Clinical trial NCT02954458
Conditions: Short Bowel Syndrome
Sponsor: Shire
Start date: 2017-01-09; Completion date: 2020-11-05
Enrollment: 61 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will follow participants who completed the TED-C14-006 study. The purpose of this study is to evaluate the long-term safety and efficacy of teduglutide in pediatric participants with Short Bowel Syndrome (SBS). This study will also offer teduglutide treatment to eligible participants, regardless of treatment received in TED-C14-006 or SHP633-301.

Detailed description:

Arms: arm 1: Participants will receive 0.05 milligram per kilogram (mg/kg) of teduglutide subcutaneous (SC) injections once daily into 1 of the 4 quadrants of the abdomen or into either the thigh or arm as needed in addition to SOC treatment.
Interventions: intervention 1: TED intervention 2: SOC intervention 3: Syringe intervention 4: Needle
Intervention descriptions: intervention 1: 0.05 mg/kg SC injection once daily. intervention 2: Standard safety assessments and adjustments in nutritional support. intervention 3: Teduglutide will be administered using syringe. intervention 4: Teduglutide will be administered using needle.

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
 
 
NCT Number:   
NCT02954458 
 
Study Title:  
A Prospective, Open-label, Long-term Safety and Efficacy Study of Teduglutide in 
Pediatric Patients with Short Bowel Syndrome Who Completed TED-C14-006 
 
Study Number:  
SHP633-304 
 
 
Protocol Version and Date:  
 
Original Protocol:  
08 Apr 2016 
Amendment 1:  
22 Nov 2016 
Amendment 2:  
23 Mar 2017 
Amendment 3:  
16 May 2018 
Amendment 4:   
01 Oct 2019 
 


PROTOCOL: SHP633-304
TITLE:
A Prospective, Open-label, Long-term Safety and Efficacy Study of 
Teduglutide in Pediatric Patients with Short Bowel Syndrome Who 
Completed TED-C14-006
DRUG:
Teduglutide
IND:
IND# 058213
EUDRACT NO.:
2016-000849-30
SPONSOR:
Shire Human Genetic Therapies, Inc.
300 Shire Way, Lexington, MA 02421 USA
PROTOCOL 
HISTORY:
Original Protocol: 08 April 2016
This document contains confidential and proprietary information of Shire and is disclosed pursuant to 
confidentiality and non-disclosure obligations. This information should be used solely for the purposes for which 
it was provided and should not be copied, shared with, or disclosed to any third party without the express written 
consent of Shire.
For non-commercial use only


Shire 
Protocol SHP633-304 
CONFIDENTIAL 
Page2 
08 Apri12016 
PROTOCOL SIGNATURE PAGE 
Sponsor's (Shire) Approval 
 
Global Clinical Development 
Investigator's Acknowledgement 
I have read this protocol for Shire Study SHP633-304. 
! Date: 
Title: A prospective, open label, long-term safety and efficacy study of teduglutide in pediatric 
patients with short bowel syndrome who completed TED-Cl4-006 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Conference on Harmonization (ICH) guidelines on Good Clinical 
Practice (GCP) and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Address: 
(please hand print or type) 
For non-commercial use only


Shire
CONFIDENTIAL
Page 3
Protocol SHP633-304
08 April 2016
EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Adverse Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as 
Required by Protocol within 24 hours to the Shire Global Pharmacovigilance and Risk 
Management Department. Applicable fax numbers and e-mail address can be found on the form 
(sent under separate cover). A copy of this form must also be sent to the contract research 
organization Shire Medical Monitor by fax or e-mail using the details below.
, MD PhD
Email: 
Fax: 
For protocol- or safety-related issues during normal business hours (9 am to 5 pm Eastern 
Standard Time), the investigator must contact the Shire Medical Monitor:
, MD PhD, 
Phone: 
Mobile: 
Email: 
Fax: 
For protocol- or safety-related issues outside of normal business hours, the investigator 
must contact Quintiles Medical Support:
, MD, 
Phone: 
 (medical emergencies – US & Canada)
Phone:
 (medical emergencies – global)
Email: 
For non-commercial use only


Shire
CONFIDENTIAL
Page 4
Protocol SHP633-304
08 April 2016
PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
European Union and Rest of World
Telephone numbers (provided for reference): 
 Shire (USA) 
For non-commercial use only


Shire
CONFIDENTIAL
Page 5
Protocol SHP633-304
08 April 2016
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
PRODUCT QUALITY COMPLAINTS..........................................................................................4
LIST OF TABLES...........................................................................................................................9
LIST OF FIGURES .........................................................................................................................9
ABBREVIATIONS .......................................................................................................................10
STUDY SYNOPSIS ......................................................................................................................12
STUDY SCHEDULE(S) ...............................................................................................................17
1
BACKGROUND INFORMATION.......................................................................................22
1.1
Indication and Current Treatment Options...............................................................22
1.2
Product Background.................................................................................................22
2
STUDY OBJECTIVES AND PURPOSE ..............................................................................24
2.1
Rationale for the Study.............................................................................................24
2.2
Study Objectives ......................................................................................................24
2.2.1
Primary Objectives.................................................................................................24
2.2.2
Secondary Objectives.............................................................................................24
3
STUDY DESIGN ...................................................................................................................25
3.1
Study Design and Flow Chart ..................................................................................25
3.2
Duration and Study Completion Definition .............................................................27
4
STUDY POPULATION.........................................................................................................28
4.1
Study Inclusion Eligibility Criteria ..........................................................................28
4.2
Study Exclusion Eligibility Criteria .........................................................................28
4.3
Teduglutide Eligibility Criteria ................................................................................28
4.4
Teduglutide Treatment Inclusion Criteria................................................................28
4.5
Teduglutide Treatment Exclusion Criteria...............................................................29
4.6
Follow-up Period Escape Criteria ............................................................................30
4.7
Reproductive Potential .............................................................................................30
4.7.1
Female Contraception............................................................................................30
4.8
Discontinuation of Subjects .....................................................................................31
4.8.1
Teduglutide Discontinuation..................................................................................31
4.8.2
Study Withdrawal ..................................................................................................31
4.8.3
Reasons for Discontinuation..................................................................................31
4.8.3.1
Subjects ‘Lost to Follow-up’ Prior to Last Scheduled Visit ..................32
5
CONCOMITANT TREATMENT..........................................................................................33
5.1
Concomitant Medications and GI Procedures..........................................................33
5.1.1
Permitted Treatment...............................................................................................33
For non-commercial use only


Shire
CONFIDENTIAL
Page 6
Protocol SHP633-304
08 April 2016
5.1.2
Prohibited Treatment .............................................................................................33
6
INVESTIGATIONAL PRODUCT ........................................................................................34
6.1
Identity of Investigational Product...........................................................................34
6.1.1
Blinding the Treatment Assignment......................................................................34
6.2
Administration of Investigational Product(s)...........................................................34
6.2.1
Interactive Response Technology (IRT) for Investigational Product 
Management...........................................................................................................34
6.2.2
Allocation of Subjects to Treatment ......................................................................34
6.2.3
Dosing....................................................................................................................34
6.2.4
Unblinding the Treatment Assignment..................................................................35
6.3
Labeling, Packaging, Storage, and Handling ...........................................................35
6.3.1
Labeling .................................................................................................................35
6.3.2
Packaging...............................................................................................................35
6.3.3
Storage ...................................................................................................................35
6.4
Drug Accountability.................................................................................................36
6.5
Subject Compliance..................................................................................................37
7
STUDY PROCEDURES........................................................................................................38
7.1
Study Schedule.........................................................................................................38
7.1.1
Screening................................................................................................................38
7.1.2
Visits for Subjects Not Receiving Teduglutide .....................................................38
7.1.3
Visits for Subjects Receiving Teduglutide ............................................................39
7.1.3.1
Pre-treatment Visit .................................................................................39
7.1.3.2
Teduglutide Treatment Period (CxD1-CxW24).....................................40
7.1.3.3
Site Visits during Teduglutide Treatment Period...................................40
7.1.3.4
Phone Visits............................................................................................41
7.1.4
Teduglutide Follow-up Period...............................................................................41
7.1.4.1
Study Completion/Early Termination Visit (EOS/ET Visit) .................41
7.2
Study Evaluations and Procedures ...........................................................................42
7.2.1
Demographics, Medical History, and SBS History ...............................................42
7.2.2
Physical Examination.............................................................................................42
7.2.3
Vital Signs, Body Weight, Height, Head Circumference and Body Mass 
Index (BMI) ...........................................................................................................42
7.2.4
Clinical Laboratory Tests.......................................................................................43
7.2.5
Serum Sampling.....................................................................................................44
7.2.6
Pregnancy Testing..................................................................................................45
7.2.7
Antibody Testing ...................................................................................................45
7.2.8
Volume of Blood....................................................................................................45
7.2.9
Gastrointestinal-specific Testing ...........................................................................46
7.2.9.1
Fecal Occult Blood Testing....................................................................46
For non-commercial use only


Shire
CONFIDENTIAL
Page 7
Protocol SHP633-304
08 April 2016
7.2.9.2
Colonoscopy...........................................................................................46
7.2.10 Nutritional Support ................................................................................................46
7.2.11 Intake Diary ...........................................................................................................46
7.2.12 Output Diary ..........................................................................................................47
7.2.13 Health-related Quality of Life Assessments ..........................................................47
7.2.13.1
Pediatric Quality of Life Generic Core Scale (PedsQL™), Acute 
version ....................................................................................................48
7.2.13.2
Pediatric Quality of Life Family Impact Module (PedsQL™), Acute 
version ....................................................................................................49
7.2.13.3
PedsQL Gastrointestinal Symptoms Module (PedsQL™), Acute 
version ....................................................................................................49
8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................50
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................50
8.1.1
Severity Categorization..........................................................................................50
8.1.2
Relationship Categorization...................................................................................51
8.1.3
Outcome Categorization ........................................................................................51
8.1.4
Symptoms of the Disease under Study ..................................................................52
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................52
8.1.6
Pregnancy...............................................................................................................52
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................53
8.2
Serious Adverse Event Procedures ..........................................................................53
8.2.1
Reference Safety Information................................................................................53
8.2.2
Reporting Procedures.............................................................................................53
8.2.3
Serious Adverse Event Definition .........................................................................54
8.2.4
Serious Adverse Event Collection Time Frame.....................................................54
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................55
8.2.6
Fatal Outcome........................................................................................................55
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................55
8.3
Adverse Events of Special Interest...........................................................................55
8.4
Dose Interruption and Permanent Discontinuation ..................................................56
8.4.1
Dose Interruption Criteria Based on Known or Possible Risks of 
Teduglutide ............................................................................................................56
8.4.2
Dose Interruption Criteria Based on Drug-Induced Liver Injury ..........................58
8.5
Early Termination of the Clinical Study ..................................................................59
9
DATA MANAGEMENT AND STATISTICAL METHODS...............................................60
9.1
Data Collection.........................................................................................................60
9.2
Clinical Data Management.......................................................................................60
For non-commercial use only


