFIDENTIAL
Page 8
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
SYNOPSIS
Sponsor:
Shire Human Genetic Therapies, Inc. 
300 Shire Way
Lexington, MA  02421, United States
Name of Finished Product:
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
Name of Active Ingredient:
rhHNS, HGT-1410
Name of Inactive Ingredient:
N/A
Names of Devices:  
SOPH-A-PORTMini S, Implantable Access Port, Spinal, Mini Unattached, with 
Guidewire (SOPH-A-PORT Mini S)
and
PORT-A-CATHII Low ProfileIntrathecal Implantable Access System 
(PORT-A-CATH)
Study Title:
An Open-Label Extension of Study HGT-SAN-055 Evaluating Long-Term Safety and 
Clinical Outcomes of Intrathecal Administration of rhHNS in Patients with Sanfilippo 
Syndrome Type A (MPS IIIA) 
Study Number:
HGT-SAN-067
Study Phase:  I/II
Device, Intended Use
The SOPH-A-PORT Mini S is a system intended for implantation by physicians. The 
SOPH-A-PORT Mini S, once implanted, allows healthcare personnel to administer 
HGT-1410 indicated for intrathecal delivery intermittently over a long period of time.
Prior to approval of Amendment 4, patients were implanted with a PORT-A-CATH 
(Smith’s device). After approval of Amendment 4 all PORT-A-CATH IDDDs requiring 
revision or replacement will be replaced with a SOPH-A-PORT at a time judged 
appropriate by the investigator.
Study Objectives:
Primary Objective: 
The primary objective of this study is:

To collect long-term safety and tolerability data in patients with Sanfilippo Syndrome 
Type A (MPS IIIA) who received HGT-1410 via a surgically implanted intrathecal 
drug delivery device (IDDD) in study HGT-SAN-055 and elected to continue therapy 

Shire
CONFIDENTIAL
Page 9
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
in study HGT-SAN-067.
Secondary Objectives:
The secondary objectives of this study are:

To collect as measures of drug efficacy, over an extended treatment period (as change 
from baseline), the following:  clinical, neurological, cognitive, behavioral, 
functional, and quality of life (QoL) assessments, together with potential imaging and 
biochemical biomarkers.
Study Endpoints: 
Primary Endpoints:
The primary endpoints of this study are related to the long-term safety of intrathecal 
HGT-1410 administration. The safety endpoints are:

adverse events (type and severity)

changes in clinical laboratory testing (serum chemistry including  liver function tests, 
hematology, and urinalysis)

electrocardiograms (ECG)

cerebrospinal fluid (CSF) chemistries (including cell counts and inflammatory 
markers)

anti-rhHNS antibodies (in CSF and serum).
Secondary Endpoints:
The secondary endpoints of this study are to collect over an extended treatment period (as 
change from baseline) clinical and potential surrogate biomarker efficacy data:

Standardized neurocognitive and behavioral assessments, Sanfilippo-specific 
behavioral rating scales, gross and fine motor assessments, functional adaptive rating 
scales, quality of life questionnaires, and Children’s Sleep Habits Rating Scale.

Concentration of safety and potential surrogate efficacy biomarkers in CSF, urine, 
and serum.

Concentration of heparan sulfate and heparan sulfate derivatives in CSF and 
glycosaminoglycans (GAG), including heparan sulfate and heparan sulfate 
derivatives, in urine.

Brain magnetic resonance imaging (MRI) and auditory brainstem response (ABR), 
Brainstem Auditory Evoked Potentials).
Study Design:
This study, HGT-SAN-067, is an open-label, long term, multicenter, extension of 
Study HGT-SAN-055.  The study is designed to evaluate the long-term safety, clinical 
activity, and biomarker outcomes of intrathecal (IT) administration of 3 dose levels 
(10 mg, 45 mg, and 90 mg once per month [Q4W]) of HGT-1410 via an IDDD in patients 
with MPS IIIA who successfully complete the Phase I/II study HGT-SAN-055 (including 
end of study [EOS] assessments) and elect to continue to receive HGT-1410 treatment.  
Initially, patients will continue in the same treatment group they were assigned to in the 
HGT-SAN-055 study. Following approval of Protocol Amendment 4, patients in the 
10 mg group had their dose increased to 45 mg per month.

Shire
CONFIDENTIAL
Page 10
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
For nomenclature of chronology purposes, the Baseline Visit for this extension study will 
be considered to be the first day the patient received his/her IT dose of HGT-1410 in 
Study HGT-SAN-055.  The HGT-SAN-055 EOS assessment information will provide the 
screening/start of study information for patients who continue into the HGT-SAN-067 
extension study.  Note:  HGT-SAN-055 EOS data must be recorded in the context of the 
HGT-SAN-055 trial, and a copy of those data can be used for HGT-SAN-067 screening.  
Once eligibility is confirmed, informed consent must be obtained prior to performing any 
study-related procedures that are specific to HGT-SAN-067.  
Informed consent will be provided by the patient’s parent(s)/legally authorized 
representative(s) prior to the start of the extension study procedures.  Informed consent 
may be obtained anytime from week 20 in HGT-SAN-055.  This would allow a patient to 
have a nonfunctional IDDD replaced or revised prior to the first HGT-1410 dose in 
HGT-SAN-067.
Enrolled patients will check in to the study center 1 day before each of the scheduled 
HGT-1410 dosing days for safety assessments (designated Day 1). If no safety concerns 
exist, the patient will subsequently receive IT administration of HGT-1410 on Day 2 
(±2 days). However, if feasible and there are no safety concerns in the opinion of the 
investigator, the Day 1 and Day 2 assessments may be combined and performed on 
Day 2; if this is done the results will be recorded as Day 2. Patients will remain in the 
study center for at least 4 hours following dosing with HGT-1410 and will be discharged 
from the unit when deemed clinically stable by the investigator.
All patients will have received a series of standardized neurodevelopment assessments in 
the HGT-SAN-055 study.  These assessments will have occurred at Baseline and either 
prior to or at the 6-month time point. Patients will continue in HGT-SAN-067, during the 
treatment period, with whichever age specific assessment they began with in HGT-SAN-
055. If, however, a patient’s capability improves and they become capable of completing 
assessments at a higher level, such additional assessments may be added. Any additional 
assessments would be performed after the original assessments (those previously used in 
study HGT-SAN-055) have been carried out, during the treatment period of the study. An 
MRI of the head will be performed at Months 12, 24, 36, 54, 60, 72, 84, 96, and 102 and 
ABR testing will be performed at Months 12, 24, and 36 (note that assessment time point 
nomenclature includes the 6 months in the HGT-SAN-055 study), during the treatment 
period. Note: X-rays may be performed to investigate device malfunction, migration, and 
to verify correct catheter and port placement following surgical implantation or revision. 
In addition, fluoroscopy should be employed intraoperatively to guide catheter placement. 
Thus, patients may undergo 3 X-ray examinations in association with each episode of 
IDDD malfunction and subsequent IDDD revision or replacement. Since the number of 
IDDD revisions/replacements is limited to 2 in any 6-month period (including the time in 
the HGT-SAN-055 study), the number of protocol-associated X-ray evaluations is limited 
to 6 exposures in any 6-month period (including time in the HGT-SAN-055).
Patients will be evaluated for safety throughout the study.  Adverse events that occur in 
HGT-SAN-055 and that are ongoing at enrollment in HGT-SAN-067 will be captured in 

Shire
CONFIDENTIAL
Page 11
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
the case report forms (CRFs) for study HGT-SAN-067.  Specific safety stopping criteria 
will be applied and will be based on the types and severity of adverse events (AEs) 
reported while on-study.  These data will be reviewed to inform the decision to 
discontinue a patient, a dose group, or the study as a whole. 
All patients will have an EOS visit, during the treatment period, 30 (±7) days following 
their last administration of HGT-1410 (ie, Month 102). The EOS procedures will include 
standard clinical laboratory tests (serum chemistry, hematology, and urinalysis) in CSF 
and blood, protocol specific laboratory testing (eg, anti-rhHNS antibody testing), 
neurodevelopmental testing, child health questionnaires, and MRI.  
Use of concomitant medications, therapies, and procedures will be recorded and AEs will 
be monitored. 
All patients will be contacted by telephone or will have a visit for a Final Safety 
Follow-up, to be conducted at 30 (±7) days after the EOS visit of the treatment period (ie, 
Month 103) to collect updated information on AEs and concomitant medications, 
therapies, and procedures. 
If the patient is discontinued from the study, the IDDD should be removed and a modified 
end of study visit should be completed within 30 days after withdrawal. These visits may 
be combined into one visit, in which case follow-up via a phone call should be completed 
within 14 days after the device removal to collect safety information. If the investigator 
determines that the IDDD should not be removed from the patient based upon a safety 
assessment and the IDDD (full or partial) remains in the patient, then the patient will 
continue in the study under the safety follow-up period upon completion of their last 
treatment period visit.
It is anticipated that the IDDD will be used to obtain CSF samples and to deliver 
administrations of HGT-1410.  However, if a patient’s IDDD appears nonfunctional or if 
its use is precluded on a scheduled day of dosing, site personnel will refer to the 
operations manual (for PORT-A-CATH) or the IDDD Manual (for SOPH-A-PORT), 
which describes the investigation and management of IDDD-related issues.  This will 
include possible partial revision or complete replacement of the IDDD.  As noted above, 
a maximum of 2 partial revisions and/or complete replacements can occur in any 6 month 
period.  If revision or replacement of the IDDD cannot be scheduled in time to avoid a 
delay of the next scheduled dose of HGT-1410, or if the patient experiences more than 
2 IDDD malfunctions in a 6 month period (including participation in study 
HGT-SAN-055), HGT-1410 will be administered via lumbar puncture (LP).  
If there are medical contra-indications to the re-implantation of a new device, or if the 
patient so desires, repeat monthly lumbar punctures may be considered as an alternative 
way of delivering the study drug and obtaining CSF samples under limited circumstances. 
If no safety risks are identified by the investigator, up to 12 consecutive lumbar punctures 
may be performed across the studies HGT-SAN-055 and HGT-SAN-067. Once a patient 
has reached the maximum of 12 consecutive lumbar punctures, a new IDDD may be 
re-implanted for subsequent dosing, unless, in the opinion of the investigator and medical 

Shire
CONFIDENTIAL
Page 12
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
monitor, assessment of risk/benefit favors continued dosing via lumbar puncture.
Continued treatment via lumbar puncture beyond the stipulated 12 consecutive monthly 
doses can be considered only in individual cases where this treatment is very well 
tolerated and the investigator has not identified any safety concerns associated with repeat 
lumbar puncture and repeat sedation/anesthesia. 
During the treatment period, if there was no significant safety risk in the opinion of the 
investigator, a non-functional IDDD may have been left in situ for up to 3 months.
In light of the higher than expected complications experienced with the PORT-A-CATH 
IDDD, the SOPH-A-PORT Mini S device will be introduced for those patients requiring 
replacement or revision.  This new device has design features anticipated to reduce 
complications encountered with the PORT-A-CATH IDDD device.  Specific device 
assessments are included in the protocol to collect information with respect to 
information specific to SOPH-A-PORT Mini S device safety and function.  
During the treatment period, patients who discontinue or are withdrawn before receiving 
3 monthly IT injections will not have to undergo the EOS evaluations but will have their 
IDDD removed.  
Patients should have the IDDD removed when they discontinue from or complete the 
treatment period of the study, unless the Investigator determines that it should not be 
removed based upon safety assessments. The device can remain in the patient (partial 
[catheter only] or full [port, catheter, and suture wings]) if the patient is doing clinically 
well and there are no further known risk factors such as infection (eg, meningitis).  The 
device may be partially or fully removed as medically required and determined by the 
neurosurgeon at a future date.
Patients who do not have the IDDD removed (partial or full device) at the end of the 
treatment period will continue to be observed during a safety follow-up period with visits 
at the site every 6 months to evaluate patient safety of the device until the IDDD has been 
fully explanted.
An overview of the study appears in the Schedule of Events.
Study Population: 
A maximum of 12 patients are planned for this study.  To be eligible for participation 
patients will have completed all study requirements in Study HGT-SAN-055, including 
the EOS visit, and will have elected to continue treatment with HGT-1410. 
Test Product; Dose; and Mode of Administration: Recombinant human heparan 
N-sulfatase (rhHNS, HGT-1410) will be administered via an IDDD according to the same 
dose to which the patient was assigned in HGT-SAN-055 (ie, 10 mg, 45 mg, or 90 mg 
monthly). Patients assigned to the 10 mg monthly dose had their dose increased to 45 mg 
once per month (Q4W) at the first administration of HGT-1410.
Reference Therapy; Dose; and Mode of Administration: 
N/A

Shire
CONFIDENTIAL
Page 13
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
Diagnosis and Main Criteria for Inclusion
Inclusion Criteria:
Each patient must meet the following criteria to be enrolled in this study.
1. The patient must have completed Study HGT-SAN-055 and, in the opinion of the 
investigator, have no safety or medical issues that contraindicate participation. 
2. The patient, patient’s parent(s) or legally authorized representative(s) has voluntarily 
signed an Institutional Review Board/Independent Ethics Committee-approved 
informed consent (and assent, if applicable) form after all relevant aspects of the 
study have been explained and discussed with them.  Informed consent/assent must be 
obtained prior to any study specific procedures.
3. The patient received at least 5 of the 6 planned infusions of HGT-1410 in the 
HGT-SAN-055 study. 
4. The patient must be medically stable, in the opinion of the investigator, to 
accommodate the protocol requirements, including travel, assessments, and IDDD 
surgery (if necessary for replacement purposes), without placing an undue burden on 
the patient/patient's family.
Exclusion Criteria: 
Patients will be excluded from the study if there is evidence of any of the following:
1. The patient has experienced an adverse reaction to study drug in Study 
HGT-SAN-055 that contraindicates further treatment with HGT-1410.
2. The patient has a known hypersensitivity to the active ingredient or any excipients in 
HGT-1410 drug product.
3. The patient has non-MPS IIIA related central nervous system (CNS) impairment or 
behavioral disturbances that would confound the scientific integrity or interpretation 
of study assessments, as determined by the investigator.
4. The patient has MPS IIIA behavioral-related issues, as determined by the investigator, 
which would preclude performance of study neurocognitive and developmental 
testing procedures.
5. The patient is pregnant, breast feeding, or is a patient of childbearing potential who 
will not or cannot comply with the use of an acceptable method of birth control, such 
as condoms, barrier method, oral contraception, etc.
6. The patient has any known or suspected hypersensitivity to anesthesia or is thought to 
have an unacceptably high risk for anesthesia due to airway compromise or other 
conditions.
7. The patient has a history of a poorly controlled seizure disorder. 
8. The patient is currently receiving psychotropic or other medications, which in the 
investigator’s opinion, would be likely to substantially confound test results and the 
dose and regimen of which cannot be kept constant throughout the study.
9. The patient cannot sustain absence from aspirin, non-steroidal medications, or 
medications that affect blood clotting within 1 week prior to a relevant study-related 
procedure (eg, device re-implantation if applicable), or has ingested such medications 
within 1 week before any procedures in which any change in clotting activity would 

Shire
CONFIDENTIAL
Page 14
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
be deleterious.
10. The patient has received treatment with any investigational drug (other than 
HGT-1410) intended as a treatment for MPS IIIA within the 30 days prior to, during 
the study, or is currently enrolled in another study that involves an investigational 
drug or device (screening through safety follow-up contact).
11. The patient has received a hematopoietic stem cell or bone marrow transplant.
For patients to be implanted with the SOPH-A-PORT Mini S IDDD the following 
conditions are contraindicated, as described in the Instructions for Use: 
1. The patient has had, or may have, an allergic reaction to the materials of construction 
of the SOPH-A-PORT Mini S device.
2. The patient’s body size is too small to support the size of the SOPH-A-PORT Mini S 
Access Port, as judged by the investigator.
3. The patient has a known or suspected local or general infection.
4. The patient is at risk of abnormal bleeding due to a medical condition or therapy.
5. The patient has one or more spinal abnormalities that could complicate safe 
implantation or fixation.
6. The patient has a functioning CSF shunt device.
7. The patient has shown an intolerance to an implanted device.
Duration of Treatment: 
The study duration allows patients who completed Study HGT-SAN-055 and elected to 
continue treatment with HGT-1410 in Study HGT-SAN-067 to receive treatment with 
HGT-1410 up to 8 years.
For those patients with a partial or full device still in place after completion of the 
treatment period, patients may be followed for safety up to an additional 3 years or until 
the device is removed in the last patient.
The LPLV will be the safety follow-up visit after the final device (partial and/or full) is 
removed from the last patient during the safety follow-up period.
Pharmacokinetic Variables:
N/A.
Safety Assessments: 
Safety evaluations will include vital signs, physical examinations, AE assessments, 
electrocardiograms (ECG); serum chemistry, hematology, urine laboratory tests, and 
screening for antibodies to rhHNS (in CSF and serum).  

Shire
CONFIDENTIAL
Page 15
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
Statistical Methods: The statistical methodology supporting the trial will focus on 
descriptive rather than inferential approaches, given the early phase and objectives of the 
trial. Data will be plotted and the mean, standard deviation, median, minimum, and 
maximum for each variable will be tabulated by dose group to look for gross trends over 
time, which may be attributed to treatment. For continuous data, 95% confidence interval 
(CI) around the mean will also be estimated and presented.
The analysis population consists of all eligible patients from HGT-SAN-055 who have 
completed Study HGT-SAN-055 and agreed to participate in this extension study.  Safety 
analyses will be performed using the above mentioned population.  The data will be 
presented by dose group.
Date of Original Protocol: 21 June 2010
Date of Amendment 8: 01 February 2017 

Shire
CONFIDENTIAL
Page 16
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ABR
auditory brainstem response
AE
adverse event
ALB
albumin
ALK-P
alkaline phosphatase
ALT
alanine aminotransferase (SGPT)
AST
aspartate aminotransferase (SGOT)
βhCG
human chorionic gonadotropin
BSID-III
Bayley Scales of Infant Development, Third Edition
BBB
blood brain barrier
BUN
blood urea nitrogen
Ca
calcium
CE
Conformité Européenne
CFR
Code of Federal Regulations
CHQ-50
Child Health Questionnaire™ Parent Form 50
CHQ-87
Child Health Questionnaire™ Child Form 87
CK
creatine kinase
Cl
chloride
CNS
central nervous system
CO2
carbon dioxide
CTCAE
Common Terminology Criteria for Adverse Events
CRO
contract research organization
CRIM
cross-reacting immunologic material 
CS
clinically significant
CSF
cerebrospinal fluid
ECG
electrocardiogram
eCRF
electronic case report form
EDC
Electronic Data Capture 

Shire
CONFIDENTIAL
Page 17
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
Abbreviation
Definition
ERT
enzyme replacement therapy
EOS
end of study
EOW
every other week
EU
European Union
FDA
Food and Drug Administration
FPSS/TDS
Four-Point Scoring System/Total Disability Score
GAG
glycosaminoglycan
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
Hct
hematocrit
Hgb
hemoglobin
HS
heparan sulfate
ICH
International Conference on Harmonization 
IDDD
intrathecal drug delivery device
IEC
Independent Ethics Committee
IFU
instructions for use
IND
Investigational New Drug 
IRB
Institutional Review Board
IT
intrathecal
ITQOL
Infant Toddler Quality of Life Questionnaire™
IV
intravenous
K
potassium
KABC-II
Kaufman Assessment Battery for Children, Second Edition
LDH
lactic dehydrogenase
LP
lumbar puncture 
LSD
lysosomal storage disease
M6P
mannose-6-phosphate
MABC-2
Movement Assessment Battery for Children, Second Edition

Shire
CONFIDENTIAL
Page 18
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
Abbreviation
Definition
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MPS
Mucopolysaccharidosis 
MPS IIIA
Mucopolysaccharidosis IIIA or Sanfilippo syndrome Type A
MRI
magnetic resonance imaging
Na
sodium 
NCI
National Cancer Institute
NCS
not clinically significant
PE
pressure-equalization
QoL
quality of life
Q4W
once per month
RBC
red blood cell (count)
rhHNS
recombinant human heparan N-sulfatase
RNA
ribonucleic acid
SAE
serious adverse event
SAP
Statistical Analysis Plan
SBRS
The Sanfilippo Behavior Rating Scale
SGOT
serum glutamic oxaloacetic transaminase (AST)
SGPT
serum glutamic pyruvic transaminase (ALT)
Shire HGT
Shire Human Genetic Therapies, Inc.
TMF
Trial Master File
TX
treatment
UADE
unanticipated adverse device effect
US
United States
VABS-II
Vineland Adaptive Behavior Scales 
WBC
white blood cell (count)
WHO-DD
World Health Organization-Drug Dictionary 

Shire
CONFIDENTIAL
Page 19
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
1
INTRODUCTION
The progressive and irreversible nature of lysosomal storage diseases (LSDs) present a challenge 
in the interpretation of clinical benefit derived from treatment in studies using enzyme 
replacement therapy (ERT).  Any short-term improvement and/or stabilization of clinically 
important manifestations of the disease may be viewed as clinically meaningful.  However, the 
demonstration of the different aspects of a long-term, clinically-meaningful improvement may be 
limited by the short duration of treatment in clinical studies.  Extended access to treatment 
through extension studies provides an opportunity for further evaluation of long-term safety and 
clinical outcomes for treated patients.  In this extension study, patients who completed study 
HGT-SAN-055, a phase I/II safety and dose-escalation trial, and elected to continue to receive 
recombinant human heparan N-sulfatase (rhHNS), will receive treatment through this extension 
protocol.  Initially, the patient’s treatment group and dosing regimen will be the same as that 
employed in study HGT-SAN-055. Following the analysis of data from HGT-SAN-055, patients 
in the lowest dose group had their dose increased to 45 mg, as outlined in Section 1.3, below.
1.1
Disease Background
Sanfilippo syndrome, or Mucopolysaccharidosis (MPS) III, is LSD caused by loss in activity of 
1 of 4 enzymes necessary for degradation of the glycosaminoglycan (GAG) heparan sulfate (HS) 
in lysosomes.  Four different subtypes (A, B, C, and D) have been identified and are each due to 
a specific enzyme deficiency involved in the lysosomal catabolism of HS.  
Mucopolysaccharidosis IIIA or Sanfilippo syndrome Type A (MPS IIIA) results from deficiency 
of the enzyme heparan N-sulfatase (sulfamidase).  In the absence of this enzyme, intermediates 
of the HS degradation process accumulate in the lysosomes of neurons and glial cells, with lesser 
accumulation outside the brain.  
MPS III is the most prevalent of all mucopolysaccharidoses, with subtype A the most common of 
these.1  The birth prevalence of MPS IIIA has been estimated as 1.28 in 100,000 in Australia, 
1.16 in 100,000 in the Netherlands, and 0.88 in 100,000 in Germany.1-3 In summary, MPS IIIA 
is a rare genetic disorder with apparently widespread geographic distribution and an average 
global birth incidence of approximately 1 in 100,000.
In a recent detailed review of all MPS IIIA patients diagnosed in the Netherlands, it was reported 
that among 81 patients in whom information was available, first symptoms arose at a median of 
2.5 years (range 0.5 to 7 years).4  Owing to the rarity of the disease and the non-specific and 
often subtle nature of its initial manifestations, diagnosis is usually delayed until an average age 
of 4 to 4.5 years.4, 5 Patients present a wide spectrum and severity of clinical symptoms.  The 
central nervous system (CNS) is the most severely affected organ system in patients with MPS 
IIIA, evidenced by deficits in language development, motor skills, and intellectual development.5  
In addition, there are abnormal behaviors including, but not limited to, aggression and excess 
motor activity/hyperactivity that contribute to disturbances in sleep.5-7 In contrast with other 
MPS types, the viscera are mildly affected, with transient enlargement of liver and spleen during 
childhood with no evidence of dysfunction.  There are also reports of unexplained, recurrent and 
severe diarrhea.8  Overall, individuals with MPS IIIA have a marked developmental delay and 
significantly reduced lifespan of 15 years of age on average.8  

Shire
CONFIDENTIAL
Page 20
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
A milder variant has recently been identified with slower progression and survival to later age in 
approximately 10% of German patients with MPS IIIA.9
No effective, disease-modifying therapies are currently approved as treatments for this rare, 
devastating and disabling disease.  
A long-range goal of Shire Human Genetic Therapies, Inc. (Shire HGT) is to develop a 
recombinant human sulfamidase ERT for patients with MPS IIIA.  A particular problem for 
LSDs that damage the brain such as MPS III is how to target ERT to the brain.10  In animal 
studies, ERT was administered into the cerebrospinal fluid (CSF) via an intrathecal (IT) route, 
because when administered intravenously (IV), it was shown to not cross the blood brain barrier 
(BBB) after the immediate postnatal period of life.11, 12  
As the CNS in patients with MPS IIIA is the most severely affected body system, the main focus 
of the HGT-1410 clinical development program has been the development of ERT specifically 
for delivery directly to the CNS.  Recombinant human heparan N-sulfatase has been developed 
specifically for delivery into the CSF via an intrathecal drug delivery device (IDDD) due to the 
acknowledged impermeability of the BBB to macromolecules. 
Heparan N-sulfatase is a highly purified recombinant form of the naturally occurring human 
lysosomal enzyme sulfamidase.  It is expressed from the well characterized continuous human 
HT-1080 cell line as a 482 amino acid peptide, following cleavage of the 20 amino acid 
N-terminal signal peptide.  The mature protein in solution is a homodimeric glycoprotein of 
approximately 122 kDa, which undergoes post-translational modifications by conversion of 
Cys50 to formylglycine, required for enzyme activity, and glycosylation at 4 of the 5 potential 
N-linked glycosylation sites.  The rhHNS glycans contain mannose-6-phosphate (M6P) residues 
which target the protein for cellular uptake and internalization in its lysosomal site of action via 
the membrane-bound M6P receptors.13, 14-16
The first precedent for intraspinal ERT was recently published and has been shown to be both 
safe and effective for spinal cord compression in MPS I.17  In this study, a patient with MPS I 
received 4 IT doses of enzyme (Laronidase [recombinant α-L- Iduronidase]) at 1-month 
intervals.  Safety evaluations included CSF opening pressure, serum chemistry and CSF protein, 
glucose and cell count, in addition to clinical efficacy studies.  No changes in safety evaluations 
were observed.
In another recent study, a patient with MPS VI and spinal cord compression received IT 
injections of enzyme (Galsulfase) monthly, for 4 months.  CSF analysis revealed no 
inflammatory reaction; no other side effects were noted.18
Several MPS I patients have been treated since 2005 with IT Laronidase in 2 ongoing clinical 
trials (clinicaltrials.gov identifiers NCT00215527 and NCT00786968) studying efficacy on 
spinal cord compression. No results of these trials have yet been published. However, in 
June 2009 a study further investigating the effectiveness of IT ERT as a treatment for another 
neurological symptom in MPS I, cognitive decline, was initiated (clinicaltrials.gov identifier 
NCT00852358). 

Shire
CONFIDENTIAL
Page 21
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
This study is a 24-month, open label, prospective, randomized trial in 16 patients with 
MPS I, 6 years of age or older, who have documented evidence of cognitive decline. In this 
study, the clinical safety of the regimen will be assessed by adverse event (AE) monitoring, CSF 
laboratory assessments, and clinical evaluations.  This study is ongoing; no efficacy or safety 
data have yet been published as of October 2011.19 
In addition, there are 4 ongoing Shire-sponsored studies that are evaluating IT administration of 
ERT:  A Phase I/II safety and dose escalation study of monthly idursulfase-IT injection for 
cognitively impaired patients with Hunter syndrome (Study HGT-HIT-045; NCT00920647), the 
open-label extension to this study (HGT-HIT-046); a Phase I/II ascending dose and dose 
frequency study of monthly IT injection of HGT-1410 in patients with Sanfilippo Syndrome 
Type A (Study HGT-SAN-055; NCT01155778), and the open-label extension to this study 
(HGT-SAN-067; NCT 01299727).
In light of the higher than expected complications experienced with the PORT-A-CATH IDDD, 
the SOPH-A-PORT Mini S device will be introduced for those patients requiring replacement or 
revision.  This new device has design features anticipated to reduce complications encountered 
with the PORT-A-CATH IDDD device.  Specific device assessments are included in the protocol 
to collect information with respect to information specific to SOPH-A-PORT Mini S device 
safety and function.  
1.2
Nonclinical Overview
To circumvent the restriction of the BBB, HGT-1410 was administered into the CSF of rats and 
monkeys via an IT route.  The non-clinical data demonstrate that IT administration of HGT-1410 
leads to uptake by target CNS tissues with appropriate efficacy and distribution.  In addition, 
there were no findings noted in the toxicity studies, allowing for a 6.2-fold safety margin from 
the results in the juvenile cynomolgus monkey.  Intermittent bolus injection of HGT-1410 to the 
brain via the IT route of administration is hypothesized to be of benefit in stabilizing, improving, 
or preventing the CNS manifestations of disease. 
The doses tested in the non-clinical studies adequately support the efficacy of the planned doses 
(10, 45 or 90 mg/month, normalized to the brain weight of the human) in the ongoing Phase I/II 
study, HGT-SAN-055.  Specifically, in the San A mouse, the 100 μg dose corresponds to a 
2.2-fold increase (per kg brain weight) from the highest anticipated human dose (90 mg) (human 
brain = 1 kg).  The 20 μg dose given IT every other week (EOW) or monthly, for which efficacy 
was also observed, corresponds to a 40 mg (per kg brain weight) human dose.  In the Huntaway 
(Sanfilippo A) dogs, the 3 mgHGT-1410 given IT weekly (corresponding to a 33 mg/kg of brain 
weight in man), was not only well tolerated but resulted in significant effects on biomarkers of 
disease activity and improved histopathology. 
1.2.1
Toxicology in Monkeys
In the pivotal, 6-month IT toxicity study in juvenile cynomolgus monkeys, and the highest dose 
of HGT-1410 was 8.3 mg given EOW.  This translates into a 138 mg/kg brain-weight dose (ie, 
based on a 60 g juvenile monkey brain).  Since no HGT-1410-related adverse effects were noted, 
the nonclinical study provides for the proposed Phase I/II clinical trial a ~13.8 × safety margin 

Shire
CONFIDENTIAL
Page 22
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
relative to the starting clinical dose (10 mg), and a 1.5× safety margin relative to the highest 
clinical dose (90 mg).    
1.2.2
Efficacy in Murine and Canine Models of MPS IIIA
Non-clinical proof of concept efficacy studies were conducted using mouse and dog models of 
MPS IIIA, both of which contain naturally-occurring mutations in the HNS gene.  
In the MPS IIIA mouse, direct injection into the CNS had a beneficial effect on clinical signs, 
impaired neurobehavioral, and the biochemical and histopathologic markers of disease activity.  
In Huntaway (Sanfilippo A) dogs, HGT-1410 (3 mg) given IT weekly had a significant effect on 
biomarkers of disease activity and improved histopathology.
Efficacy has been demonstrated at a range of doses in nonclinical mouse and canine models.  In 
MPS IIIA mice, a dose-dependent reduction in the level of a heparan sulfate-derived monosulfate 
disaccharide was observed within the brain (up to 62% reduction compared with vehicle-treated 
mice) and spinal cord (up to 71% reduction).  An ultrastructural examination revealed a 
reduction in lysosomal vesicle formation in various cell types and fewer (ubiquitin-positive) 
axonal spheroids in several brain regions after repeated injections (5 to 20 µg) of HGT-1410 into 
the CSF of MPS III mutant mice via the cisterna magna (ie, IT).  The biochemical changes were 
accompanied by improved behavior, particularly in mice treated more frequently.20
In the MPS IIIA mutant mouse model, intracisternal (ie, IT) injection of a single dose of 100 µg 
HGT-1410 resulted in a substantial (and sustained) reduction of biomarkers of disease activity 
(heparan sulfate-derived disaccharides, microgliosis and astrogliosis).21   Equally impressive was 
the improvement in neurobehavioral parameters (learning in the Morris water maze, 
normalization of aggression) in these mice post-dose.21  One-hundred µg HGT-1410 per mouse 
translates into 200 mg/kg brain weight (ie, based on a 0.5 g mutant mouse brain).  Efficacy at 
lower doses of HGT-1410 (eg, 20 µg, given IT, EOW or monthly) has been demonstrated.11  A 
20 µg injection translates into a 40 mg human dose (ie, 40 mg per kilogram of brain weight).  
Thus, this data further suggests that efficacy will be seen at the highest clinical dose (90 mg, per 
month) in the proposed Phase I/II study. 
In the tolerized Huntaway (San A) dogs, 3 mg HGT-1410 was initially given IT on a weekly 
basis, then EOW, and had a significant effect on biomarkers of disease activity.22  The 3 mg dose 
in the dog translates into a 33 mg (per kg brain weight) human dose (based on a 90 g Huntaway 
dog brain). 
1.3
HGT-SAN-067 Study Rationale
This extension study (Study HGT-SAN-067) will evaluate the effects of long-term HGT-1410 
administration on safety, clinical activity, and biomarker outcomes in patients who completed 
Study HGT-SAN-055 and elected to continue therapy with HGT-1410.
Patients who were enrolled in Study HGT-SAN-055 through Week 26 and completed the end of 
study (EOS) evaluations are eligible for enrollment in this open-label extension study. All 
patients enrolled in this study will initially receive HGT-1410 at the same dose and schedule as 

Shire
CONFIDENTIAL
Page 23
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
they received in Study HGT-SAN-055. Patients assigned to 10 mg monthly had their dose 
increased to 45 mg monthly once per month (Q4W) at the first administration of HGT-1410 
following full approval of Protocol Amendment 4. Based on analyses performed at the 
completion of Study HGT-SAN-055 a decline in the primary pharmacodynamic parameter, CSF 
heparan sulfate, was observed. This response to therapy was exhibited at all dose levels, 
however, the greatest impact was at the 2 higher dose levels. An effect on CSF heparan sulfate 
demonstrated in vivo activity of HGT-1410 in the target anatomical compartment. This effect is 
thought to have central importance in mediating the potential therapeutic benefit of HGT-1410. 
As no apparent difference in safety profile was observed between the 3 dose groups, it was 
believed that the increase in the potential therapeutic benefit of the higher dose outweighed any 
potential increase in risks for this lowest dose group.  
Please refer to the current edition of the Investigator’s Brochure for further information 
concerning the safety and clinical development of HGT-1410 and PORT-A-CATH IDDD and 
SOPH-A-PORT Mini S device.

Shire
CONFIDENTIAL
Page 24
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
2
STUDY OBJECTIVES
2.1
Primary Objective 
The primary objective of this study is:

To collect long-term safety and tolerability data in patients with Sanfilippo Syndrome 
Type A (MPS IIIA) who received HGT-1410 via a surgically implanted IDDD in study 
HGT-SAN-055 and elect to continue therapy in study HGT-SAN-067.
2.2
Secondary Objectives 
The secondary objectives of this study are:

To collect, as measures of drug efficacy, over an extended treatment period (as change from 
baseline), the following:  clinical, neurological, cognitive, behavioral, functional, and quality 
of life (QoL) assessments, together with potential imaging and biochemical biomarkers.
2.3
Exploratory Objective
An exploratory objective of this study is:


Shire
CONFIDENTIAL
Page 25
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
3
STUDY ENDPOINTS
3.1
Primary Endpoint
The primary endpoints of this study are related to the long-term safety of intrathecal HGT-1410 
administration. The safety endpoints are:

adverse events (type and severity)

changes in clinical laboratory testing (serum chemistry including  liver function tests, 
hematology, and urinalysis)

electrocardiograms (ECG)

CSF chemistries (including cell counts and inflammatory markers)

anti-rhHNS antibodies (in CSF and serum).
3.2
Secondary Endpoints 
The secondary endpoints of this study are to collect over an extended treatment period (as the 
change from baseline [defined as the start of the HGT-SAN-055 study]) clinical and potential 
surrogate biomarker efficacy data: 

Measures of standardized neurocognitive and behavioral assessments, Sanfilippo-specific 
behavioral rating scales, gross and fine motor assessments, functional adaptive rating scales, 
QoL questionnaires, and Children’s Sleep Habits Rating Scale.

Concentration of safety and potential surrogate efficacy biomarkers in CSF, urine, and 
serum.

Concentration of heparan sulfate and heparan sulfate derivatives in CSF and GAG, including 
heparan sulfate and heparan sulfate derivatives, in urine.

Brain magnetic resonance imaging (MRI) and auditory brainstem response (ABR), (also 
known as Brainstem Auditory Evoked Potentials).
3.3
SOPH-A-PORT Mini S Assessments

Shire
CONFIDENTIAL
Page 26
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
4
INVESTIGATIONAL PLAN
4.1
Overall Study Design and Plan
Study HGT-SAN-067, is an open-label, long term, multicenter, extension of Study 
HGT-SAN-055.  This study is designed to evaluate the long-term safety, clinical activity, and 
biomarker outcomes of IT administration of 3 dose levels (10 mg, 45 mg, and 90 mg once per 
month [Q4W]) of HGT-1410 via an IDDD in patients with MPS IIIA who successfully 
completed HGT-SAN-055 (including the EOS assessments) and elect to continue to receive 
uninterrupted HGT-1410 treatment.  Patients will initially continue in the same treatment group 
they were assigned to in the HGT-SAN-055 study: 

Group 1:  HGT-1410 administered by IT injection 10 mg once per month (Q4W) 

Group 2:  HGT-1410 administered by IT injection 45 mg once per month (Q4W)

Group 3:  HGT-1410 administered by IT injection 90 mg once per month (Q4W) 
Patients assigned to Group 1 will initially receive 10 mg monthly but had their dose increased to 
45 mg monthly (Q4W) at the first administration of HGT-1410 following full approval of 
protocol Amendment 4.
Primarily main sites will be utilized; however, the sponsor and investigator will consider the 
feasibility of transitioning the patient’s IT dosing to local sites to reduce the burden imposed by 
travel. At Month 18 (12 months after study start), patients that already received IT dosing at the 
main site may be eligible to transfer to a local site if in the opinion of the investigator there are 
no safety or medical concerns precluding this transition. Subsequent IT injections of HGT-4110 
may be performed at either the main site or the local site. The local sites will be selected and 
approved by the sponsor, and the patient must have no safety or medical issues that would 
preclude transitioning to a local site (Note: the main site may serve as a local site as needed; and 
in this case, the main site will follow the assessments scheduled for a local site). The 
qualification requirements for physicians at local sites will be identical to those for the main 
sites.  Local sites will be trained if inexperienced with IT administration via an IDDD.  Patients 
will be discharged a minimum of 4 hours after dosing and when deemed clinically stable by the 
investigator. Dosing by IT injection may take place at the main site, rather than local site, if 
scheduled study assessments include MRI and cognitive assessments.  Patients must review and 
agree to written informed consent/assent from the local site to participate in study procedures to 
be conducted at the local site prior to the conduct of these procedures.
In order to maintain a nomenclature system based on study chronology across the original 
HGT-SAN-055 study and this extension study, the Baseline Visit for this extension study will be 
considered to be the day the patient received their first IT dose of HGT-1410 in 
Study HGT-SAN-055.  The HGT-SAN-055 EOS assessment information will provide the 
screening/start of study information for patients who continue into the HGT-SAN-067 extension 
study.  Note: HGT-SAN-055 EOS data must be recorded in the context of the HGT-SAN-055 
trial, and a copy of those data can be used for HGT-SAN-067 screening.  Once eligibility is 
confirmed, informed consent (and assent, if applicable), provided by the patient’s 
parent(s)/legally authorized representative(s), must be obtained prior to performing any 

Shire
CONFIDENTIAL
Page 27
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
HGT-SAN-067 study-related procedures.  Informed consent may be obtained anytime from 
Week 20 in HGT-SAN-055.  This would allow a patient to have a nonfunctional IDDD replaced 
or revised prior to the first HGT-1410 dose in HGT-SAN-067.  
Enrolled patients will check in to the study center 1 day before each of the scheduled HGT-1410 
dosing days for safety assessments (designated Day 1).  If no safety concerns exist, the patient 
will subsequently receive IT administration of HGT-1410 on Day 2 (±2 days).  However, if 
feasible and there are no safety concerns in the opinion of the investigator, the Day 1 and Day 2 
assessments may be combined and performed on Day 2; if this is done the results will be 
recorded as Day 2.  Patients will remain in the study center for at least 4 hours following dosing 
with HGT-1410 and will be discharged from the unit when deemed clinically stable by the 
investigator.  
All patients will have received a series of standardized neurodevelopment assessments; in the 
HGT-SAN-055 study, these will have occurred at Baseline and either prior to or at the 6-month 
time point.  Patients will continue in HGT-SAN-067, during the treatment period, with 
whichever age specific assessment they began with in HGT-SAN-055.  If, however, a patient’s 
capability improves and they become capable of completing assessments at a higher level, such 
additional assessments may be added.  Any additional assessments are to be performed after the 
original assessments (those used in study HGT-SAN-055) have been carried out, during the 
treatment period of the study.  
An MRI of the head will be performed at Months 12, 24, 36, 54, 60, 72, 84, 96, and 102 and 
ABR testing will be performed at Months 12, 24, 36 and 54 (note that assessment time point 
nomenclature includes the 6 months in the HGT-SAN-055 study), during the treatment period of 
the study. 
In the event of a device malfunction, X-rays may be performed to investigate, as well as to verify 
correct catheter and port placement following surgical IDDD implantation or revision.  In 
addition, fluoroscopy may be employed intra-operatively to guide catheter placement.  Patients 
may undergo 3 X-ray examinations in association with each episode of IDDD malfunction and 
subsequent IDDD revision or replacement.  The number of IDDD revisions/replacements is 
limited to 2 in any 6-month period (including the time in the HGT-SAN-055 study), and the 
number of protocol-associated X-ray evaluations is limited to 6 exposures in any 6-month period 
(including time in study HGT-SAN-055). 
Patients will be evaluated for safety throughout the study.  Adverse events that occur in 
HGT-SAN-055 and are ongoing at enrollment in HGT-SAN-067 will be captured as ongoing in 
the HGT-SAN-055 study and also be reported as a concurrent condition in the HGT-SAN-067 
eCRFs.  Specific safety stopping criteria will be applied and will be based on the types and 
severity of AEs reported while on-study.  These data will be reviewed to inform the decision to 
discontinue a patient, a dose group, or the study as a whole. 
All patients will have an EOS visit during the treatment period, 30 (±7) days following their last 
administration of HGT-1410 (ie, Month 102).  The EOS procedures will include standard clinical 
laboratory tests (serum chemistry, hematology, and urinalysis) in CSF and blood, protocol
specific laboratory testing (eg, anti-rhHNS antibody testing), neurodevelopmental testing, child 

Shire
CONFIDENTIAL
Page 28
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
health questionnaires, and MRI.  Use of concomitant medications, therapies, and procedures will 
be recorded and AEs will be monitored. 
All patients will be contacted by telephone or will have a visit for a Final Safety Follow-up, 
conducted at 30 (±7) days after the EOS visit, of the treatment period, (ie, Month 103) to collect 
updated information on AEs and concomitant medications, therapies, and procedures. 
If the patient is discontinued from the study, the IDDD should be removed and a modified end of 
study visit should be completed within 30 days after withdrawal. These visits may be combined 
into one visit, in which case follow-up via a phone call should be completed within 14 days after 
the device removal to collect safety information. If the investigator determines that the IDDD 
should not be removed from the patient based upon a safety assessment and the IDDD (full or 
partial) remains in the patient, then the patient will continue in the study under the safety follow-
up period upon completion of their last treatment period visit.
It is anticipated that the IDDD will be used to obtain CSF samples and to administer HGT-1410. 
However, if a patient’s PORT-A-CATH IDDD appears nonfunctional or if its use is precluded 
on a scheduled day of dosing, site personnel will refer to the PORT-A-CATH Instructions for 
Use (IFU), which describes the investigation and management of IDDD-related issues with this 
device. This will include possible partial revision or complete replacement of the PORT-A-
CATH IDDD with a SOPH-A-PORT IDDD. For malfunctions involving the SOPH-A-PORT 
Mini S, site personnel will refer to the SOPH-A-PORT IFU.  For either IDDD, a maximum of 
2 partial revisions and/or complete replacements are permitted in any 6 month period (including 
participation in study HGT-SAN-055). If a revision or replacement of the IDDD cannot be 
scheduled in time to avoid a delay of the next scheduled dose of HGT-1410, or if the patient 
experiences more than 2 IDDD malfunctions in a 6 month period, HGT-1410 will be 
administered via lumbar puncture (LP). If implantation of a replacement IDDD is not possible, 
investigational drug may be administered by LP for a maximum of 12 successive monthly doses.  
At that point, a safety discussion needs to take place between the investigator and the sponsor to 
determine the risk/benefit of further dosing by LP.
If there is no significant safety risk in the opinion of the investigator, a non-functional IDDD 
may be left in situ for up to 3 months during the treatment period.
Patients who discontinue or are withdrawn before receiving 3 monthly IT injections will not have 
to undergo the EOS evaluations but will have their IDDD removed.  
If during the treatment period, a patient discontinues, or withdraws from the study, or the study is 
stopped by the sponsor, the IDDD should be removed unless the Investigator determines that it 
should not be removed based upon safety assessments. The device can remain in the patient 
(partial [catheter only] or full [port, catheter, and suture wings]) if the patient is doing clinically 
well and there are no further known risk factors such as infection (eg, meningitis).  The device 
may be partially or fully removed as medically required and determined by the neurosurgeon at a 
future date.