Shire
CONFIDENTIAL
Page 8
Protocol SHP633-304
08 April 2016
9.3
Statistical Analysis Process......................................................................................60
9.4
Planned Interim Analysis, and Data Monitoring Committee...................................60
9.5
Sample Size Calculation and Power Considerations................................................61
9.6
Study Population ......................................................................................................61
9.7
Efficacy Analyses.....................................................................................................61
9.7.1
Efficacy Endpoints.................................................................................................61
9.8
Safety Analyses........................................................................................................61
9.8.1
Safety Endpoints....................................................................................................61
9.9
Other Analyses .........................................................................................................62
9.9.1
Health-related Quality of Life Analyses................................................................62
10 SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................64
10.1
Sponsor’s Responsibilities .......................................................................................64
10.1.1 Good Clinical Practice Compliance.......................................................................64
10.1.2 Indemnity/Liability and Insurance.........................................................................64
10.1.3 Public Posting of Study Information......................................................................64
10.1.4 Submission of Summary of Clinical Study Report (CSR) to Competent 
Authorities of Member States Concerned and Ethics Committees........................64
10.1.5 Study Suspension, Termination, and Completion..................................................65
10.2
Investigator’s Responsibilities .................................................................................65
10.2.1 Good Clinical Practice Compliance.......................................................................65
10.2.2 Protocol Adherence and Investigator Agreement..................................................65
10.2.3 Documentation and Retention of Records.............................................................66
10.2.3.1
Case Report Forms.................................................................................66
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................66
10.2.3.3
Audit/Inspection.....................................................................................66
10.2.3.4
Financial Disclosure...............................................................................67
10.3
Ethical Considerations..............................................................................................67
10.3.1 Informed Consent...................................................................................................67
10.3.2 Institutional Review Board or Ethics Committee..................................................67
10.4
Privacy and Confidentiality......................................................................................68
10.5
Study Results / Publication Policy ...........................................................................69
11 REFERENCES .......................................................................................................................70
12 APPENDICES ........................................................................................................................71
For non-commercial use only


Shire
CONFIDENTIAL
Page 9
Protocol SHP633-304
08 April 2016
LIST OF TABLES
Table 1-1:
Schedule of Events Required for All Subjects ..............................................17
Table 1-2: 
Schedule of Events for Subjects Not Receiving Teduglutide .......................18
Table 1-3: 
Schedule of Events for Subjects While Receiving Teduglutide....................19
Table 5-1: 
Prohibited Treatment.....................................................................................33
Table 7-1:
Approximate Volume of Blood to be Drawn from Each Subject 
Annually ........................................................................................................45
Table 7-2:
Developmentally Appropriate PedsQL™Generic Core Scales .....................48
Table 8-1:
CTCAE Criteria for Adverse Events that May Lead to Dose 
Interruption....................................................................................................57
LIST OF FIGURES
Figure 3-1:
Study Design Flow Chart ..............................................................................27
LIST OF APPENDICES
Appendix 1
Guidelines for Nutritional Support Management During the Study .............72
For non-commercial use only


Shire
CONFIDENTIAL
Page 10
Protocol SHP633-304
08 April 2016
ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
-HCG
beta-human chorionic gonadotropin
BMI
body mass index
CRA
clinical research associate
CRO
contract research organization
CSR
clinical study report
CTCAE
common terminology criteria for adverse events
DILI
drug-induced livery injury
DMC
data monitoring committee
DPP-4
dipeptidyl peptidase 4
EC
ethics committee
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EN
enteral nutrition
EOS
end of study
EOT
end of treatment
ET
early termination
EU
European Union
FDA
Food and Drug Administration
FOBT
fecal occult blood test
FOCBT
female of child-bearing potential
GCP
Good Clinical Practice
GI
gastrointestinal
GLP-1
glucagon-like peptide 1
GLP-2
glucagon-like peptide 2
HIPAA
Health Insurance Portability and Accountability Act
ICF
informed consent form
ICH
International Conference on Harmonization
IGF-1
insulin-like growth factor 1
IRB
institutional review board
IRT
interactive response technology
IV
intravenous
IWRS
interactive web-based response system
MedDRA
Medical Dictionary for Regulatory Activities
NCI
National Cancer Institute
NDA
new drug application
For non-commercial use only


Shire
CONFIDENTIAL
Page 11
Protocol SHP633-304
08 April 2016
NTT
no-teduglutide treatment
PDA
patent ductus arteriosus
PedsQL
Pediatric Quality of Life inventory
PS
parenteral support
PT/INR
prothrombin time/international normalized ratio
QD
once daily
SAE
serious adverse event
SAP
statistical analysis plan
SBS
short bowel syndrome
SC
subcutaneous
SOC
standard of care
t1/2
elimination half-life
TESAE
treatment-emergent serious adverse event
UK
United Kingdom
ULN
upper limit of normal
US
United States
WHO-DD
World Health Organization – Drug Dictionary
For non-commercial use only


Shire
CONFIDENTIAL
Page 12
Protocol SHP633-304
08 April 2016
STUDY SYNOPSIS
Protocol number: SHP633-304
Drug: Teduglutide
Title of the study: A Prospective, Open-label, Long-term Safety and Efficacy Study of Teduglutide in Pediatric 
Patients with Short Bowel Syndrome (SBS) Who Completed TED-C14-006
Number of subjects (total and for each treatment arm):
Approximately 34 subjects who completed the TED-C14-006 study, including subjects in the standard of care 
treatment arm, are expected to enroll in this extension study. This study will enroll up to as many subjects as 
complete the TED-C14-006 study.
Investigator(s): Multicenter study
Site(s) and Region(s): 
Approximately 28 investigational sites in North America and Europe will participate in this extension study
Study period (planned):
October 2016 – September 2019
Clinical phase:
3 Extension
Objectives:
Primary: To evaluate the long-term safety and tolerability of teduglutide treatment in pediatric subjects with SBS.
Secondary: To evaluate long-term efficacy of teduglutide treatment in pediatric subjects with SBS.
Rationale:
This is a Phase 3, prospective, open-label, long-term extension study to evaluate the safety and efficacy of 
teduglutide in pediatric subjects with short bowel syndrome (SBS) who completed the TED-C14-006 study (the 
core study). In addition to evaluating the long-term safety and durability of efficacy after 24-weeks of treatment, 
this extension study will evaluate the need for additional teduglutide treatment in these subjects, and will allow 
the study of first-time treatment of teduglutide-naïve subjects who participated in the standard of care (SOC) 
treatment arm in TED-C14-006. 
Investigational product, dose, and mode of administration:
This study will allow repeat doses of teduglutide 0.05 mg/kg subcutaneous (SC) once daily (QD) injection for 
eligible pediatric subjects. There is no active comparator or reference product.
Methodology:
This is a Phase 3, prospective, open-label, long-term extension study to evaluate the safety and efficacy of 
teduglutide in pediatric subjects who completed the TED-C14-006 study (core study).
Once the informed consent (and if applicable, informed assent) have been reviewed and signed, demographics, 
medical history, and short bowel syndrome history will be obtained. Subjects not receiving teduglutide treatment 
(ie, in a no-teduglutide treatment [NTT] period), will be seen every 12 weeks for safety, parenteral support (PS) 
requirements, and quality of life. The first NTT visit will occur approximately 12 weeks after the screening visit. 
At any point after screening, including during a NTT period, subjects who meet ≥1 teduglutide treatment
inclusion criteria, may proceed immediately to the pre-treatment visit if the investigator, subject, and parent 
agree to proceed with teduglutide therapy.
After the pre-treatment visit, subjects who meet ≥1 of the teduglutide treatment inclusion criteria, and meet none 
of the teduglutide treatment exclusion criteria, will start a 28- week cycle, consisting of 24 weeks of teduglutide 
treatment at 0.05 mg/kg SC once daily, followed by a 4- week follow-up period (during which no teduglutide is 
administered) (Figure 3-1). During the 28-week cycle, clinic visits will occur at weeks 1, 2, 4, 6, 9, 12, 16, 20, 24, 
and 28. Phone visits are required approximately 1 week after adjustments in PS during the TED treatment period, 
between weeks 1-24, and weekly during the TED follow-up period, between weeks 24 and 28. Safety and PS 
requirements will be evaluated at every visit, and quality of life assessments will be made approximately every 12 
weeks. If a subject has clinical deterioration and meets follow-up period escape criteria after stopping teduglutide, 
For non-commercial use only


Shire
CONFIDENTIAL
Page 13
Protocol SHP633-304
08 April 2016
the subject may "escape" the follow-up period early and proceed immediately to another pre-treatment visit. 
Following completion of the 28-week treatment cycle, the subject will proceed to the NTT. The first NTT visit, 
for a subject that completes a treatment cycle, will occur approximately 12 weeks after the Week 28 (CxW28) 
visit.     
At all site visits and telephone contacts, safety will be monitored and nutritional support will be reviewed and
adjusted as needed. To maintain consistency across centers, all attempts should be made to follow the nutritional
support adjustment guidelines (developed with SBS expert input and provided in the protocol) for decisions
regarding PS support reduction and advances in enteral feeds based on weight gain, urine and stool output, and
clinical stability. Departure from the guidelines, however, is not considered a protocol deviation. (Appendix 1).
Study Design Flow Chart 
Figure legend: Safety and efficacy data for subjects not receiving teduglutide treatment are captured every 12 weeks, but 
subjects may proceed to the pre-treatment visit at any time in order to assess eligibility for teduglutide therapy. Eligible 
subjects will enter a 28-week teduglutide cycle. During this cycle, subjects will return to the site for safety and efficacy 
assessments at weeks 1, 2, 4, 6, 9, 12, 16, 20, and 24 (solid black lines). Phone visits are required approximately 1 week 
after adjustments in PS during the intervening weeks between weeks 2 and 24 (dashed grey lines). Subjects discontinue 
teduglutide at week 24 and enter a 4-week follow-up (no-treatment) period, during which phone visits will be performed 
weekly (solid grey lines). If an escape criterion is met during the follow-up period, subjects may proceed directly to 
another pre-treatment visit.
Study Inclusion Criteria: 
The subject will be considered eligible for the study if they meet all of the study inclusion criteria. Teduglutide 
treatment eligibility does not impact study eligibility.
1.
Subject provides written informed consent (subject, parent or legal guardian and, as appropriate, 
informed assent) to participate in the study before completing any study-related procedures.
2.
Subject completed the TED-C14-006 study (including subjects in the standard of care treatment arm).
3.
Subject understands and is willing and able to fully adhere to study requirements as defined in this 
protocol. 
Study Exclusion Criteria: There are no exclusion criteria for this study.
Teduglutide Eligibility Criteria: Subjects are eligible for teduglutide treatment if at least one (≥1) of the 
teduglutide treatment inclusion criteria, and none of the teduglutide treatment exclusion criteria, are met. In 
addition, the investigator and the subject (and/or parent or legal guardian, as appropriate) must agree to proceed 
with treatment.
Teduglutide Treatment Inclusion Criteria:
1.
Subject is teduglutide-naïve, receiving PS, and unable to significantly reduce PS or advance enteral feeds 
(eg, 10% or less change in PS or advance in feeds) for at least 3 months prior to and during the 
For non-commercial use only


Shire
CONFIDENTIAL
Page 14
Protocol SHP633-304
08 April 2016
teduglutide pre-treatment visit, as assessed by the investigator. Transient instability for events such as 
interruption of central access or treatment for sepsis is allowed if the PS returns to within 10% of 
baseline prior to the event.
2.
Subject was previously treated with teduglutide and at least one of the following criteria is satisfied:
a.
Increasing PS requirements following teduglutide discontinuation.
b.
Decreased PS requirement during prior teduglutide treatment, followed by cessation of 
improvement after teduglutide discontinuation.
c.
Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal tolerated 
enteral nutrition following teduglutide discontinuation.
d.
Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and electrolyte 
intake following teduglutide discontinuation.
e.
Severe diarrhea related to teduglutide discontinuation.
Teduglutide Treatment Exclusion Criteria:
1.
Body weight <10 kg at the pre-treatment visit.
2.
Unresected gastrointestinal (GI) polyp, known polyposis condition, pre-malignant change, or 
malignancy, in the GI tract.
3.
History of cancer in the previous 5 years except surgically curative skin cancers.
4.
Serial transverse enteroplasty or other major intestinal surgery within 3 months preceding the teduglutide 
pre-treatment visit. Insertion of a feeding tube, anastomotic ulcer repair, minor intestinal resections ≤10 
cm, and endoscopic procedures are allowed.
5.
Intestinal or other major surgery planned or scheduled to occur during the 28-week cycle.
6.
Clinically significant intestinal stricture or obstruction.
7.
Clinically significant, active or recurrent pancreatic or biliary disease.
8.
Active, severe, or unstable, clinically significant hepatic impairment or injury, including the following 
laboratory values at the pre-treatment visit:
a.
Total bilirubin ≥2 × upper limit of normal (ULN)
b.
Aspartate aminotransferase (AST) ≥7 × ULN
c.
Alanine aminotransferase (ALT) ≥7 × ULN
9.
Renal dysfunction shown by results of an estimated glomerular filtration rate (eGFR) below 
50 mL/min/1.73 m2 at the pre-treatment visit.
10. Unstable cardiac disease, congenital heart disease or cyanotic disease, with the exception of subjects 
who had undergone ventricular or atrial septal defect repair, or patent ductus arteriosus (PDA) ligation.
11. Participation in a clinical study using an experimental drug (other than glutamine or Omegaven) within 
3 months or 5.5 half-lives of the experimental drug, whichever is longer, prior to the pre-treatment visit 
and for the duration of the 28-week cycle.
12. Treatment with analogs of glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2) (not 
including teduglutide), insulin-like growth factor-1 (IGF-1), or growth hormone, within 1 month 
preceding the teduglutide pretreatment visit.
13. Treatment with octreotide or dipeptidyl peptidase 4 (DPP-4) inhibitors within 3 months prior to the pre-
treatment visit.
14. Known or suspected intolerance or hypersensitivity to the investigational product, closely-related 
compounds, or any of the stated ingredients.
15. Known history of alcohol or other substance abuse within 1 year prior to the pre-treatment visit.
16. Pregnant or lactating female subjects.
For non-commercial use only


Shire
CONFIDENTIAL
Page 15
Protocol SHP633-304
08 April 2016
17. Sexually active female subjects of child-bearing potential unwilling to use approved contraception 
during teduglutide treatment and for 30 days after the treatment period.
18. Any condition, disease, illness, or circumstance that in the investigator’s opinion puts the subject at any 
undue risk, prevents completion of the study, or interferes with analysis of the study results.
Follow-up Period Escape Criteria: At the discretion of the investigator, the follow-up period may be interrupted 
and the subject may proceed directly to the pre-treatment visit, if 1 of the following criteria is met:
1.
Increasing PS requirements following teduglutide discontinuation
2.
Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal tolerated enteral 
nutrition following teduglutide discontinuation.
3.
Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and electrolyte intake 
following teduglutide discontinuation.
4.
Severe diarrhea related to teduglutide discontinuation.
Maximum duration of subject involvement in the study:
A subject will be considered enrolled in the study once the subject has provided signed consent, and meets all of 
the Study Inclusion Criteria. Subjects may participate in multiple NTT periods and/or multiple 28-week treatment 
cycles. The study will continue for at least 1 year, and until each subject has access (as needed) to teduglutide. 
The subject’s maximum duration of participation is expected to be approximately 3 years. A subject will be 
considered as having completed the study if the subject has not withdrawn early from the study for any reason 
prior to completing End of Study (EOS) visit.

Planned duration of no teduglutide treatment periods: variable, depending on disease course 

Planned duration of the teduglutide pre-treatment visit: 1 to 21 days

Planned cycle duration: 28 weeks. Each cycle consists of 24 weeks of teduglutide treatment followed 
by a 4-week follow-up period (no treatment)
Endpoints and statistical analysis: 

The safety population will consist of all enrolled subjects. The safety population will be used for both 
safety and efficacy analysis.
Efficacy Endpoints
The following efficacy/PD endpoints will be measured. For each endpoint, analyses will be performed using the 
baseline of this extension study at the following time points: 1) End of each teduglutide treatment period (week 
24 or EOT), and 2) each study visit. In addition, the Efficacy/PD endpoints will be analyzed using the baseline of 
the Core study (TED-C14-006) and the baseline of each treatment cycle. The derivations of the weekly PS 
volume and 3 baselines will be described in the study Statistical Analysis Plan (SAP) in detail. 

Reduction in PS volume of at least 20%

Absolute and relative change in PS volume

Complete weaning off PS

Change in days per week of PS
Health Economics and Outcomes Research (HEOR) Endpoints 
The following HEOR endpoints will be measured. For each endpoint, analyses will be performed using the 
Baseline of this extension study. In addition, the HEOR endpoints will be analyzed using the Baseline of each 
treatment cycle at approximately 12 week intervals (weeks 12 and 24 of each teduglutide treatment cycle, and 
every 12 weeks for subjects not on teduglutide).

Change in Pediatric Quality of Life Inventory (PedsQL) score

Change in PedsQL Family Impact Module score

Change in PedsQL Gastrointestinal Symptoms Module Sub-Scales scores: 
For non-commercial use only


Shire
CONFIDENTIAL
Page 16
Protocol SHP633-304
08 April 2016

Food and Drink Limits

Diarrhea 
Safety Endpoints 
The following safety endpoints will be measured. For each endpoint, analyses will be performed using the 
Baseline of this extension study. In addition, the safety endpoints will be analyzed using the Baseline of the Core 
study (TED-C14-006).

Adverse events, including those pertaining to GI symptoms

Vital signs, including temperature, heart rate, blood pressure

Body weight, height (or length), head circumference (up to 36 months of age) trends on growth charts, 
BMI; z-scores will be calculated for height (or length), weight, head circumference and BMI

Laboratory safety data (ie, clinical chemistry, hematology, and urinalysis)

Urine output

Stool output

Antibodies to teduglutide

Gastrointestinal-specific testing (teduglutide treatment eligible subjects only) including colonoscopy or 
sigmoidoscopy, abdominal ultrasound, and FOBT, upper GI series with small bowel follow through 
Statistical Methodology for Efficacy Analysis
No claims of statistical significance will be made; however, 95% confidence intervals will be provided, if 
applicable. Continuous variables, including those assessed on a discrete scale, will be summarized using 
descriptive statistics including number of subjects, mean, median, standard deviation , maximum, and minimum. 
For categorical variables, statistical summaries will include number of subjects and percentages.
Statistical Methodology for Safety Analysis 
Safety data, including laboratory tests and vital signs assessments, will be summarized by visit. AEs will also be 
collected and summarized. Descriptive statistics will be calculated for quantitative safety data as well as for the 
difference from baseline, if applicable. Frequency counts will be compiled for classification of qualitative safety 
data.
Sample Size Justification 
As this is an extension study, the maximum number of subjects will be determined by enrollment in 
TED-C14-006.
For non-commercial use only