Shire
CONFIDENTIAL
Page 29
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
Patients who do not have the IDDD removed (partial or full device) at the end of the treatment 
period will continue to be observed during a safety follow-up period with visits at the site every 
6 months to evaluate patient safety of the device until the IDDD has been fully explanted.
An overview of the study appears in the Schedule of Events (Appendix 1). See Appendix 1, 
Table A1-2 for the Study Schedule of Events for the safety follow-up period for patients with 
partial or full devices in place after the end of the treatment period.  
4.2
Rationale for Study Design and Control Group
The original study, Study HGT-SAN-055, is an ongoing Phase I/II safety and ascending dose 
ranging study of IT administration of HGT-1410 via an IDDD, in patients 3 years of age and 
older with MPS IIIA and early cognitive impairment.  This extension study is proposed to 
continue evaluation of the effects of IT HGT-1410 administration on long-term safety and 
clinical outcomes for patients who completed Study HGT-SAN-055 and elected to continue 
treatment with HGT-1410 in the HGT-SAN-067 study. 
In order to traverse the blood-brain barrier, Shire is evaluating HGT-1410 delivered directly to 
the CNS using an IDDD. The advantage of using an IDDD is that it obviates the need for 
multiple lumbar punctures for drug delivery. Drug products will be administered through this 
port or, if the IDDD is non functional, via lumbar puncture.
If patients in the study require revision and/or replacement of the PORT-A-CATH IDDD, it will 
be removed and replaced with the SOPH-A-PORT Mini S device at a time judged appropriate by 
the investigator.
SOPH-A-PORT Mini S revision, implantation or explantation will be performed at the main site. 
However, if in the opinion of the investigator, emergency removal is clinically necessary, device 
explantation may be performed at the patient’s local site.
4.3
Study Duration and Dates
The study duration allows patients who completed Study HGT-SAN-055 and elected to continue 
treatment with HGT-1410 in Study HGT-SAN-067 to receive treatment with HGT-1410 up to 
8 years.
Patients with a partial or full device still in place after completion of the treatment period, may 
be followed for safety up to an additional 3 years or until the device is removed in the last 
patient. 
The LPLV will be the safety follow-up visit after the final device (partial and/or full) is removed 
from the last patient during the safety follow-up period.

Shire
CONFIDENTIAL
Page 30
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
5
STUDY POPULATION SELECTION
5.1
Study Population
Patients who have completed all study requirements in Study-HGT-SAN-055 and who elected to 
continue HGT-1410 treatment will be eligible to participate; a maximum of 12 patients are 
planned for this study. 
5.2
Inclusion Criteria
Each patient must meet the following criteria to be considered eligible for enrollment in this 
study.
1. The patient must have completed Study HGT-SAN-055 and, in the opinion of the 
investigator, have no safety or medical issues that contraindicate participation. 
2. The patient, patient’s parent(s) or legally authorized representative(s) has voluntarily signed 
an Institutional Review Board/Independent Ethics Committee-approved informed consent 
(and assent, if applicable) form after all relevant aspects of the study have been explained and 
discussed with them.  Informed consent/assent must be obtained prior to any study specific 
procedures.
3. The patient has received at least 5 of the 6 planned infusions of HGT-1410 in the 
HGT-SAN-055 study. 
4. The patient must be medically stable, in the opinion of the investigator, to accommodate the 
protocol requirements, including travel, assessments, and IDDD surgery (if necessary for 
replacement purposes), without placing an undue burden on the patient/patient's family.
5.3
Exclusion Criteria
Patients will be excluded from the study if there is evidence of any of the following: 
1. The patient has experienced an adverse reaction to study drug in Study HGT-SAN-055 that 
contraindicates further treatment with HGT-1410.
2. The patient has a known hypersensitivity to the active ingredient or any excipients in 
HGT-1410 drug product.
3. The patient has significant non-MPS IIIA related central nervous system impairment or 
behavioral disturbances that would confound the scientific integrity or interpretation of study 
assessments, as determined by the investigator.
4. The patient has MPS IIIA behavioral-related issues, as determined by the investigator, which 
would preclude performance of study neurocognitive and developmental testing procedures.
5. The patient is pregnant, breast feeding, or is of childbearing potential who will not or cannot 
comply with the use of an acceptable method of birth control, such as condoms, barrier 
method, oral contraception, etc.
6. The patient has any known or suspected hypersensitivity to anesthesia or is thought to have 
an unacceptably high risk for anesthesia due to airway compromise or other conditions.
7. The patient has a history of a poorly controlled seizure disorder. 

Shire
CONFIDENTIAL
Page 31
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
8. The patient is currently receiving psychotropic or other medications, which in the 
investigator’s opinion, would be likely to substantially confound test results and the dose and 
regimen of which cannot be kept constant throughout the study.
9. The patient cannot sustain absence of aspirin, non-steroidal medications, or medications that 
affect blood clotting within 1 week prior to a relevant study-related procedure (eg, device 
re-implantation if applicable), or has ingested such medications within 1 week before any 
procedures in which any change in clotting activity would be deleterious.
10. The patient has received treatment with any investigational drug (other than HGT-1410) 
intended as a treatment for MPS IIIA within the 30 days prior to, during the study, or is 
currently enrolled in another study that involves an investigational drug or device (screening 
through safety follow-up contact).
11. The patient has received a hematopoietic stem cell or bone marrow transplant.
For patients to be implanted with the SOPH-A-PORT Mini S IDDD the following conditions are 
contraindicated, as described in the Instructions for Use: 
1. The patient has had, or may have, an allergic reaction to the materials of construction of the 
SOPH-A-PORT Mini S device.
2. The patient’s body size is too small to support the size of the SOPH-A-PORT Mini S Access 
Port, as judged by the investigator .
3. The patient has a known or suspected local or general infection.
4. The patient is at risk of abnormal bleeding due to a medical condition or therapy.
5. The patient has one or more spinal abnormalities that could complicate safe implantation or 
fixation.
6. The patient has a functioning CSF shunt device.
7. The patient has shown an intolerance to an implanted device.

Shire
CONFIDENTIAL
Page 32
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
6
STUDY TREATMENT(S)
6.1
Description of Treatment(s)
6.1.1
Study Drug
Recombinant human heparan N-sulfatase (HGT-1410 drug product) formulation is a sterile 
solution for injection in single-use vials for IT administration.  It is formulated in an aqueous 
isotonic solution containing 15.0 mg/mL HGT-1410 in 145 mM sodium chloride, 0.02% (v/v) 
polysorbate 20, 5 mM sodium phosphate at pH 7.0.
6.1.2
Intrathecal Drug Delivery Device
The PORT-A-CATH will continue to be used for the administration of drug product for each 
patient until such time as an IDDD replacement may be required. Following implementation of 
protocol Amendment 4, any replacements will be performed using the SOPH-A-PORT Mini S.   
After IDDD replacement the drug product will be administered via the SOPH-A-PORT Mini S 
Implantable Access Port.  The SOPH-A-PORT Mini S device is intended for long-term, 
intermittent access to the IT space for the delivery of investigational drug.
The SOPH-A-PORT Mini S is comprised of the following 7 components:

One SOPH-A-PORT Mini S Access Port

One intrathecal port closed-tip catheter

One guidewire

Two suture wings

One 14-gauge Tuohy needle

One 22-gauge non-coring Huber needle

One Luer lock Connector.
Further details are provided in the Instructions for Use.
6.1.3
Placebo or Control
This study will not employ a placebo or control.  
6.2
Treatment Administered
HGT-1410 for IT administration will be provided by Shire.  HGT-1410 will be administered by 
an IDDD.  Following the review and signing of informed consent (and assent, if applicable), 
eligible patients will initially receive the same dose of HGT-1410 they received in Study HGT-
SAN-055:

Group 1:  HGT-1410 administered by IT injection 10 mg once per month (Q4W) 

Group 2:  HGT-1410 administered by IT injection 45 mg once per month (Q4W)

Group 3:  HGT-1410 administered by IT injection 90 mg once per month (Q4W)

Shire
CONFIDENTIAL
Page 33
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
Patients assigned to Group 1 had their dose increased to 45 mg once per month (Q4W) at the first 
administration of HGT-1410 following full approval of protocol Amendment 4.
The study drug will be administered through an IDDD.
The initial implantation and revision and/or explantation of the PORT-A-CATH IDDD or 
SOPH-A-PORT Mini S will be performed by pediatric or general neurosurgeons or 
anesthesiologists who have experience in port and catheter implant procedures and 
intrathecal-access procedures. Please refer to the relevant IFU for further details.
Drug administration will be performed in a clinical setting by appropriately trained and skilled 
healthcare providers (nurses or physicians) with knowledge of the patient’s drug regimen and 
experienced in accessing vascular or CNS ports or CNS infusion pumps. Patients and patients’ 
families will not be directly using the device to administer drugs and will have limited direct 
interaction with the device as there is minimal care required during the immediate postoperative 
period as the implant site heals, or at times of drug administration.
As previously noted in Section 4.1, under the appropriate conditions, IT HGT-1410 may be 
administered at local sites rather than main sites to reduce the burden of monthly travel.
6.3
Selection and Timing of Dose for Each Patient
Patients will check into the study center 1 day prior to IT HGT-1410 dosing for safety 
assessments, designated Day 1, on each HGT-1410 treatment week, and if no safety concerns 
exist, will receive IT administration of HGT-1410 on Day 2 (±2 days).  However, if feasible and 
there are no safety concerns in the opinion of the investigator, the Day 1 and Day 2 assessments 
and dosing may be combined and performed on Day 2; if this is done the results will be recorded 
as Day 2.  Patients will remain in the study center for at least 4 hours following dosing with 
HGT-1410 and will be discharged from the unit when deemed clinically stable by the 
investigator.  
The IT injections are to be administered every 28 days (±7 days).  If a patient’s IDDD becomes 
nonfunctional, it may be revised (partial or complete) (a maximum of twice in a 6 month period) 
so that the patient can remain on study (see Section 7.12 for details).
6.3.1
Cerebral Spinal Fluid Sample Procedure
CSF samples will be obtained prior to each injection for clinical laboratory evaluation and 
potential biomarker studies.  The IDDD will be used for CSF sampling and a topical anesthetic 
agent may be applied over the skin covering the IDDD reservoir prior to sampling. Site 
personnel should refer to the operations manual for instructions on the use of topical anesthesia 
prior to accessing the IDDD reservoir.
If use of the IDDD is precluded on a scheduled day of dosing, CSF samples may be obtained by 
LP, as described in the IDDD Manual and Section 6.3.2. Intrathecal Administration of 
HGT-1410.

Shire
CONFIDENTIAL
Page 34
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
A visual examination of both the port and catheter track will be performed before each IT 
injection.
HGT-1410 will be administered using an IDDD.  After appropriate pre-procedure assessments 
are completed, anesthesia cream will be applied to the skin over the port.  Patients may receive 
sedation as necessary to alleviate anxiety and/or to facilitate drug delivery.
Patients will receive HGT-1410 via slow push/injection through an appropriately sized syringe
(see the Pharmacy Manual).  Replacement of fluid, including drug, to the CSF will be an 
approximate equal volume to that removed.  The patient’s vital signs will be continuously 
monitored.  The patient will also be monitored closely during study drug administration and 
through the next 4 hours for any adverse clinical reactions.  The patient will be encouraged to lie 
down comfortably for 1 to 3 hours post injection, although this may be difficult for the most 
hyperactive patients.
For the Soph-A-Port Mini S, a 22-gauge Huber non-coring needle is to be used for access to the 
implanted port; standard hypodermic needles would damage the septum and may cause leakage. 
If no needle-free connector is present, either a stopcock of the Huber needle infusion set’s clamp 
is to be used to prevent CSF backflow and to mitigate the risk of air entering the system. It is 
possible to use other brands of Huber non-coring needles, provided that their specifications are 
identical to that of the Huber needle supplied by Sophysa in the SOPH-A-PORT Mini S (22G).
The injection date, injection start/stop time, planned dose, injection volume, and flush volume 
will be recorded on the patient’s eCRF.  
In the event of IDDD malfunction, CSF collection and study drug administration may be
performed via LP (see Section 6.3.2).  The investigation and management of a malfunctioning 
IDDD is detailed in the PORT-A-CATH or SOPH-A-PORT IFUs. Partial or complete 
replacement of the IDDD may be necessary (only permitted twice in a 6-month period, including 
the time a patient was in study HGT-SAN-055), and will require scheduling of the appropriate 
procedure.  The definitive diagnosis of the cause of IDDD failure may not be possible until the 
time of exploratory surgery.  Surgery will take place at the earliest convenience, so the patient 
may remain on, or as close as possible to their treatment schedule. 
6.3.2
Administration of HGT-1410 via Lumbar Puncture Guidance Concerning 
Performance of Lumbar Puncture for Study Drug Administration and 
Cerebrospinal Fluid Sample Collection
It is intended that the IDDD will be used to deliver all IT injections of study drug and to obtain 
CSF samples.  If the IDDD appears to be nonfunctional, or if its use is precluded on a scheduled 
day of dosing, site personnel will refer to the IDDD manual (s), which provides details on the 
investigation and management of any IDDD-related issues.  This may include possible partial 
revision or complete replacement of the IDDD as indicated.  If the nonfunctional IDDD is a 
PORT-A-CATH device, then it will be replaced by a SOPH-A-PORT Mini S device. 
If there are medical contra-indication to the re-implantation of a new device, or if the patient so 
desires, repeat monthly lumbar punctures may be considered as an alternative way of delivering

Shire
CONFIDENTIAL
Page 35
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
the study drug and obtaining CSF samples under limited circumstances.  If no safety risks are 
identified by the investigator, up to 12 consecutive lumbar punctures may be performed across 
studies HGT-SAN-055 and HGT-SAN-067.  Once a patient has reached the maximum of 
12 consecutive lumbar punctures, a new IDDD will be re-implanted for subsequent dosing, 
unless, in the opinion of the investigator and medical monitor, assessment of risk/benefit favors 
continued dosing via lumbar puncture.
Continued treatment via repeat lumbar puncture beyond the stipulated 12 consecutive monthly 
doses can be considered only in individual cases of patients where this treatment is very well 
tolerated and the investigator has not identified any safety concerns associated with repeat 
lumbar puncture and repeat sedation/anesthesia.
6.4
Method of Assigning Patients to Treatment Groups
This is an open-label, non-randomized study; all patients enrolled in this study will be treated 
with HGT-1410. Patients will initially receive the same dose of HGT-1410 they received in 
Study HGT-SAN-055. Patients assigned to Group 1 (10 mg once per month [Q4W]) had their 
dose increased to 45 mg once per month (Q4W) at the first administration of HGT-1410 
following full approval of protocol Amendment 4.
6.5
Blinding
Not applicable; as this trial is not blinded.
6.6
Concomitant Therapy
All non-protocol treatments and procedures that occur from the time of informed consent (and 
assent, if applicable) through the safety follow-up contact are regarded as concomitant and will 
be documented on the appropriate pages of the eCRF.  Concomitant therapy includes 
medications (including Genistein), therapies/interventions administered to patients, and 
medical/surgical procedures performed on the patients. 
Every effort should be made to keep the patient’s symptomatic Sanfilippo syndrome Type A 
treatment constant throughout the study.  However, changes in medications are acceptable if 
necessary according to clinical judgment.  All changes will be recorded on the appropriate eCRF. 
Concomitant medication will be coded using World Health Organization Drug Dictionary 
(WHO-DD).
6.7
Restrictions
6.7.1
Prior Therapy
Prior therapy excluded for this study consists of the following:

Psychotropic or other medications, which in the investigator’s opinion would be likely to 
substantially confound test results, and the dose and regimen of which cannot be kept 
constant throughout the study.

Shire
CONFIDENTIAL
Page 36
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

The patient cannot sustain absence from aspirin, non-steroidal medications, or medications 
that affect blood clotting within 1 week prior to a relevant study related procedure (eg, device 
implantation if applicable) or medications within 1 week before any procedures in which any 
change in clotting activity would be deleterious.

The patient has received any investigational drug or device intended as a treatment for 
MPS IIIA within the 30 days prior to the study other than HGT-1410 or is enrolled in another 
study that involves an investigational drug or device.

Hematopoietic stem cell or bone marrow transplant.
6.7.2
Fluid and Food Intake 
Food and fluid intake are not restricted over the course of the study, with the exception of 
hospital standard pre-anesthesia dietary restrictions.
6.7.3
Patient Activity Restrictions
For patients implanted with the SOPH-A-PORT Mini S please refer to the SOPH-A-PORT Mini 
S IFU for details regarding patient activity restrictions for patients to be implanted with this 
device.
6.8
Treatment Compliance
HGT-1410 is administered under controlled conditions by the investigator; therefore, full patient 
compliance with study treatment is anticipated in this study. 
6.9
Packaging and Labeling
6.9.1
Drug Product
Drug product will be supplied in a 3 mL clear, colorless glass (Type 1) vial. Each vial holds an 
extractable volume of 1 mL of HGT-1410. The closure is a gray, 13 mm stopper composed of 
butyl rubber with a fluoro resin lamination. The overseal is an aluminium seal with a flip-off, 
plastic, tamper evident cap. 
See the Pharmacy Manual for additional details.
6.9.2
SOPH-A-PORT Mini S Access Port
The SOPH-A-PORT Mini S Access Port is available in one size, individually packaged, with 
other SOPH-A-PORT Mini S components in double peel-off, sterile, pyrogen-free packaging, 
sterilized with Ethylene Oxide.  Instructions for use are also included in the packaging. A 
guidewire is provided in separate double pouch, sterile, pyrogen-free packaging.
Labels are provided on the outer carton, and on both the SOPH-A-PORT Mini S box and 
guidewire/cannula package inside.

Shire
CONFIDENTIAL
Page 37
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
6.10
Storage and Accountability
6.10.1
Investigational Product
Drug product should be stored refrigerated (2°C to 8°C); drug product may not be stored beyond 
the expiration date on the vial.
All HGT-1410 study drug delivered to an investigator will be recorded and accounted for 
throughout the study.  All HGT-1410 study drug must be recorded on a patient-by-patient basis.  
The lot number of the IDDD and the date and time of administration of the study medication will 
be documented on the appropriate eCRF.
All unused study medication and other study materials are to be returned to the sponsor or its 
designee or disposed of after sponsor approval per site policy after study completion.
6.10.2
Intrathecal Drug Delivery Device
6.10.2.1
PORT-A-CATH IDDD
Please refer to the operations manual for return instructions.
6.10.2.2
SOPH-A-PORT Mini S IDDD
The disposition of all SOPH-A-PORT Mini S intrathecal drug delivery devices delivered to a 
principal investigator must be recorded on a patient-by-patient basis by completing the 
Accountability Log.  The date and time of administration of the investigational product and use 
of the SOPH-A-PORT Mini S device must be documented on the patient’s appropriate eCRF.
The principal investigator, clinical research coordinator, or designee (eg, pharmacist) must 
ensure that all documentation regarding receipt, storage, dispensing, loss/damaged 
SOPH-A-PORT Mini S intrathecal drug delivery devices and return of used/unused intrathecal 
drug delivery devices) is complete, accurate, and ready for review at each monitoring visit and/or 
audit.  The sites must ensure that the SOPH-A-PORT Mini S devices are available for the 
monitor to inventory and prepare for return shipment to the sponsor or designee, if required.
The SOPH-A-PORT Mini S and its components are sterile, single-use devices.
Please refer to the relevant IDDD Manual for device return instructions.
6.11
Investigational Product Retention at Study Site
All HGT-1410 study drug delivered to an investigator will be recorded and accounted for 
throughout the study.  All HGT-1410 study drug must be recorded on a patient-by-patient basis.  
The lot number of the IDDD and the date and time of administration of the study medication will 
be documented on the appropriate eCRF.
All unused study medication and other study materials are to be returned to the sponsor or its 
designee or disposed of after sponsor approval per site policy after study completion.

Shire
CONFIDENTIAL
Page 38
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
7
STUDY PROCEDURES
7.1
Informed Consent
Study procedures will be conducted only after written informed consent for the patient to 
participate in this study is provided by the parent(s) or the patient’s legally authorized 
representative(s) and assent from the patient (if applicable).  Detailed descriptions of patient 
evaluations required for this protocol are described in this section.  These evaluations will be 
performed during the indicated days and weeks of each study month (see Appendix 1, Table A1-
1 and A1-2 Schedule of Events).
All data collected are to be recorded on the appropriate eCRF. Blood, urine and CSF volumes to
be collected for each clinical laboratory measurement are described in detail in the Laboratory 
Manual.
After the treatment period ends, informed consent from patients who do not have the IDDD 
removed (partial or full device) will be obtained for the safety follow-up period.
7.2
Physical Examination
A full physical examination or a symptom-directed physical examination of each patient will be 
performed at time points detailed in Appendix 1, Table A1-1 Schedule of Events, for the 
duration of the treatment period. The physical examinations for the safety follow-up period will 
be symptom-directed, see Appendix 1, Table A1-2 Schedule of Events, for details. 
Any changes from the screening physical examination will be captured as AEs in the eCRF.  If 
the patient experiences an AE associated with genitourinary evaluation, the patient may have the 
genitourinary evaluation performed by their primary care provider and a follow-up report will be 
sent to the investigator.  Therefore, the genitourinary evaluation may not need to be performed 
again if the examination occurred within the visit window for that time point.
Note:  if the patient’s hearing cannot be assessed during the physical examination, the patient 
will have an Ears, Nose, and Throat Evaluation performed under anesthesia at the screening/start 
of study visit.  If it is determined that the patient requires pressure-equalization (PE) tubes, they 
may be implanted during that evaluation (see Section 7.9).  Note:  PE tubes may be re-implanted 
if they fall out during this study.

Shire
CONFIDENTIAL
Page 39
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
The physical examination findings will be recorded on the eCRF and will include a review of the 
patient’s general appearance as well as the following evaluations:
-
Head and neck
-
Eyes, ears, nose, and throat
-
Chest and lungs
-
Cardiovascular
-
Abdomen
-
Skin
-
Lymphatic
-
Musculoskeletal
-
Neurological (symptom directed and 
at least every 12 months)
-
Endocrine
-
Genitourinary (as per referring 
physician)
7.3
Height and Weight
Height or length (cm), and weight (kg) will be measured once and recorded on the eCRF.
7.4
Head Circumference
Head circumference (cm) will be measured and recorded on the eCRF.
7.5
Vital Signs
Vital signs (blood pressure, heart rate, respiratory rate, and temperature measurements) will be 
measured and recorded on the eCRF.
7.6
Electrocardiography
7.6.1
Electrocardiograms
An ECG will be performed.  Each ECG will include an assessment of heart rate, sinus rhythm, 
atrial or ventricular hypertrophy, PR, QRS, QT, and QTc intervals.  The ECGs will be conducted 
in accordance with the clinical site’s standard practice(s), and will be read locally at the clinical 
site.  Identification of any clinically significant findings and/or conduction abnormalities will be 
recorded on the eCRF. 
7.7
Clinical Laboratory Tests
Blood, urine, and CSF samples will be collected as described below for clinical laboratory 
testing. Procedures for collection and handling of samples are included in the Laboratory 
Manual. The conduct of a clinical trial in an extremely rare disease such as MPS IIIA provides a 
unique opportunity to collect samples for potential biomarker research. In the context of this 
study, a biomarker is defined as a characteristic that is objectively measured and evaluated as an 
indicator of the MPS IIIA pathogenic process, or a pharmacologic response to experimental 
therapy with HGT-1410. In addition to exploration of potential biomarkers, as part of the 
assessment of the SOPH-A-PORT Mini S, it may be necessary to determine the levels of 
leachables from the device into the CSF and blood. 

Shire
CONFIDENTIAL
Page 40
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
For patients who do not have the IDDD removed (partial or full device) at the end of the 
treatment period, clinical laboratory testing will only be performed when indicated for a device-
related AE during the safety follow-up period.
Patients will be in a seated or supine position during blood collection.  Clinical laboratory tests 
will include hematology, serum chemistry, and urinalysis.
Laboratory Parameters 
Clinical laboratory tests will be performed at a central laboratory.  Clinical laboratory tests will 
include the following:
7.7.1
Hematology

Hematocrit (Hct)

Hemoglobin (Hgb)

Mean corpuscular hemoglobin (MCH)

Mean corpuscular hemoglobin 
concentration (MCHC)

Mean corpuscular volume (MCV)

Platelet count

Red blood cell (RBC) count 

White blood cell (WBC) count with 
differential 
7.7.2
Serum Chemistry

Albumin (ALB)

Alkaline phosphatase (ALK-P)

Alanine aminotransferase (ALT; SGPT)

Aspartate aminotransferase (AST; 
SGOT)

Blood urea nitrogen (BUN)

Calcium (Ca)

Carbon dioxide (CO2)

Chloride (Cl)

Creatinine

Creatine kinase (CK) and subtypes

Gamma-glutamyl transferase (GGT)

Globulin

Glucose

Lactate dehydrogenase (LDH)

Phosphorus

Potassium (K)

Sodium (Na)

Total bilirubin

Direct bilirubin

Total cholesterol

Total protein

Triglycerides

Uric acid

Human Chorionic Gonadotropin 
(βhCG) Pregnancy Test
In addition a leukocyte pellet will be prepared, stored frozen, and will be used for additional 
disease-related laboratory studies, including possible assessment of cross-reactive immunologic 
material (CRIM).
7.7.3
Pregnancy Test
A pregnancy test will be performed on Day 1 of each dosing week.  Pregnancy testing will be 
performed using either a serum or urine sample (at the discretion of the site), and only on 
females who have reached menarche.  All pregnancy testing and the reporting of results will be 
performed locally by the clinical site staff.  Study drug must not be administered in the event of a 
positive or inconclusive pregnancy result. 

Shire
CONFIDENTIAL
Page 41
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
7.7.4
Serum Anti-rhHNS Antibody and Sample Storage 
Blood samples will be collected and evaluated at Shire or Shire-designated laboratories for the 
determination of anti-rhHNS antibodies. Samples will be reserved in accordance with local 
regulations for potential future MPS IIIA research that may determine biomarkers of disease 
severity and progression. 
Two blood samples will be collected from each patient at each designated time point. One 
sample will be collected in tubes intended for serum specimens, while the second sample will be 
collected in tubes intended for plasma specimens. Blood sample collection, processing, and 
shipping instructions will be provided in the Laboratory Manual.
7.7.5
Urinalysis 
Patient catheterization may be required for obtaining urine samples (if deemed necessary by the 
investigator).  
7.7.5.1
Standard Urinalysis
The following urinalysis parameters will be performed at a central laboratory:  pH, macroscopic 
and microscopic evaluations.
7.7.5.2
Urine Glycosaminoglycans 
A urine sample will be collected for the determination of GAG (including heparan sulfate and 
heparan sulfate derivatives) and the analysis will be performed at Shire, or Shire designated 
laboratories. A urine sample from each visit will be reserved for possible exploratory biomarker 
studies that may provide new indicators or markers of MPS IIIA disease severity or progression.
7.7.6
Cerebrospinal Fluid Assessments
Cerebrospinal fluid sample collection, processing, and shipping instructions will be provided in 
the Laboratory Manual. A CSF sample will be reserved for possible exploratory biomarker 
studies for MPS IIIA disease.
Each CSF sample collected will be assessed for appearance and will be analyzed using the assays 
listed in Sections 7.7.6.1, 7.7.6.2, and 7.7.6.4.  In addition, as more is learned about Sanfilippo 
CNS pathology and etiology, future exploratory assays of CSF metabolites, protein or 
ribonucleic acid (RNA) may become used as they become available in the future.
7.7.6.1
Cerebrospinal Fluid Cell Counts
An aliquot of each CSF sample collected will be evaluated for CSF standard chemistries,
glucose, protein, and cell counts.  These assessments will be performed at the local laboratory.
7.7.6.2
Cerebrospinal Fluid Heparan Sulfate Levels and Heparan Sulfate 
Derivatives
An aliquot of each CSF sample collected will be quick frozen as per the Laboratory Manual for 
subsequent determination of CSF heparan sulfate and heparan sulfate derivatives at Shire 
designated laboratories.

Shire
CONFIDENTIAL
Page 42
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
7.7.6.3
Anti-rhHNS Antibodies
An aliquot of each CSF sample collected will be quick frozen as per the Laboratory Manual for 
subsequent determination of anti-rhHNS antibodies at Shire or Shire designated laboratories.
7.7.6.4
Cerebrospinal Fluid Biomarkers 
An aliquot of each CSF sample collected will be quick frozen as per the Laboratory Manual for 
subsequent determination of MPS exploratory biomarkers at Shire or Shire-designated 
laboratories.
7.7.7
Sample Collection, Storage, and Shipping
Sample collection, processing, and shipping instructions will be provided in the Laboratory 
Manual to be provided by Shire.
CSF, urine, and serum samples may be reserved for potential, future, biomarker studies.  
Samples will be stored securely to ensure patient confidentiality.  
7.8
Anesthesia
Administration of anesthesia/sedation will be given prior to obtaining CSF (when the use of the 
IDDD is precluded), prior to performing a MRI of the head, the ABR, the CSF opening pressure, 
and the partial revision or replacement of the IDDD (if applicable).  
See Appendix 1 for the Schedule of Events. When logistically feasible, the MRI, ABR, and 
surgical implantation of the IDDD may be performed together to reduce exposure to 
general anesthesia.
Note:  The neurologic exam and the neurocognitive and developmental assessments must be 
performed prior to the administration of anesthesia.
7.9
Audiometry and Auditory Brainstem Response
The rare attenuated patients with MPS IIIA with high levels of cognitive functioning will have 
hearing tests via clinical audiometry measurement performed using age-appropriate testing 
methods based on the child’s developmental age at the time of the testing.  It is anticipated that 
most of the cognitively-impaired and/or behaviorally-deteriorated patients with Sanfilippo A will 
be unable to cooperate with a (conscious) hearing evaluation.  In these instances, the investigator 
will utilize his best clinical judgment to estimate the extent of hearing loss (if any) during the 
physical examination.  In this situation, a specific evaluation of hearing loss will occur during an 
examination of waveforms in the ABR (see below).  If the patient has a history of multiple 
instances of otitis media or evidence of clinically-significant otitis media on physical 
examination, which the investigator believes causes significant conductive hearing loss and 
impairment of daily living, the investigator will discuss and offer the parent or legally authorized 
representative(s) placement of PE tubes as part of the scheduled anesthesia.  A patient’s PE tubes 
may be replaced if they fall out during the course of this study.

Shire
CONFIDENTIAL
Page 43
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
The ABR will be conducted under anesthesia.  The ABR findings will be considered within 
normal limits if, after applying appropriate correction factors, the waveforms reveal normal 
morphology. 
7.10
Magnetic Resonance Imaging of the Head
The regional brain volume will be assessed through a MRI, of the head.  The patient will be 
under general anesthesia for this assessment.  All MRIs will be centrally read by the University 
of Minnesota Medical Center.  Refer to the Study Operations Manual for specific procedures and 
precautions.
7.11
Device Data
7.12
Surgical Re-implantation of the IDDD
If a patient’s IDDD becomes nonfunctional or infected, it will be replaced or revised so that the 
patient can remain on study. After full approval of protocol Amendment 4, all IDDD 
replacements will be made with the SOPH-A-PORT IDDD. If the IDDD device is a 
PORT-A-CATH IDDD, it will be replaced by a SOPH-A PORT IDDD. Management details for 
the PORT-A- CATH IDDD or for the SOPH-A PORT IDDD are provided in the respective 
device's IFU. Procedures for implantation are detailed in the relevant device’s Instructions for 
Use Manual and in the training materials provided by Shire. The patient will be under general 
anesthesia for this procedure. Standard hospital procedure for surgery will be followed and will 
include an X-ray to confirm that the device has been (1) surgically implanted correctly, and (2) 
positioned so that the intrathecal catheter tip is at the mid-thoracic level (a check list is provided 
in the IDDD Manual). 
A post-operative check of the IDDD and incision will be performed on Day 4 following surgery.  
X-rays may be performed to check placement of the device, as needed, throughout the study (see 
Section 7.12.1 for limits on the number of x-rays and IDDD revisions and or replacement).
7.12.1
Restrictions on the Number of Revision and/or re-implantation of the IDDD
A non-functional IDDD can be replaced or revised twice in a 6-month period, including the time 
a patient was in study HGT-SAN-055.  Similarly, 6 X-rays may be taken in a 6-month period 
(including the time in HGT-SAN-055).

Shire
CONFIDENTIAL
Page 44
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
7.13
Device Related Study Procedures
7.13.1
IDDD Implantation or Revision Procedures
The IDDD will be surgically implanted or revised at the clinical site. Procedures for implantation 
and revision are detailed in the device’s IFU. Standard hospital procedures for surgery will be 
followed; the patient will be under general anesthesia for this procedure.  It is planned that 
device explantation will occur at the main site unless urgent device removal is medically 
indicated requiring the procedure to be performed locally or patient travel to the main site is 
medically inadvisable. 
An additional medical device, the catheter passer, is necessary for the implantation procedure, 
for patients receiving the SOPH-A-PORT Mini S.  The catheter passer is a sterile, single use 
device that will be used in the subcutaneous placement of the catheter.  The Phoenix Neuro 
Disposable Catheter Passer, manufactured by Sophysa is CE marked in the European Union 
(EU) and cleared under K853370 in the United States (US). Other catheter passers that are 
compatible with the SOPH-A-PORT Mini S may be used.
Details of the implantation/revision and malfunctions/failure for the SOPH-A-PORT will be 
documented on the patient’s eCRF.
7.13.2
X-ray Verification of Intrathecal Drug Delivery Device Placement 
A postoperative x-ray check of the IDDD will be performed following surgery to verify proper 
installation and confirmation of IDDD placement at the mid-thoracic level. The x-rays may be 
performed to check placement of the device, migration, or malfunction of the device as needed, 
throughout the treatment period or the safety follow-up period of the study. At a minimum, the 
date of the x-ray verifying correct IDDD placement will be documented on the patient’s eCRF. If 
the device requires revision or replacement during the treatment period of the study, additional x-
rays will be taken to document proper positioning of the device. If an IDDD malfunctions, an x-
ray may be performed to assess the potential cause of malfunction. Fluoroscopy may be used 
during device implant or revision procedures.
7.13.3
CSF Sampling Procedure
Cerebrospinal fluid will be sampled via the device. If this is not possible, and if CSF sampling is 
necessary, either for adherence to the protocol, or to investigate clinical concerns, an LP may be 
performed to sample CSF, either with or without administration of drug afterwards. 
7.13.4
Device Removal
If at the time of a scheduled dosing it is not possible to administer a full medication dosage as 
per the standard administration steps detailed in the device’s IFU due to a device-related issue, 
the IDDD will be declared a device malfunction. If the device malfunction is irreversible and 
cannot be corrected without a device surgical intervention, the IDDD will be declared a device 
failure, starting from the date of the initial malfunction. 
The IDDD will then be surgically removed or revised and a new device and/or device 
components will be re-implanted at the earliest possible opportunity, preferably at the same time. 

Shire
CONFIDENTIAL
Page 45
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
Patients who have a PORT-A-CATH IDDD device failure will have this device replaced by a 
SOPH-A-PORT Mini S.
Details of the device removal will be recorded in the patient’s eCRF. Refer to the relevant IFU 
for further details.
If the IT space is not accessible via the IDDD, study drug may be administered by LP up to 
5 times.
Patients should have the IDDD removed when they discontinue from the treatment period of the 
study, unless the Investigator determines that it should not be removed based upon safety 
assessments. The device can remain in the patient (partial [catheter only] or full [port, catheter, 
and suture wings]) if the patient is doing clinically well and there are no further known risk 
factors such as infection (eg, meningitis).  The device may be partially or fully removed as 
medically required and determined by the neurosurgeon at a future date.
7.14
Cerebrospinal Fluid Opening Pressure Measurement
A CSF opening pressure measurement (cm of H2O) will be conducted as per standard hospital 
practice.  The measurement will be obtained whenever a LP is performed and an IDDD revision 
or replacement is done. Following implementation of Amendment 6 the CSF opening pressure 
measurement will not be required with the LP.
7.15
Dispensing Study Drug
A visual examination of both the port and catheter track will be performed before each IT 
injection.
HGT-1410 will be administered IT by means of an IDDD (or via LP if necessary) to patients on 
Day 2 (±2 days) of Week 1 of each treatment month. 
The patient may be sedated for this procedure.  HGT-1410 will be administered through an 
appropriately sized syringe (see the Pharmacy Manual).  If the IT space is not accessible via the 
IDDD, HGT-1410 may be administered via LP.  See Section 6.3.2 for details.
For the Soph-A-Port Mini S, a 22-gauge Huber non-coring needle is to be used for access to the 
implanted port; standard hypodermic needles would damage the septum and may cause leakage. 
If no needle-free connector is present, either a stopcock or the Huber needle infusion set’s clamp 
is to be used to prevent CSF backflow and to mitigate the risk of air entering the system. It is 
possible to use other brands of Huber non-coring needles, provided that their specifications are 
identical to that of the Huber needle supplied by Sophysa in the SOPH-A-PORT Mini S (22G).
7.16
Pharmacokinetic Assessments
Pharmacokinetic assessments are not included in this study.

Shire
CONFIDENTIAL
Page 46
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
7.17
Neurological Examination
A neurological examination to monitor CNS changes in a patient’s neurological status will be 
conducted during this study.  See Appendix 2 for a complete list of the neurological 
examinations.
The neurological exam should not occur sooner than 4 hours after study drug administration or 
before the patient has fully recovered from any anesthesia administered for the dosing, 
whichever occurs later.
7.18
Neurocognitive and Developmental Assessments
Patients will undergo neurocognitive and neurobehavioral development testing.  The assessments 
are estimated to last between 2 and 4 hours and must be conducted prior to sedation or 
anesthesia. 
A full neurodevelopmental assessment, including global development, cognition, adaptive 
behavior, receptive and expressive language, and gross motor function, will be evaluated using 
standardized developmental and behavioral tests to provide a surrogate and quantifiable measure 
of global CNS neurodevelopmental/neurobehavioral function. 
All patients will have received a series of standardized neurodevelopment assessments; in the 
HGT-SAN-055 study, patients in HGT-SAN-067 will continue with the age specific assessment 
they began with in HGT-SAN-055.  If, however, a patient’s capability improves and they 
become capable of completing assessments at a higher level, any such additional assessments 
may be added.  Any additional assessments would be performed after the original assessments 
have been carried out.  
For this study, outcome measures will be computed for each patient enrolled.  The psychometric 
instruments and Sanfilippo-specific assessments are summarized below in Table 7-1 and 
Table 7-2, respectively.  See Appendix 2 for details on these assessments.
Table 7-1
Neurodevelopmental Assessments Tests 
Developmental or Cognitive 
Domain(s)
Patient Age:  Representative Cognitive Test or 
Scale
COGNITIVE DEVELOPMENT ASSESSMENT
Summary score and sub-domains:
- Cognitive
- Motor
- Social/emotional
0 to 42 months:  Bayley Scales of Infant Development-III 
Bayley Scales of Infant Development, Third Edition 
(BSID-III)23
- Cognitive 
- Processing skills
3 to 18 years:  Kaufman Assessment Battery for Children, 
Second Edition (KABC-II)24

Shire
CONFIDENTIAL
Page 47
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
Table 7-1
Neurodevelopmental Assessments Tests 
Developmental or Cognitive 
Domain(s)
Patient Age:  Representative Cognitive Test or 
Scale
GROSS AND FINE MOTOR SKILLS ASSESSMENT AND VOLUNTARY MOVEMENT
Motor
3.0 to 16:11 years:  Movement Assessment Battery for 
Children II (MABC-2)25
- Cognitive
- Motor
0 to 5 ½ years:  Bayley Scales of Infant Development III 
(BSID-III)23
ADAPTIVE BEHAVIOR
Communication
Daily Living
Socialization
Motor Skills
0 to 90 years:  Vineland Adaptive Behavior Scales (VABS-II)  
Second Edition26
Table 7-2
Sanfilippo-Specific Disability Assessment And Behavior Rating Scales
DEVELOPMENTAL OR COGNITIVE 
DOMAIN(S)
SANFILIPPO SPECIFIC ASSESSMENTS
Parent-scored behavioral inventory
- communication:  understanding
- communication:  expression
- tantrums
- specific behaviors inventory
- mood & emotions inventory
Sanfilippo Behavior Rating Scale (SBRS)
MPS-specific disability score 
- cognitive functioning
- expressive language
- motor score
Four-Point Scoring System/Total Disability Score 
(FPSS/TDS)5  
7.19
Sleep Questionnaire:  Children’s Sleep Habits Rating Scale 
A sleep questionnaire, Children’s Sleep Habits Rating Scale, will be administered to the patient's 
parent(s)/legally authorized representative(s).
7.20
Age-Dependent, Health-Related Quality of Life in Children
The Quality of Life questionnaires will be administered as outlined in Sections 7.20.1, 7.20.2, 
and 7.20.3.

Shire
CONFIDENTIAL
Page 48
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
7.20.1
Quality of Life Indicator:  CHQ-50
The Child Health Questionnaire™ Parent Form 50 Questions (CHQ-50) will be administered 
during the study.  The questionnaire is a generic quality of life instrument, measuring 14 unique 
physical and psychosocial concepts, which was developed for children from 5 to 18 years of age.
7.20.2
Quality of Life Indicator:  CHQ-87
The Child Health Questionnaire™ Child Form 87 (CHQ-87) will be administered during the 
study.  The CHQ-87 is a child and adolescent self-report, developed for ages 10 and older, which 
assesses the child’s self-perceived physical and psychosocial well-being.
7.20.3
Quality of Life Indicator:  ITQOL
The Infant Toddler Quality of Life Questionnaire™ (ITQOL) will be administered during the 
study.  The ITQOL was developed for children at least 2 months of age up to 5 years and 
assesses the physical, mental, and social well being of the child and assesses the quality of the 
parent/legally authorized representative(s) life.  
7.21
Concomitant Medications, Therapies and Medical/Surgical Procedures
All non-protocol treatments that occur from the time of informed consent (and assent, if 
applicable) through the safety follow-up contact are regarded as concomitant and will be 
documented on the appropriate pages of the eCRF.  Concomitant therapy includes medication
(including Genistein), therapies/interventions administered to patients, and medical/surgical 
procedures performed on the patients.
Every effort should be made to keep symptomatic Sanfilippo syndrome Type A treatment 
constant throughout the study.  However, changes in medications are acceptable if necessary 
according to clinical judgment.  All changes will be recorded on the appropriate eCRF.  
Concomitant medication will be coded using WHO-DD.
7.22
Adverse Events
7.22.1
Definitions of Adverse Events and Serious Adverse Events
7.22.1.1
Adverse Event
An AE is any noxious, pathologic, or unintended change in anatomical, physiologic, or 
metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in 
any phase of a clinical study, whether or not considered study drug-related.  This includes an 
exacerbation of a pre-existing condition.  Once the informed consent is signed and dated, any 
adverse event prior to the start of study drug must be reported. 
AEs include:

Worsening (change in nature, severity, or frequency) of conditions present at the onset of the 
study

Intercurrent illnesses

Drug interactions

Shire
CONFIDENTIAL
Page 49
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

Events related to or possibly related to concomitant medications

Abnormal laboratory values (this includes significant shifts from baseline  within the range 
of normal that the investigator considers to be clinically important)

Clinically significant abnormalities in physical examination, vital signs, and weight
Throughout the study, the investigator must record all AEs on the AE eCRF, regardless of the 
severity or relationship to study drug.  The investigator should treat patients with AEs 
appropriately and observe them at suitable intervals until the events stabilize or resolve.  AEs 
may be discovered through observation or examination of the patient, questioning of the patient, 
complaint by the patient, or by abnormal clinical laboratory values.
In addition, AEs may also include laboratory values that become significantly out of range.  In 
the event of an out-of-range value, the laboratory test should be repeated until it returns to 
normal or can be explained and the patient’s safety is not at risk.  
All AEs should be recorded with causality assessment.
The information presented below is intended to provide issues to consider for AEs associated 
with intrathecal injections of HGT-1410.  In general, these AEs can be classified as follows: 

Adverse events due to systemic exposure to HGT-1410 caused by the drug diffusion from the 
CSF to the peripheral circulation; 

Adverse events related to the direct delivery of HGT-1410 to the intrathecal CSF space and 
meninges, and subsequent diffusion into brain parenchyma, via an intrathecal route 

IDDD–related AEs  
Note:  the classification of potential AEs and the examples presented below are based on purely 
theoretical considerations and/or published literature as there is limited human experience with 
intrathecal HGT-1410 therapy to date.
7.22.1.2
Potential Adverse Events:  Intrathecal recombinant human heparan 
N-sulfatase 
ADVERSE EVENTS RELATED TO THE DIRECT DELIVERY OF HGT-1410 TO THE CNS
THROUGH INTRATHECAL ADMINISTRATION
Examples of AEs observed in other published clinical trials with intrathecally-administered 
peptides or proteins, include, but are not limited to the following:  headache, fever, feeling of 
warmth, sensory paresthesias (including feelings of warmth, tingling, or pain) or autonomic 
symptoms such as dry mouth or gustatory abnormalities (including loss of smell and metallic 
taste).  Changes in mental cognitive status or level of consciousness that are not caused by 
pre-medication may either occur acutely or develop post-injection, over time.
ADVERSE EVENTS DUE TO SYSTEMIC EXPOSURE TO HGT-1410
Although HGT-1410 is given intrathecally only, some proportion of the drug will diffuse from 
the CSF into the peripheral circulation.  The resulting systemic exposure may cause events that 

Shire
CONFIDENTIAL
Page 50
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
are typically seen in patients receiving ERT via an intravenous administration, known as 
infusion-related reactions.  An infusion-related reaction is defined as an adverse event that 
(1) begins either during or within 24 hours after the start of the infusion, and (2) is judged as 
possibly or probably related to study drug.  Other AEs that occur prior to the infusion, along with 
AEs associated with protocol-defined testing and assessments (laboratory testing and physical 
examinations) that were performed prior to the infusion will not be defined as infusion-related 
reactions.
7.22.1.3
Infusion/Hypersensitivity Reactions and Management
Infusions of proteins can be associated with reactions to the infusion that may or may not be 
immune-mediated (hypersensitivity reactions).  Thus, potential reactions to the infusion of 
investigational drug are unpredictable.  It is often difficult to clinically distinguish infusion 
reactions from hypersensitivity reactions.  Symptoms may include headache, fever, sensory 
paresthesias (including feeling of warmth, tingling, or pain), rash, pruritus, or autonomic 
symptoms, such as dry mouth or gustatory abnormalities (including loss of smell and metallic 
taste).  Changes in mental status or level of consciousness that are not caused by pre-medication 
may either occur acutely or develop post-injection over time.
The management of infusion reactions and hypersensitivity reactions is similar.  The following 
steps may be taken, at the discretion of the investigator, in the event of a suspected infusion 
related/hypersensitivity reaction and the management of such reactions should be based on the 
severity of the reaction:

Treatment with medications such as antihistamines, antipyretics, and/or corticosteroids

Stopping and resuming treatment

Pretreatment with antihistamines and/or corticosteroids may prevent subsequent reactions in 
those cases where symptomatic treatment was required
7.22.1.4
IDDD-related Adverse Events 
IDDD ADVERSE EVENTS
Examples of AEs related to use of the IDDD include, but are not limited to, the following: device 
failure, device malfunction, incorrect connection of IDDD components, erosion of the 
portal/catheter through the skin, fibrin sheath formation around the catheter tip, hematoma, 
implant rejection, migration of the portal/catheter, occlusion of the portal/catheter, portal site, or 
subcutaneous tract infection. The device may also need to be replaced or repaired as needed. A 
malfunction of the device (defined in Section 7.22.2.2) should not be entered as an AE unless it 
has physiological consequences.  In the event of a device failure (defined in Section 7.22.2.3), 
the device may need to be replaced or repaired. Hospitalization for such a procedure will be 
reported as a serious adverse event (SAE).  Details of the cause of IDDD malfunction or failure 
will be recorded on the Device Malfunction/Failure CRF.  A list of the more common IDDD 
AEs is included in Appendix 3.

Shire
CONFIDENTIAL
Page 51
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
DEVICE SURGICAL PROCEDURE-RELATED ADVERSE EVENTS
Examples of AEs related to device surgical procedures include, but are not limited to, the 
following: events that occur during or following IDDD implant/explant, IDDD adjustment, full 
revision, partial revision, IDDD removal, and delayed re-implantation after previous IDDD 
removal (such as complications of anesthesia, excessive bleeding, wound hematoma) and post 
operative complications (such as post-operative infection).
IT ADMINISTRATION PROCESS ADVERSE EVENTS 
Intrathecal administration process AEs include those caused by anesthesia during drug 
administration, drug administration issues (eg, extravasation during infusion or hematoma due to 
Huber needle) or complications of lumbar puncture.
RISKS ASSOCIATED WITH ANESTHESIA REQUIRED FOR STUDY ASSESSMENTS
The use of an IDDD has been chosen to minimize the risks inherent in utilizing novel delivery 
systems and to alleviate the need for multiple administrations of anesthesia required for drug 
injection via repeated LP. The risks from anesthesia include respiratory depression, aspiration, 
cardiac events, hypoxia, hypotension and hypertension, difficult intubations and extubations, 
stroke, rapid changes in body temperature, laryngospasm or laryngeal edema, allergic reaction, 
and death. Patients will be closely monitored for changes in vital signs and related events.
RISKS ASSOCIATED WITH LUMBAR PUNCTURE
Risks associated with LP include pain at the injection site, infection, meningitis, encephalitis, 
cerebritis, failed procedure, bleeding, dural tears, spinal headache, spinal fluid leakage, nerve 
damage, and focal and non-focal neurological injury (including paralysis). Patients may require 
anesthesia prior to an LP. Risks from anesthesia are discussed separately in this section 
(Section 7.22.1.4).  
7.22.1.5
Serious Adverse Event
1. An SAE is any AE occurring at any dose of investigational drug or at any procedure that 
results in any of the following outcomes:

Death

Is life-threatening

Requires inpatient hospitalization

Requires prolongation of existing hospitalization

A persistent or significant disability or incapacity 

A congenital anomaly or birth defect
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include allergic 

Shire
CONFIDENTIAL
Page 52
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization. Hospitalizations, which are the 
result of elective or previously scheduled surgery for pre-existing conditions, which have not 
worsened after initiation of treatment, should not be classified as SAEs. For example, an 
admission for a previously scheduled ventral hernia repair would not be classified as an SAE; 
however, complication(s) resulting from a hospitalization for an elective or previously scheduled 
surgery that meet(s) serious criteria must be reported as SAE(s). Furthermore, this does not 
apply to device failures resulting in scheduled surgical revisions, which should be reported as 
SAEs.”
2.  Unanticipated Adverse Device Effect (UADE) - Any serious adverse effect on health or 
safety or any life-threatening problem or death caused by, or associated with, a device, if that 
effect, problem, or death was not previously identified in nature, severity, or degree of incidence 
in the investigational plan or application (including a supplementary plan or application), or any 
other unanticipated serious problem associated with a device that relates to the rights, safety, or 
welfare of patients. (21CFR812.3[s] or other regulatory requirements, as applicable).
7.22.2
Device-Associated Definitions
7.22.2.1
Device Revision (Partial and Full)
Partial device revision: surgical revision/replacement of one or more component(s) of the device; 
other component(s) of the original device remain implanted and are not affected (eg, port 
revision).
Full device revision: the device is removed (explanted) in its entirety and a completely new 
device is implanted.
7.22.2.2
Device Malfunction
The device does not perform as intended, based on the description in the device’s IFU, but does 
not require either a partial or full device revision.
7.22.2.3
Device Failure
The device irreversibly fails to perform as intended and requires either a partial or full device 
revision or removal.
7.22.2.4
Device Adjustment
Surgery of the device which does not result in partial or complete device revision or removal (eg, 
surgical exploration only or placement of additional sutures, tissue glue, and/or fascial repair).  
7.22.3
Classification of Adverse Events and Serious Adverse Events
The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) 
version 3.0 grading scale should be referenced when assessing the severity of an AE (see 
Appendix 6).  If an AE is not described in the NCI CTC, the severity should be recorded based 
on the scale provided in Table 7-3. The severity of all AEs/SAEs should be recorded on the 

Shire
CONFIDENTIAL
Page 53
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
appropriate eCRF page. Adverse events are graded as Grade 1, 2, 3, 4, or 5 corresponding, 
respectively, to a severity of mild, moderate, severe, life-threatening, or death. 
Table 7-3
Adverse Event Severity
Severity
Definition
Grade 1 (Mild)
No limitation of usual activities.
Grade 2 (Moderate)
Some limitation of usual activities.
Grade 3 (Severe)
Inability to carry out usual activities.
Grade 4 (Life-threatening)
Immediate risk of death.
Grade 5 (Death related to an AE)
Death
7.22.4
Relatedness of Adverse Events and Serious Adverse Events
Relationship of an AE or SAE to investigational product, device, device surgical procedure, or 
IT administration process is to be determined by the investigator based on the definitions in 
Table 7-4:
Table 7-4
Adverse Event Relatedness
Relationship to Product(s)
Definition
Not Related
Unrelated to study drug, device, device surgical procedure, or IT 
administration process. 
Possibly Related
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of study drug, device, device surgical 
procedure, or IT administration process but which could also be 
explained by concurrent disease or other drugs or chemicals.
Probably Related
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of study drug, device, device surgical 
procedure, or IT administration process unlikely to be attributable to 
concurrent disease or other drugs and chemicals and which follows a 
clinically reasonable response on de-challenge.  The association of the 
clinical event or laboratory abnormality must also have some biologic 
plausibility, at least on theoretical grounds.
Definitely Related
The event follows a reasonable temporal sequence from administration 
of the medication,  device, device surgical procedure, or IT 
administration process follows a known or suspected response pattern 
to the medication, is confirmed by improvement upon stopping the 
medication (dechallenge) and reappears upon repeated exposure 
(rechallenge).  
Note that this is not to be construed as requiring re-exposure of the 
patient to study drug; however, the determination of definitely related 
can only be used when recurrence of event is observed.

Shire
CONFIDENTIAL
Page 54
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
7.22.5
Procedures for Recording and Reporting Adverse Events
7.22.5.1
Reporting Serious Adverse Events Related to Study Procedures
Any SAE regardless of relationship to investigational product, device, device surgical procedure, 
or IT administration process that occurs in a patient after informed consent (and assent if 
applicable) should be recorded by the clinical site on an SAE form that is to be transmitted to the 
Shire Medical Monitor and to the Shire Pharmacovigilance and Risk Management Department at 
the contact number provided below.  The SAE must be completely described on the patient’s 
eCRF, including the judgment of the investigator as to the relationship of the SAE to the 
investigational product and or device.  The investigator will promptly supply all information 
identified and requested by the sponsor (and/or contract research organization [CRO]) regarding 
the SAE as to the relationship of the SAE to study drug, device, or procedure. 
The investigator must report the SAE to the Shire Pharmacovigilance and Risk Management 
Department AND to the Shire Medical Monitor on an SAE form.  The SAE form must be 
completed and FAXED or scanned and EMAILED (PDF sent by e-mail) within 24 hours of the 
investigator’s learning of the event to: 
Any follow-up information must also be completed on an SAE form and faxed or scanned to the 
same numbers or e-mail address listed above.
In the event of a severe and unexpected, fatal, or life-threatening SAE, the clinical site must 
contact the Shire Medical Monitor by telephone; this is in addition to completing and 
Shire Pharmacovigilance and Risk Management Department:
International FAX: 
United Kingdom OR 
United States FAX: 
Email: 
AND
Shire HGT Medical Monitor:
FAX: 
(United States)
The investigator may also call the medical monitor directly (optional):
Shire HGT Medical Monitor: 
 DO
Shire HGT
Work:
Cell:
(24 hour access)
Email: 
AND
Clinical Project Manager CC’d: 

Shire
CONFIDENTIAL
Page 55
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
transmitting the SAE form as stated above.  The following provides contact information for the 
Shire Medical Monitor.
If an SAE is assessed as severe and unexpected, or life-threatening, contact:
 DO
Shire Human Genetic Therapies, Inc.
300 Shire Way
Lexington, MA  02421,  United States
Telephone: 
Fax: 
(United States)
Mobile: 
(24-hour access)
The investigator must promptly report all required information to the Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC).  It is the responsibility of the sponsor to ensure that 
each investigator receives a copy of any CIOMS I/MedWatch report that has been submitted to 
the appropriate regulatory agencies notifying them of an unexpected related SAE.  The 
investigator or sponsor must ensure that the IRB/IEC receives a copy of the report and that a 
copy is also filed within their study files.  In addition, the sponsor will also notify the 
investigators and IRBs/IECs of all deaths that occur during the study, irrespective of relationship 
to study medication.
7.22.5.2
Eliciting Adverse Events
Patients should be asked non-leading questions (eg, “How do you feel?”) and further questions 
should be posed if there is indication of an AE.  The questioning should be conducted with due 
regard for objectivity and, in particular, the questioner should gather information regarding AEs 
from questioning the patient, the patient’s parent/guardian, spontaneous report by the patient or 
parent/guardian, laboratory reports, and any health care provider’s observations.
The onset date, resolution date, treatment administered, and outcome of each AE must be 
recorded on the appropriate eCRF. The relationship of each AE to study medication must be 
recorded. In addition AEs may be considered to be related to the IDDD, the IDDD surgical 
procedure, or the IT administration process. Since the AE may be deemed to be related to more 
than one of these factors, as many of these IDDD-related options as apply should be indicated on 
the eCRF.
7.22.5.3
Protocol Deviations for Medical Emergency or Adverse Event
During and following a patient’s participation in the study, the investigator should ensure that 
adequate medical care is provided to a patient for any AEs, including clinically significant 
laboratory test results.  
The investigator should inform the patient, the patient’s parent(s), or the patient’s legally 
authorized representative when medical care is needed for intercurrent illness(es) of which the 

Shire
CONFIDENTIAL
Page 56
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
investigator becomes aware.  In an emergency situation, the investigator should contact the Shire 
Medical Monitor (see Section 7.22.5.1).
Only when an emergency occurs that requires an immediate deviation from the protocol for the 
safety of a patient, will there be such a deviation and this will be only for that patient.  
The investigator or other physician in attendance in such an emergency must contact the Shire 
Medical Monitor as soon as possible.  
The investigator, along with the Shire Medical Monitor, will make a decision as to whether or 
not the patient should continue in the study prior to the next scheduled dose.  The departure from 
the protocol and the grounds for it should be stated in the eCRF.
7.23
Abuse, Overdose and Medication Errors
Abuse, misuse, overdose or medication error must be reported to the sponsor according to the 
SAE reporting procedure whether or not they result in an AE/SAE as described in Section 7.22.

Abuse – Persistent or sporadic intentional intake of investigational medicinal product at a 
dose higher than prescribed per protocol (but below the dose defined for overdose) or when 
used for non-medical purpose (eg, altering one’s state of consciousness)

Misuse – Intentional or unintentional use of investigational medicinal product other than as 
directed or indicated at any dose, which is at or below the dose defined for overdose (Note: 
This includes a situation where the test article is not used as directed at the dose prescribed 
by the protocol.)

Overdose – Overdosage with adverse clinical consequences is not anticipated with the use of 
HGT-1410. Additionally, HGT-1410 will be given in a clinical setting by a health care 
provider. 

Medication Error – A mistake made in prescribing, dispensing, administration and/or use of 
the investigational medicinal product.
7.24
Safety-related Study Stopping Rules
If any patient experiences a life-threatening (Grade 4) adverse event or death which is considered 
by the sponsor to be possibly, probably, or definitely related to study drug or the IDDD, or if 
2 or more patients experience a Grade 3 adverse event during the trial that is considered by the 
sponsor to be possibly, probably, or definitely related to the study drug or the IDDD, then the 
site will be instructed to halt further HGT-1410 administration to all patients and the safety data 
reviewed. Following a review of safety data, the study will be either:

Resumed unchanged

Resumed with modifications to the protocol or

Terminated
Patient safety will be monitored on a continuous basis during this study until the last patient 
completes his or her last scheduled study visit/assessment.  

Shire
CONFIDENTIAL
Page 57
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
7.25
Pregnancy
Pregnancy and breast feeding are exclusion criteria.  Only female patients who have 
reached menarche will be tested for pregnancy in HGT-SAN-067.  If applicable, this will occur 
at study start and before each dose of HGT-1410 throughout the study.  Pregnancy testing will be 
performed on a blood or urine sample.  Patients with a positive or inconclusive result will not be 
eligible for this study.
At study start, a pregnancy test will be performed if more than 30 days have passed since the 
initial screening sample.  Throughout the study pregnancy testing will occur prior to each dose of 
HGT-1410.  The clinical site’s local laboratory will analyze and report all pregnancy testing 
results.  If a pregnancy test is positive the patient will be discontinued from the study, and the 
investigator must contact the Shire Medical Monitor. 
Pregnancy is not to be reported as an AE; the Pregnancy Reporting Form, found in the Study 
Operations Manual along with instructions for completion, should be used to report the 
pregnancy.  The pregnancy will be followed up through delivery or final outcome.
7.26
Removal of Patients from the Trial or Study Drug
The patient's parent or legally authorized representative acting on behalf of the patient is free to 
withdraw consent and discontinue participation in the study at any time without prejudice to 
further treatment.  Since this is an extension trial, there will be no replacement of patients who 
discontinue the study for any reason.
A patient’s participation in the study may be discontinued at any time at the discretion of the 
investigator, sponsor, or medical monitor.  The following may be justifiable reasons for the 
investigator, sponsor, or medical monitor to remove a patient from the study:

Adverse Event:  If a patient experiences an AE which, in the judgment of the investigator, the 
sponsor, or the medical monitor, presents an unacceptable consequence or risk to the patient.

Adverse Laboratory Experience:  If a patient has an adverse laboratory experience which, in 
the judgment of the investigator, the sponsor, or the medical monitor, presents an 
unacceptable consequence or risk to the patient, the patient may be withdrawn from the 
study.

Comorbidity:  If a patient develops comorbidity during the course of the study that is 
independent of the study indication, and treatment is required that is not consistent with 
protocol requirements. 

Intercurrent Illness:  If a patient develops an illness during the course of the study that is not 
associated with the condition under study, and which requires treatment that is not consistent 
with protocol requirements.

Refusal of Treatment:  If the patient, the patient’s parent(s) or legally authorized 
representative(s) discontinues participation in the study, or the patient is discontinued by the 
investigator, reasonable efforts will be made to follow the patient through the end of study 
assessments.  The reason for refusal will be documented on the eCRF.  

Shire
CONFIDENTIAL
Page 58
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

Withdrawal of Informed Consent:  A patient’s parent or legally authorized representative 
may withdraw his informed consent to participate in the study at any time.

Cerebrospinal fluid leukocyte count >100 cells per cubic millimeter for 2 consecutive 
months.

New onset seizure.

Anaphylactic reaction beyond reasonable management as described in the Investigator’s 
Brochure.

Clinically problematic intubations or extubations, which may preclude safe airway 
management and anesthesia.

Development of refractory spinal fluid leakage. 

Clinically significant prolonged (eg, greater than 24 to 48 hours) worsening in mental status, 
including development of new focal or non-focal neurological symptoms, or recurrence of a 
previously stable prior medical problem judged due to study drug or participation that is 
exclusive of effects from anesthesia.

Non-compliance, including failure to appear at 1 or more study visits.

The patient was erroneously included in the study.

The patient develops an exclusion criterion.

The study is terminated by the sponsor.

The patient becomes pregnant during the trial.
If a patient discontinues the study the Patient Completion/Discontinuation eCRF describing the 
reason for discontinuation must be completed.  Any AE’s experienced up to the point of 
discontinuation must be documented on the AE eCRF.  
If AEs are present when the patient withdraws from the study, the patient will be re-evaluated 
within 30 days of withdrawal.  All ongoing SAEs at the time of withdrawal will be followed until 
resolution.
At the time of discontinuation or withdrawal, patients will be asked to participate in all safety 
and efficacy evaluations required for the end of study visit and for the safety follow-up visit for 
the treatment period of the study.  Participation in these EOS procedures will be strongly 
encouraged, but is voluntary for those patients electing to discontinue from the study.  The 
patient should be scheduled for the removal of the IDDD. The final evaluation in the safety 
follow-up period for patients who do not have the IDDD removed (full or partial device) is 
defined as the follow-up evaluation performed for up to 3 years after the treatment period ends.
7.27
Study Discontinuation Process
If the patient is discontinued from the study, the IDDD should be removed and a modified end of 
study visit should be completed within 30 days after withdrawal. These visits may be combined 
into one visit, in which case follow-up via a phone call should be completed within 14 days after 
the device removal to collect safety information. The end of study visit only requires collection 
of safety assessments, including symptom-directed physical exam, vital signs, clinical laboratory 
tests (hematology, serum chemistry, and urinalysis), concomitant medications, therapies, and 
procedures, and AE monitoring. No MRI or cognitive assessments are required. No study-
required CSF collection is needed at the IDDD removal, unless required for AE resolution.

Shire
CONFIDENTIAL
Page 59
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
If the investigator determines that the IDDD should not be removed from the patient based upon 
a safety assessment and the IDDD (full or partial) remains in the patient, then the patient will 
continue in the study under the safety follow-up period upon completion of their last treatment 
period visit. This last treatment period visit only requires collection of safety assessments, 
including symptom-directed physical exam, vital signs, clinical laboratory tests (hematology, 
serum chemistry, and urinalysis), concomitant medications, therapies, and procedures, and AE 
monitoring. No MRI or cognitive assessments are required. No study-required CSF collection is 
needed at the IDDD removal, unless required for AE resolution. Once the patient completes their 
last treatment period visit, they will return for their first safety follow up visit in six months. The 
patient will continue in the safety follow-up period with a clinic visit every 6 months for up to 
3 years or until the device is removed in the last patient.  An end of study follow-up via a phone 
call should be completed within 14 days after the device removal to collect safety information 
(refer to Section 8.5).
7.28
Other Study Procedures
This section is not applicable.
7.29
Appropriateness of Measurements
The neurocognitive and developmental assessments are intended to gauge which domains can be 
accurately measured, with which specific tools, despite the considerable behavioral and cognitive 
challenges in Sanfilippo syndrome.  The evaluation of these domains and the analysis of CSF, 
serum, and urine biomarkers may provide the pivotal data necessary to inform the clinical 
assessments and biomarkers used in possible future Sanfilippo syndrome ERT trials.

Shire
CONFIDENTIAL
Page 60
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
8
STUDY ACTIVITIES
Patients who participated in Study HGT-SAN-055 through Week 26 and completed the EOS 
evaluations may be eligible for enrollment in this open-label extension study.  Informed consent 
(and assent, if applicable) must be obtained prior to performing any study related procedures that 
are specific to HGT-SAN-067.  Informed consent may be obtained anytime from Week 20 in 
HGT-SAN-055.  This would allow a patient to have a nonfunctional IDDD replaced or revised 
prior to the first HGT-1410 dose in HGT-SAN-067.
8.1
Screening Visit/Study Start Visit – Main Site
All Screening assessments for this study are to have been performed during the Week 26 EOS 
procedures in HGT-SAN-055 (ie, 30 [±7] days after the last HGT-1410 administration).  If less 
than 60 days have elapsed since completion of the EOS assessments for HGT-SAN-055, and the 
start of HGT-SAN-067, the assessments detailed in this Screening visit do not need to be 
repeated.  The Baseline visit for this study will be the first day the patient received their first 
dose of HGT-1410 in the HGT-SAN-055 Study.  
If more than 60 days have elapsed following the HGT-SAN-055 EOS procedures, patients will 
be evaluated for enrollment in HGT-SAN-067 on a case-by-case basis by the investigator.  A 
decision about enrollment will be made following discussion with the medical monitor.  If the 
patient is enrolled, the following assessments are to be repeated within 30 days prior to the first 
scheduled intrathecal HGT-1410 dose:

Physical examination

Height and weight

Head circumference

ECG

Vital signs

Hematology 

Leukocyte pellet preparation to be used for additional disease-related laboratory studies, 
including possible assessment of cross-reactive immunologic material (if this is not collected 
at baseline, it can be collected at any subsequent pre-dosing time point)

Serum chemistry 

Pregnancy testing (for post menarche premenopausal females only)

Urinalysis 

Urine GAG, including heparan sulfate and heparan sulfate derivatives

Plasma collection for biomarkers

Anti-rhHNS antibody testing (serum and CSF)

General anesthesia:  administration of anesthesia will be given prior to the following 
assessments:

ABR

MRI of the head

Neurological examination (performed prior to the administration of anesthesia)

Shire
CONFIDENTIAL
Page 61
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

Full Neurodevelopmental assessments, including Vineland Adaptive Behavior Scales, 
Second Edition (VABS-II; all assessments performed prior to the administration of 
anesthesia)

CSF sample collection (chemistry, cell count, heparan sulfate and heparan sulfate derivatives, 
and other MPS exploratory biomarkers) via the IDDD

Children’s Sleep Habits Rating Scale 

CHQ-50

CHQ-87

ITQOL

Concomitant medications, therapies, and procedures

AE assessments
8.2
Treatment:  Drug Administration and Weekly Assessments – Main or Local Site
Patients will receive HGT-1410 IDDD monthly (Q4W), on Day 2 (±2 days), Week 1.  
Patient assessments for safety, biochemical, and neurological baseline measures (Day 1, Week 1) 
will occur on the day before the first IT injection.  Note:  Day 1 assessments may be performed 
on the same day as the administration of study drug (Day 2).  This can occur if it is feasible for 
the patient to arrive at the study site early in the day, and if it is deemed clinically appropriate by 
the investigator.  If the procedures on Day 1 and Day 2 are combined in this way, the 
assessments will be recorded as occurring on Day 2.
CSF samples will be obtained from these patients on Day 2, immediately prior to the first IT 
study drug injection.  
8.2.1
Week 1 
8.2.1.1
Day 1 (Pre-treatment) Assessments Performed Prior to Each Dose

Physical examination

Height and weight

Vital signs (may be performed on Day 2 if feasible for the patient to arrive at the study site 
early in the day and if deemed clinically appropriate by the investigator)

Hematology (after Month 54 frequency reduced to Q3 Months)

Serum chemistry (after Month 54 frequency reduced to Q3 Months)

Urinalysis (after Month 54 frequency reduced to Q3 Months)

Pregnancy testing (applicable females only)

Neurological examination (to be performed if symptom directed prior to the administration of 
anesthesia and the HGT-1410 IT injection and at a minimum of every 12 months)

Concomitant medications, therapies, and procedures

AE assessments

Shire
CONFIDENTIAL
Page 62
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
Note: If the HGT-SAN-055 EOS (or HGT-SAN-067 Screening) assessments were performed 
within 7 days of first intrathecal HGT-1410 treatment in this study, the pre-treatment 
assessments described in this section do not need to be completed prior to the first treatment in 
study HGT-SAN-067.
DAY 1 (PRE-TREATMENT) ADDITIONAL ASSESSMENTS PERFORMED AT MONTHS 12, 24,
36, 54, 60, 72, 84, 96, AND 102

Head circumference

Visual and hearing assessments 

Urine GAG, including heparan sulfate and heparan sulfate derivatives (performed at Months 
60, 66, 72, 78, 84, 90, and 96, ie, Q6 Months following Month 54)

Plasma collection for biomarkers

Anti-rhHNS antibody testing (performed at Months 60, 66, 72, 78, 84, 90, and 96, ie, Q6 
Months following Month 54)

ABR (not performed after Month 54, ie not on Months 60, 66, 72, 84, 96, or 102)

MRI of the head 

Full neurodevelopmental testing, including VABS-II (performed prior to the administration 
of anesthesia and the HGT-1410 IT injection)

Children’s Sleep Habits Rating Scale 

Child health questionnaire-50 

Child health questionnaire-87 

Infant toddler QoL Questionnaire 
8.2.1.2
Day 2 (±2 days) Assessments and Administration of HGT-1410
Patients may be discharged from the clinical site 4 hours after dosing, if deemed stable by the 
investigator.

Physical examination (after Month 54 the full physical examination will be performed on an 
annual basis at Months 66, 78, 90, and 102. The remainder of the physical examinations will 
be symptom-directed.)

ECG (performed following IT study drug injection)(after Month 54 performed Q3 months)

Vital signs (to be performed at the discretion of the investigator)

CSF sample collection (obtained prior to IT study drug injection)

HGT-1410 IT injection (Day 2 ±2 days)

Neurological examination (to be performed if symptom directed and at a minimum of every 
12 months)

Concomitant medications, therapies, and procedures

AE assessments
The neurological exam should not occur sooner than 4 hours after study drug administration or 
before the patient has fully recovered from any anesthesia administered for the dosing, 
whichever occurs later.

Shire
CONFIDENTIAL
Page 63
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
8.3
End of Study/Early Termination Procedures for Treatment Period:  Month 103 –
Main Site
Patients who complete the study or who discontinue prior to the end of the study during the 
treatment period, will have EOS assessments performed 30 (±7 days) after their last dose of 
HGT-1410.  
Patients who discontinue or are withdrawn prior to study completion will be asked to participate 
in the EOS procedures at the time of discontinuation for the treatment period of the study.  
Participation in these EOS procedures will be strongly encouraged, but is voluntary for those 
patients electing to discontinue from the study.  Note:  Patients should have the IDDD removed 
when they discontinue from the treatment period of the study, unless the Investigator determines 
that it should not be removed based upon safety assessments. The device can remain in the 
patient (partial [catheter only] or full [port, catheter, and suture wings]) if the patient is doing 
clinically well and there are no further known risk factors such as infection (eg, meningitis).  The 
device may be partially or fully removed as medically required and determined by the 
neurosurgeon at a future date.
Physical examination

Height and weight

Head circumference

Visual and hearing assessment

ECG

Vital signs

Hematology

Serum chemistries

Urinalysis

Pregnancy testing (applicable females only)

Urine GAG, including heparan sulfate and heparan sulfate derivatives 

Plasma collection for biomarkers

Anti-rhHNS antibody testing (serum and CSF)

MRI of the head (unless performed at Month 102)

CSF sample collection (unless performed at Month 102)

Neurological examination

Full neurodevelopmental testing, including VABS-II 

Children’s Sleep Habits Rating Scale 

CHQ-50 

CHQ-87 

Infant toddler QoL Questionnaire 

Concomitant medications, therapies, and procedures

AE assessments

Shire
CONFIDENTIAL
Page 64
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
All patients who discontinue the study early should have their IDDD removed, unless, as 
indicated above, the Investigator determines that it should not be removed based upon safety 
assessments.
During the treatment period, patients who withdraw or discontinue after having received fewer 
than 3 IT injections will not need to complete the EOS visit.  
Patients who withdraw or discontinue from the study after having received 3 or more IT 
injections, will be asked to complete the EOS visit and undergo all the scheduled assessments.
8.4
Safety Follow-up (by Telephone or Visit) Month 104
Patients who complete the study or withdraw early will have a safety follow-up telephone call or 
visit 30 Days (±7 days) after the last study visit.  This will assess:

Concomitant medications, therapies, and procedures

AE assessments
8.5
Safety Follow-up Period if Device Not Removed
All patients who do not have the IDDD removed (partial or full device) will have safety follow-
up visits every 6 months at the site, with the following assessments performed: 

Informed consent (at the first assessment)

Symptom-directed PE

Clinical laboratory tests; only if indicated for a device-related AE

X-ray monitoring; only for migration or device-related issue

Concomitant medications, therapies, and procedures; only if indicated for a device-related 
AE

AE monitoring only for device-related events
During the 3-year safety follow-up period, the patient may have the device removed at any time, 
as deemed medically necessary.  A post-operative evaluation, including a postoperative check of 
the incision and collection of safety information, should occur within 1-3 days after the IDDD 
explantation. An end of study safety follow-up via a phone call should be completed within 14 
days after the device removal to collect safety information.

Shire
CONFIDENTIAL
Page 65
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
9
QUALITY CONTROL AND ASSURANCE
Training will occur at an investigator meeting or at the site initiation visit or both, and instruction 
manuals (eg, laboratory manuals and pharmacy manuals) will be provided to aid consistency in 
data collection and reporting across sites.
Clinical sites will be monitored by Shire or its designee to ensure the accuracy of data against 
source documents.  The required data will be captured in a validated clinical data management 
system that is compliant with the Food and Drug Administration (FDA) 21 Code of Federal 
Regulations (CFR) Part 11 Guidance.  The clinical trial database will include an audit trail to 
document any evidence of data processing or activity on each data field by each user.  Users will 
be trained and given restricted access, based on their role in the study, through a password 
protected environment.  
Data entered in the system will be reviewed manually for validity and completeness against the 
source documents by a clinical monitor from Shire or its designee.  If necessary, the study site 
will be contacted for corrections or clarifications; all missing data will be accounted for.
SAE information captured in the clinical trial database will be reconciled with the information 
captured in the Pharmacovigilance database.

Shire
CONFIDENTIAL
Page 66
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
10
PLANNED STATISTICAL METHODS
10.1
General Statistical Methodology
This is an open-label extension of study HGT-SAN-055 to evaluate the long-term safety and 
clinical outcomes of intrathecal administration of HGT-1410 in patients with MPS IIIA.  The 
statistical methodology supporting the trial will focus on descriptive rather than inferential 
approaches, given the early phase and objectives of this trial. 
Data will be summarized by dose group (10 mg, 45 mg, and 90 mg) with respect to demographic 
and baseline characteristics, efficacy variables, and safety variables. Summary statistics for 
continuous variables will include the n, mean, standard deviation, median, minimum and 
maximum. Categorical variables will be summarized in a contingency table by the frequency and 
percentage of patients in each category. Data will be plotted to assess trends across time as 
appropriate.
No a priori hypotheses will be tested.  Exploratory hypotheses may emerge from the data
analysis, in which case, appropriate testing methods will be applied and specified in the 
statistical analysis plan.
There are no formal hypotheses associated with the evaluation of the safety and performance of 
the IDDD device (SOPH-A-PORT Mini S). All analyses of device safety and performance will 
be descriptive and no statistical testing will be performed. Device related analyses will be based 
on patients for whom the device implant procedure was performed and are described in the 
sections below.
10.2
Determination of Sample Size
Since this is an extension study, sample size is determined by the number of patients who 
completed HGT-SAN-055 (maximum of 12 patients) and elected to continue treatment with 
HGT-1410 in this study. Hence no statistical estimation of the sample size was performed.
10.3
Analysis Populations
The primary analysis population consists of all eligible patients from HGT-SAN-055 who have 
agreed to participate in the extension study. This population will be used to perform both safety 
and efficacy analyses. The collection of detailed data pertaining to the SOPH-A-PORT mini S 
will permit device-related analyses to be conducted in the subset of patients in the primary 
analysis population who had the SOPH-A-PORT Mini S implant procedure performed.
10.4
Demographics and Baseline Characteristics
Patient disposition for those enrolled will be presented in a summary table using number and 
percentage of patients enrolled, completed or discontinued/withdrew. The reasons for 
discontinuation/withdrawal will also be presented.

Shire
CONFIDENTIAL
Page 67
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
Demographic and baseline characteristics (eg, age, race, ethnicity, medical history, and surgical 
history) will be reported in summary tables.
10.5
Statistical Analysis of Pharmacokinetic Variables
Not applicable.
10.6
Efficacy, Safety, and Pharmacodynamic Evaluations    
10.6.1
Primary Analyses
10.6.1.1
Safety Analysis
In general, safety assessments will be based on all assessments post-baseline.  The assessment of 
safety will be based primarily on the frequency of AEs, and on the frequency of clinically 
notable abnormal vital sign and laboratory values.  Changes from baseline will be calculated by 
subtracting the baseline value from the post-baseline value.
All enrolled patients who had an IDDD surgical procedure and/or received administration of 
HGT-1410 will be included in the safety analysis.  
Adverse events will be recorded throughout the study and at early termination.  Adverse events 
and medical conditions will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). 
Adverse events will be summarized by presenting, for each dose group during the treatment 
period, the number and percentage of patients having any AE, having an AE in system organ 
class, and having each individual AE. In addition, those events which resulted in death or were 
otherwise classified as serious will be presented in a separate listing. The incidence of treatment-
emergent adverse events , defined as all AEs from the time of the surgery for IDDD implantation 
to the last follow up contact, ie, 30 days after the last HGT-1410 administration, (new or 
worsened from baseline) during the treatment period, will be summarized by system organ class, 
severity, type of adverse event and relationship to trial medication/procedure. 
Treatment-emergent AEs, of the treatment period, deemed related to HGT-1410 administration 
will be summarized separately.
IDDD and procedure-related AEs will be summarized within system organ class by preferred 
term. IDDD and procedure-related AEs will be tabulated by severity (mild, moderate, severe) 
and degree of relatedness.  Separate tabulations will be provided for adverse events related to the 
IDDD, device surgical procedure (including post-implant infections) and IT administration 
process.  These summaries will be presented by device and overall, as appropriate. 
Descriptive summaries of clinical laboratory evaluations (hematology, serum chemistry, 
urinalysis and CSF) results will be presented in summary tables by evaluation visit.  Changes 
from baseline will be summarized for each post-baseline visit.  Each laboratory result will be 
categorized as a patient having had (1) an Abnormal and Clinically Significant (CS) value at any 
time, (2) no CS values at any time but had at least one Abnormal and not CS (NCS) value, and 

Shire
CONFIDENTIAL
Page 68
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
(3) no CS or NCS values at any time; the number and percentage in each category will be 
presented.  For any patient who experiences a CS laboratory result at any time that was not CS at 
baseline (or the most recent non-missing value prior to the start of the treatment), their entire 
profile for that particular laboratory parameter will be presented as a listing.
The observed values and changes from baseline for vital sign data will be summarized for each 
dose group.  Shift tables may be presented, utilizing reference ranges.  Patients with notably 
abnormal values will be identified and listed separately along with their values.
The observed values and changes from baseline for ECG data will be summarized for each dose 
group.  Patients with any clinically significant findings and/or conduction abnormalities will be 
listed separately along with their values. 
Anti-rhHNS antibody formation will be monitored throughout the study.  Results will be 
presented in summary tables by number and percentage of positive and negative specimens by 
evaluation visit, and number and percentage of positive and negative specimens overall.  The 
effect of antibodies on other safety parameters will be assessed by presenting summary tables by 
antibody status.  
For those patients who fail to complete the study, the reason for discontinuation will be listed by 
patient and dose group. 
Listings of all study safety data will be presented.
10.6.2
Other Observations Related to Safety
10.6.2.1
IDDD Performance
IDDD safety and performance will be summarized in detail for patients implanted with the 
SOPH-A-PORT Mini S. Difficulties associated with the implant procedure (e.g. excessive 
bleeding, CSF leakage, etc.) will be summarized.  A summary of abnormal findings from the 
IDDD radiological assessments will also be presented.  
The proportion of patients with at least one IDDD failure and/or malfunction, as well as the 
number of and reasons for IDDD failures/malfunctions will be summarized.  The rate of IDDD 
failures/malfunctions and 95% confidence interval will also be estimated.  The time from initial 
implant surgery to first IDDD failure and/or malfunction will be summarized.  Patients without 
an IDDD failure/malfunction will be censored at their last study drug injection date.  A by-
patient listing of the device failure/malfunction data will be displayed.
The proportion of patients for whom a successful first injection of study drug occurred will be 
reported among those for whom a first injection was attempted (i.e. those who had an apparently 
successful implantation and did not suffer a device removal or revision prior to first scheduled 
injection). The proportion of patients who had no failed injection attempts during the study will 
also be summarized. The corresponding 95% confidence intervals of the proportion of interest 
will be estimated, where appropriate. Injections not given for patient reasons (e.g. patient 
uncooperative, competing medical issue, etc.) will not be included in the determination of these 
success proportions.

Shire
CONFIDENTIAL
Page 69
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
10.6.3
Secondary Analysis
10.6.3.1
Clinical Assessments
The change from baseline in neurocognitive assessment based scores will be examined by dose 
group.  Furthermore, the effect of HGT-1410 administration on QoL measures will be examined 
by presenting mean change from baseline by dose groups.  Other relevant assessments which 
might help in the understanding of clinical activity will also be analyzed.
10.6.3.2
Pharmacodynamic Analyses
To determine the effects of HGT-1410 administration on biomarkers, mean change from baseline 
will be assessed at selected time points.  The heparan sulfate reduction (in CSF) will be 
examined using mean change and the corresponding 95% confidence interval.  Other exploratory 
biomarkers in CSF, serum, and urine may also be examined.
The effect of anti- rhHNS antibodies on the changes in CSF biomarkers may also be examined 
by presenting summary tables by antibody status.
10.6.4
Interim Analysis
Interim analyses may be conducted before trial completion for safety monitoring, regulatory 
reporting, publication or general study planning purposes. Analyses will be descriptive in nature, 
with no formal comparisons planned and no hypotheses formally tested.
The planned final analyses and presentations will be defined in the Statistical Analysis Plan 
(SAP).