Shire
CONFIDENTIAL
Page 17
Protocol SHP633-304
08 April 2016
STUDY SCHEDULE(S) 
Table 1-1: Schedule of Events Required for All Subjects 
Period
Screening
End of Study or Early Termination
Scr
EOS/ET
Visit Type
Site
Site
Informed consent/assenta
X
Study eligibility
X
Demographics, Medical historyb, SBS historyc
X
Dispense intake and output diaries
X
Evaluate teduglutide treatment inclusion criteriad
X
Adverse events
X
X
Concomitant medications and GI procedurese
X
X
Physical examination and vital signs, including weight
X
Height and head circumferencef
X
Review intake and output diariesg 
X
Record PS and EN prescriptions, and adjust as neededh
X
Safety laboratory testsi
X
PedsQL Generic Core Scale/PedsQL Family Impact Module/ 
PedsQL Gastrointestinal Symptoms Module Sub-Scales
X
Antibodies to teduglutidej
X
Fecal occult blood testingk
(X)
Colonoscopyl
(X)
Pregnancy testingm
(X)
EN=enteral nutrition; EOS =end of study; ET=early termination; GI=gastrointestinal; NTx=no treatment; 
PedsQL=Pediatric Quality of Life Inventory; PS=parenteral support; SBS=Short Bowel Syndrome; Scr =Screening.
Note: (X) denotes conditional requirement for a given assessment if the subject meets certain conditions per protocol.
a Informed Consent (and informed assent, if applicable) must be obtained prior to performing any study-related procedures; consent (and 
informed assent, if applicable) may be obtained anytime during the Week 28 (or EOS) visit for the TED-C14-006 study. Subject will 
have up to 7 days after completion of the TED-C14-006 study to sign consent to participate in the SHP633-304 study.
b Updates to the medical history will be collected, consisting of adverse events that were ongoing at the time of completion of TED-C14-
006, and events that occurred during the period between completion of TED-C14-006 and informed consent to SHP-633-304. New data 
to be collected as medical history include gestational age at birth and parental heights.
c If the subject has any changes to the SBS history that had been collected at the baseline of the TED-C14-006, then the updated SBS 
history will be collected.
d Subjects who meet ≥1 teduglutide treatment inclusion criteria, may proceed to the pre-treatment visit if the investigator, subject, and 
parent or legal guardian agrees to proceed with teduglutide therapy. (Table 1-3).
e Concomitant GI procedures include (but are not limited to) endoscopy, radiographic studies, GI and liver biopsies and associated 
pathology results.
f Head circumference will be measured in subjects 36 months of age and younger.
g Intake diaries will collect actual PS volume and hours per day, and actual EN volume per day, completed daily for a minimum of 2 
weeks prior to each site visit (Section 7.2.11). Urine and stool output should be recorded in the output diary over a 48-hour period of PS 
and EN stability before every clinic visit (See Section 7.2.12 for more detail).
h PS adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for 
nutrition support adjustment provided in Appendix 1. 
i Safety laboratory assessments at site visits will consist of clinical chemistry, hematology, and urinalysis, with results processed by a 
central laboratory. For pediatric subjects in diapers, urine specimen collection should be attempted as part of the safety labs, but lack of 
urinalysis will not constitute a protocol deviation.
j Required for all teduglutide-exposed subjects
kFOBT should be performed on teduglutide-exposed subjects on an annual basis, approximately every 48-60 weeks at a minimum.
lThe need for colonoscopy in response to a positive FOBT during a no-teduglutide treatment period is at the discretion of the 
investigator, but all teduglutide-exposed subjects will undergo colonoscopy after they have received the equivalent of 2 treatment cycles 
(48 weeks of study drug exposure), and subjects who continue to receive teduglutide will undergo colonoscopy at 5 year intervals or 
more often as needed. See Section 7.2.9 for details.
m Pregnancy testing is required for FOCBP at an ET visit if the subject has not had a pregnancy test at least 30 days after study drug 
discontinuation.
For non-commercial use only


Shire
CONFIDENTIAL
Page 18
Protocol SHP633-304
08 April 2016
Table 1-2: Schedule of Events for Subjects Not Receiving Teduglutide 
Visit Number
NTx
Visit Type
Site
Visit Frequency
Every 12 weeks 
Window (days)
±7
Dispense intake and output diaries
X
Evaluate teduglutide treatment inclusion criteriaa
X
Adverse events
X
Concomitant medications and GI proceduresb
X
Physical examination and vital signs, including weight
X
Height and head circumferencec
X
Review intake and output diariesd 
X
Record PS and EN prescriptions, and adjust as needede
X
Safety laboratory testsf
X
PedsQL Generic Core Scale/PedsQL Family Impact Module/ 
PedsQL Gastrointestinal Symptoms Module Sub-Scales
X
Antibodies to teduglutideg
(X)
Fecal occult blood testingh
Annually 
Colonoscopyi
(X)
Serum samplej
Every 24 weeks
EN=enteral nutrition; NTT = no teduglutide treatment; PedsQL = Pediatric Quality of Life Inventory; PS= 
parenteral support.
Note: (X) denotes conditional requirement for a given assessment if the subject meets certain conditions per 
protocol.
a Subjects who meet ≥1 teduglutide treatment inclusion criteria, may proceed to the pre-treatment visit if the 
investigator, subject, and parent or guardian agree to proceed with teduglutide therapy (Table 1-3).
b Concomitant GI procedures include (but are not limited to) endoscopy, radiographic studies, GI and liver biopsies 
and associated pathology results.
c Head circumference will be measured in subjects 36 months of age and younger.
d Intake diaries will collect actual PS volume and hours per day, and actual EN volume per day, completed daily for 
a minimum of 2 weeks prior to each study visit (Section 7.2.11). Urine and stool output should be recorded in the 
output diary over a 48-hour period of PS and EN stability before every clinic visit (See Section 7.2.12 for more 
detail).
e PS adjustments should be made after review of the intake and output diaries and the safety lab data according to 
the guidance for nutrition support adjustment provided in Appendix 1. 
f Safety laboratory assessments at site visits will consist of clinical chemistry, hematology, and urinalysis, with 
results processed by a central laboratory. For pediatric subjects in diapers, urine specimen collection should be 
attempted as part of the safety labs, but lack of urinalysis will not constitute a protocol deviation.
g Subjects who have been treated previously and test positive/specific for TED antibodies should have follow-up 
samples collected every 12 weeks during the study until a negative result is obtained.
h FOBT should be performed on teduglutide-exposed subjects on an annual basis, approximately every 48-60 weeks 
at a minimum.
i The need for colonoscopy in response to a positive FOBT during a no-teduglutide treatment period is at the 
discretion of the investigator, but all teduglutide-exposed subjects will undergo colonoscopy after they have received 
the equivalent of 2 treatment cycles (48 weeks of study drug exposure) and subjects who continue to receive 
teduglutide will undergo colonoscopy at 5 year intervals or more often as needed. See Section 7.2.9 for details.
j Lack of collection of serum samples will not constitute a protocol deviation.
For non-commercial use only


Shire
CONFIDENTIAL
Page 19
Protocol SHP633-304
08 April 2016
Table 1-3: Schedule of Events for Subjects While Receiving Teduglutide
Period
Pre-
treatment
Teduglutide Treatment
Follow-up
Visit Number
Px
Cx
D1
Cx
W1
Cx
W2
Phone contact is required approximately 1 week after PS adjustment
Cx
W4
Phone contact is required approximately 1 week after PS adjustment
Cx 
W6
Phone contact is required approximately 1 week after PS adjustment
Cx 
W9
Phone contact is required approximately 1 week after PS adjustment
Cx 
W12
Phone contact is required approximately 1 week after PS adjustment
Cx 
W16
Phone contact is required approximately 1 week after PS adjustment
Cx 
W20
Phone contact is required approximately 1 week after PS adjustment
CxW24 
(EOT)
CxW25 
CxW26 
CxW27
CxW28
EOS/ET
Visit Type
Site
Site
Site
Site
Site
Site
Site
Site
Site
Site
Site
Phonea
Site
Cycle Day
-21 to 0
1
8
15
29
43
64
85
113
141
169
176
197
183
190
Window (days)
-21 to 0
±2
±2
±2
±2
±4
±4
±4
±4
±4
±2
±2
Evaluate teduglutide 
eligibility (inclusion 
and exclusion) criteria
X
Xb
Dispense intake and 
output diaries
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications and GI
proceduresc
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination 
and vital signs, 
including weight
X
X
X
X
X
X
X
X
X
X
X
X
Height and head 
circumferenced
X
X
X
X
Review intake and 
output diariese
X
X
X
X
X
X
X
X
X
X
X
X
X
Record PS and EN Rx, 
and adjust as neededf
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety laboratory 
testsg
Xh
X
X
X
X
X
X
X
X
X
X
(X)
X
PedsQL Generic Core 
Scale/ Family Impact 
Module/ GI 
Symptoms Module 
Sub-Scales
X
X
X
Antibodies to 
teduglutide
X
X
X
X
Fecal occult blood 
testingh
X
X
X
Colonoscopyi
(X)
(X)
(X)
Pregnancy testingj
X
X
X
X
X
X
X
X
X
Serum samplek
X
X
For non-commercial use only


Shire
CONFIDENTIAL
Page 20
Protocol SHP633-304
08 April 2016
Table 1-3: Schedule of Events for Subjects While Receiving Teduglutide
Period
Pre-
treatment
Teduglutide Treatment
Follow-up
Evaluate escape 
criterial
X
X
Dispense study drugm
X
X
X
X
X
X
X
X
X
EN=enteral nutrition; EOF = end of follow-up; EOS = end of study; EOT = end of treatment; ET = early termination; FOBT = fecal occult blood test; FU = follow-up; GI = 
gastrointestinal; PedsQL = Pediatric Quality of Life Inventory; PS= parenteral support; SBS = Short Bowel Syndrome; SC = subcutaneous; Scr = Screening; TED = Teduglutide; 
Tx = treatment.
Note: (X) denotes conditional requirement for a given assessment if the subject meets certain conditions per protocol.
a Phone visits are required approximately 1 week after adjustments in PS. The assessments to be performed at phone visits are the same as those described for CxW25-27 (except 
for evaluation of escape criteria). 
b Eligibility will need to be re-confirmed prior to the first dose in the cycle. Negative urine pregnancy test is required prior to the first dose of teduglutide, but results of other labs 
obtained at the CxD1 visit are not required to determine teduglutide treatment eligibility.
c Concomitant GI procedures include (but are not limited to) endoscopy, radiographic studies, GI and liver biopsies and associated pathology results.
d Head circumference will be measured in subjects 36 months of age and younger.
e Intake diaries will collect actual PS volume and hours per day, and actual EN volume per day. Two weeks of intake diary data are required before drug is administered at 
CxD1.Diaries should be completed daily from CXD1 up to CXW6 visit during Teduglutide treatment. After CXW6 visit, diaries should be completed daily for a minimum of 2 
weeks prior to each study visit during Teduglutide treatment (Section 7.2.11). During the 24 week teduglutide treatment period, the intake diary will also be completed for 1 week 
following PS adjustment, and daily during the 4-week follow-up period. Urine and stool output should be recorded in the output diary over a 48-hour period of PS and EN stability 
before every clinic visit, and within 1 week of implementing a change in the PS prescription (See Section 7.2.11 for more detail).
f PS adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment provided in
Appendix 1. 
g Safety laboratory assessments at site visits will consist of clinical chemistry, hematology, and urinalysis, with results processed by a central laboratory. Clinical chemistry and 
urinalysis must also be performed within approximately 5-7 days of any adjustment to the PS prescription. Safety labs performed between clinic visits may be performed locally. 
Unscheduled lab results will not be captured in the eCRFs. If abnormal results are considered an adverse event, an AE form will be completed. Collect PT/INR at the pre-treatment 
visit. Additional collection will occur if a potential drug-induced liver injury signal is observed. For pediatric subjects in diapers, urine specimen collection should be attempted as 
part of the safety labs, but lack of urinalysis will not constitute a protocol deviation.
hFOBT should be performed on teduglutide-exposed subjects on an annual basis.
i The Teduglutide-naïve subjects age 12 and older will undergo colonoscopy at the pre-treatment visit if one has not been performed within 1 year. Subjects of any age with newly 
positive FOBT results at the pre-treatment visit for which a readily detectable cause cannot be identified (eg, anal fissure) will undergo a colonoscopy prior to receiving 
teduglutide. If newly positive FOBT results (for which a readily detectable cause cannot be identified) are obtained at the end of a teduglutide treatment cycle (CxW24/EOT), 
colonoscopy will be performed. The need for colonoscopy in response to positive FOBTs at CxW12 is at the discretion of the investigator. Teduglutide-exposed subjects who have 
received the equivalent of 2 treatment cycles (48 weeks of study drug exposure) will undergo colonoscopy. See Section 7.2.9 for details.
j A serum pregnancy test is performed on all females of child-bearing potential (FOCBP) at the teduglutide pre-treatment visit. Urine pregnancy tests will be administered at all 
other visits according to the study schedules, or if pregnancy is suspected, or as specified per protocol upon withdrawal of the subject from the study
k Lack of collection of serum samples will not constitute a protocol deviation
l If escape criteria are met, the subject may proceed directly to another pre-treatment visit at the discretion of the investigator
m The first SC injection of teduglutide in treatment-naïve subjects will be administered under the supervision of the investigator/designee after which the subject will be observed 
For non-commercial use only