Shire
CONFIDENTIAL
Page 70
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
11
ADMINISTRATIVE CONSIDERATIONS
11.1
Investigators and Study Administrative Structure
Before initiation of the study, the investigators must provide the sponsor with a completed Form 
FDA 1572 or Investigator Agreement.  Study medications may be administered only under the 
supervision of the investigators listed on this form.  Curriculum vitae must be provided for the 
investigators and sub-investigators listed on Form FDA 1572 or Investigator Agreement.
The investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, any amendments to the protocol, the study treatments, and their study related 
duties and functions.  The investigator must maintain a list of sub-investigators and other 
appropriately qualified persons to whom he or she has delegated significant study related duties.
11.2
Institutional Review Board or Independent Ethics Committee Approval
Before initiation of the study, the investigator must provide the sponsor with a copy of the 
written IRB or IEC approval of the protocol and the informed consent form.  This approval must 
refer to the informed consent form and to the study title, study number, and version and date of 
issue of the study protocol, as given by the sponsor on the cover page of the protocol.  
Status reports must be submitted to the IRB/IEC at least once per year.  The IRB/IEC must be 
notified of completion of the study.  Within 3 months of study completion or termination, a final 
report must be provided to the IRB/IEC.  A copy of these reports will be sent to the study clinical 
monitor.  The investigators must maintain an accurate and complete record of all submissions 
made to the IRB/IEC, including a list of all reports and documents submitted.  AEs which are 
reported to the US FDA or other Regulatory agencies (Investigational New Drug [IND] Safety 
Reports) must be submitted promptly to the IRB/IEC.
11.3
Ethical Conduct of the Study
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and investigators abide by 
good clinical practice (GCP) as described in the 21 CFR Parts 50, 56, and 312 and the 
International Conference on Harmonization (ICH) GCP Guidelines. 
11.4
Patient Information and Consent
Before enrolling in the clinical study, the patient’s parent(s), or the patient’s legally authorized 
representative(s) must consent to participate after the nature, scope, and possible consequences 
of the clinical study have been explained in a form understandable to him or her.  An informed 
consent form that includes information about the study will be prepared and given to the 
patient’s parent(s), or the patient’s legally authorized representative(s).  This document will 
contain all FDA and ICH-required elements.  

Shire
CONFIDENTIAL
Page 71
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
The informed consent form must be in a language understandable to the patient’s parent(s), or 
the patient’s legally authorized representative(s) and must specify who informed the patient’s 
parent(s) or the patient’s legally authorized representative.
After reading the informed consent document, the patient, patient’s parent(s), or the patient’s 
legally authorized representative(s) must give consent in writing.  The patient’s consent must be 
confirmed at the time of consent by the personally dated signature of the patient, patient’s 
parent(s) or the patient’s legally authorized representative(s) and by the personally dated 
signature of the person conducting the informed consent discussions.  If the patient, patient’s 
parent(s), or the patient’s legally authorized representative(s) is unable to read, oral presentation 
and explanation of the written informed consent form and information to be supplied must take 
place in the presence of an impartial witness.  Consent (or assent) must be confirmed at the time 
of consent orally and by the personally dated signature of the patient, patient’s parent(s) or by the 
patient’s legally authorized representative(s).  The witness and the person conducting the 
informed consent discussions must also sign and personally date the informed consent document.  
It should also be recorded and dated in the source document that consent was given.
A copy of the signed and dated consent document(s) must be given to the patient’s parent(s), or 
the patient’s legally authorized representative(s).  The original signed and dated consent 
document will be retained by the investigator.
The investigator will not undertake any measures specifically required solely for the clinical 
study until valid consent has been obtained.
A model of the informed consent form to be used in this study will be provided to the sites 
separately from this protocol.  
Where applicable, signed assent(s) to participate in the study must be obtained.
11.5
Patient Confidentiality
Patient names will not be supplied to the sponsor.  Only the patient number and patient initials 
will be recorded in the eCRF, and if the patient name appears on any other document, it must be 
obliterated before a copy of the document is supplied to the sponsor.  Study findings stored on a 
computer will be stored in accordance with local data protection laws.  The patients will be told 
that representatives of the sponsor, a designated CRO, the IRB/IEC, or regulatory authorities 
may inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws.  The investigator will maintain a personal patient 
identification list (patient numbers with the corresponding patient names) to enable records to be 
identified.
11.6
Study Monitoring
Monitoring procedures that comply with current GCP guidelines will be followed.  On-site 
review of the eCRFs for completeness and clarity, cross-checking with source documents, and 
clarification of administrative matters will be performed.

Shire
CONFIDENTIAL
Page 72
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
The study will be monitored by the sponsor or its designee.  On site monitoring will be 
performed by a representative of the sponsor (clinical study monitor) who will review the CRFs 
and source documents.  The site monitor will ensure that the investigation is conducted 
according to protocol design and regulatory requirements by frequent site visits and 
communications (letter, telephone, and facsimile).
11.7
Case Report Forms and Study Records
Case report forms are provided for each patient in electronic format.  Electronic Data Capture 
(EDC) will be used for this study.  The study data will be recorded from the source documents 
into the eCRF.  The electronic files will be considered as the CRFs. 
All forms must be filled out by authorized study personnel.  All corrections to the original eCRF 
entry must indicate the reason for change.  The investigator is required to sign the eCRF after all 
data have been captured for each patient.  If corrections are made after review and signature by 
the investigator, he or she must be made aware of the changes, and his or her awareness 
documented by re-signing the eCRF.   
11.7.1
Critical Documents
Before Shire initiates the trial (ie, obtains informed consent [assent if applicable] from the first 
patient), it is the responsibility of the investigator to ensure that the following documents are 
available to Shire or their designee:

Curricula vitae of investigator and sub-investigator(s) (current, dated and signed or supported 
by an official regulatory document)

Current medical license of investigator and sub-investigator(s)

Signed and dated agreement of the final protocol

Signed and dated agreement of any amendment(s), if applicable

Approval/favorable opinion from the IRB/IEC clearly identifying the documents reviewed:  
protocol, any amendments, Patient Information/Informed Consent Form (Assent form if 
applicable), and any other written information to be provided regarding patients recruitment 
procedures

Copy of IRB/IEC approved Patient Information/Informed Consent Form (Assent Form if 
applicable)/any other written information/advertisement

Any additional regulatory approvals, ie national regulatory approvals

List of IRB/IEC Committee members/constitution

Financial agreement(s)

Documentation from central or local laboratory as applicable
•
Reference ranges
•
Certification/QA scheme/other documentation
Regulatory approval and notification as required must also be available; these are the 
responsibility of Shire.  All trial documents will be available in a Trial Master File (TMF) at the 
investigator/trial site and at Shire.     

Shire
CONFIDENTIAL
Page 73
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
11.8
Device Failure Review Process
The final cause for device failures will be reviewed by a Shire team by examining the clinical 
database, safety database, and manufacturer investigation of returned devices.
11.9
Protocol Violations/Deviations
The investigator will conduct the study in compliance with the protocol.  The protocol will not 
be initiated until the IRB/IEC and the appropriate regulatory authorities have given 
approval/favorable opinion.  Modifications to the protocol will not be made without agreement 
of the sponsor.  Changes to the protocol will require written IRB/IEC approval/favorable opinion 
prior to implementation, except when the modification is needed to eliminate an immediate 
hazard(s) to patients.  The IRB/IEC may provide, if applicable regulatory authorities permit, 
expedited review and approval/favorable opinion for minor change(s) in ongoing studies that 
have the approval/favorable opinion of the IRB/IEC.  The sponsor will submit all protocol 
modifications to the regulatory authorities in accordance with the governing regulations.  A 
record of patients screened, but not entered into the study, is also to be maintained.  There will be 
no protocol exemptions granted for this study.
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
patients, the investigator will contact the sponsor or its designee, if circumstances permit, to 
discuss the planned course of action.  Any departures from the protocol must be fully 
documented as a protocol deviation.  Protocol deviations will need to be reviewed by the medical 
monitor and may also be required to be submitted to the IRB/IEC.
Protocol modifications will only be initiated by the sponsor and must be approved by the 
IRB/IEC and submitted to the FDA or other applicable international regulatory authority before 
initiation.
11.10 Access to Source Documentation
Regulatory authorities, the IEC/IRB, or the sponsor may request access to all source documents, 
CRFs, and other study documentation for on-site audit or inspection.  Direct access to these 
documents must be guaranteed by the investigator, who must provide support at all times for 
these activities.  Monitoring and auditing procedures that comply with current GCP guidelines 
will be followed.  On-site review of the CRFs for completeness and clarity, crosschecking with 
source documents, and clarification of administrative matters will be performed.
11.11 Data Generation and Analysis
The clinical database will be developed and maintained by a contract research organization or an 
electronic data capture technology provider as designated by Shire.  Shire or its designee will be 
responsible for performing study data management activities. 
Adverse events will be coded using MedDRA.  Concomitant medication will be coded using 
WHO-DD.  Centralized laboratories will be employed as described in the study manual to aid in 
consistent measurement of efficacy and safety parameters.

Shire
CONFIDENTIAL
Page 74
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
11.12 Premature Closure of the Study
11.12.1
Study Termination
If the sponsor or an investigator discovers conditions arising during the study which indicate that 
the clinical investigation should be halted due to an unacceptable patient risk, the study may be 
terminated after appropriate consultation between Shire and the investigators.  In addition, a 
decision on the part of Shire to suspend or discontinue development of the study material may be 
made at any time.
11.12.2
Site Termination
A specific site may be terminated separate from the general study for, but not limited to, the 
following conditions:

The discovery of an unexpected, significant, or unacceptable risk to the patients enrolled at 
the site.

Failure of the investigator to enter patients at an acceptable rate.

Insufficient adherence by the investigator to protocol requirements.
11.13 Retention of Data
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application and until there are no pending or contemplated marketing applications or 
at least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product.  The sponsor will notify the investigator if these documents must be 
retained for a longer period of time.  It is the responsibility of the sponsor to inform the 
investigator or institution as to when these documents no longer need to be retained. 
Biological samples may be reserved for potential, future, biomarker studies (see Section 7.7.7).  
11.14 Financial Disclosure
The investigator should disclose any financial interests in the sponsor as described in 21 CFR 
Part 54 prior to beginning this study.  The appropriate form will be provided to the investigator 
by the sponsor, which will be signed and dated by the investigator, prior to the start of the study. 
11.15 Publication and Disclosure Policy
All information concerning the study material, such as patent applications, manufacturing 
processes, basic scientific data, and formulation information supplied by the sponsor and not 
previously published are considered confidential and will remain the sole property of the 
sponsor.  The investigator agrees to use this information only in accomplishing this study and 
will not use it for other purposes.
It is understood by the investigator that the information developed in the clinical study may be 
disclosed as required to the authorized regulatory authorities and governmental agencies.  

Shire
CONFIDENTIAL
Page 75
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
In order to allow for the use of the information derived from the clinical studies, it is understood 
that there is an obligation to provide the sponsor with complete test results and all data developed 
in the study in a timely manner.
The investigator and any other clinical personnel associated with this study will not publish the 
results of the study, in whole or in part, at any time, unless they have consulted with Shire, 
provided Shire a copy of the draft document intended for publication, and obtained Shire’s 
written consent for such publication.  All information obtained during the conduct of this study 
will be regarded as confidential.  Shire will use the information for registration purposes and for 
the general development of the drug.
Shire may perform analyses of interim and/or final locked study data for the purpose of 
publication.

Shire
CONFIDENTIAL
Page 76
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
12
LIST OF REFERENCES
1. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. 
JAMA : the journal of the American Medical Association 1999;281:249-54.
2. Poorthuis BJ, Wevers RA, Kleijer WJ, et al. The frequency of lysosomal storage diseases in 
The Netherlands. Human genetics 1999;105:151-6.
3. Baehner F, Schmiedeskamp C, Krummenauer F, et al. Cumulative incidence rates of the 
mucopolysaccharidoses in Germany. J Inherit Metab Dis 2005;28:1011-7.
4. Valstar MJ, Bruggenwirth HT, Olmer R, et al. Mucopolysaccharidosis type IIIB may 
predominantly present with an attenuated clinical phenotype. Journal of inherited metabolic 
disease 2010;33:759-67.
5. Meyer A, Kossow K, Gal A, et al. Scoring evaluation of the natural course of 
mucopolysaccharidosis type IIIA (Sanfilippo syndrome type A). Pediatrics 
2007;120:e1255-61.
6. Cleary MA, Wraith JE. Management of mucopolysaccharidosis type III. Arch Dis Child 
1993;69:403-6.
7. Fraser J, Wraith JE, Delatycki MB. Sleep disturbance in mucopolysaccharidosis type III 
(Sanfilippo syndrome): a survey of managing clinicians. Clin Genet 2002;62:418-21.
8. Neufeld E, Muenzer J. The Mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, 
Valle D, eds. The metabolic and molecular bases of inherited disease. 8th ed. New York: 
McGraw-Hill; 2001:4 v. (xivii, 6338, I-104 p.).
9. Meyer A, Kossow K, Gal A, et al. The mutation p.Ser298Pro in the sulphamidase gene 
(SGSH) is associated with a slowly progressive clinical phenotype in mucopolysaccharidosis 
type IIIA (Sanfilippo A syndrome). Hum Mutat 2008;29:770.
10. Vellodi A. Lysosomal storage disorders. Br J Haematol 2005;128:413-31.
11. Hemsley KM, Beard H, King BM, Hopwood JJ. Effect of high dose, repeated intra-CSF 
injection of sulphamidase on neuropathology in MPS IIIA mice. Genes Brain Behav 2008.
12. Urayama A, Grubb JH, Sly WS, Banks WA. Mannose 6-phosphate receptor-mediated 
transport of sulfamidase across the blood-brain barrier in the newborn mouse. Mol Ther 
2008;16:1261-6.
13. Bielicki J, Hopwood JJ, Melville EL, Anson DS. Recombinant human sulphamidase: 
expression, amplification, purification and characterization. Biochem J 1998;329 ( Pt 
1):145-50.
14. Di Natale P, Vanacore B, Daniele A, Esposito S. Heparan N-sulfatase: in vitro mutagenesis 
of potential N-glycosylation sites. Biochem Biophys Res Commun 2001;280:1251-7.

Shire
CONFIDENTIAL
Page 77
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
15. Daniele A, Di Natale P. Heparan N-sulfatase: cysteine 70 plays a role in the enzyme catalysis 
and processing. FEBS Lett 2001;505:445-8.
16. Perkins KJ, Byers S, Yogalingam G, Weber B, Hopwood JJ. Expression and characterization 
of wild type and mutant recombinant human sulfamidase. Implications for Sanfilippo 
(Mucopolysaccharidosis IIIA) syndrome. J Biol Chem 1999;274:37193-9.
17. Munoz-Rojas MV, Vieira T, Costa R, et al. Intrathecal enzyme replacement therapy in a 
patient with mucopolysaccharidosis type I and symptomatic spinal cord compression. Am J 
Med Genet A 2008;146A:2538-44.
18. Muñoz-Rojas M, Dain D, Horovitz G, et al. Intrathecal administration of recombinant human 
N-acetylgalactosamine 4-sulfatase to a MPS VI patient with pachymeningitis cervicalis. 
Molecular Genetics and Metabolism 2010;99:346-50.
19. Chen A, Dickson P, Shapiro E, Lyons B, Kan S, Guillaume D. A study of intrathecal enzyme 
replacement for cognitivedecline in mucopolysaccharidosis. Mol Genet Metab 
2010;99:S13-S4.
20. Hemsley K, King B, Hopwood J. Injection of recombinant human sulfamidase into the CSF 
via the cerebellomedullary cistern in MPS IIIA mice. Mol Genet Metab 2007;90:313-28.
21. Hemsley KM, Luck AJ, Crawley AC, et al. Examination of intravenous and intra-CSF 
protein delivery for treatment of neurological disease. Eur J Neurosci 2009;29:1197-214.
22. Hemsley KM, Norman EJ, Crawley AC, et al. Effect of cisternal sulfamidase delivery in 
MPS IIIA Huntaway dogs-A proof of principle study. Mol Genet Metab 2009.
23. Bayley N. Bayley Scales of Infant and Toddler Development: Third Edition. San Antonio, 
TX The Psychological Corporation; 2005.
24. Kaufman S, Kaufman N. Kaufman Assessment Battery for Children (KABC-II). 2nd ed.
25. Henderson S, Sugden D, Barnett A. Movement Assessment Battery for Children (second 
ed.). London: Harcourt Assessment; 2007.
26. Sparrow S, Balla D, Cicchetti D. Vineland Adaptive Behavior Scales (Second Edition). 4201 
Woodland Road Circle Pines, MN 55014-1796: American Guidance Service, Inc; 2005.

Shire
CONFIDENTIAL
Page 78
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
Appendix 1
Schedule of Events 
Table A1-1
HGT-SAN-067 Study Assessments for Patients Who Have Received 6 Months of HGT-1410 Treatment in Study 
HGT-SAN-055
Assessment
Month 7 through Month 104 (from the start of HGT-SAN-055)
Dosed every 28 (±7) days 
(ie, Q4W)
Screening/or 
HGT-SAN-
055 EOS 
Visitj
(Month 6 
from the 
start of 
HGT-SAN-
055)
Pre-Tx
Day 1a
IT dosing
Day 2 (±2)
Months 12, 
24, 36, 54, 
60, 72, 84, 96 
and 102 
(from the 
start of 
HGT-SAN-
055)
Additional 
Assessments 
at Months 
66, 78, and 
90 (from the 
start of 
HGT-SAN-
055)
Months 9, 
15, 18, 21, 
27, 30, 33, 
39, 42, 45, 
48, and 51 
(from the 
start of 
HGT-SAN-
055)
EOSe
Month 103 
(from the 
start of 
HGT-SAN-
055)
Month 104 
Safety 
Follow-upf
Main Site 
only
Main or 
Local Site
Main or 
Local Site
Main Site 
only
Main Site 
only
Main Site 
only
Main Site 
only
Informed Consent/Enrollment
●
Physical Examination 
●
●p
●p
●p
Symptom-Directed Physical Examination
●p
●p
●
Neurological Examinationh
●
●s
●s
●
Height and Weight
●
●
●
Head Circumference
●
●
●
Visual and Hearing Assessment
●
●
ECG
●
●b 
●
Vital Signs
●
●s
●s
●
Hematology
●
●
●
Serum Chemistry
●
●
●
anti-rhHNS antibody testing (serum)k
●
●t
●t
●
Plasma storage for biomarkers
●
●
●
●
Pregnancy Testingl
●
●
●

Shire
CONFIDENTIAL
Page 79
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
Table A1-1
HGT-SAN-067 Study Assessments for Patients Who Have Received 6 Months of HGT-1410 Treatment in Study 
HGT-SAN-055
Assessment
Month 7 through Month 104 (from the start of HGT-SAN-055)
Dosed every 28 (±7) days 
(ie, Q4W)
Screening/or 
HGT-SAN-
055 EOS 
Visitj
(Month 6 
from the 
start of 
HGT-SAN-
055)
Pre-Tx
Day 1a
IT dosing
Day 2 (±2)
Months 12, 
24, 36, 54, 
60, 72, 84, 96 
and 102 
(from the 
start of 
HGT-SAN-
055)
Additional 
Assessments 
at Months 
66, 78, and 
90 (from the 
start of 
HGT-SAN-
055)
Months 9, 
15, 18, 21, 
27, 30, 33, 
39, 42, 45, 
48, and 51 
(from the 
start of 
HGT-SAN-
055)
EOSe
Month 103 
(from the 
start of 
HGT-SAN-
055)
Month 104 
Safety 
Follow-upf
Main Site 
only
Main or 
Local Site
Main or 
Local Site
Main Site 
only
Main Site 
only
Main Site 
only
Main Site 
only
Urinalysis
●
●
●
Urine GAGs
●
●t
●t
●
Leukocyte pellet preparationm
●
CSF chemistry and cell countsc
●
●
●
CSF sample storagec,o
●
●
●
CSF Heparan Sulfate and Heparan 
Sulfate Derivativesc
●
●t
●t
●
Anti-rhHNS antibody testing (CSF)c
●
●t
●t
●
Auditory Brainstem Response (ABR)q
●
●
MRI of the Head
●
●
●n
HGT-1410 dosing: every 28 (7) daysd,g
●
Full Neurodevelopmental Testingi
●
●
●
Children’s Sleep Habits Rating Scale
●
●
●
Child Health Questionnaire-50
●
●
●
Child Health Questionnaire-87
●
●
●
Infant Toddler QOL Questionnaire
●
●
●

Shire
CONFIDENTIAL
Page 80
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
Table A1-1
HGT-SAN-067 Study Assessments for Patients Who Have Received 6 Months of HGT-1410 Treatment in Study 
HGT-SAN-055
Assessment
Month 7 through Month 104 (from the start of HGT-SAN-055)
Dosed every 28 (±7) days 
(ie, Q4W)
Screening/or 
HGT-SAN-
055 EOS 
Visitj
(Month 6 
from the 
start of 
HGT-SAN-
055)
Pre-Tx
Day 1a
IT dosing
Day 2 (±2)
Months 12, 
24, 36, 54, 
60, 72, 84, 96 
and 102 
(from the 
start of 
HGT-SAN-
055)
Additional 
Assessments 
at Months 
66, 78, and 
90 (from the 
start of 
HGT-SAN-
055)
Months 9, 
15, 18, 21, 
27, 30, 33, 
39, 42, 45, 
48, and 51 
(from the 
start of 
HGT-SAN-
055)
EOSe
Month 103 
(from the 
start of 
HGT-SAN-
055)
Month 104 
Safety 
Follow-upf
Main Site 
only
Main or 
Local Site
Main or 
Local Site
Main Site 
only
Main Site 
only
Main Site 
only
Main Site 
only
Concomitant Medications, Therapies, 
and Procedures
●
●
●
●
●
Adverse Event Monitoring
●
●
●
●
●
Abbreviations:ABR = Auditory brainstem response; CSF = cerebrospinal fluid; EOS  = end of study ; ECG = electrocardiogram; IT = intrathecal; 
MRI = Magnetic resonance imaging; TX = treatment
Note:
The timing of assessments is calculated from the start of HGT-SAN-055. Therefore, for example, the end-of-study visit, as presented here at Month 102, corresponds to 
Month 102 in HGT-SAN-067, but represents a total of 102 months of study treatment (102 months in HGT-SAN-067 + 6 months in HGT-SAN-055).
a
Week 1 only, and only performed if >7 days have elapsed since HGT-SAN-055 EOS visit assessments.
b
ECG to be performed following administration of study drug, after Month 54 it is to be performed every 3 months.
c
CSF samples will be obtained according to the process within the study laboratory manual. An attempt will be made to obtain a CSF sample via the IDDD prior to each 
administration of HGT-1410 and at the End of Study visit. If it is not possible to obtain a CSF using the IDDD, the IDDD may be replaced (up to twice in a 6 month period 
[including the time in the HGT-SAN-055 study]) or an LP may be performed.
d
Patients may be discharged as early as 4 hours post HGT-1410 infusion (ie, on Day 2) when deemed clinically stable by the investigator. 
e
All patients who complete the study will have end of study assessments performed 30 (±7 days) after their last dose of study drug.
f
A safety follow up telephone call will be made 30 (±7 days) after End of Study Procedures.
g
If a patient’s IDDD becomes nonfunctional or infected; it will be replaced (up to 2 times in a 6 month period; including the time in Study HGT-SAN-055).
h
The neurological exam should not occur sooner than 4 hours after administration of study drug or before the patient has fully recovered from any anesthesia administered for 
the dosing, whichever occurs later.  
i
Full neurodevelopmental testing includes an assessment with the Vineland Adaptive Behavior Scales, Second Edition (VABS-II).

Shire
CONFIDENTIAL
Page 81
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
Table A1-1
HGT-SAN-067 Study Assessments for Patients Who Have Received 6 Months of HGT-1410 Treatment in Study 
HGT-SAN-055
Assessment
Month 7 through Month 104 (from the start of HGT-SAN-055)
Dosed every 28 (±7) days 
(ie, Q4W)
Screening/or 
HGT-SAN-
055 EOS 
Visitj
(Month 6 
from the 
start of 
HGT-SAN-
055)
Pre-Tx
Day 1a
IT dosing
Day 2 (±2)
Months 12, 
24, 36, 54, 
60, 72, 84, 96 
and 102 
(from the 
start of 
HGT-SAN-
055)
Additional 
Assessments 
at Months 
66, 78, and 
90 (from the 
start of 
HGT-SAN-
055)
Months 9, 
15, 18, 21, 
27, 30, 33, 
39, 42, 45, 
48, and 51 
(from the 
start of 
HGT-SAN-
055)
EOSe
Month 103 
(from the 
start of 
HGT-SAN-
055)
Month 104 
Safety 
Follow-upf
Main Site 
only
Main or 
Local Site
Main or 
Local Site
Main Site 
only
Main Site 
only
Main Site 
only
Main Site 
only
j
Assessments will be required only if more than 60 days have elapsed following the HGT-SAN-055 procedures.  These assessments would be repeated within 30 days prior to 
the first scheduled HGT-1410 IT dose.
k
Blood sample drawn before IT injection of HGT-1410.
l
A pregnancy test will be carried out on pre-treatment Day 1 in females who are postmenarche to premenopause (childbearing).  The results must be negative before study drug 
can be administered.
m
A blood sample for leukocyte pellet preparation is to be taken at baseline, before dosing.  This pellet should be stored frozen, and will be used for additional disease-related 
laboratory studies, including possible assessment of cross-reactive immunologic material.  If this is not drawn at baseline, it can be drawn at any subsequent visit, but it must 
be taken before dosing.  This only needs to be taken once during the study.
n
These assessments are not to be performed at an EOS visit conducted at Month 103 if they were performed at the Month 102 visit.
o
CSF samples will be tested for MPS exploratory biomarkers, and possibly extractables and leachables.
p
After Month 54 the Symptom-Directed PE is to be done monthly. Full PE is done monthly to Month 54 and then at least yearly (ie, Months 66, 78, 90, and 102), or more 
frequently at the investigator’s discretion.  Genitourinary AEs may be evaluated by the patient's primary care physician and a follow-up report will be sent to the study site.
q
ABR will not be performed after Month 54.
r
Informed consent will be obtained at Screening and Month 54.
s
These Day 1 assessments may be performed on the same day as the administration of study drug (Day 2).  This can occur if it is feasible for the patient to arrive at the study 
site early in the day, and if it is deemed clinically appropriate by the investigator.  If the procedures on Day 1 and Day 2 are combined in this way, the assessments will be 
recorded as occurring on Day 2.
t
Urine GAG, including heparan sulfate and heparan sulfate derivatives, and anti-rhHNS antibody testing will be performed at Months 60, 66, 72, 78, 84, 90, and 96, ie, Q6 
Months following Month 54); these assessments must be performed at the main site. 

Shire
CONFIDENTIAL
Page 82
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
Table A1-2
HGT-SAN-067 Study Assessments for the Safety Follow-up Period for Patients with Implanted Partial or Full 
Device After Treatment Completion
Procedure
Every 6 Months from 
Last Visit
(±14 Days)b
End of Study
Device Explantatione
Post-operative 
Evaluation
Safety Follow-up Call
Day 1
Days 2-4f
14 days post device explantation
Informed consenta
●
Symptom-directed PE
●
●
Hematologyc
●
Serum chemistryc
●
Urinalysisc
●
Standard CSF safety labsc
●
X-rayd
●
Con meds, therapies, and 
procedures
●
●
●
●
Device-related AE monitoring
●
●
●
●
Postoperative check of IDDD 
incision
●
Abbreviations: AE= adverse event; IDDD= intrathecal drug delivery device; PE=physical examination
a
Informed consent will be captured at the first 6 month visit after the end of the treatment period.
b
From the patient’s last follow-up visit and every 6 months thereafter up until the device is removed
c
To be acquired only as indicated by a device-related AE.
d
To check IDDD placement or for any device-related AEs.
e
During the 3-year safety follow-up period, the patient may have the device removed at any time, as deemed medically necessary
f
Post-operative evaluation can occur within 1-3 days after IDDD explantation.

Shire
CONFIDENTIAL
Page 83
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
Appendix 2
Neurodevelopmental and Behavioural Assessments 
Tables A2-1 and A2-2 detail the specific psychometric instruments that will be used to provide 
measures of each of relevant neurobehavioral or developmental domain assessed.  The tables 
also summarize the rules used to select a test for a patient, the subtests included in each test, and 
the subscales generated by the test battery.
Table A2-1
Summary of Neurodevelopmental Outcome Measures
Domain
Age
Test
Summary score and 
subdomains:
- Cognitive
- Motor
- Social/Emotional
0 to 42 months
Bayley Scales of Infant Development, Third Edition (BSID-
III)23
- Cognitive 
- Processing skills
3 to 18 years
Kaufman Assessment Battery for Children, Second Edition 
(KABC-II)24  
Motor
3.0 to 16:11 years
Movement Assessment Battery for Children, Second Edition 
(MABC-2)25  
Communication
Daily Living
Socialization
Motor Skills
0 to 90 years
Vineland Adaptive Behavior Scales, Second Edition 
(VABS-II)26
Table A2-2
Summary of Sanfilippo-specific Assessments
Domain
Assessment
Parent-scored behavioral inventory
- communication:  understanding
- communication:  expression
- tantrums
- specific behaviors inventory
- mood & emotions inventory
Sanfilippo Behavior Rating Scale
MPS-specific four-point scoring system/total 
disability score
- cognition
- expressive language
- motor score
Four-Point Scoring System/Total Disability Score 
(FPSS/TDS)5
The term “neurodevelopmental” refers to the process by which the neurological system matures 
and changes over time.  Assessing these changes in a population of children whose neurological 
system is progressively more affected can be very challenging.  

Shire
CONFIDENTIAL
Page 84
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
Typically, neurodevelopmental progress is reflected by the child’s abilities to perform certain 
skills (sitting, walking, and talking).  
However, a child with a neurological disorder may be able to perform age appropriate skills, but 
with atypical patterns.  For example, the child may be able to walk, but his gait is not normal.  
Most assessments will therefore measure the skills, but are not designed to capture the 
abnormalities in pattern or quality of the skill.  
These qualitative differences will be evident to the skilled test administrator/clinician who is 
familiar with the disorder.  However, only longitudinal tracking and repeated measures will 
reveal the significance of these abnormalities in overall function to the less experienced clinician.   
The rate at which different skills develop or regress over time will give insight into the disease 
process.  The next step is to determine how the learned skills are used for daily functional 
activities so that as the children grow up they become independent from caregivers.  These 
functional skills can be tracked to reflect quality of life issues for both parents and children. 
Neurodevelopmental assessments described below will be scheduled for administration in the 
morning and estimated to last between 2 and 4 hours.
The list of assessments and algorithm is discussed in detail in the Study Operations Manual and 
includes:
Bayley Scales of Infant Development, Third Edition (BSID-III)23
The Bayley Scales of Infant Development is a standard series of measurements used primarily to 
assess the motor (fine and gross), language (receptive and expressive), and cognitive 
development of infants and toddlers, ages 0 to 42 months.  This measure consists of a series of 
developmental play tasks and takes between 45 and 60 minutes to administer.  Raw scores of 
successfully completed items are converted to scale scores and to composite scores.  These 
scores are used to determine the child's performance compared with norms taken from typically 
developing children of their age (in months).  The assessment is often used in conjunction with 
the Social-Emotional Adaptive Behavior Questionnaire.  Completed by the parent or caregiver, 
this questionnaire establishes the range of adaptive behaviors that the child can currently achieve 
and enables comparison with age norms.
Kaufman Assessment Battery for Children, Second Edition (KABC-II)24
Purpose:
The KABC-II measures a child’s cognitive ability and processing skills and was designed to 
minimize verbal instructions and responses.  In addition, the assessment contains little cultural 
content to provide a more accurate assessment of children from diverse backgrounds.  Thus 
language difficulties or cultural differences are minimized in the test battery’s results.

Shire
CONFIDENTIAL
Page 85
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
Description:
Investigators may choose either the Cattell-Horn-Carroll or the Luria model for a patient’s 
assessment.  
The Cattell-Horn-Carroll model is used with children from a mainstream cultural and language 
background and the Luria model is used for children with significantly limited verbal ability.  
Subtests are administered on four or five ability scales and interpreted using the chosen model. 
Movement Assessment Battery for Children, Second Edition (MABC-2)25
Purpose:
The Movement Assessment Battery for Children, Second Edition identifies, describes and guides 
treatment of motor impairment in children from 3.0 to 16:11 years of age.
Description:
The MABC-2 checklist is administered individually over approximately 30 minutes.  It yields 
both normative and qualitative measures of movement competence, manual dexterity, ball skills, 
static and dynamic balance.
Vineland Adaptive Behavior Scales, Second Edition (VABS-II)26
Purpose:
The test measures adaptive behaviors, including the ability to cope with environmental changes, 
to learn new everyday skills and to demonstrate independence.  It is an instrument that supports 
the diagnosis of intellectual and developmental disabilities.  It encompasses ages from birth to 
90 years. 
Description:
Adaptive behavior is a composite of various dimensions.  This test measures 5 domains:  
communication, daily living skills, socialization, motor skills, and maladaptive behavior 
(optional) and is administered in a semi-structured interview in through a questionnaire.  The 
scales of the VABS-II were organized within a 3-domain structure:  Communication, Daily 
Living, and Socialization.  This structure corresponds to the 3 broad domains of adaptive 
functioning by the American Association of Intellectual and Developmental Disabilities:  
Conceptual, Practical, and Social.  In addition, VABS-II offers a Motor Skills Domain and an 
optional Maladaptive Behavior Index.  The scores are interpreted by means of score equivalents 
for the raw scores in each domain, percentile ranks, age equivalents, adaptive levels, and 
maladaptive levels.

Shire
CONFIDENTIAL
Page 86
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
Sanfilippo Behavior Rating Scale (SBRS)
The Sanfilippo Behavior Rating Scale (SBRS) is a newly-developed scale designed by Drs. Elsa 
Shapiro and Michael Potegal to measure a cluster of behaviors known to occur in Sanfilippo 
syndrome.  The SBRS is a parent-scored behavioral inventory measuring (1) comprehensive 
language skills, (2) expressive language skills, (3) tantrums, (4) mood and emotions, and 
(5) other behaviors not otherwise classified.
Four-Point Scoring System/Total Disability Score (FPSS/TDS)5
The FPSS assesses motor function, expressive language, and cognitive function on a 0 to 3 point 
scale and can be used for individuals of all ages.  The total disability score is the average of the 
motor function, speech, and cognitive function scores.

Shire
CONFIDENTIAL
Page 87
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
Appendix 3
Expected Adverse Device Effects
Procedure-Related Complications

Components handled improperly before, during, or after implantation 

Access port implanted incorrectly

Catheter positioned improperly

Injection through septum performed incorrectly

Injection of incorrect medication through access port

Injection outside the access port into pocket or subcutaneous tissue or extravasation

Pocket seroma, hematoma, erosion, or infection
Intrathecal Access Complications

Surgical complications such as hemorrhage or hematoma

Infection of the implant site or catheter track

Radiculitis or arachnoiditis

Intrathecal space infection resulting in meningitis or encephalitis

Bleeding 

Spinal cord damage or trauma to the spinal cord or nerve roots

Post-lumbar puncture, cerebrospinal fluid (CSF) leak, leading to headache, or  subcutaneous 
CSF collection

Epidural instead of intrathecal placement of catheter

Inflammatory mass resulting in neurological impairment, including paralysis

Pain on injection

Complications of anesthesia

Pseudomeningocele

Shire
CONFIDENTIAL
Page 88
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
System-Related Complications

Improperly positioned access port

Erosion of the skin because of the underlying access port or the catheter

Wound dehiscence

Access port migration, fracture, breakage or occlusion

Catheter damage, dislodgement, migration, disconnection, kinking or occlusion, fibrosis, or 
hygroma, resulting in tissue damage or a loss of or change in therapy, or other potentially 
serious adverse health consequences

Catheter breakage and migration of residual catheter fragments, potentially resulting in 
serious adverse health consequences and the need for surgical removal 

Local immunological or fibrous reaction to the presence of a foreign body (the device)

End of device service life or component failure, requiring surgical replacement

Component failure, resulting in loss of therapy

Access port inversion (“flipping”), rotation, or extrusion

Access port or catheter rejection 

Fibrin sheath formation around catheter tip

Shire
CONFIDENTIAL
Page 89
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
Appendix 4
Protocol Amendment 8 Summary of Changes 
AMENDMENT SUMMARY AND RATIONALE
Clinical protocol HGT-SAN-067 has been amended to include language to allow for patients to 
retain a full or partial IDDD in situ after they discontinue or complete the treatment period of the 
study, at the discretion of the investigator based upon safety assessment. These patients who do 
not have the IDDD removed at the end of the treatment period will continue to be observed 
during a safety follow-up period with visits every 6 months to evaluate patient safety of the 
device up to an additional 3 years or until the device is removed in the last patient.
Previous Amendment:  Amendment 7, 08 February 2016
DETAILED SUMMARY OF CHANGES FOR THE AMENDMENT 
This is a section that has been updated to describe the changes from the previous protocol 
version.  Significant changes and additions to the protocol text are captured below.  Bold text 
indicates new text.  Strikethrough text indicates deleted text.
Change:  Clarification that explantation events will be included as SOPH-A-PORT Mini S 
assessments.
Section impacted by this change: Section 3.3, SOPH-A-PORT Mini S Assessments
Revised Text:
For the subset of patients who will have a PORT-A-CATH IDDD replaced by a SOPH-A-
PORT Mini S, information relative to the safety and performance of the SOPH-A-PORT 
Mini S will be collected in a structured manner. SOPH-A-PORT Mini S assessments will 
include measures of device implantation, device function, device longevity, record of 
revisions, removalsexplantation events, and replacements of the implanted IDDD, and 
AEs associated with the device. These data will be collected in the patient’s electronic 
case report form (eCRF) from the time of implantation and continue through the study as 
long as the SOPH-A-PORT Mini S remains implanted.
Other sections impacted by this change: Synopsis; Section 7.11, Device Data
Change:  Clarification that if a patient is discontinued from the study, the IDDD should be 
removed and a modified end of study visit completed.  However, if the IDDD is not 
removed, the patient will continue to be observed during a safety follow-up period with 
visits every 6 months until the IDDD has been fully explanted.
Section impacted by this change: Section 4.1, Overall Study Design and Plan
Revised Text:
All patients will have received a series of standardized neurodevelopment assessments; in 
the HGT-SAN-055 study, these will have occurred at Baseline and either prior to or at the 
6-month time point.  Patients will continue in HGT-SAN-067, during the treatment 
period, with whichever age specific assessment they began with in HGT-SAN-055.  If, 
however, a patient’s capability improves and they become capable of completing 

Shire
CONFIDENTIAL
Page 90
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
assessments at a higher level, such additional assessments may be added.  Any additional 
assessments are to be performed after the original assessments (those used in study HGT-
SAN-055) have been carried out, during the treatment period of the study.  
An MRI of the head will be performed at Months 12, 24, 36, 54, 60, 72, 84, 96, and 102 
and ABR testing will be performed at Months 12, 24, 36 and 54 (note that assessment 
time point nomenclature includes the 6 months in the HGT-SAN-055 study), during the 
treatment period of the study. 
In the event of a device malfunction, X-rays may be performed to investigate, as well as to 
verify correct catheter and port placement following surgical IDDD implantation or 
revision.  In addition, fluoroscopy may be employed intra-operatively to guide catheter 
placement.  Patients may undergo 3 X-ray examinations in association with each episode 
of IDDD malfunction and subsequent IDDD revision or replacement.  The number of 
IDDD revisions/replacements is limited to 2 in any 6-month period (including the time in 
the HGT-SAN-055 study), and the number of protocol-associated X-ray evaluations is 
limited to 6 exposures in any 6-month period (including time in study HGT-SAN-055). If 
patients are to continue to receive HGT-1410 using the IDDD beyond the duration of this 
study, they will also have X-ray examinations of the device performed at the EOS visit, to 
document correct positioning.
…
All patients will have an EOS visit during the treatment period, 30 (±7) days following 
their last administration of HGT-1410 (ie, Month 102).  The EOS procedures will include 
standard clinical laboratory tests (serum chemistry, hematology, and urinalysis) in CSF 
and blood, protocol specific laboratory testing (eg, anti-rhHNS antibody testing), 
neurodevelopmental testing, child health questionnaires, and MRI.  Use of concomitant 
medications, therapies, and procedures will be recorded and AEs will be monitored. 
All patients will be contacted by telephone or will have a visit for a Final Safety Follow-
up, conducted at 30 (±7) days after the EOS visit, of the treatment period, (ie, Month 
103) to collect updated information on AEs and concomitant medications, therapies, and 
procedures. 
If the patient is discontinued from the study, the IDDD should be removed and a 
modified end of study visit should be completed within 30 days after withdrawal. 
These visits may be combined into one visit, in which case follow-up via a phone call 
should be completed within 14 days after the device removal to collect safety 
information. If the investigator determines that the IDDD should not be removed 
from the patient based upon a safety assessment and the IDDD (full or partial) 
remains in the patient, then the patient will continue in the study under the safety 
follow-up period upon completion of their last treatment period visit.
…
If there is no significant safety risk in the opinion of the investigator, a non-functional 

Shire
CONFIDENTIAL
Page 91
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
IDDD may be left in situ for up to 3 months during the treatment period.
Patients who discontinue or are withdrawn before receiving 3 monthly IT injections will 
not have to undergo the EOS evaluations but will have their IDDD removed.  
If during the treatment period, a patient discontinues, or withdraws from the study, or 
the study is stopped by the sponsor, the IDDD should will be removed as part of the EOS 
Procedures. unless the Investigator determines that it should not be removed based 
upon safety assessments. The device can remain in the patient (partial [catheter only] 
or full [port, catheter, and suture wings]) if the patient is doing clinically well and 
there are no further known risk factors such as infection (eg, meningitis).  The device 
may be partially or fully removed as medically required and determined by the 
neurosurgeon at a future date.
Patients who do not have the IDDD removed (partial or full device) at the end of the 
treatment period will continue to be observed during a safety follow-up period with 
visits at the site every 6 months to evaluate patient safety of the device until the 
IDDD has been fully explanted.
An overview of the study appears in the Schedule of Events (Appendix 1). See Appendix 
1, Table A1-2 for the Study Schedule of Events for the safety follow-up period for 
patients with partial or full devices in place after the end of the treatment period.  
Other sections impacted by this change: Synopsis; Section 7.13.4, Device Removal
Change:  Definition provided for LPLV and clarification that the study duration has been 
extended to up to an additional 3 years or until the device is removed in the patient, for 
patients with a partial for full device in place after the treatment period.
Section impacted by this change: Section 4.3, Study Duration and Dates
Revised Text:
Patients with a partial or full device still in place after completion of the treatment 
period, may be followed for safety up to an additional 3 years or until the device is 
removed in the last patient. 
The LPLV will be the safety follow-up visit after the final device (partial and/or full) 
is removed from the last patient during the safety follow-up period.
Other sections impacted by this change: Synopsis
Change:  Informed consent will be obtained from patients who did not have the device 
removed.
Section impacted by this change:  Section 7.1, Informed Consent
Revised Text: 
After the treatment period ends, informed consent from patients who do not have the 