Shire
CONFIDENTIAL
Page 21
Protocol SHP633-304
08 April 2016
Table 1-3: Schedule of Events for Subjects While Receiving Teduglutide
Period
Pre-
treatment
Teduglutide Treatment
Follow-up
for hypersensitivity reactions for at least 4 hours. The site of administration (arm, thigh, abdomen) of the first teduglutide dose must be specified and recorded in the eCRF
For non-commercial use only


Shire
CONFIDENTIAL
Page 22
Protocol SHP633-304
08 April 2016
1
BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options 
Short bowel syndrome (SBS) is a rare disorder resulting from congenital abnormalities or severe 
intestinal diseases that result in major surgical resections of the small intestine. It is estimated 
that, at most, there are a few hundred pediatric subjects 1 year and older with (Khan et al. 
2015;Wales et al. 2004). Unlike the adult population, the majority of cases of SBS in pediatric 
subjects are due to congenital anomalies or catastrophic events that occur during infancy. 
Although the small intestine is capable of remarkable adaptation, excessive loss of absorptive 
surface area or specialized functions can lead to dependence on parenteral nutrition or 
intravenous (IV) fluids (parenteral support [PS]). Treatment of both pediatric and adult patients 
is focused on achieving adequate intestinal absorption to allow for minimization or 
discontinuation of PS. About 30% of infants with SBS become independent of PS requirements 
by 12 months of age, and an additional 10% wean off PS by 24 months of age. After this time, 
linear intestinal growth slows. About 60% of pediatric subjects with SBS are able to become 
independent of PS within 5 years of the initial diagnosis (Khan et al. 2015). Nevertheless, despite 
optimal medical management, many pediatric subjects remain dependent on PS. Complications 
of long-term PS include liver disease, catheter-related blood stream infections, central line-
associated venous thrombosis and dwindling central venous access. Sepsis is the leading cause of 
death in these patients and quality of life is poor (Squires et al. 2012). Accelerating the adaptive 
process and achieving enteral autonomy is an urgent goal for all patients with SBS who are 
dependent on PS (Khan et al. 2015;Squires et al. 2012).
Intestinal adaptation is driven by hormonal cues in response to nutrient malabsorption (Drucker 
and Yusta 2014). Chief among these is hormones glucagon-like peptide 2 (GLP-2), which is 
secreted from L-type enteroendocrine cells that reside in the intestinal epithelium in the ileum 
and colon. Resection of these regions impairs the adaptive response by limiting endogenous 
production of GLP-2. 
1.2
Product Background 
Teduglutide is a novel, recombinant analog of naturally occurring human GLP-2 that regulates 
the functional and structural integrity of the cells lining the gastrointestinal (GI) tract. 
Teduglutide is a 33-amino acid peptide that differs from native GLP-2 in the substitution of 
glycine for alanine at the second position at the N-terminus. As a result, teduglutide demonstrates 
resistance to degradation by dipeptidyl peptidase-IV (DPP-4) and therefore maintains a longer 
elimination half-life (t1/2) in adults of approximately 2 hours compared to the native peptide, 
which has a t1/2 of approximately 7 minutes. Teduglutide has been shown in animal studies and 
previous human clinical trials to increase villus height and crypt depth in the intestinal 
epithelium, thereby increasing the absorptive surface area of the intestines (Tappenden et al. 
2013;Thymann et al. 2014). The European Commission granted a centralized marketing 
authorization valid throughout the European Union (EU) for teduglutide (REVESTIVE™) on 30 
August 2012 and a New Drug Application (NDA) for teduglutide (GATTEX®) was approved by 
the United States (US) Food and Drug Administration (FDA) on 21 December 2012 for the 
treatment of adult patients with SBS who are dependent on PS. Teduglutide is not currently 
approved for use in pediatric subjects. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 23
Protocol SHP633-304
08 April 2016
1.3 Clinical Studies with Teduglutide in Pediatric subjects
One Phase 3 study, TED-C13-003, was completed in pediatric SBS subjects in the US and 
United Kingdom (UK). In this study, teduglutide was administered to 3 cohorts of pediatric 
subjects from ages 1-17. Thirty-seven pediatric subjects received teduglutide at doses of 0.0125, 
0.025, or 0.05 mg/kg/day for 12 weeks. Five additional pediatric subjects were enrolled in an 
observational standard of care (SOC) cohort. There were clear dose-dependent effects of 
teduglutide seen at the 0.025 and 0.05 mg/kg/day doses compared to SOC and the 0.0125 
mg/kg/day dose. In the 0.025 mg/kg/day cohort there was a reduction in PS volume at Week 12 
of 37%, including complete independence from PS support in 1 subject, and a reduction of 3.94 
hours per day infusion time. In the 0.05 mg/kg/day cohort there was a reduction in PS volume at 
Week 12 of 39%, including complete independence from PS support in 3 subjects, and a 
reduction of 4.18 hours per day infusion time. Teduglutide was generally safe and well tolerated 
by pediatric subjects in all dosing cohorts. There were no deaths during the study and no 
treatment-emergent serious adverse events (TESAEs) related to teduglutide were reported. No 
discontinuations from study were due to adverse events (AEs).
TED-C14-006 is an ongoing study which includes 2 treatment arms: a teduglutide treatment arm 
and a standard of care treatment arm. Subjects in both arms participate in a 2-week minimum 
screening period, a 24-week treatment period, and a 4-week follow-up period. During the 
screening period, subjects will choose into which arm to enroll. During the 24-week treatment 
period, subjects in the SOC treatment arm will receive standard medical therapy for SBS; while 
those in the teduglutide treatment arm will receive daily subcutaneous (SC) injections of 
teduglutide (study drug) in addition to standard medical therapy. The subjects enrolling in the 
teduglutide treatment arm will be randomized 1:1 in a double-blinded manner into 2 parallel dose 
groups: 0.025 mg/kg/day or 0.05 mg/kg/day of teduglutide administered subcutaneously for 24 
weeks.
Always refer to the latest version of the investigator’s brochure for the overall risk/benefit 
assessment and the most accurate and current information regarding the drug metabolism, 
pharmacokinetics, efficacy and safety of teduglutide (SHP633). 
For non-commercial use only


Shire
CONFIDENTIAL
Page 24
Protocol SHP633-304
08 April 2016
2
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study 
This is a Phase 3, prospective, open-label, long-term extension study to evaluate the safety and 
efficacy of teduglutide in pediatric subjects with SBS who completed the TED-C14-006 study. In 
addition to evaluating the long-term safety and durability of efficacy after 24 weeks of treatment, 
this extension study will evaluate the need for additional teduglutide treatment in these subjects, 
and will allow for the first-time treatment of teduglutide-naïve subjects who participated in the 
SOC treatment arm in TED-C14-006.
2.2
Study Objectives
2.2.1
Primary Objectives
The primary objective of the study is to evaluate the long-term safety and tolerability of 
teduglutide treatment in pediatric subjects with SBS who completed TED-C14-006.
2.2.2
Secondary Objectives
The secondary objective of this study is to evaluate the long-term efficacy of teduglutide 
treatment in pediatric subjects with SBS who completed TED-C14-006.
For non-commercial use only