Shire
CONFIDENTIAL
Page 92
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
IDDD removed (partial or full device) will be obtained for the safety follow-up 
period.
Other sections impacted by this change:  NA
Change:  Symptom-directed physical examinations to be performed during the safety 
follow-up period.
Section impacted by this change:  Section 7.2, Physical Examination
Revised Text: 
A full physical examination or a symptom-directed physical examination of each patient 
will be performed at time points detailed in Appendix 1 Table A1-1 Schedule of Events, 
for the duration of the treatment period. The physical examinations for the safety 
follow-up period will be symptom-directed, see Appendix 1, Table A1-2 Schedule of 
Events for details.
Other sections impacted by this change:  NA
Change:  Clinical laboratory testing only performed for device-related AEs during the 
safety follow-up period.
Section impacted by this change:  Section 7.7, Clinical Laboratory Tests
Revised Text: 
For patients who do not have the IDDD removed (partial or full device) at the end of 
the treatment period, clinical laboratory testing will only be performed when 
indicated for a device-related AE during the safety follow-up period.
Other sections impacted by this change:  NA
Change:  Clarification regarding x-ray verification during safety follow-up period.
Section impacted by this change:  Section 7.13.2, X-ray Verification of Intrathecal Drug 
Delivery Device Placement
Revised Text: 
A postoperative x-ray check of the IDDD will be performed following surgery to verify 
proper installation and confirmation of IDDD placement at the mid-thoracic level. The x-
rays may be performed to check placement of the device, migration, or malfunction of 
the device as needed, throughout the treatment period or the safety follow-up period of 
the study. If the patient is to receive intrathecal HGT-1410 beyond the end of the study, 
an X-ray will be performed at the end of the study to verify that the IDDD is in the correct 
position. At a minimum, the date of the x-ray verifying correct IDDD placement will be 
documented on the patient’s eCRF. If the device requires revision or replacement during 
the treatment period of the study, additional x-rays will be taken to document proper 
positioning of the device. If an IDDD malfunctions, an x-ray may be performed to assess 
the potential cause of malfunction. Fluoroscopy may be used during device implant or 

Shire
CONFIDENTIAL
Page 93
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
revision procedures.
Other sections impacted by this change:  NA
Change:  Final evaluation in the safety follow-up period defined.
Section impacted by this change:  Section 7.26, Removal of Patients from the Trial or 
Study Drug
Revised Text: 
At the time of discontinuation or withdrawal, patients will be asked to participate in all 
safety and efficacy evaluations required for the end of study visit and for the safety 
follow-up visit for the treatment period of the study.  Participation in these EOS 
procedures will be strongly encouraged, but is voluntary for those patients electing to 
discontinue from the study.  The patient will should be scheduled for the removal of the 
IDDD. The final evaluation in the safety follow-up period for patients who do not 
have the IDDD removed (full or partial device) is defined as the follow-up evaluation 
performed for up to 3 years after the treatment period ends.
Other sections impacted by this change:  NA
Change:  Study discontinuation process defined.
Section impacted by this change:  Section 7.27, Study Discontinuation Process
Revised Text: 
If the patient is discontinued from the study, the IDDD should be removed and a 
modified end of study visit should be completed within 30 days after withdrawal. 
These visits may be combined into one visit, in which case follow-up via a phone call 
should be completed within 14 days after the device removal to collect safety 
information. The end of study visit only requires collection of safety assessments, 
including symptom-directed physical exam, vital signs, clinical laboratory tests 
(hematology, serum chemistry, and urinalysis), concomitant medications, therapies, 
and procedures, and AE monitoring. No MRI or cognitive assessments are required. 
No study-required CSF collection is needed at the IDDD removal, unless required 
for AE resolution.
If the investigator determines that the IDDD should not be removed from the patient 
based upon a safety assessment and the IDDD (full or partial) remains in the patient, 
then the patient will continue in the study under the safety follow-up period upon 
completion of their last treatment period visit. This last treatment period visit only 
requires collection of safety assessments, including symptom-directed physical exam, 
vital signs, clinical laboratory tests (hematology, serum chemistry, and urinalysis), 
concomitant medications, therapies, and procedures, and AE monitoring. No MRI or 
cognitive assessments are required. No study-required CSF collection is needed at 
the IDDD removal, unless required for AE resolution. Once the patient completes 
their last treatment period visit, they will return for their first safety follow up visit 

Shire
CONFIDENTIAL
Page 94
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
in six months. The patient will continue in the safety follow-up period with a clinic 
visit every 6 months for up to 3 years or until the device is removed in the last 
patient.  An end of study follow-up via a phone call should be completed within 14 
days after the device removal to collect safety information (refer to Section 8.5).
Other sections impacted by this change:  NA
Change:  Clarification regarding the EOS/early termination procedures for the treatment 
period.
Section impacted by this change:  Section 8.3, End of Study/Early Termination 
Procedures for Treatment Period:  Month 103 – Main Site
Revised Text: 
Patients who complete the study or who discontinue prior to the end of the study during 
the treatment period, will have EOS assessments performed 30 (±7 days) after their last 
dose of HGT-1410.  
Patients who discontinue or are withdrawn prior to study completion will be asked to 
participate in the EOS procedures at the time of discontinuation for the treatment period 
of the study.  Participation in these EOS procedures will be strongly encouraged, but is 
voluntary for those patients electing to discontinue from the study.  Note:  Patients will
should have the IDDD removed when they discontinue from the treatment period of the
study, unless the patient is continuing to receive treatment through another mechanism 
(eg, extension study, expanded access, commercially available). Investigator determines 
that it should not be removed based upon safety assessments. The device can remain 
in the patient (partial [catheter only] or full [port, catheter, and suture wings]) if the 
patient is doing clinically well and there are no further known risk factors such as 
infection (eg, meningitis).  The device may be partially or fully removed as medically 
required and determined by the neurosurgeon at a future date.
…
All patients who discontinue the study early will should have their IDDD removed, 
unless, as indicated above, the Investigator determines that it should not be removed 
based upon safety assessments.
Patients who withdraw or discontinue after having received fewer than 3 IT injections 
during the treatment period will not need to complete the EOS visit.  
Other sections impacted by this change:  NA
Change:  Assessments during safety follow-up period if device not removed described.
Section impacted by this change:  Section 8.5, Safety Follow-up Period if Device Not 
Removed
Revised Text: 

Shire
CONFIDENTIAL
Page 95
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
All patients who do not have the IDDD removed (partial or full device) will have 
safety follow-up visits every 6 months at the site, with the following assessments 
performed: 

Informed consent

Symptom-directed PE

Clinical laboratory tests; only if indicated for a device-related AE

X-ray monitoring; only for migration or device-related issue

Concomitant medications, therapies, and procedures; only if indicated for a 
device-related AE

AE monitoring only for device-related events
During the 3-year safety follow-up period, the patient may have the device removed 
at any time, as deemed medically necessary.  A post-operative evaluation, including a 
postoperative check of the incision and collection of safety information, should occur 
within 1-3 days after the IDDD explantation. An end of study safety follow-up via a 
phone call should be completed within 14 days after the device removal to collect 
safety information.
Other sections impacted by this change:  Table A1-2, HGT-SAN-067 Study Assessments 
for the Safety Follow-up Period for Patients with Implanted Partial or Full Device After 
Treatment Completion
Change:  Clarification regarding statistical analysis of TEAEs and treatment period.
Section impacted by this change:  Section 10.6.1.1
Revised Text: 
Adverse events will be summarized by presenting, for each dose group during the 
treatment period, the number and percentage of patients having any AE, having an AE in 
system organ class, and having each individual AE. In addition, those events which 
resulted in death or were otherwise classified as serious will be presented in a separate 
listing. The incidence of treatment-emergent adverse events , defined as all AEs from the 
time of the surgery for IDDD implantation to the last follow up contact, ie, 30 days after 
the last HGT-1410 administration, (new or worsened from baseline) during the 
treatment period, will be summarized by system organ class, severity, type of adverse 
event and relationship to trial medication/procedure. 
Treatment-emergent AEs, of the treatment period, deemed related to HGT-1410 
administration will be summarized separately.
Other sections impacted by this change:  NA
Change:  Language added indicating interim analysis may be performed.
Section impacted by this change:  Section 10.6.4, Interim Analysis

Shire
CONFIDENTIAL
Page 96
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
Revised Text: 
Interim analyses may be conducted before trial completion for safety monitoring, 
regulatory reporting, publication or general study planning purposes. Analyses will 
be descriptive in nature, with no formal comparisons planned and no hypotheses 
formally tested. No formal analysis or interim statistical testing for early stopping of the 
trial is planned.  Descriptive analyses of the data before trial completion may be 
performed for safety monitoring, regulatory reporting, publication, or general planning 
purposes.
Other sections impacted by this change:  NA

Shire 
CONFIDENTIAL 
Page 97 
Clinical Trial Protocol: HGT-SAN-067 Amendment 8 
Recombinant human heparan N-sulfatase (rbHNS, HGT-1410) 
01 Feb 2017 
Appendix 5 
Protocol Signature Page 
Study Title: 
An Open-Label Extension of Study HGT -SAN-055 Evaluating 
Long-Tetm Safety and Clinical Outcomes oflntrathecal 
Administration of rhHNS in Patients with Sanfilippo Syndrome 
Type A (MPS IliA) 
Study Number: 
HGT-SAN-067 Amendment 7 
Fiual Date: 
21 June 2010 
Amendment 1 Date: 
Amendment 2 Date: 
Amendment 3 Date: 
Amendment 4 Date: 
Amendment 5 Date: 
Amendment 6 Date: 
Amendment 7 Date: 
Amendment 8 Date: 
22 January 2011 
13 January 2012 
28 August 2012 
3 May 2013 
17 January 2014 
10 July 2014 
08 Febmary 2016 
01 Febmary 2017 
I have read the protocol described above. I agree to comply with all applicable regulations and 
to conduct the study as described in the protocol. 
Signatory: 
Investigator 
Signature 
Printed Name 
I have read and approve the protocol described above. 
Signatory: 
Shire Medical 
Monitor 
Signature 
 DO 
Printed Name 
Date 
Date 

Shire
CONFIDENTIAL
Page 98
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017
Appendix 6
The National Cancer Institute Common Terminology Criteria version 3.0

Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, Version 3.0, DCTD, NCI, NIH, DHHS 
 
March 31, 2003 (http://ctep.cancer.gov), Publish Date: August 9, 2006 
Common Terminology Criteria for Adverse Events v3.0 (CTCAE) 
Publish Date: August 9, 2006 
Quick Reference 
The NCI Common Terminology Criteria for Adverse Events 
v3.0 is a descriptive terminology which can be utilized for 
Adverse Event (AE) reporting. A grading (severity) scale is 
provided for each AE term. 
Components and Organization  
CATEGORY 
A CATEGORY is a broad classification of AEs based on 
anatomy and/or pathophysiology. Within each CATEGORY, 
AEs are listed accompanied by their descriptions of severity 
(Grade). 
Adverse Event Terms 
An AE is any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medical treatment or procedure 
that may or may not be considered related to the medical 
treatment or procedure. An AE is a term that is a unique 
representation of a specific event used for medical 
documentation and scientific analyses. Each AE term is 
mapped to a MedDRA term and code. AEs are listed 
alphabetically within CATEGORIES. 
Short AE Name 
The ‘SHORT NAME’ column is new and it is used to simplify 
documentation of AE names on Case Report Forms.   
Supra-ordinate Terms  
A supra-ordinate term is located within a CATEGORY and is a 
grouping term based on disease process, signs, symptoms, 
or diagnosis. A supra-ordinate term is followed by the word 
‘Select’ and is accompanied by specific AEs that are all 
related to the supra-ordinate term. Supra-ordinate terms 
provide clustering and consistent representation of Grade for 
related AEs. Supra-ordinate terms are not AEs, are not 
mapped to a MedDRA term and code, cannot be graded and 
cannot be used for reporting. 
REMARK 
A ‘REMARK’ is a clarification of an AE. 
ALSO CONSIDER 
An ‘ALSO CONSIDER’ indicates additional AEs that are to be 
graded if they are clinically significant. 
NAVIGATION NOTE 
A ‘NAVIGATION NOTE’ indicates the location of an AE term 
within the CTCAE document. It lists signs/symptoms 
alphabetically and the CTCAE term will appear in the same 
CATEGORY unless the ‘NAVIGATION NOTE’ states differently. 
Grades 
Grade refers to the severity of the AE. The CTCAE v3.0 
displays Grades 1 through 5 with unique clinical descriptions 
of severity for each AE based on this general guideline: 
Grade 1 
Mild AE  
Grade 2 
Moderate AE 
Grade 3 
Severe AE 
Grade 4 
Life-threatening or disabling AE 
Grade 5 
Death related to AE 
A Semi-colon indicates ‘or’ within the description of the grade. 
An ‘Em dash’ (—) indicates a grade not available. 
Not all Grades are appropriate for all AEs. Therefore, some 
AEs are listed with fewer than five options for Grade 
selection. 
Grade 5 
Grade 5 (Death) is not appropriate for some AEs and 
therefore is not an option. 
The DEATH CATEGORY is new. Only one Supra-ordinate 
term is listed in this CATEGORY: ‘Death not associated with 
CTCAE term – Select’ with 4 AE options: Death NOS; 
Disease progression NOS; Multi-organ failure; Sudden death. 
Important: 
• 
Grade 5 is the only appropriate Grade 
• 
This AE is to be used in the situation where 
a death  
1. cannot be reported using a CTCAE v3.0 
term associated with Grade 5, or 
2. cannot be reported within a CTCAE 
CATEGORY as ‘Other (Specify)’ 
 
 
 
 
 
Contents 
ALLERGY/IMMUNOLOGY ............................................1 
AUDITORY/EAR............................................................2 
BLOOD/BONE MARROW .............................................4 
CARDIAC ARRHYTHMIA..............................................5 
CARDIAC GENERAL ....................................................7 
COAGULATION ..........................................................10 
CONSTITUTIONAL SYMPTOMS................................11 
DEATH ........................................................................13 
DERMATOLOGY/SKIN ...............................................14 
ENDOCRINE...............................................................17 
GASTROINTESTINAL.................................................19 
GROWTH AND DEVELOPMENT................................29 
HEMORRHAGE/BLEEDING ....................................... 30 
HEPATOBILIARY/PANCREAS ................................... 34 
INFECTION................................................................. 35 
LYMPHATICS ............................................................. 38 
METABOLIC/LABORATORY ...................................... 40 
MUSCULOSKELETAL/SOFT TISSUE........................ 43 
NEUROLOGY ............................................................. 47 
OCULAR/VISUAL........................................................ 52 
PAIN............................................................................ 55 
PULMONARY/UPPER RESPIRATORY...................... 56 
RENAL/GENITOURINARY.......................................... 60 
SECONDARY MALIGNANCY..................................... 63 
SEXUAL/REPRODUCTIVE FUNCTION ..................... 64 
SURGERY/INTRA-OPERATIVE INJURY ................... 66 
SYNDROMES............................................................. 68 
VASCULAR................................................................. 70 
 
Page 99
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
ALLERGY/IMMUNOLOGY 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 1 - 
March 31, 2003, Publish Date: August 9, 2006 
Allergic reaction/ 
hypersensitivity  
(including drug fever) 
Allergic reaction 
Transient flushing or 
rash; drug fever <38°C 
(<100.4°F) 
Rash; flushing; urticaria; 
dyspnea; drug fever 
≥38°C (≥100.4°F) 
Symptomatic 
bronchospasm, with or 
without urticaria; 
parenteral medication(s) 
indicated; allergy-related 
edema/angioedema; 
hypotension 
Anaphylaxis 
Death 
REMARK: Urticaria with manifestations of allergic or hypersensitivity reaction is graded as Allergic reaction/hypersensitivity (including drug fever). 
ALSO CONSIDER: Cytokine release syndrome/acute infusion reaction. 
Allergic rhinitis  
(including sneezing, 
nasal stuffiness, 
postnasal drip) 
Rhinitis 
Mild, intervention not 
indicated  
Moderate, intervention 
indicated 
— 
— 
— 
REMARK: Rhinitis associated with obstruction or stenosis is graded as Obstruction/stenosis of airway – Select in the PULMONARY/UPPER RESPIRATORY CATEGORY. 
Autoimmune reaction 
Autoimmune reaction 
Asymptomatic and 
serologic or other 
evidence of autoimmune 
reaction, with normal 
organ function and 
intervention not indicated 
Evidence of autoimmune 
reaction involving a non-
essential organ or 
function (e.g., 
hypothyroidism) 
Reversible autoimmune 
reaction involving function 
of a major organ or other 
adverse event (e.g., 
transient colitis or 
anemia)  
Autoimmune reaction with 
life-threatening 
consequences 
Death 
ALSO CONSIDER: Colitis; Hemoglobin; Hemolysis (e.g., immune hemolytic anemia, drug-related hemolysis); Thyroid function, low (hypothyroidism). 
Serum sickness 
Serum sickness 
— 
— 
Present 
— 
Death 
NAVIGATION NOTE: Splenic function is graded in the BLOOD/BONE MARROW CATEGORY. 
NAVIGATION NOTE: Urticaria as an isolated symptom is graded as Urticaria (hives, welts, wheals) in the DERMATOLOGY/SKIN CATEGORY. 
Vasculitis 
Vasculitis 
Mild, intervention not 
indicated 
Symptomatic, non-
steroidal medical 
intervention indicated 
Steroids indicated 
Ischemic changes; 
amputation indicated 
Death 
Allergy/Immunology – 
Other (Specify, __) 
Allergy – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Page 100
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
AUDITORY/EAR 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 2 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Earache (otalgia) is graded as Pain – Select in the PAIN CATEGORY. 
Hearing:  
patients with/without 
baseline audiogram and 
enrolled in a monitoring 
program1 
Hearing (monitoring 
program) 
Threshold shift or loss of 
15 – 25 dB relative to 
baseline, averaged at 2 
or more contiguous test 
frequencies in at least 
one ear; or subjective 
change in the absence of 
a Grade 1 threshold shift 
Threshold shift or loss of 
>25 – 90 dB, averaged at 
2 contiguous test 
frequencies in at least 
one ear 
Adult only: Threshold shift 
of >25 – 90 dB, averaged 
at 3 contiguous test 
frequencies in at least 
one ear  
Pediatric:  
Hearing loss sufficient to 
indicate therapeutic 
intervention, including 
hearing aids (e.g., ≥20 dB 
bilateral HL in the speech 
frequencies; ≥30 dB 
unilateral HL; and 
requiring additional 
speech-language related 
services) 
Adult only: Profound 
bilateral hearing loss 
(>90 dB) 
Pediatric:  
Audiologic indication for 
cochlear implant and 
requiring additional 
speech-language related 
services  
— 
REMARK: Pediatric recommendations are identical to those for adults, unless specified. For children and adolescents (≤18 years of age) without a baseline test, pre-exposure/pre-
treatment hearing should be considered to be <5 dB loss. 
Hearing: 
patients without baseline 
audiogram and not 
enrolled in a monitoring 
program1  
Hearing (without 
monitoring program) 
— 
Hearing loss not requiring 
hearing aid or 
intervention (i.e., not 
interfering with ADL) 
Hearing loss requiring 
hearing aid or 
intervention (i.e., 
interfering with ADL) 
Profound bilateral hearing 
loss (>90 dB) 
— 
REMARK: Pediatric recommendations are identical to those for adults, unless specified. For children and adolescents (≤18 years of age) without a baseline test, pre-exposure/pre-
treatment hearing should be considered to be <5 dB loss. 
Otitis, external ear 
(non-infectious) 
Otitis, external  
External otitis with 
erythema or dry 
desquamation  
External otitis with moist 
desquamation, edema, 
enhanced cerumen or 
discharge; tympanic 
membrane perforation; 
tympanostomy 
External otitis with 
mastoiditis; stenosis or 
osteomyelitis 
Necrosis of soft tissue or 
bone 
Death 
ALSO CONSIDER: Hearing: patients with/without baseline audiogram and enrolled in a monitoring program1; Hearing: patients without baseline audiogram and not enrolled in a 
monitoring program1.  
Otitis, middle ear  
(non-infectious) 
Otitis, middle 
Serous otitis  
Serous otitis, medical 
intervention indicated 
Otitis with discharge; 
mastoiditis  
Necrosis of the canal soft 
tissue or bone 
Death 
Page 101
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
AUDITORY/EAR 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 3 - 
March 31, 2003, Publish Date: August 9, 2006 
Tinnitus 
Tinnitus 
— 
Tinnitus not interfering 
with ADL 
Tinnitus interfering with 
ADL 
Disabling 
— 
ALSO CONSIDER: Hearing: patients with/without baseline audiogram and enrolled in a monitoring program1; Hearing: patients without baseline audiogram and not enrolled in a 
monitoring program1. 
Auditory/Ear – Other 
(Specify, __) 
Auditory/Ear – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
 
 
 
 
 
 
                                            
1 Drug-induced ototoxicity should be distinguished from age-related threshold decrements or unrelated cochlear insult. When considering whether an adverse event has occurred, it is 
first necessary to classify the patient into one of two groups. (1) The patient is under standard treatment/enrolled in a clinical trial <2.5 years, and has a 15 dB or greater threshold 
shift averaged across two contiguous frequencies; or (2) The patient is under standard treatment/enrolled in a clinical trial >2.5 years, and the difference between the expected age-
related and the observed threshold shifts is 15 dB or greater averaged across two contiguous frequencies. Consult standard references for appropriate age- and gender-specific 
hearing norms, e.g., Morrell, et al. Age- and gender-specific reference ranges for hearing level and longitudinal changes in hearing level. Journal of the Acoustical Society of America 
100:1949-1967, 1996; or Shotland, et al. Recommendations for cancer prevention trials using potentially ototoxic test agents. Journal of Clinical Oncology 19:1658-1663, 2001.  
In the absence of a baseline prior to initial treatment, subsequent audiograms should be referenced to an appropriate database of normals. ANSI. (1996) 
American National Standard: Determination of occupational noise exposure and estimation of noise-induced hearing impairment, ANSI S 3.44-1996. (Standard S 3.44). New York: 
American National Standards Institute. The recommended ANSI S3.44 database is Annex B. 
Page 102
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
BLOOD/BONE MARROW 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 4 - 
March 31, 2003, Publish Date: August 9, 2006 
Bone marrow cellularity 
Bone marrow cellularity 
Mildly hypocellular or  
≤25% reduction from 
normal cellularity for age 
Moderately hypocellular 
or >25 – ≤50% reduction 
from normal cellularity for 
age  
Severely hypocellular or 
>50 – ≤75% reduction 
cellularity from normal for 
age  
— 
Death 
CD4 count  
CD4 count 
<LLN – 500/mm3 
<LLN – 0.5 x 109 /L 
<500 – 200/mm3  
<0.5 – 0.2 x 109 /L 
<200 – 50/mm3  
<0.2 x 0.05 – 109 /L 
<50/mm3  
<0.05 x 109 /L 
Death 
Haptoglobin  
Haptoglobin 
<LLN  
— 
Absent 
— 
Death 
Hemoglobin  
Hemoglobin 
<LLN – 10.0 g/dL  
<LLN – 6.2 mmol/L  
<LLN – 100 g/L 
<10.0 – 8.0 g/dL 
<6.2 – 4.9 mmol/L  
<100 – 80g/L 
<8.0 – 6.5 g/dL 
<4.9 – 4.0 mmol/L 
<80 – 65 g/L 
<6.5 g/dL 
<4.0 mmol/L  
<65 g/L 
Death 
Hemolysis (e.g., immune 
hemolytic anemia, drug-
related hemolysis) 
Hemolysis 
Laboratory evidence of 
hemolysis only (e.g., 
direct antiglobulin test 
[DAT, Coombs’] 
schistocytes) 
Evidence of red cell 
destruction and ≥2 gm 
decrease in hemoglobin, 
no transfusion 
Transfusion or medical 
intervention (e.g., 
steroids) indicated 
Catastrophic 
consequences of 
hemolysis (e.g., renal 
failure, hypotension, 
bronchospasm, 
emergency splenectomy) 
Death 
ALSO CONSIDER: Haptoglobin; Hemoglobin. 
Iron overload 
Iron overload 
— 
Asymptomatic iron 
overload, intervention not 
indicated  
Iron overload, 
intervention indicated  
Organ impairment (e.g., 
endocrinopathy, 
cardiopathy) 
Death 
Leukocytes (total WBC) 
Leukocytes 
<LLN – 3000/mm3 
<LLN – 3.0 x 109 /L  
<3000 – 2000/mm3 
<3.0 – 2.0 x 109 /L 
<2000 – 1000/mm3 
<2.0 – 1.0 x 109 /L 
<1000/mm3  
<1.0 x 109 /L 
Death 
Lymphopenia  
Lymphopenia 
<LLN – 800/mm3 
<LLN x 0.8 – 109 /L 
<800 – 500/mm3 
<0.8 – 0.5 x 109 /L 
<500 – 200 mm3 
<0.5 – 0.2 x 109 /L 
<200/mm3 
<0.2 x 109 /L 
Death 
Myelodysplasia 
Myelodysplasia 
— 
— 
Abnormal marrow 
cytogenetics (marrow 
blasts ≤5%)  
RAEB or RAEB-T 
(marrow blasts >5%) 
Death 
Neutrophils/granulocytes 
(ANC/AGC) 
Neutrophils 
<LLN – 1500/mm3  
<LLN – 1.5 x 109 /L 
<1500 – 1000/mm3 
<1.5 – 1.0 x 109 /L  
<1000 – 500/mm3 
<1.0 – 0.5 x 109 /L 
<500/mm3 
<0.5 x 109 /L 
Death 
Platelets 
Platelets 
<LLN – 75,000/mm3 
<LLN – 75.0 x 109 /L 
<75,000 – 50,000/mm3 
<75.0 – 50.0 x 109 /L 
<50,000 – 25,000/mm3  
<50.0 – 25.0 x 109 /L 
<25,000/mm3  
<25.0 x 109 /L 
Death 
Splenic function 
Splenic function 
Incidental findings (e.g., 
Howell-Jolly bodies) 
Prophylactic antibiotics 
indicated 
—  
Life-threatening 
consequences 
Death 
Blood/Bone Marrow – 
Other (Specify, __) 
Blood – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Page 103
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
CARDIAC ARRHYTHMIA 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 5 - 
March 31, 2003, Publish Date: August 9, 2006 
Conduction abnormality/ 
atrioventricular heart 
block  
– Select:  
Conduction abnormality 
– Select 
Asymptomatic, 
intervention not indicated 
– Asystole 
– AV Block-First degree 
– AV Block-Second degree Mobitz Type I (Wenckebach)  
– AV Block-Second degree Mobitz Type II 
– AV Block-Third degree (Complete AV block) 
– Conduction abnormality NOS 
– Sick Sinus Syndrome  
– Stokes-Adams Syndrome 
– Wolff-Parkinson-White Syndrome 
Non-urgent medical 
intervention indicated 
Incompletely controlled 
medically or controlled  
with device (e.g., 
pacemaker) 
Life-threatening (e.g., 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
Death 
Palpitations 
Palpitations 
Present 
Present with associated 
symptoms (e.g., 
lightheadedness, 
shortness of breath) 
— 
— 
— 
REMARK: Grade palpitations only in the absence of a documented arrhythmia. 
Prolonged QTc interval 
Prolonged QTc 
QTc >0.45 – 0.47 second 
 QTc >0.47 – 0.50 
second; ≥0.06 second 
above baseline 
QTc >0.50 second 
QTc >0.50 second; life-
threatening signs or 
symptoms (e.g., 
arrhythmia, CHF, 
hypotension, shock 
syncope); Torsade de 
pointes 
Death 
Supraventricular and 
nodal arrhythmia  
– Select: 
Supraventricular 
arrhythmia – Select 
Asymptomatic, 
intervention not indicated 
Non-urgent medical 
intervention indicated 
– Atrial fibrillation 
– Atrial flutter  
– Atrial tachycardia/Paroxysmal Atrial Tachycardia 
– Nodal/Junctional 
– Sinus arrhythmia  
– Sinus bradycardia 
– Sinus tachycardia  
– Supraventricular arrhythmia NOS 
– Supraventricular extrasystoles (Premature Atrial Contractions; Premature Nodal/Junctional Contractions) 
– Supraventricular tachycardia 
Symptomatic and 
incompletely controlled 
medically, or controlled 
with device (e.g., 
pacemaker) 
Life-threatening (e.g., 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
Death 
NAVIGATION NOTE: Syncope is graded as Syncope (fainting) in the NEUROLOGY CATEGORY. 
Page 104
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
CARDIAC ARRHYTHMIA 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 6 - 
March 31, 2003, Publish Date: August 9, 2006 
Vasovagal episode 
Vasovagal episode 
— 
Present without loss of 
consciousness 
Present with loss of 
consciousness 
Life-threatening 
consequences  
Death 
Ventricular arrhythmia 
– Select: 
Ventricular arrhythmia 
– Select 
– Bigeminy 
– Idioventricular rhythm 
– PVCs 
– Torsade de pointes 
– Trigeminy 
– Ventricular arrhythmia NOS 
– Ventricular fibrillation  
– Ventricular flutter 
– Ventricular tachycardia 
Asymptomatic, no 
intervention indicated 
Non-urgent medical 
intervention indicated 
Symptomatic and 
incompletely controlled 
medically or controlled 
with device (e.g., 
defibrillator) 
Life-threatening (e.g., 
arrhythmia associated 
with CHF, hypotension, 
syncope, shock) 
Death 
Cardiac Arrhythmia  
– Other (Specify, __) 
Cardiac Arrhythmia – 
Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling  
Death 
Page 105
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
CARDIAC GENERAL 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 7 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Angina is graded as Cardiac ischemia/infarction in the CARDIAC GENERAL CATEGORY. 
Cardiac 
ischemia/infarction 
Cardiac 
ischemia/infarction 
Asymptomatic arterial 
narrowing without 
ischemia 
Asymptomatic and testing 
suggesting ischemia; 
stable angina  
Symptomatic and testing 
consistent with ischemia; 
unstable angina; 
intervention indicated 
Acute myocardial 
infarction 
Death 
Cardiac troponin I (cTnI) 
cTnI 
— 
— 
Levels consistent with 
unstable angina as 
defined by the 
manufacturer 
Levels consistent with 
myocardial infarction as 
defined by the 
manufacturer 
Death 
Cardiac troponin T (cTnT) 
cTnT 
0.03 – <0.05 ng/mL 
0.05 – <0.1 ng/mL 
0.1 – <0.2 ng/mL 
0.2 ng/mL 
Death 
Cardiopulmonary arrest, 
cause unknown 
(non-fatal) 
Cardiopulmonary arrest 
— 
— 
— 
Life-threatening  
— 
REMARK: Grade 4 (non-fatal) is the only appropriate grade. CTCAE provides three alternatives for reporting Death: 
1. A CTCAE term associated with Grade 5.  
2. A CTCAE 'Other (Specify, __)’ within any CATEGORY. 
3. Death not associated with CTCAE term – Select in the DEATH CATEGORY. 
NAVIGATION NOTE: Chest pain (non-cardiac and non-pleuritic) is graded as Pain – Select in the PAIN CATEGORY. 
NAVIGATION NOTE: CNS ischemia is graded as CNS cerebrovascular ischemia in the NEUROLOGY CATEGORY. 
Hypertension 
Hypertension 
Asymptomatic, transient 
(<24 hrs) increase by >20 
mmHg (diastolic) or to 
>150/100 if previously 
WNL; intervention not 
indicated  
Pediatric: 
Asymptomatic, transient 
(<24 hrs) BP increase 
>ULN; intervention not 
indicated 
Recurrent or persistent 
(≥24 hrs) or symptomatic 
increase by >20 mmHg 
(diastolic) or to >150/100 
if previously WNL; 
monotherapy may be 
indicated  
Pediatric: 
Recurrent or persistent 
(≥24 hrs) BP >ULN; 
monotherapy may be 
indicated 
Requiring more than one 
drug or more intensive 
therapy than previously 
Pediatric: 
Same as adult 
Life-threatening 
consequences (e.g., 
hypertensive crisis) 
Pediatric: 
Same as adult 
Death 
REMARK: Use age and gender-appropriate normal values >95th percentile ULN for pediatric patients. 
Page 106
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
CARDIAC GENERAL 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 8 - 
March 31, 2003, Publish Date: August 9, 2006 
Hypotension 
Hypotension 
Changes, intervention not 
indicated 
Brief (<24 hrs) fluid 
replacement or other 
therapy; no physiologic 
consequences 
Sustained (≥24 hrs) 
therapy, resolves without 
persisting physiologic 
consequences 
Shock (e.g., acidemia; 
impairment of vital organ 
function)  
Death 
ALSO CONSIDER: Syncope (fainting). 
Left ventricular diastolic 
dysfunction 
Left ventricular diastolic 
dysfunction 
Asymptomatic diagnostic 
finding; intervention not 
indicated 
Asymptomatic, 
intervention indicated 
Symptomatic CHF 
responsive to intervention 
Refractory CHF, poorly 
controlled; intervention 
such as ventricular assist 
device or heart transplant 
indicated  
Death 
Left ventricular systolic 
dysfunction 
Left ventricular systolic 
dysfunction 
Asymptomatic, resting 
ejection fraction (EF)  
<60 – 50%; shortening 
fraction (SF) <30 – 24% 
Asymptomatic, resting  
EF <50 – 40%; 
SF <24 – 15% 
Symptomatic CHF 
responsive to 
intervention; 
EF <40 – 20% 
SF <15% 
Refractory CHF or poorly 
controlled; EF <20%; 
intervention such as 
ventricular assist device, 
ventricular reduction 
surgery, or heart 
transplant indicated 
Death 
NAVIGATION NOTE: Myocardial infarction is graded as Cardiac ischemia/infarction in the CARDIAC GENERAL CATEGORY. 
Myocarditis 
Myocarditis 
— 
— 
CHF responsive to 
intervention 
Severe or refractory CHF 
Death 
Pericardial effusion 
(non-malignant) 
Pericardial effusion 
Asymptomatic effusion  
—  
Effusion with physiologic 
consequences 
Life-threatening 
consequences (e.g., 
tamponade); emergency 
intervention indicated 
Death 
Pericarditis 
Pericarditis 
Asymptomatic, ECG or 
physical exam (rub) 
changes consistent with 
pericarditis 
Symptomatic pericarditis 
(e.g., chest pain) 
Pericarditis with 
physiologic 
consequences (e.g., 
pericardial constriction) 
Life-threatening 
consequences; 
emergency intervention 
indicated 
Death 
NAVIGATION NOTE: Pleuritic pain is graded as Pain – Select in the PAIN CATEGORY. 
Pulmonary hypertension 
Pulmonary hypertension 
Asymptomatic without 
therapy 
Asymptomatic, therapy 
indicated 
Symptomatic 
hypertension, responsive 
to therapy 
Symptomatic 
hypertension, poorly 
controlled 
Death 
Restrictive 
cardiomyopathy  
Restrictive 
cardiomyopathy  
Asymptomatic, therapy 
not indicated 
Asymptomatic, therapy 
indicated 
Symptomatic CHF 
responsive to intervention 
Refractory CHF, poorly 
controlled; intervention 
such as ventricular assist 
device, or heart 
transplant indicated  
Death 
Page 107
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
CARDIAC GENERAL 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 9 - 
March 31, 2003, Publish Date: August 9, 2006 
Right ventricular 
dysfunction 
(cor pulmonale) 
Right ventricular 
dysfunction 
Asymptomatic without 
therapy 
Asymptomatic, therapy 
indicated 
Symptomatic cor 
pulmonale, responsive to 
intervention 
Symptomatic cor 
pulmonale poorly 
controlled; intervention 
such as ventricular assist 
device, or heart 
transplant indicated  
Death 
Valvular heart disease 
Valvular heart disease 
Asymptomatic valvular 
thickening with or without 
mild valvular regurgitation 
or stenosis; treatment 
other than endocarditis 
prophylaxis not indicated 
Asymptomatic; moderate 
regurgitation or stenosis 
by imaging 
Symptomatic; severe 
regurgitation or stenosis; 
symptoms controlled with 
medical therapy 
Life-threatening; 
disabling; intervention 
(e.g., valve replacement, 
valvuloplasty) indicated 
Death 
Cardiac General – Other 
(Specify, __) 
Cardiac General – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Page 108
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
COAGULATION 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 10 - 
March 31, 2003, Publish Date: August 9, 2006 
DIC (disseminated 
intravascular coagulation) 
DIC 
— 
Laboratory findings with 
no bleeding 
Laboratory findings and 
bleeding 
Laboratory findings, life-
threatening or disabling 
consequences (e.g., CNS 
hemorrhage, organ 
damage, or 
hemodynamically 
significant blood loss) 
Death 
REMARK: DIC (disseminated intravascular coagulation) must have increased fibrin split products or D-dimer.  
ALSO CONSIDER: Platelets. 
 
Fibrinogen  
Fibrinogen 
<1.0 – 0.75 x LLN 
or <25% decrease from 
baseline 
<0.75 – 0.5 x LLN 
or 25 – <50% decrease 
from baseline 
<0.5 – 0.25 x LLN 
or 50 – <75% decrease 
from baseline 
<0.25 x LLN  
or 75% decrease from 
baseline or absolute 
value <50 mg/dL  
Death 
REMARK: Use % decrease only when baseline is <LLN (local laboratory value). 
INR (International 
Normalized Ratio of 
prothrombin time) 
INR 
 
>1 – 1.5 x ULN 
>1.5 – 2 x ULN 
>2 x ULN 
— 
— 
ALSO CONSIDER: Hemorrhage, CNS; Hemorrhage, GI – Select; Hemorrhage, GU – Select; Hemorrhage, pulmonary/upper respiratory – Select. 
PTT (Partial 
Thromboplastin Time)  
PTT 
>1 – 1.5 x ULN 
>1.5 – 2 x ULN 
>2 x ULN 
— 
— 
ALSO CONSIDER: Hemorrhage, CNS; Hemorrhage, GI – Select; Hemorrhage, GU – Select; Hemorrhage, pulmonary/upper respiratory – Select. 
Thrombotic 
microangiopathy (e.g., 
thrombotic 
thrombocytopenic 
purpura [TTP] or 
hemolytic uremic 
syndrome [HUS]) 
Thrombotic 
microangiopathy 
Evidence of RBC 
destruction 
(schistocytosis) without 
clinical consequences 
— 
Laboratory findings 
present with clinical 
consequences (e.g., renal 
insufficiency, petechiae) 
Laboratory findings and 
life-threatening or 
disabling consequences, 
(e.g., CNS hemorrhage/ 
bleeding or thrombosis/ 
embolism or renal failure) 
Death 
REMARK: Must have microangiopathic changes on blood smear (e.g., schistocytes, helmet cells, red cell fragments). 
ALSO CONSIDER: Creatinine; Hemoglobin; Platelets. 
Coagulation – Other 
(Specify, __) 
Coagulation – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Page 109
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
CONSTITUTIONAL SYMPTOMS 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 11 - 
March 31, 2003, Publish Date: August 9, 2006 
Fatigue  
(asthenia, lethargy, 
malaise) 
Fatigue 
Mild fatigue over baseline 
Moderate or causing 
difficulty performing some 
ADL 
Severe fatigue interfering 
with ADL 
Disabling 
— 
Fever  
(in the absence of 
neutropenia, where 
neutropenia is defined as 
ANC <1.0 x 109/L) 
Fever 
38.0 – 39.0°C  
(100.4 – 102.2°F) 
>39.0 – 40.0°C 
(102.3 – 104.0°F)  
>40.0°C 
(>104.0°F) for ≤24 hrs  
>40.0°C 
(>104.0°F) for >24 hrs 
Death 
REMARK: The temperature measurements listed are oral or tympanic. 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever).  
NAVIGATION NOTE: Hot flashes are graded as Hot flashes/flushes in the ENDOCRINE CATEGORY. 
Hypothermia 
Hypothermia 
— 
35 – >32°C 
95 – >89.6°F 
32 – >28°C  
89.6 – >82.4° F 
≤28 °C  
82.4°F or life-threatening 
consequences (e.g., 
coma, hypotension, 
pulmonary edema, 
acidemia, ventricular 
fibrillation) 
Death 
Insomnia 
Insomnia 
Occasional difficulty 
sleeping, not interfering 
with function 
Difficulty sleeping, 
interfering with function 
but not interfering with 
ADL 
Frequent difficulty 
sleeping, interfering with 
ADL 
Disabling 
— 
REMARK: If pain or other symptoms interfere with sleep, do NOT grade as insomnia. Grade primary event(s) causing insomnia. 
Obesity2 
Obesity 
— 
BMI 25 – 29.9 kg/m2 
BMI 30 – 39.99 kg/m2 
BMI ≥40 kg/m2 
— 
REMARK: BMI = (weight [kg]) / (height [m])2 
Odor  
(patient odor) 
Patient odor 
Mild odor 
Pronounced odor 
— 
— 
— 
Rigors/chills 
Rigors/chills 
Mild 
Moderate, narcotics 
indicated 
Severe or prolonged, not 
responsive to narcotics 
— 
— 
                                            