Shire
CONFIDENTIAL
Page 25
Protocol SHP633-304
08 April 2016
3
STUDY DESIGN
3.1
Study Design and Flow Chart
This is a Phase 3, prospective, open-label, long-term extension study to evaluate the safety and 
efficacy of teduglutide in pediatric subjects who completed the TED-C14-006 study (core study). 
At the time of entry into the TED-C14-006 study, subjects were less than 18 years of age, were 
dependent on parenteral nutrition to provide at least 30% of their caloric or fluid needs, and had 
not been able to significantly reduce PS for at least 3 months prior to enrollment. During the core 
study, pediatric subjects in the teduglutide treatment arm were randomized to 0.025 mg/kg or 
0.05 mg/kg QD dosing in a double-blinded manner. The TED-C14-006 study will also be 
referred to as the core study interchangeably throughout this protocol.
Approximately 28 subjects who complete the core study are expected to enroll in this extension 
study. Subjects who previously received teduglutide during TED-C14-006, as well as subjects 
who were in the SOC treatment group, may be eligible to receive teduglutide treatment in this 
extension study. To be eligible, subjects must meet ≥1 of the teduglutide treatment inclusion 
criteria and none of the teduglutide treatment exclusion criteria.
Re-challenge
Subjects not receiving teduglutide treatment (ie, in a “no teduglutide treatment period”), will be 
seen every 12 weeks for safety, parenteral support (PS) requirements, and quality of life. At any 
point during a no teduglutide treatment period, subjects who meet ≥1 teduglutide treatment 
inclusion may proceed directly to the pre-treatment visit if the investigator, subject, and parent 
agree to proceed with teduglutide therapy.
Rationale: Some pediatric subjects may have a durable beneficial effect after 24 weeks of 
teduglutide treatment and thus long-term follow-up without additional teduglutide treatment may 
be appropriate. However, there may be some pediatric subjects who deteriorate or stop 
improving after discontinuation of teduglutide treatment. In these pediatric subjects, additional 
teduglutide treatment may be beneficial. 
Dose Selection 
Analysis suggested that pediatric patients, ages 1 to 17 years old, are likely to require the same 
dose as used in adults, namely 0.05 mg/kg/day (Mouksassi et al. 2009). In this extension study to 
TED-C14-006, repeat doses of teduglutide 0.05 mg/kg QD will be administered to eligible 
pediatric subjects who previously received teduglutide 0.05 or 0.025 mg/kg in Study TED-C14-
006.
Rationale: Teduglutide is approved for adult use in the United States and European Union at a 
dose of 0.05 mg/kg SC once daily. The completed 12-week pediatric study (TED-C13-003) 
demonstrated that teduglutide dosing at 0.025 and 0.05 mg/kg/day was associated with a 
favorable benefit/risk profile. In addition, population pharmacokinetic modeling and simulations 
were conducted to determine the effective dose to be used in pediatric subjects using data from 8 
adult clinical studies including adult Phase 1 studies and Phases 2/3 studies as well as the 
pediatric study (TED- C13- 003) and suggested that the dose in pediatric subjects is likely to be 
same as the dose in adults (O'Keefe et al. 2006). 
For non-commercial use only


Shire
CONFIDENTIAL
Page 26
Protocol SHP633-304
08 April 2016
Duration of Treatment
The duration of teduglutide treatment in this study mirrors that of the TED-C14-006 study, 
consisting of 24 weeks of teduglutide treatment, followed by a 4-week follow-up period. The 
follow-up period is a mechanism to evaluate whether continued teduglutide is needed. If a 
subject deteriorates during the follow-up period, the subject may be evaluated immediately for 
additional teduglutide treatment. Subjects who clinically deteriorate or stop improving at any 
time after the end of the follow-up period will also be assessed for additional treatment.
Rationale: During the teduglutide treatment cycle, visit frequency is similar to frequencies 
performed in TED-C13-003 and TED-C14-006, to ensure sufficient safety monitoring and 
weaning of PS. During the No TED treatment, visits occur every 12 weeks, a frequency that is 
consistent with standard medical practices.
Measures and Parameters
Following the review and signing of the informed consent (and informed assent, if applicable), 
screening visit procedures will begin including demographics, medical history, and short bowel 
syndrome history. Subjects who meet ≥1 of the teduglutide treatment inclusion criteria may 
proceed to the pre-treatment visit.
After the pre-treatment visit, subjects who still meet ≥1 of the teduglutide treatment inclusion 
criteria, and meet none of the teduglutide treatment exclusion criteria, will start a 28-week cycle, 
consisting of 24 weeks of teduglutide treatment at 0.05 mg/kg SC once daily, followed by a 4-
week follow-up (no treatment) period (Figure 3-1). During the 28-week cycle, clinic visits will 
occur at weeks 1, 2, 4, 6, 9, 12, 16, 20, 24, and 28. Phone visits are required approximately 1 
week after adjustments in PS during the TED treatment period, between weeks 1-24, and weekly 
during the TED follow-up period, between weeks 24 and 28.
Safety and PS requirements will be evaluated on a weekly basis, and quality of life assessments 
will be made approximately every 12 weeks. At all site visits and telephone contacts, safety will 
be monitored and nutritional support will be reviewed and adjusted as needed. To maintain 
consistency across centers, all attempts should be made to follow the nutritional support 
adjustment guidelines (developed with SBS expert input and provided in the protocol) for 
decisions regarding PS reduction and advances in enteral feeds based on weight gain, urine and 
stool output, and clinical stability. Departure from the guidelines, however, is not considered a 
protocol deviation (Appendix 1).
Rationale: Measures of long term safety will include adverse events, growth parameters and 
anti-drug antibodies. Measure of long term efficacy will include durability of effect as measured 
by reduction in PS and improvement in pediatric quality of life measures (PedsQL, PedsQL 
Family Impact Module). A reduction in PS volume of at least 20% at end of treatment (EOT) was 
used as the primary endpoint in pivotal phase 3 adult clinical trials and the completed phase 3 
pediatric study (TED-C13-003), and will be used as an endpoint in this extension study. In 
previous clinical studies, a reduction of this magnitude was associated with a reduction in the 
number of days per week of PS, and increases in enteral intake. Reduction in volume and time of 
PS due to improved enteral absorption may provide a pediatric subject with opportunities for 
more age-appropriate activities including oral rehabilitation. Quality of life assessments will be 
performed in this study to quantitate this effect.
For non-commercial use only


Shire
CONFIDENTIAL
Page 27
Protocol SHP633-304
08 April 2016
Teduglutide has been found to have a targeted intestinotrophic effect. Taking into account the 
patient population and the pharmacologic effect of teduglutide, GI-specific screening tests, 
including fecal occult blood testing and colonoscopy, which are commonly part of the routine 
care of these subjects, will be performed to ensure safety. This study captures long-term safety 
data on polyps and other colonic mucosal changes in teduglutide-exposed subjects using the 
surveillance strategy proposed in Section 7.2.9. 
Figure 3-1:
Study Design Flow Chart
Figure legend: Safety and efficacy data for subjects not receiving teduglutide treatment are captured every 12 weeks, but subjects 
may proceed to the pre-treatment visit at any time in order to assess eligibility for teduglutide therapy. Eligible subjects will enter 
a 28-week teduglutide cycle. During this cycle, subjects will return to the site for safety and efficacy assessments at weeks 1, 2, 4, 
6, 9, 12, 16, 20, and 24 (solid black lines). Phone visits are required approximately 1 week after adjustments in PS during the 
intervening weeks between weeks 2 and 24 (dashed grey lines). Subjects discontinue teduglutide at week 24 and enter a 4-week 
follow-up (no-treatment) period, during which phone visits will be performed weekly (solid grey lines). If an escape criterion is 
met during the follow-up period, subjects may proceed directly to another pre-treatment visit.
3.2
Duration and Study Completion Definition
A subject will be considered enrolled in the study once the subject has provided signed consent, 
and meets all of the Inclusion Criteria. The study will continue for at least 1 year and until each 
subject has access, as needed, to teduglutide. The subject’s maximum duration of participation is 
expected to be approximately 3 years. The study will be completed in approximately 40 months.
A subject will be considered as having completed the study if the subject has not withdrawn 
early from the study for any reason, and has completed the End of Study (EOS) visit.
The study completion date is defined as the date the final subject, across all sites, completes their 
final protocol-defined assessment. Please note that this includes the follow-up visit or contact 
(last safety contact), whichever is later. The study completion date will be used to ascertain 
timing for study results posting and reporting.
For non-commercial use only


Shire
CONFIDENTIAL
Page 28
Protocol SHP633-304
08 April 2016
4
STUDY POPULATION
Each subject must review and sign the informed consent (and informed assent, if applicable) 
before any study-related procedures specified in the protocol are performed. Teduglutide 
treatment eligibility does not impact study eligibility.
4.1
Study Inclusion Eligibility Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1. Subject provides written informed consent (subject, parent or legal guardian and, as 
appropriate, subject informed assent) to participate in the study before completing any 
study-related procedures. 
2. Subject completed the TED-C14-006 study (including subjects in the standard of care 
treatment arm).
3. Subject understands and is willing and able to fully adhere to study requirements as 
defined in this protocol.
4.2
Study Exclusion Eligibility Criteria
There are no exclusion criteria for this study.
4.3
Teduglutide Eligibility Criteria
Subjects are eligible for teduglutide treatment if at least 1 (≥1) of the teduglutide treatment 
inclusion criteria, and none of the teduglutide treatment exclusion criteria can be met. In 
addition, the investigator and the subject (and/or parent or legal guardian, as appropriate) must 
agree to proceed with treatment.
4.4
Teduglutide Treatment Inclusion Criteria
1. Subject is teduglutide-naïve, receiving PS, and unable to significantly reduce PS or 
advance enteral feeds (eg, 10% or less change in PS or advance in feeds) for at least 
3 months prior to and during the teduglutide pre-treatment visit, as assessed by the 
investigator. Transient instability for events such as interruption of central access or 
treatment for sepsis is allowed if the PS returns to within 10% of baseline prior to the 
event.
2. Subject was previously treated with teduglutide and at least 1 of the following criteria is 
satisfied:
a.
Increasing PS requirements following teduglutide discontinuation.
b. Decreased PS requirement during prior teduglutide treatment, followed by 
cessation of improvement after teduglutide discontinuation.
c.
Deteriorating nutritional status eg, weight loss or growth failure) despite 
maximal tolerated enteral nutrition following teduglutide discontinuation.
d. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid 
and electrolyte intake following teduglutide discontinuation.
e.
Severe diarrhea related to teduglutide discontinuation.
For non-commercial use only


Shire
CONFIDENTIAL
Page 29
Protocol SHP633-304
08 April 2016
4.5
Teduglutide Treatment Exclusion Criteria
1. Body weight <10 kg at the pre-treatment visit.
2. Unresected GI polyp, known polyposis condition, pre-malignant change, or 
malignancy, in the GI tract
3. History of cancer in the previous 5 years except surgically curative skin cancers
4. Serial transverse enteroplasty or other major intestinal surgery within 3 months 
preceding the teduglutide pre-treatment visit. Insertion of a feeding tube, anastomotic 
ulcer repair, minor intestinal resections ≤10 cm, and endoscopic procedures are 
allowed.
5. Intestinal or other major surgery planned or scheduled to occur during the 28-week 
cycle
6. Clinically significant intestinal stricture or obstruction
7. Clinically significant, active or recurrent pancreatic or biliary disease
8. Active, severe, or unstable, clinically significant hepatic impairment or injury, 
including the following laboratory values at the pre-treatment visit:
a.
Total bilirubin ≥2 × upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥7 × ULN
c.
Alanine aminotransferase (ALT) ≥7 × ULN
9. Renal dysfunction shown by results of an estimated glomerular filtration rate (eGFR) 
below 50 mL/min/1.73 m2 at the pre-treatment visit
10. Unstable cardiac disease, congenital heart disease or cyanotic disease, with the 
exception of subjects who had undergone ventricular or atrial septal defect repair, or 
patent ductus arteriosus (PDA) ligation
11. Participation in a clinical study using an experimental drug (other than glutamine or 
Omegaven) within 3 months or 5.5 half-lives of the experimental drug, whichever is 
longer, prior to the pre-treatment visit and for the duration of the 28-week cycle
12. Treatment with analogs of glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 
(GLP-2) (not including teduglutide), insulin-like growth factor-1 (IGF-1), or growth 
hormone, within 1 month preceding the teduglutide pretreatment visit.
13. Treatment with octreotide or dipeptidyl peptidase 4 (DPP-4) inhibitors within 3 months 
prior to the pre-treatment visit
14. Known or suspected intolerance or hypersensitivity to the investigational product, 
closely-related compounds, or any of the stated ingredients
15. Known history of alcohol or other substance abuse within 1 year prior to the pre-
treatment visit
16. Pregnant or lactating female subjects 
17. Sexually active female subjects of child-bearing potential unwilling to use approved 
contraception during teduglutide treatment and for 30 days after the treatment period 
For non-commercial use only


Shire
CONFIDENTIAL
Page 30
Protocol SHP633-304
08 April 2016
18. Any condition, disease, illness, or circumstance that in the investigator’s opinion puts 
the subject at any undue risk, prevents completion of the study, or interferes with 
analysis of the study results.
4.6
Follow-up Period Escape Criteria
At the discretion of the investigator, the follow-up period may be interrupted and the subject may 
proceed directly to the pre-treatment visit, if 1 of the following criteria is met:
1. Increasing PS requirements following teduglutide discontinuation.
2. Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal 
tolerated enteral nutrition following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation.
4. Severe diarrhea related to teduglutide discontinuation.
4.7
Reproductive Potential
4.7.1
Female Contraception
To be eligible for treatment with teduglutide, sexually active females of child-bearing potential 
must use an acceptable form of contraception throughout the study period and for 30 days 
following the last dose of investigational product. If hormonal contraceptives are used, they 
should be administered according to the package insert. Females of child-bearing potential who 
are not currently sexually active must agree to use acceptable contraception, as defined below, if 
they become sexually active during the period of the study and 30 days following the last dose of 
investigational product. 
To be eligible for treatment with teduglutide, female pediatric subjects and adolescent subjects 
should be either:

Pre-menarchal and either Tanner Stage 1 or less than age 9 years, or

Females of child-bearing potential (FOCBP) with a negative serum beta-human chorionic 
gonadotropin (-HCG) pregnancy test at the teduglutide pre-treatment visit. Females of 
child-bearing potential must agree to abstain from sexual activity that could result in 
pregnancy or agree to use acceptable methods of contraception.
Acceptable methods of contraception are:

Abstinence

Intrauterine devices plus condoms

Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or foam)

Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring), stabilized for at 
least 30 days prior to the pre-treatment visit, plus condoms. Note: if subject becomes 
sexually active during the study, they should use one of the other acceptable methods 
noted above in addition to the hormonal contraceptive until it has been stabilized for 
30 days.
For non-commercial use only


Shire
CONFIDENTIAL
Page 31
Protocol SHP633-304
08 April 2016
4.8
Discontinuation of Subjects 
4.8.1
Teduglutide Discontinuation
If the investigational product is discontinued prematurely during a teduglutide treatment cycle, 
regardless of the reason, the evaluations listed for the EOT visit are to be performed as 
completely as possible. After the appropriate EOT assessments are performed, a subject may 
remain in the study. A subject who remains in the study would enter a no-teduglutide treatment 
(NTT) period and could be evaluated for subsequent teduglutide treatment eligibility according 
to the study schedules. Comments (spontaneous or elicited) or complaints made by the subject 
must be recorded in the source documents. The reason for permanent treatment discontinuation, 
dates of investigational product administered (including last date of treatment), and amount of 
investigational product taken must be recorded in the electronic case report form (eCRF) and 
source documents, as described in Section 4.8.3. The investigator is encouraged to discuss 
withdrawal of a subject from investigational product with the medical monitor, when possible.
4.8.2
Study Withdrawal
At any time during the study, the investigator or sponsor may withdraw a subject, or a subject 
may withdraw from the study, for any reason, without prejudice to their future medical care by 
the physician or at the institution.
If a subject withdraws from the study during a teduglutide cycle, the evaluations listed for the 
EOT visit are to be performed as completely as possible. Whenever possible, the subject will 
then be asked to return 4 weeks later for the early termination (ET) visit, and will be contacted 
weekly by phone during the interim period between EOT and ET for safety follow-up.
If a subject withdraws from the study during a NTT period, the evaluations listed for the ET visit 
are to be performed as completely as possible. 
Subjects who withdraw from the study will not be replaced.
4.8.3
Reasons for Discontinuation
The reason(s) for permanent discontinuation of treatment and/or withdrawal from the study must 
be determined by the investigator, and recorded in the subject’s medical record and in the eCRF. 
If a subject is withdrawn for more than 1 reason, each reason should be documented in the source 
document, and the most clinically relevant reason should be entered in the eCRF.
Reasons for discontinuation include, but are not limited to:

Adverse event 

Protocol deviation

Lack of efficacy 

Physician decision 

Withdrawal by subject 

Lost to follow-up

Pregnancy (Discontinuation of treatment only) 

Death 

Other 
For non-commercial use only


Shire
CONFIDENTIAL
Page 32
Protocol SHP633-304
08 April 2016
4.8.3.1
Subjects ‘Lost to Follow-up’ Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact (office visit or telephone contact). At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that they 
return to the site for final safety evaluations, and return any unused investigational product.
For non-commercial use only


Shire
CONFIDENTIAL
Page 33
Protocol SHP633-304
08 April 2016
5
CONCOMITANT TREATMENT
5.1
Concomitant Medications and GI Procedures
Concomitant treatment refers to all treatment taken between the dates of informed consent and 
EOS, inclusive. Concomitant treatment information must be recorded on the appropriate eCRF 
page. Concomitant treatments will be assessed at each site visit, and include all non-study 
treatments (medications, herbal treatments, vitamins, invasive and diagnostic procedures). 
Concomitant GI procedures include (but are not limited to) endoscopy, radiographic studies, GI 
and liver biopsies and associated pathology results. Concomitant treatment information must be 
recorded on the appropriate eCRF page. Details of medication changes and/or dosages will be 
recorded on the eCRF.
The mechanism of action of teduglutide may increase absorption of drugs (eg, motility 
medication including narcotics and opioids used for the management of SBS, Coumadin, 
psychotropics, metronidazole, and digoxin). Accordingly, due consideration should be given to 
modifying concomitant medication regimens. Down-titration of concomitant medications should 
be considered when drugs, especially those with a narrow therapeutic range, are prescribed at 
dosages that are higher than usual.
5.1.1
Permitted Treatment
Standard medical therapy for SBS should be continued.
5.1.2
Prohibited Treatment
The mechanism of action of teduglutide may increase enteral absorption of drugs (eg, motility 
medication including narcotics and opioids used for the management of SBS, Coumadin, 
psychotropics, metronidazole, digoxin), so consideration should be given to modifying 
concomitant enteral medication regimens. Down-titration of concomitant enteral medications 
should be considered when drugs, especially those with a narrow therapeutic range, are given at 
dosages that are higher than usual.
The following medications are prohibited during teduglutide treatment and within the provided 
timeframe prior to the pre-treatment visit:
Table 5-1: Prohibited Treatment
Prior Therapy
Time Restriction Prior to 
the Pre-Treatment Visit
Native/synthetic glucagon-like peptide-2 (not-including teduglutide)
Any
Glucagon-like peptide-1 analog or human growth hormone
1 month
Octreotide or dipeptidyl peptidase 4 inhibitors
3 months
Biological therapy (eg, antitumor necrosis factor)
6 months
For non-commercial use only


Shire
CONFIDENTIAL
Page 34
Protocol SHP633-304
08 April 2016
6
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product 
The test product is teduglutide, which will be provided in sterile, single-use 3 mL vials 
containing 5 mg or 1.25 mg teduglutide as a white lyophilized powder to be reconstituted before 
use with 0.5 mL sterile water for injection. In addition to the active ingredient (teduglutide), each 
vial of teduglutide contains L-histidine, mannitol, monobasic sodium phosphate monohydrate, 
and dibasic sodium phosphate as excipients. Additional information is provided in the current 
SHP633 investigator’s brochure.
6.1.1
Blinding the Treatment Assignment
Not applicable for this open-label study.
6.2
Administration of Investigational Product(s)
6.2.1
Interactive Response Technology (IRT) for Investigational Product 
Management
An interactive web-based response system (IWRS) will be used for screening and enrolling 
subjects, recording subject visits, investigational product supply dispensation and management, 
inventory management and supply ordering, investigational product expiration tracking and 
management, and return of investigational product. Please refer to the Study Manual for 
additional details regarding the IWRS. 
The IWRS will also be used for creating, tracking, and confirming investigational product 
shipments. A user manual with specific functions and instructions for the IWRS will be provided 
to the site, and site personnel will receive training.
6.2.2
Allocation of Subjects to Treatment 
This is an open-label study. Subjects will retain their assigned subject number from the 
TED-C14-006 study. Assessment of need for teduglutide treatment should be guided by the 
teduglutide treatment inclusion criteria. If the investigator, subject, and/or parent/guardian agree 
to proceed with treatment, a formal evaluation of teduglutide inclusion and exclusion criteria will 
be performed at the pre-treatment visit (Table 1-3). 
6.2.3
Dosing
If teduglutide treatment eligibility is established at the pre-treatment visit and again, confirmed at 
the Cycle Day 1 visit, the subject will start a teduglutide treatment period, consisting of 24 weeks 
of teduglutide treatment at 0.05 mg/kg SC once daily. The initial dose will be calculated based 
on body weight measured at the teduglutide pre-treatment visit, and adjusted as needed, based on 
body weight measured at Week 12 (CxW12). No other adjustments to dose will be made during 
the teduglutide treatment period, unless discussed with the sponsor’s medical monitor. 
Following reconstitution, teduglutide will be administered by SC injection QD into 1 of the 4 
quadrants of the abdomen (in subjects without a stoma) or into either the thigh or arm. For 
subjects with a stoma, the quadrant of the abdomen containing the stoma should not be used. 
Teduglutide should be used as soon as possible after reconstitution, but no more than 3 hours 
later.
For non-commercial use only