2 NHLBI Obesity Task Force. "Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults," The Evidence Report, Obes Res 6:51S-
209S, 1998.  
Page 110
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
CONSTITUTIONAL SYMPTOMS 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 12 - 
March 31, 2003, Publish Date: August 9, 2006 
Sweating  
(diaphoresis) 
Sweating  
Mild and occasional 
Frequent or drenching 
— 
— 
— 
ALSO CONSIDER: Hot flashes/flushes.  
Weight gain  
Weight gain 
5 – <10% of baseline 
10 – <20% of baseline 
≥20% of baseline 
— 
— 
REMARK: Edema, depending on etiology, is graded in the CARDIAC GENERAL or LYMPHATICS CATEGORIES. 
ALSO CONSIDER: Ascites (non-malignant); Pleural effusion (non-malignant). 
Weight loss 
Weight loss 
5 to <10% from baseline; 
intervention not indicated 
10 – <20% from baseline; 
nutritional support 
indicated 
≥20% from baseline; tube 
feeding or TPN indicated 
— 
— 
Constitutional Symptoms 
– Other (Specify, __) 
Constitutional Symptoms 
– Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Page 111
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
DEATH 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 13 - 
March 31, 2003, Publish Date: August 9, 2006 
Death not associated with 
CTCAE term  
– Select: 
Death not associated with 
CTCAE term – Select 
– Death NOS 
– Disease progression NOS 
– Multi-organ failure 
– Sudden death 
— 
— 
— 
— 
Death 
REMARK: Grade 5 is the only appropriate grade. 'Death not associated with CTCAE term – Select' is to be used where a death: 
1. Cannot be attributed to a CTCAE term associated with Grade 5. 
2. Cannot be reported within any CATEGORY using a CTCAE 'Other (Specify, __)’.  
Page 112
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
DERMATOLOGY/SKIN 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 14 - 
March 31, 2003, Publish Date: August 9, 2006 
Atrophy, skin 
Atrophy, skin 
Detectable 
Marked 
— 
— 
— 
Atrophy, subcutaneous 
fat 
Atrophy, subcutaneous 
fat 
Detectable 
Marked 
— 
— 
— 
ALSO CONSIDER: Induration/fibrosis (skin and subcutaneous tissue). 
Bruising  
(in absence of Grade 3 or 
4 thrombocytopenia) 
Bruising  
Localized or in a 
dependent area 
Generalized 
— 
— 
— 
Burn 
Burn 
Minimal symptoms; 
intervention not indicated  
Medical intervention; 
minimal debridement 
indicated  
Moderate to major 
debridement or 
reconstruction indicated  
Life-threatening 
consequences 
Death 
REMARK: Burn refers to all burns including radiation, chemical, etc. 
Cheilitis 
Cheilitis 
Asymptomatic 
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
— 
— 
Dry skin 
Dry skin 
Asymptomatic 
Symptomatic, not 
interfering with ADL 
Interfering with ADL 
— 
— 
Flushing 
Flushing 
Asymptomatic 
Symptomatic 
— 
— 
— 
Hair loss/alopecia 
(scalp or body) 
Alopecia 
Thinning or patchy 
Complete 
— 
— 
— 
Hyperpigmentation 
Hyperpigmentation 
Slight or localized 
Marked or generalized 
— 
— 
— 
Hypopigmentation 
Hypopigmentation 
Slight or localized 
Marked or generalized 
— 
— 
— 
Induration/fibrosis 
(skin and subcutaneous 
tissue) 
Induration  
Increased density on 
palpation 
Moderate impairment of 
function not interfering 
with ADL; marked 
increase in density and 
firmness on palpation 
with or without minimal 
retraction 
Dysfunction interfering 
with ADL; very marked 
density, retraction or 
fixation 
— 
— 
ALSO CONSIDER: Fibrosis-cosmesis; Fibrosis-deep connective tissue.  
Injection site reaction/ 
extravasation changes 
Injection site reaction 
Pain; itching; erythema 
Pain or swelling, with 
inflammation or phlebitis 
Ulceration or necrosis 
that is severe; operative 
intervention indicated  
— 
— 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever); Ulceration. 
Page 113
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
DERMATOLOGY/SKIN 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 15 - 
March 31, 2003, Publish Date: August 9, 2006 
Nail changes 
Nail changes 
Discoloration; ridging 
(koilonychias); pitting 
Partial or complete loss of 
nail(s); pain in nailbed(s) 
Interfering with ADL  
— 
— 
NAVIGATION NOTE: Petechiae is graded as Petechiae/purpura (hemorrhage/bleeding into skin or mucosa) in the HEMORRHAGE/BLEEDING CATEGORY. 
Photosensitivity 
Photosensitivity 
Painless erythema 
Painful erythema 
Erythema with 
desquamation 
Life-threatening; disabling 
Death 
Pruritus/itching 
Pruritus 
Mild or localized 
Intense or widespread 
Intense or widespread 
and interfering with ADL  
— 
— 
ALSO CONSIDER: Rash/desquamation. 
Rash/desquamation  
Rash 
Macular or papular 
eruption or erythema 
without associated 
symptoms 
Macular or papular 
eruption or erythema with 
pruritus or other 
associated symptoms; 
localized desquamation 
or other lesions covering 
<50% of body surface 
area (BSA) 
Severe, generalized 
erythroderma or macular, 
papular or vesicular 
eruption; desquamation 
covering ≥50% BSA 
Generalized exfoliative, 
ulcerative, or bullous 
dermatitis 
Death 
REMARK: Rash/desquamation may be used for GVHD. 
Rash:  
acne/acneiform 
Acne 
Intervention not indicated  
Intervention indicated 
Associated with pain, 
disfigurement, ulceration, 
or desquamation 
— 
Death 
Rash:  
dermatitis associated with 
radiation  
– Select: 
– Chemoradiation 
– Radiation 
Dermatitis – Select  
Faint erythema or dry 
desquamation 
Moderate to brisk 
erythema; patchy moist 
desquamation, mostly 
confined to skin folds and 
creases; moderate 
edema 
Moist desquamation other 
than skin folds and 
creases; bleeding 
induced by minor trauma 
or abrasion 
Skin necrosis or 
ulceration of full thickness 
dermis; spontaneous 
bleeding from involved 
site  
Death 
Rash:  
erythema multiforme 
(e.g., Stevens-Johnson 
syndrome, toxic 
epidermal necrolysis) 
Erythema multiforme 
— 
Scattered, but not 
generalized eruption 
Severe (e.g., generalized 
rash or painful stomatitis); 
IV fluids, tube feedings, 
or TPN indicated 
Life-threatening; disabling 
Death 
Rash:  
hand-foot skin reaction 
Hand-foot 
Minimal skin changes or 
dermatitis (e.g., 
erythema) without pain  
Skin changes (e.g., 
peeling, blisters, 
bleeding, edema) or pain, 
not interfering with 
function  
Ulcerative dermatitis or 
skin changes with pain 
interfering with function  
— 
— 
Page 114
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
DERMATOLOGY/SKIN 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 16 - 
March 31, 2003, Publish Date: August 9, 2006 
Skin breakdown/ 
decubitus ulcer 
Decubitus  
— 
Local wound care; 
medical intervention 
indicated 
Operative debridement or 
other invasive 
intervention indicated 
(e.g., hyperbaric oxygen)  
Life-threatening 
consequences; major 
invasive intervention 
indicated (e.g., tissue 
reconstruction, flap, or 
grafting) 
Death 
REMARK: Skin breakdown/decubitus ulcer is to be used for loss of skin integrity or decubitus ulcer from pressure or as the result of operative or medical intervention. 
Striae 
Striae 
Mild 
Cosmetically significant 
— 
— 
— 
Telangiectasia 
Telangiectasia 
Few 
Moderate number 
Many and confluent 
— 
— 
Ulceration 
Ulceration 
— 
Superficial ulceration  
<2 cm size; local wound 
care; medical intervention 
indicated 
Ulceration ≥2 cm size; 
operative debridement, 
primary closure or other 
invasive intervention 
indicated (e.g., hyperbaric 
oxygen)  
Life-threatening 
consequences; major 
invasive intervention 
indicated (e.g., complete 
resection, tissue 
reconstruction, flap, or 
grafting) 
Death 
Urticaria  
(hives, welts, wheals) 
Urticaria 
Intervention not indicated 
Intervention indicated for 
<24 hrs 
Intervention indicated for 
≥24 hrs 
— 
— 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever). 
Wound complication, 
non-infectious  
Wound complication, 
non-infectious 
Incisional separation of  
≤25% of wound, no 
deeper than superficial 
fascia 
Incisional separation 
>25% of wound with local 
care; asymptomatic 
hernia 
Symptomatic hernia 
without evidence of 
strangulation; fascial 
disruption/dehiscence 
without evisceration; 
primary wound closure or 
revision by operative 
intervention indicated; 
hospitalization or 
hyperbaric oxygen 
indicated 
Symptomatic hernia with 
evidence of strangulation; 
fascial disruption with 
evisceration; major 
reconstruction flap, 
grafting, resection, or 
amputation indicated 
Death 
REMARK: Wound complication, non-infectious is to be used for separation of incision, hernia, dehiscence, evisceration, or second surgery for wound revision. 
Dermatology/Skin – Other 
(Specify, __) 
Dermatology – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Page 115
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
ENDOCRINE 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 17 - 
March 31, 2003, Publish Date: August 9, 2006 
Adrenal insufficiency 
Adrenal insufficiency 
Asymptomatic, 
intervention not indicated 
Symptomatic, intervention 
indicated 
Hospitalization  
Life-threatening; disabling 
Death 
REMARK: Adrenal insufficiency includes any of the following signs and symptoms: abdominal pain, anorexia, constipation, diarrhea, hypotension, pigmentation of mucous membranes, 
pigmentation of skin, salt craving, syncope (fainting), vitiligo, vomiting, weakness, weight loss. Adrenal insufficiency must be confirmed by laboratory studies (low cortisol frequently 
accompanied by low aldosterone). 
ALSO CONSIDER: Potassium, serum-high (hyperkalemia); Thyroid function, low (hypothyroidism). 
Cushingoid appearance 
(e.g., moon face, buffalo 
hump, centripetal obesity, 
cutaneous striae) 
Cushingoid  
— 
Present 
— 
— 
— 
ALSO CONSIDER: Glucose, serum-high (hyperglycemia); Potassium, serum-low (hypokalemia). 
Feminization of male 
Feminization of male 
— 
— 
Present 
— 
— 
NAVIGATION NOTE: Gynecomastia is graded in the SEXUAL/REPRODUCTIVE FUNCTION CATEGORY. 
Hot flashes/flushes3 
Hot flashes 
Mild  
Moderate  
Interfering with ADL 
— 
— 
Masculinization of female 
Masculinization of female 
— 
— 
Present 
— 
— 
Neuroendocrine: 
ACTH deficiency 
ACTH  
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL; hospitalization 
indicated 
Life-threatening 
consequences (e.g., 
severe hypotension) 
Death 
Neuroendocrine: 
ADH secretion 
abnormality (e.g., SIADH 
or low ADH) 
ADH 
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL 
Life-threatening 
consequences 
Death 
Neuroendocrine: 
gonadotropin secretion 
abnormality 
Gonadotropin 
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL; osteopenia; 
fracture; infertility 
— 
— 
Neuroendocrine:  
growth hormone 
secretion abnormality 
Growth hormone  
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
— 
— 
— 
Neuroendocrine:  
prolactin hormone 
secretion abnormality 
Prolactin  
Asymptomatic 
Symptomatic, not 
interfering with ADL; 
intervention indicated 
Symptoms interfering with 
ADL; amenorrhea; 
galactorrhea 
— 
Death 
                                            
3 Sloan JA, Loprinzi CL, Novotny PJ, Barton DL, Lavasseur BI, Windschitl HJ, "Methodologic Lessons Learned from Hot Flash Studies," J Clin Oncol 2001 Dec 1;19(23):4280-90 
Page 116
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
ENDOCRINE 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 18 - 
March 31, 2003, Publish Date: August 9, 2006 
Pancreatic endocrine:  
glucose intolerance 
Diabetes 
Asymptomatic, 
intervention not indicated 
Symptomatic; dietary 
modification or oral agent 
indicated 
Symptoms interfering with 
ADL; insulin indicated 
Life-threatening 
consequences (e.g., 
ketoacidosis, 
hyperosmolar non-ketotic 
coma)  
Death 
Parathyroid function, low 
(hypoparathyroidism) 
Hypoparathyroidism 
Asymptomatic, 
intervention not indicated 
Symptomatic; intervention 
indicated 
— 
— 
— 
Thyroid function, high 
(hyperthyroidism, 
thyrotoxicosis) 
Hyperthyroidism  
Asymptomatic, 
intervention not indicated 
Symptomatic, not 
interfering with ADL; 
thyroid suppression 
therapy indicated 
Symptoms interfering with 
ADL; hospitalization 
indicated  
Life-threatening 
consequences (e.g., 
thyroid storm) 
Death 
Thyroid function, low 
(hypothyroidism) 
Hypothyroidism 
Asymptomatic, 
intervention not indicated 
Symptomatic, not 
interfering with ADL; 
thyroid replacement 
indicated 
Symptoms interfering with 
ADL; hospitalization 
indicated  
Life-threatening 
myxedema coma 
Death 
Endocrine – Other  
(Specify, __) 
Endocrine – Other  
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Page 117
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
GASTROINTESTINAL 
Page 1 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 19 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Abdominal pain or cramping is graded as Pain – Select in the PAIN CATEGORY. 
Anorexia 
Anorexia 
Loss of appetite without 
alteration in eating habits 
Oral intake altered 
without significant weight 
loss or malnutrition; oral 
nutritional supplements 
indicated 
Associated with 
significant weight loss or 
malnutrition (e.g., 
inadequate oral caloric 
and/or fluid intake); IV 
fluids, tube feedings or 
TPN indicated 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Weight loss. 
Ascites (non-malignant) 
Ascites 
Asymptomatic 
Symptomatic, medical 
intervention indicated 
Symptomatic, invasive 
procedure indicated 
Life-threatening 
consequences 
Death 
REMARK: Ascites (non-malignant) refers to documented non-malignant ascites or unknown etiology, but unlikely malignant, and includes chylous ascites. 
Colitis 
Colitis 
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain; mucus 
or blood in stool 
Abdominal pain, fever, 
change in bowel habits 
with ileus; peritoneal 
signs 
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis, toxic 
megacolon) 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select.  
Constipation 
Constipation 
Occasional or intermittent 
symptoms; occasional 
use of stool softeners, 
laxatives, dietary 
modification, or enema 
Persistent symptoms with 
regular use of laxatives 
or enemas indicated 
Symptoms interfering 
with ADL; obstipation 
with manual evacuation 
indicated  
Life-threatening 
consequences (e.g., 
obstruction, toxic 
megacolon) 
Death 
ALSO CONSIDER: Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation); Obstruction, GI – Select. 
Dehydration 
Dehydration 
Increased oral fluids 
indicated; dry mucous 
membranes; diminished 
skin turgor 
IV fluids indicated <24 
hrs 
IV fluids indicated ≥24 hrs 
Life-threatening 
consequences (e.g., 
hemodynamic collapse) 
Death 
ALSO CONSIDER: Diarrhea; Hypotension; Vomiting. 
Dental:  
dentures or prosthesis 
Dentures  
Minimal discomfort, no 
restriction in activities  
Discomfort preventing 
use in some activities 
(e.g., eating), but not 
others (e.g., speaking) 
Unable to use dentures 
or prosthesis at any time 
— 
— 
Page 118
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
GASTROINTESTINAL 
Page 2 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 20 - 
March 31, 2003, Publish Date: August 9, 2006 
Dental:  
periodontal disease  
Periodontal  
Gingival recession or 
gingivitis; limited bleeding 
on probing; mild local 
bone loss 
Moderate gingival 
recession or gingivitis; 
multiple sites of bleeding 
on probing; moderate 
bone loss 
Spontaneous bleeding; 
severe bone loss with or 
without tooth loss; 
osteonecrosis of maxilla 
or mandible  
— 
— 
REMARK: Severe periodontal disease leading to osteonecrosis is graded as Osteonecrosis (avascular necrosis) in the MUSCULOSKELETAL CATEGORY. 
Dental: 
teeth  
Teeth 
Surface stains; dental 
caries; restorable, without 
extractions 
Less than full mouth 
extractions; tooth fracture 
or crown amputation or 
repair indicated 
Full mouth extractions 
indicated 
— 
— 
Dental:  
teeth development 
Teeth development 
Hypoplasia of tooth or 
enamel not interfering 
with function 
Functional impairment 
correctable with oral 
surgery 
Maldevelopment with 
functional impairment not 
surgically correctable 
— 
— 
Diarrhea 
Diarrhea 
Increase of <4 stools per 
day over baseline; mild 
increase in ostomy output 
compared to baseline 
Increase of 4 – 6 stools 
per day over baseline; IV 
fluids indicated <24hrs; 
moderate increase in 
ostomy output compared 
to baseline; not 
interfering with ADL 
Increase of ≥7 stools per 
day over baseline; 
incontinence; IV fluids 
≥24 hrs; hospitalization; 
severe increase in 
ostomy output compared 
to baseline; interfering 
with ADL 
Life-threatening 
consequences (e.g., 
hemodynamic collapse) 
Death 
REMARK: Diarrhea includes diarrhea of small bowel or colonic origin, and/or ostomy diarrhea. 
ALSO CONSIDER: Dehydration; Hypotension. 
Distension/bloating, 
abdominal 
Distension 
Asymptomatic  
Symptomatic, but not 
interfering with GI 
function 
Symptomatic, interfering 
with GI function 
— 
— 
ALSO CONSIDER: Ascites (non-malignant); Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation); Obstruction, GI – Select.  
Page 119
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
GASTROINTESTINAL 
Page 3 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 21 - 
March 31, 2003, Publish Date: August 9, 2006 
Dry mouth/salivary gland 
(xerostomia) 
Dry mouth 
Symptomatic (dry or thick 
saliva) without significant 
dietary alteration; 
unstimulated saliva flow 
>0.2 ml/min 
Symptomatic and 
significant oral intake 
alteration (e.g., copious 
water, other lubricants, 
diet limited to purees 
and/or soft, moist foods); 
unstimulated saliva 
0.1 to 0.2 ml/min 
Symptoms leading to 
inability to adequately 
aliment orally; IV fluids, 
tube feedings, or TPN 
indicated; unstimulated 
saliva <0.1 ml/min 
— 
— 
REMARK: Dry mouth/salivary gland (xerostomia) includes descriptions of grade using both subjective and objective assessment parameters. Record this event consistently throughout 
a patient’s participation on study. If salivary flow measurements are used for initial assessment, subsequent assessments must use salivary flow. 
ALSO CONSIDER: Salivary gland changes/saliva.  
Dysphagia 
(difficulty swallowing) 
Dysphagia 
Symptomatic, able to eat 
regular diet  
Symptomatic and altered 
eating/swallowing (e.g., 
altered dietary habits, 
oral supplements); IV 
fluids indicated <24 hrs 
Symptomatic and 
severely altered 
eating/swallowing (e.g., 
inadequate oral caloric or 
fluid intake); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences (e.g., 
obstruction, perforation) 
 
Death 
REMARK: Dysphagia (difficulty swallowing) is to be used for swallowing difficulty from oral, pharyngeal, esophageal, or neurologic origin. Dysphagia requiring dilation is graded as 
Stricture/stenosis (including anastomotic), GI – Select. 
ALSO CONSIDER: Dehydration; Esophagitis. 
Enteritis  
(inflammation of the small 
bowel) 
Enteritis 
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain; mucus 
or blood in stool 
Abdominal pain, fever, 
change in bowel habits 
with ileus; peritoneal 
signs 
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis) 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select; Typhlitis (cecal inflammation).  
Esophagitis 
Esophagitis 
Asymptomatic pathologic, 
radiographic, or 
endoscopic findings only 
Symptomatic; altered 
eating/swallowing (e.g., 
altered dietary habits, 
oral supplements); IV 
fluids indicated <24 hrs 
Symptomatic and 
severely altered 
eating/swallowing (e.g., 
inadequate oral caloric or 
fluid intake); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences 
Death 
REMARK: Esophagitis includes reflux esophagitis.  
ALSO CONSIDER: Dysphagia (difficulty swallowing). 
Page 120
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
GASTROINTESTINAL 
Page 4 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 22 - 
March 31, 2003, Publish Date: August 9, 2006 
Fistula, GI 
– Select: 
Fistula, GI – Select  
– Abdomen NOS 
– Anus 
– Biliary tree  
– Colon/cecum/appendix 
– Duodenum 
– Esophagus 
– Gallbladder  
– Ileum 
– Jejunum 
– Oral cavity 
– Pancreas 
– Pharynx 
– Rectum 
– Salivary gland  
– Small bowel NOS 
– Stomach 
Asymptomatic, 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, diarrhea, 
or GI fluid loss); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered GI 
function (e.g., altered 
dietary habits, diarrhea, 
or GI fluid loss); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences  
Death 
REMARK: A fistula is defined as an abnormal communication between two body cavities, potential spaces, and/or the skin. The site indicated for a fistula should be the site from which 
the abnormal process is believed to have originated. For example, a tracheo-esophageal fistula arising in the context of a resected or irradiated esophageal cancer is graded as 
Fistula, GI – esophagus. 
Flatulence 
Flatulence 
Mild 
Moderate 
— 
— 
— 
Gastritis (including bile 
reflux gastritis) 
Gastritis 
Asymptomatic 
radiographic or 
endoscopic findings only 
Symptomatic; altered 
gastric function (e.g., 
inadequate oral caloric or 
fluid intake); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered gastric 
function (e.g., inadequate 
oral caloric or fluid 
intake); IV fluids, tube 
feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., gastrectomy)  
Death 
ALSO CONSIDER: Hemorrhage, GI – Select; Ulcer, GI – Select. 
NAVIGATION NOTE: Head and neck soft tissue necrosis is graded as Soft tissue necrosis – Select in the MUSCULOSKELETAL/SOFT TISSUE CATEGORY. 
Heartburn/dyspepsia 
Heartburn 
Mild 
Moderate 
Severe 
— 
— 
Hemorrhoids 
Hemorrhoids 
Asymptomatic 
Symptomatic; banding or 
medical intervention 
indicated 
Interfering with ADL; 
interventional radiology, 
endoscopic, or operative 
intervention indicated 
Life-threatening 
consequences 
Death 
Page 121
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
GASTROINTESTINAL 
Page 5 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 23 - 
March 31, 2003, Publish Date: August 9, 2006 
Ileus, GI (functional 
obstruction of bowel, i.e., 
neuroconstipation) 
Ileus 
Asymptomatic, 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered GI 
function; IV fluids, tube 
feeding, or TPN indicated 
≥24 hrs 
Life-threatening 
consequences 
Death 
REMARK: Ileus, GI is to be used for altered upper or lower GI function (e.g., delayed gastric or colonic emptying). 
ALSO CONSIDER: Constipation; Nausea; Obstruction, GI – Select; Vomiting. 
Incontinence, anal 
Incontinence, anal 
Occasional use of pads 
required 
Daily use of pads 
required 
Interfering with ADL; 
operative intervention 
indicated 
Permanent bowel 
diversion indicated 
Death 
REMARK: Incontinence, anal is to be used for loss of sphincter control as sequelae of operative or therapeutic intervention. 
Leak (including 
anastomotic), GI 
– Select: 
– Biliary tree 
– Esophagus 
– Large bowel 
– Leak NOS 
– Pancreas 
– Pharynx 
– Rectum 
– Small bowel  
– Stoma 
– Stomach 
Leak, GI – Select  
Asymptomatic 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and 
interfering with GI 
function; invasive or 
endoscopic intervention 
indicated  
Life-threatening 
consequences 
Death 
REMARK: Leak (including anasomotic), GI – Select is to be used for clinical signs/symptoms or radiographic confirmation of anastomotic or conduit leak (e.g., biliary, esophageal, 
intestinal, pancreatic, pharyngeal, rectal), but without development of fistula. 
Malabsorption  
Malabsorption 
— 
Altered diet; oral 
therapies indicated (e.g., 
enzymes, medications, 
dietary supplements)  
Inability to aliment 
adequately via GI tract 
(i.e., TPN indicated) 
Life-threatening 
consequences 
Death 
Page 122
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
GASTROINTESTINAL 
Page 6 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 24 - 
March 31, 2003, Publish Date: August 9, 2006 
Mucositis/stomatitis 
(clinical exam)  
– Select: 
– Anus 
– Esophagus 
– Large bowel 
– Larynx 
– Oral cavity 
– Pharynx 
– Rectum 
– Small bowel 
– Stomach 
– Trachea 
Mucositis (clinical exam) 
– Select  
Erythema of the mucosa 
Patchy ulcerations or 
pseudomembranes  
Confluent ulcerations or 
pseudomembranes; 
bleeding with minor 
trauma 
Tissue necrosis; 
significant spontaneous 
bleeding; life-threatening 
consequences 
Death 
REMARK: Mucositis/stomatitis (functional/symptomatic) may be used for mucositis of the upper aero-digestive tract caused by radiation, agents, or GVHD.  
Mucositis/stomatitis 
(functional/symptomatic)  
– Select: 
– Anus 
– Esophagus 
– Large bowel 
– Larynx 
– Oral cavity 
– Pharynx 
– Rectum 
– Small bowel 
– Stomach 
– Trachea 
Mucositis (functional/ 
symptomatic) – Select  
Upper aerodigestive tract 
sites: Minimal symptoms, 
normal diet; minimal 
respiratory symptoms but 
not interfering with 
function 
Lower GI sites: 
Minimal discomfort, 
intervention not indicated 
Upper aerodigestive tract 
sites: Symptomatic but 
can eat and swallow 
modified diet; respiratory 
symptoms interfering with 
function but not 
interfering with ADL 
Lower GI sites:  
Symptomatic, medical 
intervention indicated but 
not interfering with ADL 
Upper aerodigestive tract 
sites: Symptomatic and 
unable to adequately 
aliment or hydrate orally; 
respiratory symptoms 
interfering with ADL 
Lower GI sites: 
Stool incontinence or 
other symptoms 
interfering with ADL 
Symptoms associated 
with life-threatening 
consequences  
Death 
Nausea 
Nausea 
Loss of appetite without 
alteration in eating habits 
Oral intake decreased 
without significant weight 
loss, dehydration or 
malnutrition; IV fluids 
indicated <24 hrs 
Inadequate oral caloric or 
fluid intake; IV fluids, tube 
feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Anorexia; Vomiting. 
Page 123
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
GASTROINTESTINAL 
Page 7 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 25 - 
March 31, 2003, Publish Date: August 9, 2006 
Necrosis, GI 
– Select:  
Necrosis, GI – Select  
– Anus 
– Colon/cecum/appendix 
– Duodenum 
– Esophagus 
– Gallbladder 
– Hepatic 
– Ileum 
– Jejunum 
– Oral 
– Pancreas 
– Peritoneal cavity 
– Pharynx  
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
— 
— 
Inability to aliment 
adequately by GI tract 
(e.g., requiring enteral or 
parenteral nutrition); 
interventional radiology, 
endoscopic, or operative 
intervention indicated  
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., total colectomy)  
Death 
ALSO CONSIDER: Visceral arterial ischemia (non-myocardial). 
Obstruction, GI 
– Select: 
– Cecum 
– Colon 
– Duodenum 
– Esophagus 
– Gallbladder 
– Ileum 
– Jejunum 
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
Obstruction, GI – Select 
Asymptomatic 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, vomiting, 
diarrhea, or GI fluid loss); 
IV fluids indicated <24 
hrs 
Symptomatic and 
severely altered GI 
function (e.g., altered 
dietary habits, vomiting, 
diarrhea, or GI fluid loss); 
IV fluids, tube feedings, 
or TPN indicated ≥24 hrs; 
operative intervention 
indicated 
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., total colectomy)  
Death 
NAVIGATION NOTE: Operative injury is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY CATEGORY. 
NAVIGATION NOTE: Pelvic pain is graded as Pain – Select in the PAIN CATEGORY. 
Page 124
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
GASTROINTESTINAL 
Page 8 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 26 - 
March 31, 2003, Publish Date: August 9, 2006 
Perforation, GI 
– Select: 
– Appendix 
– Biliary tree 
– Cecum 
– Colon 
– Duodenum 
– Esophagus 
– Gallbladder 
– Ileum 
– Jejunum 
– Rectum 
– Small bowel NOS 
– Stomach 
Perforation, GI – Select 
Asymptomatic 
radiographic findings only 
Medical intervention 
indicated; IV fluids 
indicated <24 hrs 
IV fluids, tube feedings, 
or TPN indicated ≥24 hrs; 
operative intervention 
indicated 
Life-threatening 
consequences 
Death 
Proctitis  
Proctitis 
Rectal discomfort, 
intervention not indicated 
Symptoms not interfering 
with ADL; medical 
intervention indicated  
Stool incontinence or 
other symptoms 
interfering with ADL; 
operative intervention 
indicated 
Life-threatening 
consequences (e.g., 
perforation) 
Death 
Prolapse of stoma, GI 
Prolapse of stoma, GI 
Asymptomatic  
Extraordinary local care 
or maintenance; minor 
revision indicated 
Dysfunctional stoma; 
major revision indicated  
Life-threatening 
consequences 
Death 
REMARK: Other stoma complications may be graded as Fistula, GI – Select; Leak (including anastomotic), GI – Select; Obstruction, GI – Select; Perforation, GI – Select; 
Stricture/stenosis (including anastomotic), GI – Select. 
NAVIGATION NOTE: Rectal or perirectal pain (proctalgia) is graded as Pain – Select in the PAIN CATEGORY.  
Salivary gland 
changes/saliva 
Salivary gland changes 
Slightly thickened saliva; 
slightly altered taste (e.g., 
metallic) 
Thick, ropy, sticky saliva; 
markedly altered taste; 
alteration in diet 
indicated; secretion-
induced symptoms not 
interfering with ADL 
Acute salivary gland 
necrosis; severe 
secretion-induced 
symptoms interfering with 
ADL  
Disabling 
— 
ALSO CONSIDER: Dry mouth/salivary gland (xerostomia); Mucositis/stomatitis (clinical exam) – Select; Mucositis/stomatitis (functional/symptomatic) – Select; Taste alteration 
(dysgeusia). 
NAVIGATION NOTE: Splenic function is graded in the BLOOD/BONE MARROW CATEGORY. 
Page 125
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
GASTROINTESTINAL 
Page 9 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 27 - 
March 31, 2003, Publish Date: August 9, 2006 
Stricture/stenosis 
(including anastomotic), 
GI 
– Select:  
Stricture, GI – Select  
– Anus 
– Biliary tree 
– Cecum 
– Colon  
– Duodenum  
– Esophagus 
– Ileum 
– Jejunum 
– Pancreas/pancreatic duct 
– Pharynx 
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
Asymptomatic 
radiographic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, vomiting, 
bleeding, diarrhea); IV 
fluids indicated <24 hrs 
Symptomatic and 
severely altered GI 
function (e.g., altered 
dietary habits, diarrhea, 
or GI fluid loss); IV fluids, 
tube feedings, or TPN 
indicated ≥24 hrs; 
operative intervention 
indicated 
Life-threatening 
consequences; operative 
intervention requiring 
complete organ resection 
(e.g., total colectomy)  
Death 
Taste alteration 
(dysgeusia) 
Taste alteration 
Altered taste but no 
change in diet 
Altered taste with change 
in diet (e.g., oral 
supplements); noxious or 
unpleasant taste; loss of 
taste 
— 
— 
— 
Typhlitis 
(cecal inflammation) 
Typhlitis 
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain; mucus 
or blood in stool 
Abdominal pain, fever, 
change in bowel habits 
with ileus; peritoneal 
signs 
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis); 
operative intervention 
indicated 
Death 
ALSO CONSIDER: Colitis; Hemorrhage, GI – Select ; Ileus, GI (functional obstruction of bowel, i.e., neuroconstipation).  
Page 126
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
GASTROINTESTINAL 
Page 10 of 10 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 28 - 
March 31, 2003, Publish Date: August 9, 2006 
Ulcer, GI 
– Select: 
– Anus 
– Cecum 
– Colon 
– Duodenum 
– Esophagus 
– Ileum 
– Jejunum 
– Rectum 
– Small bowel NOS 
– Stoma 
– Stomach 
Ulcer, GI – Select 
Asymptomatic, 
radiographic or 
endoscopic findings only 
Symptomatic; altered GI 
function (e.g., altered 
dietary habits, oral 
supplements); IV fluids 
indicated <24 hrs 
Symptomatic and 
severely altered GI 
function (e.g., inadequate 
oral caloric or fluid 
intake); IV fluids, tube 
feedings, or TPN 
indicated ≥24 hrs 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select. 
Vomiting 
Vomiting 
1 episode in 24 hrs 
2 – 5 episodes in 24 hrs; 
IV fluids indicated  
<24 hrs 
≥6 episodes in 24 hrs; IV 
fluids, or TPN indicated 
≥24 hrs 
Life-threatening 
consequences  
Death 
ALSO CONSIDER: Dehydration. 
Gastrointestinal – Other 
(Specify, __) 
GI – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling 
Death 
Page 127
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
GROWTH AND DEVELOPMENT 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 29 - 
March 31, 2003, Publish Date: August 9, 2006 
Bone age 
(alteration in bone age) 
Bone age 
— 
+2 SD (standard 
deviation) from normal 
— 
— 
— 
Bone growth: 
femoral head; slipped 
capital femoral epiphysis 
Femoral head growth 
Mild valgus/varus 
deformity 
Moderate valgus/varus 
deformity, symptomatic, 
interfering with function 
but not interfering with 
ADL 
Mild slipped capital 
femoral epiphysis; 
operative intervention 
(e.g., fixation) indicated; 
interfering with ADL 
Disabling; severe slipped 
capital femoral epiphysis 
>60%; avascular necrosis 
— 
Bone growth: 
limb length discrepancy 
Limb length  
Mild length discrepancy 
<2 cm 
Moderate length 
discrepancy 2 – 5 cm; 
shoe lift indicated 
Severe length 
discrepancy >5 cm; 
operative intervention 
indicated; interfering with 
ADL 
Disabling; epiphysiodesis 
— 
Bone growth: 
spine kyphosis/lordosis 
Kyphosis/lordosis 
Mild radiographic 
changes  
Moderate accentuation; 
interfering with function 
but not interfering with 
ADL 
Severe accentuation; 
operative intervention 
indicated; interfering with 
ADL 
Disabling (e.g., cannot lift 
head) 
— 
Growth velocity 
(reduction in growth 
velocity) 
Reduction in growth 
velocity 
10 – 29% reduction in 
growth from the baseline 
growth curve 
30 – 49% reduction in 
growth from the baseline 
growth curve 
≥50% reduction in growth 
from the baseline growth 
curve  
— 
— 
Puberty (delayed) 
Delayed puberty 
— 
No breast development 
by age 13 yrs for females; 
no Tanner Stage 2 
development by age 14.5 
yrs for males 
No sexual development 
by age 14 yrs for girls, 
age 16 yrs for boys; 
hormone replacement 
indicated 
— 
— 
REMARK: Do not use testicular size for Tanner Stage in male cancer survivors. 
Puberty (precocious)  
Precocious puberty 
— 
Physical signs of puberty 
<7 years for females,  
<9 years for males 
— 
— 
— 
Short stature 
Short stature 
Beyond two standard 
deviations of age and 
gender mean height 
Altered ADL 
— 
— 
— 
REMARK: Short stature is secondary to growth hormone deficiency. 
ALSO CONSIDER: Neuroendocrine: growth hormone secretion abnormality. 
Growth and Development 
– Other (Specify, __) 
Growth and Development 
– Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Page 128
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
HEMORRHAGE/BLEEDING 
Page 1 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 30 - 
March 31, 2003, Publish Date: August 9, 2006 
Hematoma  
Hematoma 
Minimal symptoms, 
invasive intervention not 
indicated  
Minimally invasive 
evacuation or aspiration 
indicated 
Transfusion, 
interventional radiology, 
or operative intervention 
indicated 
Life-threatening 
consequences; major 
urgent intervention 
indicated 
Death 
REMARK: Hematoma refers to extravasation at wound or operative site or secondary to other intervention. Transfusion implies pRBC.  
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Hemorrhage/bleeding 
associated with surgery, 
intra-operative or 
postoperative 
Hemorrhage with surgery 
— 
— 
Requiring transfusion of  
2 units non-autologous 
(10 cc/kg for pediatrics) 
pRBCs beyond protocol 
specification; 
postoperative 
interventional radiology, 
endoscopic, or operative 
intervention indicated 
Life-threatening 
consequences  
Death 
REMARK: Postoperative period is defined as ≤72 hours after surgery. Verify protocol-specific acceptable guidelines regarding pRBC transfusion. 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Hemorrhage, CNS 
CNS hemorrhage 
Asymptomatic, 
radiographic findings only 
Medical intervention 
indicated  
Ventriculostomy, ICP 
monitoring, 
intraventricular 
thrombolysis, or operative 
intervention indicated 
Life-threatening 
consequences; 
neurologic deficit or 
disability 
Death 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Page 129
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
HEMORRHAGE/BLEEDING 
Page 2 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 31 - 
March 31, 2003, Publish Date: August 9, 2006 
Hemorrhage, GI  
– Select: 
– Abdomen NOS 
– Anus 
– Biliary tree  
– Cecum/appendix  
– Colon 
– Duodenum 
– Esophagus 
– Ileum 
– Jejunum 
– Liver 
– Lower GI NOS 
– Oral cavity 
– Pancreas 
– Peritoneal cavity 
– Rectum 
– Stoma 
– Stomach 
– Upper GI NOS 
– Varices (esophageal) 
– Varices (rectal) 
Hemorrhage, GI – Select 
Mild, intervention (other 
than iron supplements) 
not indicated 
Symptomatic and medical 
intervention or minor 
cauterization indicated 
Transfusion, 
interventional radiology, 
endoscopic, or operative 
intervention indicated; 
radiation therapy (i.e., 
hemostasis of bleeding 
site) 
Life-threatening 
consequences; major 
urgent intervention 
indicated  
Death 
REMARK: Transfusion implies pRBC. 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Page 130
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
HEMORRHAGE/BLEEDING 
Page 3 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 32 - 
March 31, 2003, Publish Date: August 9, 2006 
Hemorrhage, GU  
– Select:  
– Bladder 
– Fallopian tube 
– Kidney 
– Ovary 
– Prostate  
– Retroperitoneum  
– Spermatic cord 
– Stoma 
– Testes 
– Ureter 
– Urethra 
– Urinary NOS 
– Uterus 
– Vagina 
– Vas deferens 
Hemorrhage, GU – Select 
Minimal or microscopic 
bleeding; intervention not 
indicated 
Gross bleeding, medical 
intervention, or urinary 
tract irrigation indicated 
Transfusion, 
interventional radiology, 
endoscopic, or operative 
intervention indicated; 
radiation therapy (i.e., 
hemostasis of bleeding 
site) 
Life-threatening 
consequences; major 
urgent intervention 
indicated 
Death 
REMARK: Transfusion implies pRBC. 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Hemorrhage, pulmonary/ 
upper respiratory  
– Select: 
Hemorrhage pulmonary  
– Select 
– Bronchopulmonary NOS 
– Bronchus  
– Larynx  
– Lung  
– Mediastinum 
– Nose 
– Pharynx 
– Pleura 
– Respiratory tract NOS 
– Stoma 
– Trachea 
Mild, intervention not 
indicated 
Symptomatic and 
medical intervention 
indicated 
Transfusion, 
interventional radiology, 
endoscopic, or operative 
intervention indicated; 
radiation therapy (i.e., 
hemostasis of bleeding 
site) 
Life-threatening 
consequences; major 
urgent intervention 
indicated 
Death 
REMARK: Transfusion implies pRBC.  
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Petechiae/purpura 
(hemorrhage/bleeding 
into skin or mucosa) 
Petechiae 
Few petechiae 
Moderate petechiae; 
purpura 
Generalized petechiae or 
purpura 
— 
— 
ALSO CONSIDER: Fibrinogen; INR (International Normalized Ratio of prothrombin time); Platelets; PTT (Partial Thromboplastin Time). 
Page 131
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
HEMORRHAGE/BLEEDING 
Page 4 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 33 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Vitreous hemorrhage is graded in the OCULAR/VISUAL CATEGORY. 
Hemorrhage/Bleeding – 
Other (Specify, __) 
Hemorrhage – Other 
(Specify) 
Mild without transfusion 
— 
Transfusion indicated 
Catastrophic bleeding, 
requiring major non-
elective intervention 
Death 
Page 132
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
HEPATOBILIARY/PANCREAS 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 34 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Biliary tree damage is graded as Fistula, GI – Select; Leak (including anastomotic), GI – Select; Necrosis, GI – Select; Obstruction, GI – Select; Perforation, GI – 
Select; Stricture/stenosis (including anastomotic), GI – Select in the GASTROINTESTINAL CATEGORY. 
Cholecystitis 
Cholecystitis 
Asymptomatic, 
radiographic findings only 
Symptomatic, medical 
intervention indicated 
Interventional radiology, 
endoscopic, or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
sepsis or perforation)  
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection 
with unknown ANC – Select.  
Liver dysfunction/failure 
(clinical)  
Liver dysfunction  
— 
Jaundice  
Asterixis 
Encephalopathy or coma 
Death 
REMARK: Jaundice is not an AE, but occurs when the liver is not working properly or when a bile duct is blocked. It is graded as a result of liver dysfunction/failure or elevated bilirubin. 
ALSO CONSIDER: Bilirubin (hyperbilirubinemia). 
Pancreas, exocrine 
enzyme deficiency 
Pancreas, exocrine 
enzyme deficiency 
— 
Increase in stool 
frequency, bulk, or odor; 
steatorrhea 
Sequelae of absorption 
deficiency (e.g., weight 
loss)  
Life-threatening 
consequences 
Death 
ALSO CONSIDER: Diarrhea. 
Pancreatitis  
Pancreatitis 
Asymptomatic, enzyme 
elevation and/or 
radiographic findings  
Symptomatic, medical 
intervention indicated 
Interventional radiology or 
operative intervention 
indicated 
Life-threatening 
consequences 
(e.g., circulatory failure, 
hemorrhage, sepsis) 
Death 
ALSO CONSIDER: Amylase. 
NAVIGATION NOTE: Stricture (biliary tree, hepatic or pancreatic) is graded as Stricture/stenosis (including anastomotic), GI – Select in the GASTROINTESTINAL CATEGORY. 
Hepatobiliary/Pancreas – 
Other (Specify, __) 
Hepatobiliary – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Page 133
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
INFECTION 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 35 - 
March 31, 2003, Publish Date: August 9, 2006 
Colitis, infectious 
(e.g., Clostridium difficile) 
Colitis, infectious  
Asymptomatic, pathologic 
or radiographic findings 
only 
Abdominal pain with 
mucus and/or blood in 
stool 
IV antibiotics or TPN 
indicated  
Life-threatening 
consequences (e.g., 
perforation, bleeding, 
ischemia, necrosis or 
toxic megacolon); 
operative resection or 
diversion indicated 
Death 
ALSO CONSIDER: Hemorrhage, GI – Select; Typhlitis (cecal inflammation).  
Febrile neutropenia 
(fever of unknown origin 
without clinically or 
microbiologically 
documented infection) 
(ANC <1.0 x 109/L, fever 
≥38.5°C) 
Febrile neutropenia 
— 
— 
Present 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
ALSO CONSIDER: Neutrophils/granulocytes (ANC/AGC). 
Infection  
(documented clinically or 
microbiologically) with 
Grade 3 or 4 neutrophils  
(ANC <1.0 x 109/L) 
– Select  
‘Select’ AEs appear at the 
end of the CATEGORY. 
Infection (documented 
clinically) with Grade 3 or 
4 ANC – Select 
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
REMARK: Fever with Grade 3 or 4 neutrophils in the absence of documented infection is graded as Febrile neutropenia (fever of unknown origin without clinically or microbiologically 
documented infection). 
ALSO CONSIDER: Neutrophils/granulocytes (ANC/AGC). 
Infection with normal 
ANC or Grade 1 or 2 
neutrophils  
– Select  
‘Select’ AEs appear at the 
end of the CATEGORY. 
Infection with normal 
ANC – Select 
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
Page 134
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
INFECTION 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 36 - 
March 31, 2003, Publish Date: August 9, 2006 
Infection with unknown 
ANC 
– Select  
‘Select’ AEs appear at the 
end of the CATEGORY. 
Infection with unknown 
ANC – Select 
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
REMARK: Infection with unknown ANC – Select is to be used in the rare case when ANC is unknown. 
Opportunistic infection 
associated with ≥Grade 2 
Lymphopenia 
Opportunistic infection  
— 
Localized, local 
intervention indicated 
IV antibiotic, antifungal, or 
antiviral intervention 
indicated; interventional 
radiology or operative 
intervention indicated 
Life-threatening 
consequences (e.g., 
septic shock, 
hypotension, acidosis, 
necrosis) 
Death 
ALSO CONSIDER: Lymphopenia. 
Viral hepatitis 
Viral hepatitis 
Present; transaminases 
and liver function normal 
Transaminases 
abnormal, liver function 
normal  
Symptomatic liver 
dysfunction; fibrosis by 
biopsy; compensated 
cirrhosis 
Decompensated liver 
function (e.g., ascites, 
coagulopathy, 
encephalopathy, coma) 
Death 
REMARK: Non-viral hepatitis is graded as Infection – Select. 
ALSO CONSIDER: Albumin, serum-low (hypoalbuminemia); ALT, SGPT (serum glutamic pyruvic transaminase); AST, SGOT (serum glutamic oxaloacetic transaminase); Bilirubin 
(hyperbilirubinemia); Encephalopathy. 
Infection – Other 
(Specify, __) 
Infection – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Page 135
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
INFECTION – SELECT 
Page 3 of 3 
CTCAE v3.0  
- 37 - 
March 31, 2003, Publish Date: August 9, 2006 
AUDITORY/EAR 
– External ear (otitis externa) 
– Middle ear (otitis media) 
CARDIOVASCULAR 
– Artery 
– Heart (endocarditis) 
– Spleen 
– Vein 
DERMATOLOGY/SKIN  
– Lip/perioral 
– Peristomal 
– Skin (cellulitis) 
– Ungual (nails) 
GASTROINTESTINAL  
– Abdomen NOS 
– Anal/perianal 
– Appendix 
– Cecum 
– Colon 
– Dental-tooth 
– Duodenum 
– Esophagus 
– Ileum 
– Jejunum 
– Oral cavity-gums (gingivitis) 
– Peritoneal cavity 
– Rectum 
– Salivary gland 
– Small bowel NOS 
– Stomach 
GENERAL 
– Blood 
– Catheter-related 
– Foreign body (e.g., graft, implant,  
prosthesis, stent) 
– Wound  
HEPATOBILIARY/PANCREAS 
– Biliary tree 
– Gallbladder (cholecystitis) 
– Liver 
– Pancreas 
LYMPHATIC 
– Lymphatic 
MUSCULOSKELETAL 
– Bone (osteomyelitis) 
– Joint 
– Muscle (infection myositis) 
– Soft tissue NOS 
NEUROLOGY 
– Brain (encephalitis, infectious) 
– Brain + Spinal cord (encephalomyelitis) 
– Meninges (meningitis) 
– Nerve-cranial 
– Nerve-peripheral 
– Spinal cord (myelitis) 
OCULAR 
– Conjunctiva 
– Cornea 
– Eye NOS 
– Lens 
PULMONARY/UPPER RESPIRATORY 
– Bronchus 
– Larynx 
– Lung (pneumonia) 
– Mediastinum NOS 
– Mucosa 
– Neck NOS 
– Nose 
– Paranasal 
– Pharynx 
– Pleura (empyema) 
– Sinus 
– Trachea 
– Upper aerodigestive NOS 
– Upper airway NOS  
RENAL/GENITOURINARY  
– Bladder (urinary) 
– Kidney 
– Prostate 
– Ureter 
– Urethra 
– Urinary tract NOS 
SEXUAL/REPRODUCTIVE FUNCTION 
– Cervix 
– Fallopian tube 
– Pelvis NOS 
– Penis 
– Scrotum 
– Uterus 
– Vagina 
– Vulva 
 
Page 136
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
LYMPHATICS 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 38 - 
March 31, 2003, Publish Date: August 9, 2006 
Chyle or lymph leakage  
Chyle or lymph leakage 
Asymptomatic, clinical or 
radiographic findings 
Symptomatic, medical 
intervention indicated  
Interventional radiology 
or operative intervention 
indicated 
Life-threatening 
complications 
Death 
ALSO CONSIDER: Chylothorax. 
Dermal change 
lymphedema, 
phlebolymphedema  
Dermal change 
Trace thickening or faint 
discoloration 
Marked discoloration; 
leathery skin texture; 
papillary formation 
— 
— 
— 
REMARK: Dermal change lymphedema, phlebolymphedema refers to changes due to venous stasis. 
ALSO CONSIDER: Ulceration.  
Edema: 
head and neck 
Edema: head and neck 
Localized to dependent 
areas, no disability or 
functional impairment 
Localized facial or neck 
edema with functional 
impairment 
Generalized facial or 
neck edema with 
functional impairment 
(e.g., difficulty in turning 
neck or opening mouth 
compared to baseline) 
Severe with ulceration or 
cerebral edema; 
tracheotomy or feeding 
tube indicated 
Death 
Edema: 
limb 
Edema: limb 
5 – 10% inter-limb 
discrepancy in volume or 
circumference at point of 
greatest visible 
difference; swelling or 
obscuration of anatomic 
architecture on close 
inspection; pitting edema 
>10 – 30% inter-limb 
discrepancy in volume or 
circumference at point of 
greatest visible 
difference; readily 
apparent obscuration of 
anatomic architecture; 
obliteration of skin folds; 
readily apparent 
deviation from normal 
anatomic contour  
>30% inter-limb 
discrepancy in volume; 
lymphorrhea; gross 
deviation from normal 
anatomic contour; 
interfering with ADL 
Progression to 
malignancy (i.e., 
lymphangiosarcoma); 
amputation indicated; 
disabling 
Death 
Edema: 
trunk/genital 
Edema: trunk/genital 
Swelling or obscuration 
of anatomic architecture 
on close inspection; 
pitting edema 
Readily apparent 
obscuration of anatomic 
architecture; obliteration 
of skin folds; readily 
apparent deviation from 
normal anatomic contour 
Lymphorrhea; interfering 
with ADL; gross deviation 
from normal anatomic 
contour 
Progression to 
malignancy (i.e., 
lymphangiosarcoma); 
disabling  
Death 
Edema: 
viscera 
Edema: viscera 
Asymptomatic; clinical or 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and unable 
to aliment adequately 
orally; interventional 
radiology or operative 
intervention indicated  
Life-threatening 
consequences 
Death 
Page 137
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
LYMPHATICS 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 39 - 
March 31, 2003, Publish Date: August 9, 2006 
Lymphedema-related 
fibrosis 
Lymphedema-related 
fibrosis 
Minimal to moderate 
redundant soft tissue, 
unresponsive to elevation 
or compression, with 
moderately firm texture or 
spongy feel 
Marked increase in 
density and firmness, 
with or without tethering 
Very marked density and 
firmness with tethering 
affecting ≥40% of the 
edematous area 
— 
— 
Lymphocele 
Lymphocele 
Asymptomatic, clinical or 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and 
interventional radiology 
or operative intervention 
indicated 
— 
— 
Phlebolymphatic cording  
Phlebolymphatic cording 
Asymptomatic, clinical 
findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic and leading 
to contracture or reduced 
range of motion 
— 
— 
Lymphatics – Other  
(Specify, __) 
Lymphatics – Other  
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling 
Death 
Page 138
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
METABOLIC/LABORATORY 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 40 - 
March 31, 2003, Publish Date: August 9, 2006 
Acidosis  
(metabolic or respiratory) 
Acidosis  
pH <normal, but ≥7.3 
— 
pH <7.3 
pH <7.3 with life-
threatening 
consequences 
Death 
Albumin, serum-low 
(hypoalbuminemia)  
Hypoalbuminemia 
<LLN – 3 g/dL  
<LLN – 30 g/L 
<3 – 2 g/dL 
<30 – 20 g/L  
<2 g/dL  
<20 g/L 
— 
Death 
Alkaline phosphatase 
Alkaline phosphatase 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Alkalosis  
(metabolic or respiratory) 
Alkalosis 
pH >normal, but ≤7.5 
— 
pH >7.5 
pH >7.5 with life-
threatening 
consequences 
Death 
ALT, SGPT  
(serum glutamic pyruvic 
transaminase) 
ALT 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Amylase 
Amylase 
>ULN – 1.5 x ULN 
>1.5 – 2.0 x ULN 
>2.0 – 5.0 x ULN 
>5.0 x ULN 
— 
AST, SGOT 
(serum glutamic 
oxaloacetic 
transaminase) 
AST 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Bicarbonate, serum-low  
Bicarbonate, serum-low 
<LLN – 16 mmol/L 
<16 – 11 mmol/L 
<11 – 8 mmol/L 
<8 mmol/L 
Death 
Bilirubin 
(hyperbilirubinemia) 
Bilirubin 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x ULN 
>3.0 – 10.0 x ULN 
>10.0 x ULN 
— 
REMARK: Jaundice is not an AE, but may be a manifestation of liver dysfunction/failure or elevated bilirubin. If jaundice is associated with elevated bilirubin, grade bilirubin. 
Calcium, serum-low 
(hypocalcemia) 
Hypocalcemia 
<LLN – 8.0 mg/dL 
<LLN – 2.0 mmol/L 
Ionized calcium: 
<LLN – 1.0 mmol/L 
<8.0 – 7.0 mg/dL 
<2.0 – 1.75 mmol/L 
Ionized calcium: 
<1.0 – 0.9 mmol/L 
<7.0 – 6.0 mg/dL 
<1.75 – 1.5 mmol/L 
Ionized calcium: 
<0.9 – 0.8 mmol/L 
<6.0 mg/dL 
<1.5 mmol/L 
Ionized calcium: 
<0.8 mmol/L 
Death 
REMARK: Calcium can be falsely low if hypoalbuminemia is present. Serum albumin is <4.0 g/dL, hypocalcemia is reported after the following corrective calculation has been 
performed: Corrected Calcium (mg/dL) = Total Calcium (mg/dL) – 0.8 [Albumin (g/dL) – 4] 4. Alternatively, direct measurement of ionized calcium is the definitive method to diagnose 
metabolically relevant alterations in serum calcium. 
                                            
4Crit Rev Clin Lab Sci 1984;21(1):51-97 
Page 139
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
METABOLIC/LABORATORY 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 41 - 
March 31, 2003, Publish Date: August 9, 2006 
Calcium, serum-high 
(hypercalcemia) 
Hypercalcemia 
>ULN – 11.5 mg/dL 
>ULN – 2.9 mmol/L 
Ionized calcium: 
>ULN – 1.5 mmol/L 
>11.5 – 12.5 mg/dL 
>2.9 – 3.1 mmol/L 
Ionized calcium: 
>1.5 – 1.6 mmol/L 
>12.5 – 13.5 mg/dL 
>3.1 – 3.4 mmol/L 
Ionized calcium: 
>1.6 – 1.8 mmol/L 
>13.5 mg/dL 
>3.4 mmol/L 
Ionized calcium: 
>1.8 mmol/L 
Death 
Cholesterol, serum-high 
(hypercholesteremia) 
Cholesterol 
>ULN – 300 mg/dL 
>ULN – 7.75 mmol/L 
>300 – 400 mg/dL 
>7.75 – 10.34 mmol/L 
>400 – 500 mg/dL 
>10.34 – 12.92 mmol/L 
>500 mg/dL 
>12.92 mmol/L 
Death 
CPK (creatine 
phosphokinase) 
CPK 
>ULN – 2.5 x ULN 
>2.5 x ULN – 5 x ULN 
>5 x ULN – 10 x ULN 
>10 x ULN 
Death 
Creatinine 
Creatinine 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x ULN 
>3.0 – 6.0 x ULN 
>6.0 x ULN 
Death 
REMARK: Adjust to age-appropriate levels for pediatric patients.  
ALSO CONSIDER: Glomerular filtration rate. 
GGT (γ-Glutamyl 
transpeptidase) 
GGT 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
— 
Glomerular filtration rate  
GFR 
<75 – 50% LLN 
<50 – 25% LLN 
<25% LLN, chronic 
dialysis not indicated 
Chronic dialysis or renal 
transplant indicated 
Death 
ALSO CONSIDER: Creatinine. 
Glucose, serum-high 
(hyperglycemia)  
Hyperglycemia 
>ULN – 160 mg/dL 
>ULN – 8.9 mmol/L 
>160 – 250 mg/dL 
>8.9 – 13.9 mmol/L 
>250 – 500 mg/dL 
>13.9 – 27.8 mmol/L 
>500 mg/dL 
>27.8 mmol/L or acidosis 
Death 
REMARK: Hyperglycemia, in general, is defined as fasting unless otherwise specified in protocol. 
Glucose, serum-low 
(hypoglycemia) 
Hypoglycemia 
<LLN – 55 mg/dL 
<LLN – 3.0 mmol/L 
<55 – 40 mg/dL 
<3.0 – 2.2 mmol/L 
<40 – 30 mg/dL 
<2.2 – 1.7 mmol/L 
<30 mg/dL 
<1.7 mmol/L 
Death 
Hemoglobinuria 
Hemoglobinuria 
Present 
— 
— 
— 
Death 
Lipase 
Lipase 
>ULN – 1.5 x ULN 
>1.5 – 2.0 x ULN 
>2.0 – 5.0 x ULN 
>5.0 x ULN 
— 
Magnesium, serum-high 
(hypermagnesemia) 
Hypermagnesemia 
>ULN – 3.0 mg/dL 
>ULN – 1.23 mmol/L 
— 
>3.0 – 8.0 mg/dL 
>1.23 – 3.30 mmol/L 
>8.0 mg/dL 
>3.30 mmol/L 
Death 
Magnesium, serum-low 
(hypomagnesemia)  
Hypomagnesemia 
<LLN – 1.2 mg/dL 
<LLN – 0.5 mmol/L 
<1.2 – 0.9 mg/dL 
<0.5 – 0.4 mmol/L 
<0.9 – 0.7 mg/dL 
<0.4 – 0.3 mmol/L 
<0.7 mg/dL 
<0.3 mmol/L 
Death 
Phosphate, serum-low 
(hypophosphatemia)  
Hypophosphatemia 
<LLN – 2.5 mg/dL 
<LLN – 0.8 mmol/L 
<2.5 – 2.0 mg/dL  
<0.8 – 0.6 mmol/L 
<2.0 – 1.0 mg/dL 
<0.6 – 0.3 mmol/L 
<1.0 mg/dL 
<0.3 mmol/L 
Death 
Potassium, serum-high 
(hyperkalemia) 
Hyperkalemia 
>ULN – 5.5 mmol/L 
>5.5 – 6.0 mmol/L 
>6.0 – 7.0 mmol/L 
>7.0 mmol/L 
Death 
Page 140
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
METABOLIC/LABORATORY 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 42 - 
March 31, 2003, Publish Date: August 9, 2006 
Potassium, serum-low 
(hypokalemia)  
Hypokalemia 
<LLN – 3.0 mmol/L 
— 
<3.0 – 2.5 mmol/L 
<2.5 mmol/L 
Death 
Proteinuria 
Proteinuria 
1+ or 
0.15 – 1.0 g/24 hrs 
2+ to 3+ or 
>1.0 – 3.5 g/24 hrs  
4+ or 
>3.5 g/24 hrs 
Nephrotic syndrome 
Death 
Sodium, serum-high 
(hypernatremia) 
Hypernatremia 
>ULN – 150 mmol/L 
>150 – 155 mmol/L 
>155 – 160 mmol/L 
>160 mmol/L 
Death 
Sodium, serum-low 
(hyponatremia) 
Hyponatremia 
<LLN – 130 mmol/L 
— 
<130 – 120 mmol/L 
<120 mmol/L 
Death 
Triglyceride, serum-high 
(hypertriglyceridemia) 
Hypertriglyceridemia 
>ULN – 2.5 x ULN 
>2.5 – 5.0 x ULN 
>5.0 – 10 x ULN 
>10 x ULN 
Death 
Uric acid, serum-high 
(hyperuricemia) 
Hyperuricemia 
>ULN – 10 mg/dL 
≤0.59 mmol/L without 
physiologic 
consequences 
— 
>ULN – 10 mg/dL 
≤0.59 mmol/L with 
physiologic 
consequences 
>10 mg/dL 
>0.59 mmol/L 
Death 
ALSO CONSIDER: Creatinine; Potassium, serum-high (hyperkalemia); Renal failure; Tumor lysis syndrome. 
Metabolic/Laboratory – 
Other (Specify, __) 
Metabolic/Lab – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Page 141
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
MUSCULOSKELETAL/SOFT TISSUE 
Page 1 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 43 - 
March 31, 2003, Publish Date: August 9, 2006 
Arthritis (non-septic) 
Arthritis 
Mild pain with 
inflammation, erythema, 
or joint swelling, but not 
interfering with function 
Moderate pain with 
inflammation, erythema, 
or joint swelling 
interfering with function, 
but not interfering with 
ADL 
Severe pain with 
inflammation, erythema, 
or joint swelling and 
interfering with ADL 
Disabling 
Death 
REMARK: Report only when the diagnosis of arthritis (e.g., inflammation of a joint or a state characterized by inflammation of joints) is made. Arthralgia (sign or symptom of pain in a 
joint, especially non-inflammatory in character) is graded as Pain – Select in the PAIN CATEGORY.  
Bone: 
spine-scoliosis 
Scoliosis  
≤20 degrees; clinically 
undetectable 
>20 – 45 degrees; visible 
by forward flexion; 
interfering with function 
but not interfering with 
ADL 
>45 degrees; scapular 
prominence in forward 
flexion; operative 
intervention indicated; 
interfering with ADL 
Disabling (e.g., interfering 
with cardiopulmonary 
function) 
Death 
Cervical spine-range of 
motion 
Cervical spine ROM 
Mild restriction of rotation 
or flexion between  
60 – 70 degrees 
Rotation <60 degrees to 
right or left; <60 degrees 
of flexion 
Ankylosed/fused over 
multiple segments with 
no C-spine rotation 
— 
— 
REMARK: 60 – 65 degrees of rotation is required for reversing a car; 60 – 65 degrees of flexion is required to tie shoes. 
Exostosis 
Exostosis 
Asymptomatic 
Involving multiple sites; 
pain or interfering with 
function  
Excision indicated 
Progression to 
malignancy (i.e., 
chondrosarcoma) 
Death 
Extremity-lower 
(gait/walking) 
Gait/walking 
Limp evident only to 
trained observer and able 
to walk ≥1 kilometer; 
cane indicated for 
walking 
Noticeable limp, or 
limitation of limb function, 
but able to walk ≥0.1 
kilometer (1 city block); 
quad cane indicated for 
walking 
Severe limp with stride 
modified to maintain 
balance (widened base of 
support, marked 
reduction in step length); 
ambulation limited to 
walker; crutches 
indicated 
Unable to walk 
— 
ALSO CONSIDER: Ataxia (incoordination); Muscle weakness, generalized or specific area (not due to neuropathy) – Select.  
Extremity-upper 
(function)  
Extremity-upper 
(function) 
Able to perform most 
household or work 
activities with affected 
limb 
Able to perform most 
household or work 
activities with 
compensation from 
unaffected limb 
Interfering with ADL  
Disabling; no function of 
affected limb 
— 
Fibrosis-cosmesis 
Fibrosis-cosmesis 
Visible only on close 
examination 
Readily apparent but not 
disfiguring 
Significant disfigurement; 
operative intervention 
indicated if patient 
chooses 
— 
— 
Page 142
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
MUSCULOSKELETAL/SOFT TISSUE 
Page 2 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 44 - 
March 31, 2003, Publish Date: August 9, 2006 
Fibrosis-deep connective 
tissue 
Fibrosis-deep connective 
tissue  
Increased density, 
“spongy” feel 
Increased density with 
firmness or tethering 
Increased density with 
fixation of tissue; 
operative intervention 
indicated; interfering with 
ADL 
Life-threatening; 
disabling; loss of limb; 
interfering with vital organ 
function 
Death 
ALSO CONSIDER: Induration/fibrosis (skin and subcutaneous tissue); Muscle weakness, generalized or specific area (not due to neuropathy) – Select; Neuropathy: motor; Neuropathy: 
sensory. 
Fracture 
Fracture 
Asymptomatic, 
radiographic findings only 
(e.g., asymptomatic rib 
fracture on plain x-ray, 
pelvic insufficiency 
fracture on MRI, etc.) 
Symptomatic but non-
displaced; immobilization 
indicated 
Symptomatic and 
displaced or open wound 
with bone exposure; 
operative intervention 
indicated 
Disabling; amputation 
indicated 
Death 
Joint-effusion 
Joint-effusion 
Asymptomatic, clinical or 
radiographic findings only 
Symptomatic; interfering 
with function but not 
interfering with ADL 
Symptomatic and 
interfering with ADL 
Disabling 
Death 
ALSO CONSIDER: Arthritis (non-septic). 
Joint-function5 
Joint-function 
Stiffness interfering with 
athletic activity; ≤25% 
loss of range of motion 
(ROM) 
Stiffness interfering with 
function but not 
interfering with ADL;  
>25 – 50% decrease in 
ROM 
Stiffness interfering with 
ADL; >50 – 75% 
decrease in ROM  
Fixed or non-functional 
joint (arthrodesis); 
>75% decrease in ROM 
— 
ALSO CONSIDER: Arthritis (non-septic). 
Local complication –
device/prosthesis-related 
Device/prosthesis 
Asymptomatic  
Symptomatic, but not 
interfering with ADL; local 
wound care; medical 
intervention indicated 
Symptomatic, interfering 
with ADL; operative 
intervention indicated 
(e.g., hardware/device 
replacement or removal, 
reconstruction)  
Life-threatening; 
disabling; loss of limb or 
organ 
Death 
Lumbar spine-range of 
motion 
Lumbar spine ROM 
Stiffness and difficulty 
bending to the floor to 
pick up a very light object 
but able to do activity 
Some lumbar spine 
flexion but requires a 
reaching aid to pick up a 
very light object from the 
floor 
Ankylosed/fused over 
multiple segments with 
no L-spine flexion (i.e., 
unable to reach to floor to 
pick up a very light 
— 
— 
                                            
5 Adapted from the International SFTR Method of Measuring and Recording Joint Motion, International Standard Orthopedic Measurements (ISOM), Jon J. Gerhardt and Otto A. 
Russee, Bern, Switzerland, Han Huber 9 Publisher), 1975. 
Page 143
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
MUSCULOSKELETAL/SOFT TISSUE 
Page 3 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 45 - 
March 31, 2003, Publish Date: August 9, 2006 
object) 
Muscle weakness, 
generalized or specific 
area (not due to 
neuropathy)  
– Select: 
Muscle weakness  
– Select  
– Extraocular 
– Extremity-lower  
– Extremity-upper 
– Facial 
– Left-sided 
– Ocular 
– Pelvic 
– Right-sided 
– Trunk 
– Whole body/generalized  
Asymptomatic, weakness 
on physical exam 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Life-threatening; disabling 
Death 
ALSO CONSIDER: Fatigue (asthenia, lethargy, malaise). 
Muscular/skeletal 
hypoplasia 
Muscular/skeletal 
hypoplasia 
Cosmetically and 
functionally insignificant 
hypoplasia  
Deformity, hypoplasia, or 
asymmetry able to be 
remediated by prosthesis 
(e.g., shoe insert) or 
covered by clothing  
Functionally significant 
deformity, hypoplasia, or 
asymmetry, unable to be 
remediated by prosthesis 
or covered by clothing  
Disabling 
— 
Myositis 
(inflammation/damage of 
muscle) 
Myositis 
Mild pain, not interfering 
with function 
Pain interfering with 
function, but not 
interfering with ADL 
Pain interfering with ADL 
Disabling 
Death 
REMARK: Myositis implies muscle damage (i.e., elevated CPK). 
ALSO CONSIDER: CPK (creatine phosphokinase); Pain – Select. 
Osteonecrosis  
(avascular necrosis) 
Osteonecrosis 
Asymptomatic, 
radiographic findings only 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL; minimal bone 
removal indicated (i.e., 
minor sequestrectomy)  
Symptomatic and 
interfering with ADL; 
operative intervention or 
hyperbaric oxygen 
indicated 
Disabling  
Death 
Page 144
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
MUSCULOSKELETAL/SOFT TISSUE 
Page 4 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 46 - 
March 31, 2003, Publish Date: August 9, 2006 
Osteoporosis6 
Osteoporosis 
Radiographic evidence of 
osteoporosis or Bone 
Mineral Density (BMD) 
t-score –1 to –2.5 
(osteopenia) and no loss 
of height or therapy 
indicated 
BMD t-score < –2.5; loss 
of height <2 cm; anti-
osteoporotic therapy 
indicated 
Fractures; loss of height 
≥2 cm 
Disabling 
Death 
Seroma 
Seroma 
Asymptomatic 
Symptomatic; medical 
intervention or simple 
aspiration indicated 
Symptomatic, 
interventional radiology 
or operative intervention 
indicated 
— 
— 
Soft tissue necrosis 
– Select: 
– Abdomen 
– Extremity-lower 
– Extremity-upper  
– Head 
– Neck 
– Pelvic 
– Thorax 
Soft tissue necrosis 
– Select 
— 
Local wound care; 
medical intervention 
indicated 
Operative debridement or 
other invasive 
intervention indicated 
(e.g., hyperbaric oxygen)  
Life-threatening 
consequences; major 
invasive intervention 
indicated (e.g., tissue 
reconstruction, flap, or 
grafting) 
Death 
Trismus (difficulty, 
restriction or pain when 
opening mouth) 
Trismus 
Decreased range of 
motion without impaired 
eating  
Decreased range of 
motion requiring small 
bites, soft foods or 
purees 
Decreased range of 
motion with inability to 
adequately aliment or 
hydrate orally 
— 
— 
NAVIGATION NOTE: Wound-infectious is graded as Infection – Select in the INFECTION CATEGORY. 
NAVIGATION NOTE: Wound non-infectious is graded as Wound complication, non-infectious in the DERMATOLOGY/SKIN CATEGORY.  
Musculoskeletal/Soft 
Tissue – Other 
(Specify, __) 
Musculoskeletal – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
                                            
6 "Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis," Report of a WHO Study Group Technical Report Series, No. 843, 1994, v + 129 
pages [C*, E, F, R, S], ISBN 92 4 120843 0, Sw.fr. 22.-/US $19.80; in developing countries: Sw.fr. 15.40, Order no. 1100843 
Page 145
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
NEUROLOGY 
Page 1 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 47 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: ADD (Attention Deficit Disorder) is graded as Cognitive disturbance. 
NAVIGATION NOTE: Aphasia, receptive and/or expressive, is graded as Speech impairment (e.g., dysphasia or aphasia). 
Apnea 
Apnea 
— 
— 
Present 
Intubation indicated  
Death 
Arachnoiditis/ 
meningismus/radiculitis 
Arachnoiditis 
Symptomatic, not 
interfering with function; 
medical intervention 
indicated 
Symptomatic (e.g., 
photophobia, nausea) 
interfering with function 
but not interfering with 
ADL  
Symptomatic, interfering 
with ADL 
Life-threatening; disabling 
(e.g., paraplegia) 
Death 
ALSO CONSIDER: Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 109/L); Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select; Pain – Select; Vomiting. 
Ataxia (incoordination) 
Ataxia 
Asymptomatic  
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL; mechanical 
assistance indicated  
Disabling 
Death 
REMARK: Ataxia (incoordination) refers to the consequence of medical or operative intervention. 
Brachial plexopathy 
Brachial plexopathy 
Asymptomatic 
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
Disabling 
Death 
CNS cerebrovascular 
ischemia 
CNS ischemia 
— 
Asymptomatic, 
radiographic findings only 
Transient ischemic event 
or attack (TIA) ≤24 hrs 
duration 
Cerebral vascular 
accident (CVA, stroke), 
neurologic deficit 
>24 hrs  
Death 
NAVIGATION NOTE: CNS hemorrhage/bleeding is graded as Hemorrhage, CNS in the HEMORRHAGE/BLEEDING CATEGORY.  
CNS necrosis/cystic 
progression 
CNS necrosis 
Asymptomatic, 
radiographic findings only 
Symptomatic, not 
interfering with ADL; 
medical intervention 
indicated 
Symptomatic and 
interfering with ADL; 
hyperbaric oxygen 
indicated 
Life-threatening; 
disabling; operative 
intervention indicated to 
prevent or treat CNS 
necrosis/cystic 
progression 
Death 
Cognitive disturbance 
Cognitive disturbance 
Mild cognitive disability; 
not interfering with 
work/school/life 
performance; specialized 
educational 
services/devices not 
indicated 
Moderate cognitive 
disability; interfering with 
work/school/life 
performance but capable 
of independent living; 
specialized resources on 
part-time basis indicated 
Severe cognitive 
disability; significant 
impairment of 
work/school/life 
performance 
Unable to perform ADL; 
full-time specialized 
resources or 
institutionalization 
indicated 
Death 
REMARK: Cognitive disturbance may be used for Attention Deficit Disorder (ADD). 
Page 146
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
NEUROLOGY 
Page 2 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 48 - 
March 31, 2003, Publish Date: August 9, 2006 
Confusion 
Confusion 
Transient confusion, 
disorientation, or attention 
deficit 
Confusion, disorientation, 
or attention deficit 
interfering with function, 
but not interfering with 
ADL 
Confusion or delirium 
interfering with ADL 
Harmful to others or self; 
hospitalization indicated 
Death 
REMARK: Attention Deficit Disorder (ADD) is graded as Cognitive disturbance. 
NAVIGATION NOTE: Cranial neuropathy is graded as Neuropathy-cranial – Select. 
Dizziness  
Dizziness 
With head movements or 
nystagmus only; not 
interfering with function 
Interfering with function, 
but not interfering with 
ADL 
Interfering with ADL 
Disabling 
— 
REMARK: Dizziness includes disequilibrium, lightheadedness, and vertigo. 
ALSO CONSIDER: Neuropathy: cranial – Select; Syncope (fainting). 
NAVIGATION NOTE: Dysphasia, receptive and/or expressive, is graded as Speech impairment (e.g., dysphasia or aphasia). 
Encephalopathy 
Encephalopathy 
— 
Mild signs or symptoms; 
not interfering with ADL 
Signs or symptoms 
interfering with ADL; 
hospitalization indicated 
Life-threatening; disabling 
Death 
ALSO CONSIDER: Cognitive disturbance; Confusion; Dizziness; Memory impairment; Mental status; Mood alteration – Select; Psychosis (hallucinations/delusions); 
Somnolence/depressed level of consciousness. 
Extrapyramidal/ 
involuntary movement/ 
restlessness 
Involuntary movement 
Mild involuntary 
movements not 
interfering with function 
Moderate involuntary 
movements interfering 
with function, but not 
interfering with ADL 
Severe involuntary 
movements or torticollis 
interfering with ADL 
Disabling 
 
Death 
NAVIGATION NOTE: Headache/neuropathic pain (e.g., jaw pain, neurologic pain, phantom limb pain, post-infectious neuralgia, or painful neuropathies) is graded as Pain – Select in the 
PAIN CATEGORY. 
Hydrocephalus 
Hydrocephalus 
Asymptomatic, 
radiographic findings only 
Mild to moderate 
symptoms not interfering 
with ADL 
Severe symptoms or 
neurological deficit 
interfering with ADL 
Disabling  
Death 
Irritability (children <3 
years of age) 
Irritability 
Mild; easily consolable 
Moderate; requiring 
increased attention 
Severe; inconsolable 
— 
— 
Laryngeal nerve 
dysfunction  
Laryngeal nerve 
Asymptomatic, weakness 
on clinical 
examination/testing only 
Symptomatic, but not 
interfering with ADL; 
intervention not indicated 
Symptomatic, interfering 
with ADL; intervention 
indicated (e.g., 
thyroplasty, vocal cord 
injection) 
Life-threatening; 
tracheostomy indicated 
 
Death 
Page 147
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
NEUROLOGY 
Page 3 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 49 - 
March 31, 2003, Publish Date: August 9, 2006 
Leak, cerebrospinal fluid 
(CSF) 
CSF leak 
Transient headache; 
postural care indicated 
Symptomatic, not 
interfering with ADL; 
blood patch indicated 
Symptomatic, interfering 
with ADL; operative 
intervention indicated 
Life-threatening; disabling 
Death 
REMARK: Leak, cerebrospinal fluid (CSF) may be used for CSF leak associated with operation and persisting >72 hours. 
Leukoencephalopathy 
(radiographic findings) 
Leukoencephalopathy  
Mild increase in 
subarachnoid space 
(SAS); mild 
ventriculomegaly; small 
(+/- multiple) focal T2 
hyperintensities, involving 
periventricular white 
matter or <1/3 of 
susceptible areas of 
cerebrum 
Moderate increase in 
SAS; moderate 
ventriculomegaly; focal 
T2 hyperintensities 
extending into centrum 
ovale or involving 1/3 to 
2/3 of susceptible areas 
of cerebrum 
Severe increase in SAS; 
severe ventriculomegaly; 
near total white matter T2 
hyperintensities or diffuse 
low attenuation (CT) 
— 
— 
REMARK: Leukoencephalopathy is a diffuse white matter process, specifically NOT associated with necrosis. Leukoencephalopathy (radiographic findings) does not include lacunas, 
which are areas that become void of neural tissue.  
Memory impairment 
Memory impairment 
Memory impairment not 
interfering with function 
Memory impairment 
interfering with function, 
but not interfering with 
ADL 
Memory impairment 
interfering with ADL 
Amnesia 
— 
Mental status7 
Mental status 
— 
1 – 3 point below age  
and educational norm in 
Folstein Mini-Mental 
Status Exam (MMSE) 
>3 point below age and 
educational norm in 
Folstein MMSE  
— 
— 
Mood alteration  
– Select: 
– Agitation 
– Anxiety 
– Depression 
– Euphoria 
Mood alteration – Select 
Mild mood alteration not 
interfering with function 
Moderate mood alteration 
interfering with function, 
but not interfering with 
ADL; medication 
indicated 
Severe mood alteration 
interfering with ADL 
Suicidal ideation; danger 
to self or others 
Death 
Myelitis 
Myelitis 
Asymptomatic, mild signs 
(e.g., Babinski’s or 
Lhermitte’s sign) 
Weakness or sensory 
loss not interfering with 
ADL 
Weakness or sensory 
loss interfering with ADL 
Disabling 
Death 
                                            
7 Folstein MF, Folstein, SE and McHugh PR (1975) "Mini-Mental State: A Practical Method for Grading the State of Patients for the Clinician," Journal of Psychiatric Research, 12: 
189-198 
Page 148
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
NEUROLOGY 
Page 4 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 50 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Neuropathic pain is graded as Pain – Select in the PAIN CATEGORY.  
Neuropathy: 
cranial  
– Select: 
Neuropathy: cranial  
– Select 
Asymptomatic, detected 
on exam/testing only 
– CN I  
Smell 
– CN II  Vision 
– CN III  Pupil, upper eyelid, extra ocular movements 
– CN IV  Downward, inward movement of eye 
– CN V  Motor-jaw muscles; Sensory-facial 
– CN VI  Lateral deviation of eye 
– CN VII Motor-face; Sensory-taste 
– CN VIII Hearing and balance 
– CN IX Motor-pharynx; Sensory-ear, pharynx, tongue 
– CN X 
Motor-palate; pharynx, larynx 
– CN XI Motor-sternomastoid and trapezius 
– CN XII Motor-tongue 
Symptomatic, not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
Life-threatening; disabling 
Death 
Neuropathy: 
motor  
Neuropathy-motor 
Asymptomatic, weakness 
on exam/testing only 
Symptomatic weakness 
interfering with function, 
but not interfering with 
ADL 
Weakness interfering with 
ADL; bracing or 
assistance to walk (e.g., 
cane or walker) indicated 
Life-threatening; disabling 
(e.g., paralysis)  
Death 
REMARK: Cranial nerve motor neuropathy is graded as Neuropathy: cranial – Select. 
ALSO CONSIDER: Laryngeal nerve dysfunction; Phrenic nerve dysfunction.  
Neuropathy: 
sensory 
Neuropathy-sensory 
Asymptomatic; loss of 
deep tendon reflexes or 
paresthesia (including 
tingling) but not 
interfering with function 
Sensory alteration or 
paresthesia (including 
tingling), interfering with 
function, but not 
interfering with ADL 
Sensory alteration or 
paresthesia interfering 
with ADL  
Disabling  
Death 
REMARK: Cranial nerve sensory neuropathy is graded as Neuropathy: cranial – Select. 
Personality/behavioral 
Personality 
Change, but not 
adversely affecting 
patient or family 
Change, adversely 
affecting patient or family  
Mental health intervention 
indicated 
Change harmful to others 
or self; hospitalization 
indicated 
Death 
Phrenic nerve dysfunction  Phrenic nerve 
Asymptomatic weakness 
on exam/testing only 
Symptomatic but not 
interfering with ADL; 
intervention not indicated 
Significant dysfunction; 
intervention indicated 
(e.g., diaphragmatic 
plication) 
Life-threatening 
respiratory compromise; 
mechanical ventilation 
indicated 
Death 
Psychosis (hallucinations/ 
delusions) 
Psychosis 
— 
Transient episode 
Interfering with ADL; 
medication, supervision 
Harmful to others or self; 
life-threatening 
Death 
Page 149
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
NEUROLOGY 
Page 5 of 5 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 51 - 
March 31, 2003, Publish Date: August 9, 2006 
or restraints indicated  
consequences 
Pyramidal tract 
dysfunction (e.g., ↑ tone, 
hyperreflexia, positive 
Babinski, ↓ fine motor 
coordination) 
Pyramidal tract 
dysfunction 
Asymptomatic, 
abnormality on exam or 
testing only  
Symptomatic; interfering 
with function but not 
interfering with ADL 
Interfering with ADL 
Disabling; paralysis 
Death 
Seizure 
Seizure 
— 
One brief generalized 
seizure; seizure(s) well 
controlled by 
anticonvulsants or 
infrequent focal motor 
seizures not interfering 
with ADL 
Seizures in which 
consciousness is altered; 
poorly controlled seizure 
disorder, with 
breakthrough generalized 
seizures despite medical 
intervention 
Seizures of any kind 
which are prolonged, 
repetitive, or difficult to 
control (e.g., status 
epilepticus, intractable 
epilepsy) 
Death 
Somnolence/depressed 
level of consciousness 
Somnolence 
— 
Somnolence or sedation 
interfering with function, 
but not interfering with 
ADL 
Obtundation or stupor; 
difficult to arouse; 
interfering with ADL 
Coma 
Death 
Speech impairment  
(e.g., dysphasia or 
aphasia)  
Speech impairment 
— 
Awareness of receptive 
or expressive dysphasia, 
not impairing ability to 
communicate 
Receptive or expressive 
dysphasia, impairing 
ability to communicate 
Inability to communicate 
— 
REMARK: Speech impairment refers to a primary CNS process, not neuropathy or end organ dysfunction. 
ALSO CONSIDER: Laryngeal nerve dysfunction; Voice changes/dysarthria (e.g., hoarseness, loss, or alteration in voice, laryngitis). 
Syncope (fainting) 
Syncope (fainting) 
— 
— 
Present 
Life-threatening 
consequences 
Death 
ALSO CONSIDER: CNS cerebrovascular ischemia; Conduction abnormality/atrioventricular heart block – Select; Dizziness; Supraventricular and nodal arrhythmia – Select; Vasovagal 
episode; Ventricular arrhythmia – Select. 
NAVIGATION NOTE: Taste alteration (CN VII, IX) is graded as Taste alteration (dysgeusia) in the GASTROINTESTINAL CATEGORY. 
Tremor 
Tremor 
Mild and brief or 
intermittent but not 
interfering with function 
Moderate tremor 
interfering with function, 
but not interfering with 
ADL 
Severe tremor interfering 
with ADL 
Disabling 
— 
Neurology – Other 
(Specify, __) 
Neurology – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Page 150
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
OCULAR/VISUAL 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 52 - 
March 31, 2003, Publish Date: August 9, 2006 
Cataract 
Cataract 
Asymptomatic, detected 
on exam only  
Symptomatic, with 
moderate decrease in 
visual acuity  
(20/40 or better); 
decreased visual function 
correctable with glasses  
Symptomatic with marked 
decrease in visual acuity 
(worse than 20/40); 
operative intervention 
indicated (e.g., cataract 
surgery) 
— 
— 
Dry eye syndrome  
Dry eye 
Mild, intervention not 
indicated 
Symptomatic, interfering 
with function but not 
interfering with ADL; 
medical intervention 
indicated  
Symptomatic or decrease 
in visual acuity interfering 
with ADL; operative 
intervention indicated 
— 
— 
Eyelid dysfunction  
Eyelid dysfunction 
Asymptomatic  
Symptomatic, interfering 
with function but not ADL; 
requiring topical agents or 
epilation 
Symptomatic; interfering 
with ADL; surgical 
intervention indicated 
— 
— 
REMARK: Eyelid dysfunction includes canalicular stenosis, ectropion, entropion, erythema, madarosis, symblepharon, telangiectasis, thickening, and trichiasis. 
ALSO CONSIDER: Neuropathy: cranial – Select. 
Glaucoma  
Glaucoma 
Elevated intraocular 
pressure (EIOP) with 
single topical agent for 
intervention; no visual 
field deficit 
EIOP causing early visual 
field deficit (i.e., nasal 
step or arcuate deficit); 
multiple topical or oral 
agents indicated 
EIOP causing marked 
visual field deficits (i.e., 
involving both superior 
and inferior visual fields); 
operative intervention 
indicated 
EIOP resulting in 
blindness (20/200 or 
worse); enucleation 
indicated 
— 
Keratitis (corneal 
inflammation/corneal 
ulceration) 
Keratitis 
Abnormal ophthalmologic 
changes only; 
intervention not indicated 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL; 
operative intervention 
indicated 
Perforation or blindness 
(20/200 or worse)  
— 
NAVIGATION NOTE: Ocular muscle weakness is graded as Muscle weakness, generalized or specific area (not due to neuropathy) – Select in the MUSCULOSKELETAL/SOFT TISSUE 
CATEGORY.  
Night blindness 
(nyctalopia) 
Nyctalopia 
Symptomatic, not 
interfering with function 
Symptomatic and 
interfering with function 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL  
Disabling 
— 
Page 151
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
OCULAR/VISUAL 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 53 - 
March 31, 2003, Publish Date: August 9, 2006 
Nystagmus 
Nystagmus 
Asymptomatic 
Symptomatic and 
interfering with function 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
ALSO CONSIDER: Neuropathy: cranial – Select; Ophthalmoplegia/diplopia (double vision). 
Ocular surface disease  
Ocular surface disease  
Asymptomatic or 
minimally symptomatic 
but not interfering with 
function 
Symptomatic, interfering 
with function but not 
interfering with ADL; 
topical antibiotics or other 
topical intervention 
indicated 
Symptomatic, interfering 
with ADL; operative 
intervention indicated 
— 
— 
REMARK: Ocular surface disease includes conjunctivitis, keratoconjunctivitis sicca, chemosis, keratinization, and palpebral conjunctival epithelial metaplasia. 
Ophthalmoplegia/ 
diplopia (double vision) 
Diplopia 
Intermittently 
symptomatic, intervention 
not indicated 
Symptomatic and 
interfering with function 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL; 
surgical intervention 
indicated 
Disabling 
— 
ALSO CONSIDER: Neuropathy: cranial – Select. 
Optic disc edema 
Optic disc edema 
Asymptomatic 
Decreased visual acuity 
(20/40 or better); visual 
field defect present 
Decreased visual acuity 
(worse than 20/40); 
marked visual field defect 
but sparing the central 20 
degrees 
Blindness  
(20/200 or worse) 
— 
ALSO CONSIDER: Neuropathy: cranial – Select.  
Proptosis/enophthalmos 
Proptosis/enophthalmos 
Asymptomatic, 
intervention not indicated 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
— 
— 
Retinal detachment 
Retinal detachment 
Exudative; no central 
vision loss; intervention 
not indicated 
Exudative and visual 
acuity 20/40 or better but 
intervention not indicated 
Rhegmatogenous or 
exudative detachment; 
operative intervention 
indicated 
Blindness 
(20/200 or worse) 
— 
Retinopathy  
Retinopathy 
Asymptomatic  
Symptomatic with 
moderate decrease in 
visual acuity 
(20/40 or better) 
Symptomatic with marked 
decrease in visual acuity 
(worse than 20/40) 
Blindness 
(20/200 or worse) 
— 
Page 152
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
OCULAR/VISUAL 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 54 - 
March 31, 2003, Publish Date: August 9, 2006 
Scleral necrosis/melt 
Scleral necrosis 
Asymptomatic or 
symptomatic but not 
interfering with function 
Symptomatic, interfering 
with function but not 
interfering with ADL; 
moderate decrease in 
visual acuity (20/40 or 
better); medical 
intervention indicated 
Symptomatic, interfering 
with ADL; marked 
decrease in visual acuity 
(worse than 20/40); 
operative intervention 
indicated 
Blindness (20/200 or 
worse); painful eye with 
enucleation indicated 
— 
Uveitis  
Uveitis 
Asymptomatic 
Anterior uveitis; medical 
intervention indicated 
Posterior or pan-uveitis; 
operative intervention 
indicated 
Blindness 
(20/200 or worse) 
— 
Vision-blurred vision 
Blurred vision 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
Vision-flashing 
lights/floaters 
Flashing lights 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
Vision-photophobia 
Photophobia 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Disabling 
— 
Vitreous hemorrhage 
Vitreous hemorrhage 
Asymptomatic, clinical 
findings only 
Symptomatic, interfering 
with function, but not 
interfering with ADL; 
intervention not indicated 
Symptomatic, interfering 
with ADL; vitrectomy 
indicated  
— 
— 
Watery eye (epiphora, 
tearing) 
Watery eye 
Symptomatic, intervention 
not indicated 
Symptomatic, interfering 
with function but not 
interfering with ADL 
Symptomatic, interfering 
with ADL 
— 
— 
Ocular/Visual – Other  
(Specify, __) 
Ocular – Other  
(Specify) 
Symptomatic not 
interfering with function 
Symptomatic and 
interfering with function, 
but not interfering with 
ADL 
Symptomatic and 
interfering with ADL 
Blindness 
(20/200 or worse) 
Death 
Page 153
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
PAIN 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 55 - 
March 31, 2003, Publish Date: August 9, 2006 
Pain  
– Select: 
‘Select’ AEs appear at the 
end of the CATEGORY. 
Pain – Select  
Mild pain not interfering 
with function 
Moderate pain; pain or 
analgesics interfering with 
function, but not 
interfering with ADL 
Severe pain; pain or 
analgesics severely 
interfering with ADL 
Disabling 
— 
Pain – Other 
(Specify, __) 
Pain – Other (Specify) 
Mild pain not interfering 
with function 
Moderate pain; pain or 
analgesics interfering with 
function, but not 
interfering with ADL 
Severe pain; pain or 
analgesics severely 
interfering with ADL 
Disabling 
— 
PAIN – SELECT 
AUDITORY/EAR 
– External ear 
– Middle ear 
CARDIOVASCULAR 
– Cardiac/heart  
– Pericardium 
DERMATOLOGY/SKIN 
– Face 
– Lip 
– Oral-gums 
– Scalp 
– Skin 
GASTROINTESTINAL 
– Abdomen NOS 
– Anus 
– Dental/teeth/peridontal 
– Esophagus 
– Oral cavity 
– Peritoneum 
– Rectum 
– Stomach 
GENERAL 
– Pain NOS 
– Tumor pain  
HEPATOBILIARY/PANCREAS 
– Gallbladder 
– Liver  
LYMPHATIC 
– Lymph node 
MUSCULOSKELETAL 
– Back 
– Bone 
– Buttock 
– Extremity-limb 
– Intestine 
– Joint 
– Muscle 
– Neck 
– Phantom (pain associated with missing limb) 
NEUROLOGY 
– Head/headache 
– Neuralgia/peripheral nerve 
OCULAR 
– Eye 
PULMONARY/UPPER RESPIRATORY 
– Chest wall 
– Chest/thorax NOS 
PULMONARY/UPPER RESPIRATORY (continued) 
– Larynx 
– Pleura 
– Sinus 
– Throat/pharynx/larynx 
RENAL/GENITOURINARY 
– Bladder 
– Kidney 
SEXUAL/REPRODUCTIVE FUNCTION 
– Breast 
– Ovulatory 
– Pelvis 
– Penis 
– Perineum 
– Prostate 
– Scrotum 
– Testicle 
– Urethra 
– Uterus 
– Vagina 
 
 
Page 154
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
PULMONARY/UPPER RESPIRATORY 
Page 1 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 56 - 
March 31, 2003, Publish Date: August 9, 2006 
Adult Respiratory 
Distress Syndrome 
(ARDS) 
ARDS 
— 
— 
Present, intubation not 
indicated  
Present, intubation 
indicated 
Death 
ALSO CONSIDER: Dyspnea (shortness of breath); Hypoxia; Pneumonitis/pulmonary infiltrates. 
Aspiration 
Aspiration 
Asymptomatic (“silent 
aspiration”); endoscopy 
or radiographic (e.g., 
barium swallow) findings  
Symptomatic (e.g., 
altered eating habits, 
coughing or choking 
episodes consistent with 
aspiration); medical 
intervention indicated 
(e.g., antibiotics, suction 
or oxygen) 
Clinical or radiographic 
signs of pneumonia or 
pneumonitis; unable to 
aliment orally 
Life-threatening (e.g., 
aspiration pneumonia or 
pneumonitis)  
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils 
– Select; Infection with unknown ANC – Select; Laryngeal nerve dysfunction; Neuropathy: cranial – Select; Pneumonitis/pulmonary infiltrates. 
Atelectasis  
Atelectasis  
Asymptomatic  
Symptomatic (e.g., 
dyspnea, cough), medical 
intervention indicated 
(e.g., bronchoscopic 
suctioning, chest 
physiotherapy, 
suctioning)  
Operative (e.g., stent, 
laser) intervention 
indicated  
Life-threatening 
respiratory compromise 
Death 
ALSO CONSIDER: Adult Respiratory Distress Syndrome (ARDS); Cough; Dyspnea (shortness of breath); Hypoxia; Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select; Obstruction/stenosis of airway – 
Select; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes). 
Bronchospasm, 
wheezing  
Bronchospasm 
Asymptomatic  
Symptomatic not 
interfering with function 
Symptomatic interfering 
with function 
Life-threatening 
Death 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever); Dyspnea (shortness of breath).  
Carbon monoxide 
diffusion capacity (DLCO) 
DLCO 
90 – 75% of predicted 
value 
<75 – 50% of predicted 
value 
<50 – 25% of predicted 
value 
<25% of predicted value 
Death 
ALSO CONSIDER: Hypoxia; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes). 
Chylothorax  
Chylothorax 
Asymptomatic 
Symptomatic; 
thoracentesis or tube 
drainage indicated  
Operative intervention 
indicated 
Life-threatening (e.g., 
hemodynamic instability 
or ventilatory support 
indicated) 
Death 
Cough 
Cough 
Symptomatic, non-
narcotic medication only 
indicated  
Symptomatic and 
narcotic medication 
indicated  
Symptomatic and 
significantly interfering 
with sleep or ADL 
— 
— 
Page 155
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
PULMONARY/UPPER RESPIRATORY 
Page 2 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 57 - 
March 31, 2003, Publish Date: August 9, 2006 
Dyspnea (shortness of 
breath)  
Dyspnea  
Dyspnea on exertion, but 
can walk 1 flight of stairs 
without stopping 
Dyspnea on exertion but 
unable to walk 1 flight of 
stairs or 1 city block 
(0.1km) without stopping 
Dyspnea with ADL 
Dyspnea at rest; 
intubation/ventilator 
indicated  
Death 
ALSO CONSIDER: Hypoxia; Neuropathy: motor; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes). 
Edema, larynx  
Edema, larynx 
Asymptomatic edema by 
exam only 
Symptomatic edema, no 
respiratory distress  
Stridor; respiratory 
distress; interfering with 
ADL 
Life-threatening airway 
compromise; 
tracheotomy, intubation, 
or laryngectomy indicated 
Death 
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever). 
FEV1  
FEV1 
90 – 75% of predicted 
value 
<75 – 50% of predicted 
value 
<50 – 25% of predicted 
value 
<25% of predicted 
Death 
Fistula, pulmonary/upper 
respiratory  
– Select: 
– Bronchus 
– Larynx 
– Lung 
– Oral cavity 
– Pharynx  
– Pleura 
– Trachea 
Fistula, pulmonary  
– Select  
Asymptomatic, 
radiographic findings only 
Symptomatic, tube 
thoracostomy or medical 
management indicated; 
associated with altered 
respiratory function but 
not interfering with ADL 
Symptomatic and 
associated with altered 
respiratory function 
interfering with ADL; or 
endoscopic (e.g., stent) 
or primary closure by 
operative intervention 
indicated 
Life-threatening 
consequences; operative 
intervention with 
thoracoplasty, chronic 
open drainage or multiple 
thoracotomies indicated 
Death 
REMARK: A fistula is defined as an abnormal communication between two body cavities, potential spaces, and/or the skin. The site indicated for a fistula should be the site from which 
the abnormal process is believed to have arisen. For example, a tracheo-esophageal fistula arising in the context of a resected or irradiated esophageal cancer should be graded as 
Fistula, GI – esophagus in the GASTROINTESTINAL CATEGORY. 
NAVIGATION NOTE: Hemoptysis is graded as Hemorrhage, pulmonary/upper respiratory – Select in the HEMORRHAGE/BLEEDING CATEGORY.  
Hiccoughs (hiccups, 
singultus) 
Hiccoughs 
Symptomatic, 
intervention not indicated 
Symptomatic, 
intervention indicated  
Symptomatic, 
significantly interfering 
with sleep or ADL 
— 
— 
Hypoxia 
Hypoxia 
— 
Decreased O2 saturation 
with exercise (e.g., pulse 
oximeter <88%); 
intermittent supplemental 
oxygen  
Decreased O2 saturation 
at rest; continuous 
oxygen indicated 
Life-threatening; 
intubation or ventilation 
indicated  
Death 
Page 156
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
PULMONARY/UPPER RESPIRATORY 
Page 3 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 58 - 
March 31, 2003, Publish Date: August 9, 2006 
Nasal cavity/paranasal 
sinus reactions 
Nasal/paranasal 
reactions 
Asymptomatic mucosal 
crusting, blood-tinged 
secretions 
Symptomatic stenosis or 
edema/narrowing 
interfering with airflow 
Stenosis with significant 
nasal obstruction; 
interfering with ADL 
Necrosis of soft tissue or 
bone 
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils 
– Select; Infection with unknown ANC – Select. 
Obstruction/stenosis of 
airway 
– Select: 
– Bronchus 
– Larynx 
– Pharynx 
– Trachea 
Airway obstruction  
– Select  
Asymptomatic obstruction 
or stenosis on exam, 
endoscopy, or radiograph 
Symptomatic (e.g., noisy 
airway breathing), but 
causing no respiratory 
distress; medical 
management indicated 
(e.g., steroids)  
Interfering with ADL; 
stridor or endoscopic 
intervention indicated 
(e.g., stent, laser)  
Life-threatening airway 
compromise; tracheotomy 
or intubation indicated 
Death 
Pleural effusion 
(non-malignant)  
Pleural effusion 
Asymptomatic 
Symptomatic, 
intervention such as 
diuretics or up to 2 
therapeutic 
thoracenteses indicated 
Symptomatic and 
supplemental oxygen,  
>2 therapeutic 
thoracenteses, tube 
drainage, or pleurodesis 
indicated 
Life-threatening (e.g., 
causing hemodynamic 
instability or ventilatory 
support indicated)  
Death 
ALSO CONSIDER: Atelectasis; Cough; Dyspnea (shortness of breath); Hypoxia; Pneumonitis/pulmonary infiltrates; Pulmonary fibrosis (radiographic changes).  
NAVIGATION NOTE: Pleuritic pain is graded as Pain – Select in the PAIN CATEGORY. 
Pneumonitis/pulmonary 
infiltrates  
Pneumonitis 
Asymptomatic, 
radiographic findings only 
Symptomatic, not 
interfering with ADL  
Symptomatic, interfering 
with ADL; O2 indicated  
Life-threatening; 
ventilatory support 
indicated 
Death 
ALSO CONSIDER: Adult Respiratory Distress Syndrome (ARDS); Cough; Dyspnea (shortness of breath); Hypoxia; Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select; Pneumonitis/pulmonary infiltrates; 
Pulmonary fibrosis (radiographic changes). 
Pneumothorax  
Pneumothorax  
Asymptomatic, 
radiographic findings only 
Symptomatic; 
intervention indicated 
(e.g., hospitalization for 
observation, tube 
placement without 
sclerosis) 
Sclerosis and/or 
operative intervention 
indicated 
Life-threatening, causing 
hemodynamic instability 
(e.g., tension 
pneumothorax); 
ventilatory support 
indicated 
Death 
Prolonged chest tube 
drainage or air leak after 
pulmonary resection 
Chest tube drainage or 
leak 
— 
Sclerosis or additional 
tube thoracostomy 
indicated 
Operative intervention 
indicated (e.g., 
thoracotomy with stapling 
or sealant application) 
Life-threatening; 
debilitating; organ 
resection indicated 
Death 
Page 157
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
PULMONARY/UPPER RESPIRATORY 
Page 4 of 4 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 59 - 
March 31, 2003, Publish Date: August 9, 2006 
Prolonged intubation 
after pulmonary resection 
(>24 hrs after surgery)  
Prolonged intubation 
— 
Extubated within  
24 – 72 hrs 
postoperatively 
Extubated >72 hrs 
postoperatively, but 
before tracheostomy 
indicated 
Tracheostomy indicated 
Death 
NAVIGATION NOTE: Pulmonary embolism is graded as Grade 4 either as Thrombosis/embolism (vascular access-related) or Thrombosis/thrombus/embolism in the VASCULAR 
CATEGORY.  
Pulmonary fibrosis 
(radiographic changes)  
Pulmonary fibrosis 
Minimal radiographic 
findings (or patchy or bi-
basilar changes) with 
estimated radiographic 
proportion of total lung 
volume that is fibrotic of 
<25% 
Patchy or bi-basilar 
changes with estimated 
radiographic proportion of 
total lung volume that is 
fibrotic of 25 – <50% 
Dense or widespread 
infiltrates/consolidation 
with estimated 
radiographic proportion of 
total lung volume that is 
fibrotic of 50 – <75% 
Estimated radiographic 
proportion of total lung 
volume that is fibrotic is 
≥75%; honeycombing 
Death 
REMARK: Fibrosis is usually a “late effect” seen >3 months after radiation or combined modality therapy (including surgery). It is thought to represent scar/fibrotic lung tissue. It may be 
difficult to distinguish from pneumonitis that is generally seen within 3 months of radiation or combined modality therapy.  
ALSO CONSIDER: Adult Respiratory Distress Syndrome (ARDS); Cough; Dyspnea (shortness of breath); Hypoxia; Infection (documented clinically or microbiologically) with Grade 3 or 4 
neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils – Select; Infection with unknown ANC – Select. 
NAVIGATION NOTE: Recurrent laryngeal nerve dysfunction is graded as Laryngeal nerve dysfunction in the NEUROLOGY CATEGORY. 
Vital capacity  
Vital capacity 
90 – 75% of predicted 
value 
<75 – 50% of predicted 
value 
<50 – 25% of predicted 
value 
<25% of predicted value 
Death 
Voice changes/dysarthria 
(e.g., hoarseness, loss or 
alteration in voice, 
laryngitis)  
Voice changes  
Mild or intermittent 
hoarseness or voice 
change, but fully 
understandable 
Moderate or persistent 
voice changes, may 
require occasional 
repetition but 
understandable on 
telephone 
Severe voice changes 
including predominantly 
whispered speech; may 
require frequent repetition 
or face-to-face contact for 
understandability; 
requires voice aid (e.g., 
electrolarynx) for ≤50% of 
communication 
Disabling; 
non-understandable voice 
or aphonic; requires voice 
aid (e.g., electrolarynx) 
for >50% of 
communication or 
requires >50% written 
communication 
Death 
ALSO CONSIDER: Laryngeal nerve dysfunction; Speech impairment (e.g., dysphasia or aphasia). 
Pulmonary/Upper 
Respiratory – Other 
(Specify, __) 
Pulmonary – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; 
disabling 
Death 
Page 158
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
RENAL/GENITOURINARY 
Page 1 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 60 - 
March 31, 2003, Publish Date: August 9, 2006 
Bladder spasms 
Bladder spasms 
Symptomatic, intervention 
not indicated 
Symptomatic, 
antispasmodics indicated 
Narcotics indicated 
Major surgical 
intervention indicated 
(e.g., cystectomy) 
— 
Cystitis 
Cystitis 
Asymptomatic 
Frequency with dysuria; 
macroscopic hematuria 
Transfusion; IV pain 
medications; bladder 
irrigation indicated 
Catastrophic bleeding; 
major non-elective 
intervention indicated 
Death 
ALSO CONSIDER: Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils (ANC <1.0 x 109/L) – Select; Infection with normal ANC or Grade 1 or 2 neutrophils 
– Select; Infection with unknown ANC – Select; Pain – Select. 
Fistula, GU 
– Select:  
– Bladder 
– Genital tract-female 
– Kidney 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
Fistula, GU – Select  
Asymptomatic, 
radiographic findings only 
Symptomatic; 
noninvasive intervention 
indicated  
Symptomatic interfering 
with ADL; invasive 
intervention indicated  
Life-threatening 
consequences; operative 
intervention requiring 
partial or full organ 
resection; permanent 
urinary diversion  
Death 
REMARK: A fistula is defined as an abnormal communication between two body cavities, potential spaces, and/or the skin. The site indicated for a fistula should be the site from which 
the abnormal process is believed to have originated. 
Incontinence, urinary  
Incontinence, urinary 
Occasional (e.g., with 
coughing, sneezing, etc.), 
pads not indicated 
Spontaneous, pads 
indicated  
Interfering with ADL; 
intervention indicated 
(e.g., clamp, collagen 
injections) 
Operative intervention 
indicated (e.g., 
cystectomy or permanent 
urinary diversion) 
— 
Leak (including 
anastomotic), GU 
– Select: 
– Bladder 
– Fallopian tube  
– Kidney 
– Spermatic cord 
– Stoma 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Leak, GU – Select  
Asymptomatic, 
radiographic findings only 
Symptomatic; medical 
intervention indicated 
Symptomatic, interfering 
with GU function; invasive 
or endoscopic 
intervention indicated 
Life-threatening 
Death 
REMARK: Leak (including anastomotic), GU – Select refers to clinical signs and symptoms or radiographic confirmation of anastomotic leak but without development of fistula. 
Page 159
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
RENAL/GENITOURINARY 
Page 2 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 61 - 
March 31, 2003, Publish Date: August 9, 2006 
Obstruction, GU  
– Select: 
– Bladder 
– Fallopian tube 
– Prostate 
– Spermatic cord 
– Stoma 
– Testes 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Obstruction, GU – Select  
Asymptomatic, 
radiographic or 
endoscopic findings only 
Symptomatic but no 
hydronephrosis, sepsis or 
renal dysfunction; dilation 
or endoscopic repair or 
stent placement indicated 
Symptomatic and altered 
organ function (e.g., 
sepsis or hydronephrosis, 
or renal dysfunction); 
operative intervention 
indicated  
Life-threatening 
consequences; organ 
failure or operative 
intervention requiring 
complete organ resection 
indicated  
Death 
NAVIGATION NOTE: Operative injury is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY CATEGORY.  
Perforation, GU  
– Select: 
– Bladder 
– Fallopian tube 
– Kidney  
– Ovary 
– Prostate 
– Spermatic cord 
– Stoma 
– Testes 
– Ureter 
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Perforation, GU – Select 
Asymptomatic 
radiographic findings only 
Symptomatic, associated 
with altered renal/GU 
function 
Symptomatic, operative 
intervention indicated 
Life-threatening 
consequences or organ 
failure; operative 
intervention requiring 
organ resection indicated 
Death 
Prolapse of stoma, GU 
Prolapse stoma, GU 
Asymptomatic; special 
intervention, 
extraordinary care not 
indicated 
Extraordinary local care 
or maintenance; minor 
revision under local 
anesthesia indicated 
Dysfunctional stoma; 
operative intervention or 
major stomal revision 
indicated 
Life-threatening 
consequences 
Death 
REMARK: Other stoma complications may be graded as Fistula, GU – Select; Leak (including anastomotic), GU – Select; Obstruction, GU – Select; Perforation, GU – Select; 
Stricture/stenosis (including anastomotic), GU – Select. 
Renal failure  
Renal failure 
— 
— 
Chronic dialysis not 
indicated 
Chronic dialysis or renal 
transplant indicated 
Death 
ALSO CONSIDER: Glomerular filtration rate. 
Page 160
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
RENAL/GENITOURINARY 
Page 3 of 3 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 62 - 
March 31, 2003, Publish Date: August 9, 2006 
Stricture/stenosis 
(including anastomotic), 
GU 
– Select: 
– Bladder 
– Fallopian tube 
– Prostate 
– Spermatic cord 
– Stoma 
– Testes 
– Ureter  
– Urethra 
– Uterus 
– Vagina 
– Vas deferens 
Stricture, anastomotic, 
GU – Select  
Asymptomatic, 
radiographic or 
endoscopic findings only 
Symptomatic but no 
hydronephrosis, sepsis or 
renal dysfunction; dilation 
or endoscopic repair or 
stent placement indicated 
Symptomatic and altered 
organ function (e.g., 
sepsis or hydronephrosis, 
or renal dysfunction); 
operative intervention 
indicated  
Life-threatening 
consequences; organ 
failure or operative 
intervention requiring 
organ resection indicated  
Death 
ALSO CONSIDER: Obstruction, GU – Select. 
Urinary electrolyte 
wasting (e.g., Fanconi’s 
syndrome, renal tubular 
acidosis) 
Urinary electrolyte 
wasting 
Asymptomatic, 
intervention not indicated 
Mild, reversible and 
manageable with 
replacement 
Irreversible, requiring 
continued replacement  
— 
— 
ALSO CONSIDER: Acidosis (metabolic or respiratory); Bicarbonate, serum-low; Calcium, serum-low (hypocalcemia); Phosphate, serum-low (hypophosphatemia). 
Urinary 
frequency/urgency 
Urinary frequency 
Increase in frequency or 
nocturia up to 2 x normal; 
enuresis 
Increase >2 x normal but 
<hourly 
≥1 x/hr; urgency; catheter 
indicated 
— 
— 
Urinary retention 
(including neurogenic 
bladder)  
Urinary retention 
Hesitancy or dribbling, no 
significant residual urine; 
retention occurring during 
the immediate 
postoperative period 
Hesitancy requiring 
medication; or operative 
bladder atony requiring 
indwelling catheter 
beyond immediate 
postoperative period but 
for <6 weeks 
More than daily 
catheterization indicated; 
urological intervention 
indicated (e.g., TURP, 
suprapubic tube, 
urethrotomy) 
Life-threatening 
consequences; organ 
failure (e.g., bladder 
rupture); operative 
intervention requiring 
organ resection indicated 
Death 
REMARK: The etiology of retention (if known) is graded as Obstruction, GU – Select; Stricture/stenosis (including anastomotic), GU – Select. 
ALSO CONSIDER: Obstruction, GU – Select; Stricture/stenosis (including anastomotic), GU – Select. 
Urine color change  
Urine color change 
Present 
— 
— 
— 
— 
REMARK: Urine color refers to change that is not related to other dietary or physiologic cause (e.g., bilirubin, concentrated urine, and hematuria). 
Renal/Genitourinary – 
Other (Specify, __) 
Renal – Other (Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Page 161
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
SECONDARY MALIGNANCY 
Page 1 of 1 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 63 - 
March 31, 2003, Publish Date: August 9, 2006 
Secondary Malignancy – 
possibly related to cancer 
treatment (Specify, __)  
Secondary Malignancy 
(possibly related to 
cancer treatment) 
— 
— 
Non-life-threatening basal 
or squamous cell 
carcinoma of the skin 
Solid tumor, leukemia or 
lymphoma  
Death 
REMARK: Secondary malignancy excludes metastasis from initial primary. Any malignancy possibly related to cancer treatment (including AML/MDS) should be reported via the routine 
reporting mechanisms outlined in each protocol. Important: Secondary Malignancy is an exception to NCI Expedited Adverse Event Reporting Guidelines. Secondary Malignancy is 
“Grade 4, present” but NCI does not require AdEERS Expedited Reporting for any (related or unrelated to treatment) Secondary Malignancy. A diagnosis of AML/MDS following 
treatment with an NCI-sponsored investigational agent is to be reported using the form available from the CTEP Web site at http://ctep.cancer.gov. Cancers not suspected of being 
treatment-related are not to be reported here. 
Page 162
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
SEXUAL/REPRODUCTIVE FUNCTION 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 64 - 
March 31, 2003, Publish Date: August 9, 2006 
Breast function/lactation 
Breast function 
Mammary abnormality, 
not functionally significant 
Mammary abnormality, 
functionally significant 
— 
— 
— 
Breast nipple/areolar 
deformity  
Nipple/areolar 
Limited areolar 
asymmetry with no 
change in nipple/areolar 
projection 
Asymmetry of nipple 
areolar complex with 
slight deviation in nipple 
projection 
Marked deviation of 
nipple projection  
— 
— 
Breast volume/hypoplasia 
Breast 
Minimal asymmetry; 
minimal hypoplasia 
Asymmetry exists, ≤1/3 of 
the breast volume; 
moderate hypoplasia  
Asymmetry exists, >1/3 of 
the breast volume; severe 
hypoplasia 
— 
— 
REMARK: Breast volume is referenced with both arms straight overhead. 
NAVIGATION NOTE: Dysmenorrhea is graded as Pain – Select in the PAIN CATEGORY.  
NAVIGATION NOTE: Dyspareunia is graded as Pain – Select in the PAIN CATEGORY.  
NAVIGATION NOTE: Dysuria (painful urination) is graded as Pain – Select in the PAIN CATEGORY.  
Erectile dysfunction 
Erectile dysfunction 
Decrease in erectile 
function 
(frequency/rigidity of 
erections) but erectile 
aids not indicated 
Decrease in erectile 
function 
(frequency/rigidity of 
erections), erectile aids 
indicated 
Decrease in erectile 
function 
(frequency/rigidity of 
erections) but erectile 
aids not helpful; penile 
prosthesis indicated 
— 
— 
Ejaculatory dysfunction 
Ejaculatory dysfunction 
Diminished ejaculation 
Anejaculation or 
retrograde ejaculation 
— 
— 
— 
NAVIGATION NOTE: Feminization of male is graded in the ENDOCRINE CATEGORY. 
Gynecomastia 
Gynecomastia 
— 
Asymptomatic breast 
enlargement 
Symptomatic breast 
enlargement; intervention 
indicated 
— 
— 
ALSO CONSIDER: Pain – Select.  
Infertility/sterility 
Infertility/sterility 
— 
Male: oligospermia/low 
sperm count 
Female: diminished 
fertility/ovulation 
Male: sterile/azoospermia 
Female: infertile/ 
anovulatory 
— 
— 
Irregular menses  
(change from baseline) 
Irregular menses 
1 – 3 months without 
menses 
>3 – 6 months without 
menses but continuing 
menstrual cycles 
Persistent amenorrhea 
for >6 months 
— 
— 
Page 163
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
SEXUAL/REPRODUCTIVE FUNCTION 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 65 - 
March 31, 2003, Publish Date: August 9, 2006 
Libido 
Libido 
Decrease in interest but 
not affecting relationship; 
intervention not indicated 
Decrease in interest and 
adversely affecting 
relationship; intervention 
indicated 
— 
— 
— 
NAVIGATION NOTE: Masculinization of female is graded in the ENDOCRINE CATEGORY. 
Orgasmic dysfunction 
Orgasmic function 
Transient decrease 
Decrease in orgasmic 
response requiring 
intervention 
Complete inability of 
orgasmic response; not 
responding to intervention 
— 
— 
NAVIGATION NOTE: Pelvic pain is graded as Pain – Select in the PAIN CATEGORY. 
NAVIGATION NOTE: Ulcers of the labia or perineum are graded as Ulceration in DERMATOLOGY/SKIN CATEGORY. 
Vaginal discharge  
(non-infectious) 
Vaginal discharge 
Mild 
Moderate to heavy; pad 
use indicated 
— 
— 
— 
Vaginal dryness 
Vaginal dryness 
Mild 
Interfering with sexual 
function; dyspareunia; 
intervention indicated 
— 
— 
— 
ALSO CONSIDER: Pain – Select. 
Vaginal mucositis 
Vaginal mucositis 
Erythema of the mucosa; 
minimal symptoms 
Patchy ulcerations; 
moderate symptoms or 
dyspareunia 
Confluent ulcerations; 
bleeding with trauma; 
unable to tolerate vaginal 
exam, sexual intercourse 
or tampon placement  
Tissue necrosis; 
significant spontaneous 
bleeding; life-threatening 
consequences 
— 
Vaginal stenosis/length 
Vaginal stenosis 
Vaginal narrowing and/or 
shortening not interfering 
with function  
Vaginal narrowing and/or 
shortening interfering with 
function  
Complete obliteration; not 
surgically correctable 
— 
— 
Vaginitis (not due to 
infection) 
Vaginitis 
Mild, intervention not 
indicated 
Moderate, intervention 
indicated 
Severe, not relieved with 
treatment; ulceration, but 
operative intervention not 
indicated 
Ulceration and operative 
intervention indicated 
— 
Sexual/Reproductive 
Function – Other 
(Specify, __) 
Sexual – Other (Specify) 
Mild 
Moderate 
Severe 
Disabling 
Death 
Page 164
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
SURGERY/INTRA-OPERATIVE INJURY 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 66 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Intra-operative hemorrhage is graded as Hemorrhage/bleeding associated with surgery, intra-operative or postoperative in the HEMORRHAGE/BLEEDING 
CATEGORY.  
Intra-operative injury  
– Select Organ or 
Structure 
‘Select’ AEs appear at the 
end of the CATEGORY. 
Intraop injury – Select  
Primary repair of injured 
organ/structure indicated  
Partial resection of 
injured organ/structure 
indicated 
Complete resection or 
reconstruction of injured 
organ/structure indicated 
Life threatening 
consequences; disabling 
— 
REMARK: The ‘Select’ AEs are defined as significant, unanticipated injuries that are recognized at the time of surgery. These AEs do not refer to additional surgical procedures that 
must be performed because of a change in the operative plan based on intra-operative findings. Any sequelae resulting from the intra-operative injury that result in an adverse 
outcome for the patient must also be recorded and graded under the relevant CTCAE Term. 
Intra-operative Injury – 
Other (Specify, __) 
Intraop Injury – Other 
(Specify) 
Primary repair of injured 
organ/structure indicated  
Partial resection of 
injured organ/structure 
indicated 
Complete resection or 
reconstruction of injured 
organ/structure indicated 
Life threatening 
consequences; disabling 
— 
REMARK: Intra-operative Injury – Other (Specify, __) is to be used only to report an organ/structure not included in the ‘Select’ AEs found at the end of the CATEGORY. Any sequelae 
resulting from the intra-operative injury that result in an adverse outcome for the patient must also be recorded and graded under the relevant CTCAE Term. 
Page 165
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
SURGERY/INTRA-OPERATIVE INJURY – SELECT  
Page 2 of 2 
CTCAE v3.0  
- 67 - 
March 31, 2003, Publish Date: August 9, 2006 
AUDITORY/EAR 
– Inner ear  
– Middle ear  
– Outer ear NOS  
– Outer ear-Pinna  
CARDIOVASCULAR 
– Artery-aorta  
– Artery-carotid  
– Artery-cerebral  
– Artery-extremity (lower)  
– Artery-extremity (upper)  
– Artery-hepatic  
– Artery-major visceral artery  
– Artery-pulmonary  
– Artery NOS 
– Heart  
– Spleen 
– Vein-extremity (lower)  
– Vein-extremity (upper)  
– Vein-hepatic  
– Vein-inferior vena cava  
– Vein-jugular  
– Vein-major visceral vein  
– Vein-portal vein  
– Vein-pulmonary  
– Vein-superior vena cava  
– Vein NOS 
DERMATOLOGY/SKIN 
– Breast  
– Nails  
– Skin 
ENDOCRINE 
– Adrenal gland 
– Parathyroid 
– Pituitary  
ENDOCRINE (continued) 
– Thyroid 
HEAD AND NECK 
– Gingiva  
– Larynx  
– Lip/perioral area  
– Face NOS  
– Nasal cavity  
– Nasopharynx  
– Neck NOS 
– Nose  
– Oral cavity NOS  
– Parotid gland  
– Pharynx  
– Salivary duct  
– Salivary gland  
– Sinus  
– Teeth  
– Tongue  
– Upper aerodigestive NOS 
GASTROINTESTINAL 
– Abdomen NOS  
– Anal sphincter  
– Anus 
– Appendix  
– Cecum  
– Colon  
– Duodenum  
– Esophagus  
– Ileum  
– Jejunum  
– Oral  
– Peritoneal cavity  
– Rectum 
– Small bowel NOS 
GASTROINTESTINAL (continued) 
– Stoma (GI)  
– Stomach  
HEPATOBILIARY/ PANCREAS 
– Biliary tree-common bile  
duct  
– Biliary tree-common hepatic 
duct  
– Biliary tree-left hepatic duct  
– Biliary tree-right hepatic duct  
– Biliary tree NOS  
– Gallbladder  
– Liver 
– Pancreas 
– Pancreatic duct 
MUSCULOSKELETAL 
– Bone  
– Cartilage  
– Extremity-lower 
– Extremity-upper 
– Joint  
– Ligament  
– Muscle  
– Soft tissue NOS 
– Tendon 
NEUROLOGY  
– Brain  
– Meninges  
– Spinal cord 
NERVES: 
– Brachial plexus 
– CN I (olfactory) 
– CN II (optic) 
– CN III (oculomotor) 
– CN IV (trochlear)  
NEUROLOGY (continued) 
NERVES: 
– CN V (trigeminal) motor  
– CN V (trigeminal) sensory  
– CN VI (abducens)  
– CN VII (facial) motor-face  
– CN VII (facial) sensory-
taste  
– CN VIII (vestibulocochlear)  
– CN IX (glossopharyngeal) 
motor pharynx  
– CN IX (glossopharyngeal) 
sensory ear-pharynx-
tongue  
– CN X (vagus)  
– CN XI (spinal accessory)  
– CN XII (hypoglossal)  
– Cranial nerve or branch 
NOS  
– Lingual  
– Lung thoracic  
– Peripheral motor NOS 
– Peripheral sensory NOS 
– Recurrent laryngeal  
– Sacral plexus  
– Sciatic 
– Thoracodorsal 
OCULAR 
– Conjunctiva  
– Cornea  
– Eye NOS 
– Lens 
– Retina 
PULMONARY/UPPER 
RESPIRATORY 
– Bronchus  
– Lung  
– Mediastinum  
– Pleura  
– Thoracic duct  
– Trachea 
– Upper airway NOS 
RENAL/GENITOURINARY 
– Bladder  
– Cervix  
– Fallopian tube  
– Kidney  
– Ovary  
– Pelvis NOS  
– Penis  
– Prostate  
– Scrotum  
– Testis  
– Ureter  
– Urethra  
– Urinary conduit  
– Urinary tract NOS  
– Uterus  
– Vagina  
– Vulva 
 
 
Page 166
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
SYNDROMES 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 68 - 
March 31, 2003, Publish Date: August 9, 2006 
NAVIGATION NOTE: Acute vascular leak syndrome is graded in the VASCULAR CATEGORY. 
NAVIGATION NOTE: Adrenal insufficiency is graded in the ENDOCRINE CATEGORY. 
NAVIGATION NOTE: Adult Respiratory Distress Syndrome (ARDS) is graded in the PULMONARY/UPPER RESPIRATORY CATEGORY. 
Alcohol intolerance 
syndrome (antabuse-like 
syndrome) 
Alcohol intolerance 
syndrome 
— 
— 
Present 
— 
Death 
REMARK: An antabuse-like syndrome occurs with some new anti-androgens (e.g., nilutamide) when patient also consumes alcohol. 
NAVIGATION NOTE: Autoimmune reaction is graded as Autoimmune reaction/hypersensitivity (including drug fever) in the ALLERGY/IMMUNOLOGY CATEGORY. 
Cytokine release 
syndrome/acute infusion 
reaction 
Cytokine release 
syndrome 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDS, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption of 
infusion); recurrence of 
symptoms following initial 
improvement; 
hospitalization indicated 
for other clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates) 
Life-threatening; pressor 
or ventilatory support 
indicated 
Death 
REMARK: Cytokine release syndromes/acute infusion reactions are different from Allergic/hypersensitive reactions, although some of the manifestations are common to both AEs. An 
acute infusion reaction may occur with an agent that causes cytokine release (e.g., monoclonal antibodies or other biological agents). Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hrs of completion of infusion. Signs/symptoms may include: Allergic reaction/hypersensitivity (including drug 
fever); Arthralgia (joint pain); Bronchospasm; Cough; Dizziness; Dyspnea (shortness of breath); Fatigue (asthenia, lethargy, malaise); Headache; Hypertension; Hypotension; Myalgia 
(muscle pain); Nausea; Pruritis/itching; Rash/desquamation; Rigors/chills; Sweating (diaphoresis); Tachycardia; Tumor pain (onset or exacerbation of tumor pain due to treatment); 
Urticaria (hives, welts, wheals); Vomiting.  
ALSO CONSIDER: Allergic reaction/hypersensitivity (including drug fever); Bronchospasm, wheezing; Dyspnea (shortness of breath); Hypertension; Hypotension; Hypoxia; Prolonged 
QTc interval; Supraventricular and nodal arrhythmia – Select; Ventricular arrhythmia – Select.  
NAVIGATION NOTE: Disseminated intravascular coagulation (DIC) is graded in the COAGULATION CATEGORY. 
NAVIGATION NOTE: Fanconi’s syndrome is graded as Urinary electrolyte wasting (e.g., Fanconi’s syndrome, renal tubular acidosis) in the RENAL/GENITOURINARY CATEGORY. 
Flu-like syndrome 
Flu-like syndrome 
Symptoms present but 
not interfering with 
function 
Moderate or causing 
difficulty performing some 
ADL 
Severe symptoms 
interfering with ADL 
Disabling 
Death 
REMARK: Flu-like syndrome represents a constellation of symptoms which may include cough with catarrhal symptoms, fever, headache, malaise, myalgia, prostration, and is to be 
used when the symptoms occur in a cluster consistent with one single pathophysiological process. 
NAVIGATION NOTE: Renal tubular acidosis is graded as Urinary electrolyte wasting (e.g., Fanconi’s syndrome, renal tubular acidosis) in the RENAL/GENITOURINARY CATEGORY. 
Page 167
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
SYNDROMES 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 69 - 
March 31, 2003, Publish Date: August 9, 2006 
“Retinoic acid syndrome”  
“Retinoic acid syndrome” 
Fluid retention; less than 
3 kg of weight gain; 
intervention with fluid 
restriction and/or diuretics 
indicated 
Mild to moderate signs/ 
symptoms; steroids 
indicated 
Severe signs/symptoms; 
hospitalization indicated 
Life-threatening; 
ventilatory support 
indicated 
Death 
REMARK: Patients with acute promyelocytic leukemia may experience a syndrome similar to “retinoic acid syndrome” in association with other agents such as arsenic trioxide. The 
syndrome is usually manifested by otherwise unexplained fever, weight gain, respiratory distress, pulmonary infiltrates and/or pleural effusion, with or without leukocytosis.  
ALSO CONSIDER: Acute vascular leak syndrome; Pleural effusion (non-malignant); Pneumonitis/pulmonary infiltrates. 
NAVIGATION NOTE: SIADH is graded as Neuroendocrine: ADH secretion abnormality (e.g., SIADH or low ADH) in the ENDOCRINE CATEGORY.  
NAVIGATION NOTE: Stevens-Johnson syndrome is graded as Rash: erythema multiforme (e.g., Stevens-Johnson syndrome, toxic epidermal necrolysis) in the DERMATOLOGY/SKIN 
CATEGORY. 
NAVIGATION NOTE: Thrombotic microangiopathy is graded as Thrombotic microangiopathy (e.g., thrombotic thrombocytopenic purpura [TTP] or hemolytic uremic syndrome [HUS]) in 
the COAGULATION CATEGORY. 
Tumor flare 
Tumor flare 
Mild pain not interfering 
with function 
Moderate pain; pain or 
analgesics interfering with 
function, but not 
interfering with ADL 
Severe pain; pain or 
analgesics interfering with 
function and interfering 
with ADL 
Disabling 
Death 
REMARK: Tumor flare is characterized by a constellation of signs and symptoms in direct relation to initiation of therapy (e.g., anti-estrogens/androgens or additional hormones). The 
symptoms/signs include tumor pain, inflammation of visible tumor, hypercalcemia, diffuse bone pain, and other electrolyte disturbances.  
ALSO CONSIDER: Calcium, serum-high (hypercalcemia). 
Tumor lysis syndrome 
Tumor lysis syndrome 
— 
— 
Present 
— 
Death 
ALSO CONSIDER: Creatinine; Potassium, serum-high (hyperkalemia). 
Syndromes – Other 
(Specify, __) 
Syndromes – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
Page 168
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
VASCULAR 
Page 1 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 70 - 
March 31, 2003, Publish Date: August 9, 2006 
Acute vascular leak 
syndrome 
Acute vascular leak 
syndrome 
— 
Symptomatic, fluid 
support not indicated 
Respiratory compromise 
or fluids indicated 
Life-threatening; pressor 
support or ventilatory 
support indicated  
Death 
Peripheral arterial 
ischemia 
Peripheral arterial 
ischemia 
— 
Brief (<24 hrs) episode of 
ischemia managed non-
surgically and without 
permanent deficit 
Recurring or prolonged 
(≥24 hrs) and/or invasive 
intervention indicated 
Life-threatening, disabling 
and/or associated with 
end organ damage 
(e.g., limb loss) 
Death 
Phlebitis (including 
superficial thrombosis) 
Phlebitis 
— 
Present 
— 
— 
— 
ALSO CONSIDER: Injection site reaction/extravasation changes. 
Portal vein flow 
Portal flow 
— 
Decreased portal vein 
flow 
Reversal/retrograde 
portal vein flow 
— 
— 
Thrombosis/embolism 
(vascular access-related) 
Thrombosis/embolism 
(vascular access) 
— 
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
not indicated 
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
indicated 
Embolic event including 
pulmonary embolism or 
life-threatening thrombus 
Death 
Thrombosis/thrombus/ 
embolism 
Thrombosis/thrombus/ 
embolism 
— 
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
not indicated  
Deep vein thrombosis or 
cardiac thrombosis; 
intervention (e.g., 
anticoagulation, lysis, 
filter, invasive procedure) 
indicated  
Embolic event including 
pulmonary embolism or 
life-threatening thrombus 
Death 
Vessel injury-artery  
– Select:  
– Aorta 
– Carotid 
– Extremity-lower 
– Extremity-upper  
– Other NOS 
– Visceral 
Artery injury – Select 
Asymptomatic diagnostic 
finding; intervention not 
indicated 
Symptomatic (e.g., 
claudication); not 
interfering with ADL; 
repair or revision not 
indicated 
Symptomatic interfering 
with ADL; repair or 
revision indicated 
Life-threatening; 
disabling; evidence of 
end organ damage (e.g., 
stroke, MI, organ or limb 
loss) 
Death 
NAVIGATION NOTE: Vessel injury to an artery intra-operatively is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY 
CATEGORY. 
Page 169
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017

 
VASCULAR 
Page 2 of 2 
 
Grade 
Adverse Event 
Short Name 
1 
2 
3 
4 
5 
CTCAE v3.0  
- 71 - 
March 31, 2003, Publish Date: August 9, 2006 
Vessel injury-vein  
– Select: 
– Extremity-lower  
– Extremity-upper 
– IVC 
– Jugular 
– Other NOS 
– SVC 
– Viscera 
Vein injury – Select 
Asymptomatic diagnostic 
finding; intervention not 
indicated 
Symptomatic (e.g., 
claudication); not 
interfering with ADL; 
repair or revision not 
indicated  
Symptomatic interfering 
with ADL; repair or 
revision indicated 
Life-threatening; 
disabling; evidence of 
end organ damage  
Death 
NAVIGATION NOTE: Vessel injury to a vein intra-operatively is graded as Intra-operative injury – Select Organ or Structure in the SURGERY/INTRA-OPERATIVE INJURY CATEGORY. 
Visceral arterial ischemia 
(non-myocardial) 
Visceral arterial ischemia 
— 
Brief (<24 hrs) episode of 
ischemia managed 
medically and without 
permanent deficit 
Prolonged (≥24 hrs) or 
recurring symptoms 
and/or invasive 
intervention indicated 
Life-threatening; 
disabling; evidence of 
end organ damage  
Death 
ALSO CONSIDER: CNS cerebrovascular ischemia.  
Vascular – Other  
(Specify, __) 
Vascular – Other 
(Specify) 
Mild 
Moderate 
Severe 
Life-threatening; disabling 
Death 
 
Page 170
Shire
CONFIDENTIAL
Clinical Trial Protocol: HGT-SAN-067 Amendment 8
Recombinant human heparan N-sulfatase (rhHNS, HGT-1410)
01 Feb 2017