Shire
CONFIDENTIAL
Page 35
Protocol SHP633-304
08 April 2016
The subject should be dosed at approximately the same time each day. Consecutive doses should 
be separated by at least 12 hours. Each day, the injection site should be rotated.
The first SC injection in teduglutide-naïve subjects should be administered under the supervision 
of the investigator or designee and the subject observed for hypersensitivity reactions for at least 
4 hours during their initial dosing visit. The site of administration (arm, thigh, and abdomen) of 
the first teduglutide dose must be specified and recorded in the eCRF. 
Detailed instructions for reconstitution and injection of the investigational product can be found 
in the Instructions for Use. 
Following each 24-week teduglutide treatment period, subjects will enter a 4-week follow-up 
period. During the follow-up, the investigator will assess the subject via weekly telephone visits. 
At any time during the follow-up period, if escape criteria are met, the subject may proceed 
directly to another Pre-Treatment visit to assess treatment eligibility for another cycle 
(Section 4.6). Following the completion of the 4-week follow-up, the subject will continue in the 
study off teduglutide. Additional 28-week cycles may be repeated if treatment eligibility is 
established each time. 
6.2.4
Unblinding the Treatment Assignment
Not applicable for this open-label study.
6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling 
Labels containing study information and pack identification will be applied to the investigational 
product(s) container. 
The study drug will be packaged, labeled, and shipped to the study site by the sponsor or 
designee. Kits containing 7 vials of study drug will be supplied and these will be labeled in 
accordance with applicable regulatory requirements. Sterile water for injection syringes will also 
be provided separately and will be labeled in accordance with the applicable regulatory 
requirements.
All study drug used in this study will be manufactured, tested, labeled, and released according to 
current legal requirements and Good Manufacturing Practice.
6.3.2
Packaging
Investigational product is packaged in the following conditions:
Teduglutide will be provided in a sterile, single-use, glass vial as a lyophilized powder, to be 
reconstituted with 0.5 mL sterile water for injection provided as the diluent in a prefilled syringe.
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
6.3.3
Storage
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.
For non-commercial use only


Shire
CONFIDENTIAL
Page 36
Protocol SHP633-304
08 April 2016
Study drug must be kept in a locked area with access restricted to specific study personnel. Study 
drug will be stored refrigerated at a temperature between 2 to 8°C (35.6 to 46.4°F) until 
dispensed to a subject. Once dispensed to a subject, the study drug can be stored refrigerated or 
up to a controlled room temperature (acceptable range of 2 to 25°C, or 35.6 to 77°F). 
Parent/guardian will be instructed to keep the subject’s study drug and sterile water diluent at 
controlled room temperature. If there are concerns that the controlled room temperature cannot 
be maintained, the study drug may be refrigerated.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (ie, certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
Investigational products are distributed by the pharmacy or nominated member of the study 
team. The pharmacist/nominated team member will enter the unique subject identifier on the 
investigational product bottle/carton labels, as they are distributed.
6.4
Drug Accountability 
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. The 
investigator is to keep a current record of the inventory and dispensation of all clinical supplies. 
This record will be made available to the sponsor’s site monitor for the purpose of accounting for 
all clinical supplies. Any discrepancy or deficiency will be recorded and will include an 
explanation. All supplies sent to the investigator must be accounted for and in no case will 
clinical supplies be used in any unauthorized situation.
The investigator has overall responsibility for administering/dispensing investigational product. 
Where permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator. 
This delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will dispense the investigational product only to subjects eligible 
for teduglutide treatment following the procedures set out in the study protocol. All dispensed 
For non-commercial use only


Shire
CONFIDENTIAL
Page 37
Protocol SHP633-304
08 April 2016
study medication will be documented in the eCRFs and/or other investigational product record 
(eg, investigation product accountability form). The investigator is responsible for assuring the 
retrieval of all study supplies from subjects.
All used and unused study drug vials must be returned by the subjects and/or parent/guardian, 
and will be retained at the site. All original containers, whether empty or containing study drug 
will be returned to the pharmacy. Returned study drugs will NOT be relabeled or reassigned for 
use by other subjects. Contents of the study drug containers will not be combined. All used and 
unused vials must be returned to the distribution center according to the sponsor’s instruction. 
No vial/kit may be destroyed on site without approval by the sponsor. 
Please see the Pharmacy Manual for additional information.
6.5
Subject Compliance
Subjects will be instructed to bring their unused investigational product and empty/used
investigational product packaging to every visit. Drug accountability will be assessed at the 
container/packaging level for unused investigational product that is contained within the original 
tamper-evident sealed container (eg, bottles, trays, vials) or at the individual count level for 
opened containers/packaging. The pharmacist/nominated person will record details on the drug 
accountability form.
Of those subjects eligible for teduglutide treatment, subjects who have received 80% of the 
planned doses administered will be assessed as being compliant with the study protocol.
For non-commercial use only


Shire
CONFIDENTIAL
Page 38
Protocol SHP633-304
08 April 2016
7
STUDY PROCEDURES
7.1
Study Schedule
Detailed study procedures and assessments to be performed for subjects throughout the study are 
outlined in the Schedule of Assessments (Table 1-1, Table 1-2, and Table 1-3) and must be 
referred to in conjunction with the instructions provided in this section. 
7.1.1
Screening 
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent (and assent, as applicable) 
from the subject. A subject will have up to 7 days, after completion of the TED-C14-006 study, 
to sign consent to participate in the SHP633-304 study. The first visit after screening (either a 
no-teduglutide treatment visit or a pre-treatment visit), must occur within 12 weeks of screening.
The screening visit (Scr) assessments and procedures, beginning with informed consent, will be 
performed as outlined in Table 1-1, and as detailed below:

Informed consent, and informed assent (if applicable), is obtained

Study eligibility is determined. A screen failure is a subject who has given informed 
consent and failed to meet the Study Inclusion Eligibility Criteria. Subjects cannot be 
rescreened once they have been designated as a screen failure. 

Demographics, medical history, and SBS history

Intake and output diaries are dispensed

Evaluate teduglutide treatment inclusion criteria 

Adverse events, concomitant medications and concomitant GI procedures
7.1.2
Visits for Subjects Not Receiving Teduglutide
While outside of the 28-week teduglutide-treatment cycle, subjects will be followed every 
12 weeks for safety and efficacy assessments. No-teduglutide treatment visits are numbered 
sequentially (NT1, NT2, etc.), even if interrupted by the treatment cycles. Assessments will be 
performed as outlined in Table 1-2 and described below.

Intake and output diaries are dispensed

Evaluate teduglutide treatment inclusion criteria

Adverse events, concomitant medications and concomitant GI procedures

Physical examination and vital signs, including weight

Height and head circumference

Review intake and output diaries

Record PS and enteral nutrition (EN) prescriptions, and adjust as needed

Safety Laboratory Tests (ie, clinical chemistry, hematology, and urinalysis)
For non-commercial use only


Shire
CONFIDENTIAL
Page 39
Protocol SHP633-304
08 April 2016

PedsQL Generic Core Scale/PedsQL Family Impact Module/ PedsQL Gastrointestinal 
Symptoms Module Sub-Scales

Antibodies to teduglutide, if and when required

Fecal occult blood testing, as indicated (see Section 7.2.9.1)

Colonoscopy, as indicated (see Section 7.2.9.2)

Serum sample, as indicated
Teduglutide treatment may be considered at any time during the NTT period. If the investigator 
and the subject (and parent or legal guardian, as appropriate) agrees to proceed with treatment if 
the subject is eligible, the subject may proceed to the pre-treatment visit to determine eligibility.
The pre-treatment visit must occur within 12 weeks of a given NTT visit.
7.1.3
Visits for Subjects Receiving Teduglutide
7.1.3.1
Pre-treatment Visit
Subjects who meet at least 1 of the teduglutide treatment inclusion criteria during the screening 
visit or during the NTT period may proceed to the pre-treatment visit if the investigator, subject 
and parent agree to proceed with teduglutide therapy. Similarly, subjects who meet escape 
criteria during the teduglutide follow-up period may proceed to the pre-treatment visit.
The pre-treatment visit may also be combined with screening visit, and if the pre-treatment visit 
assessments occur within 7 days of the TED-C14-006 EOS visit (Week 28), both sets of 
assessments can be combined. A subject must have 2 weeks of intake diary data collected, prior 
to the first dose administration (CxD1) during any teduglutide treatment cycle. In general, pre-
treatment assessments may occur over a period of up to 21 days. The teduglutide pre-treatment 
visit (Px) assessments and procedures will be performed in Table 1-3 and as described below:

Evaluate teduglutide eligibility (treatment inclusion/exclusion criteria) 

Dispense intake and output diaries

Adverse events, concomitant medications and concomitant GI procedures

Fecal occult blood testing 

Gastrointestinal-specific testing, including colonoscopy or sigmoidoscopy as indicated

Physical examination and vital signs, including weight

Height and head circumference

Review intake and output diaries

Record PS and EM prescriptions, and adjust as needed.

Safety Laboratory Tests 
(In addition to clinical chemistry, hematology, and urinalysis, labs at this visit include 
prothrombin time [PT] international normalized ratio [INR]. Subsequent prothrombin 
time/international normalized ratio (PT/INR) measurement is only required to evaluate 
for suspected drug-induced liver injury [DILI]). 
For non-commercial use only


Shire
CONFIDENTIAL
Page 40
Protocol SHP633-304
08 April 2016

Pregnancy testing (serum)

Serum sample 
7.1.3.2
Teduglutide Treatment Period (CxD1-CxW24)
The open-label teduglutide treatment period will comprise 24 weeks, during which all 
assessments and procedures listed for Visits CxD1-CxW24 in Table 1-3 shall be completed. 
Cycles are numbered sequentially, such that the first visit of the first cycle is C1D1, and the first 
visit of the second cycle is C2D1, etc. Visit windows are calculated based upon the date of first 
investigational product administration (Visit CxD1). 
VISIT CXD1
Assessments and procedures at this visit will be performed as outlined Table 1-3 and as 
described below. 
2 weeks of intake diary data are required before drug is administered at CxD1.

Confirm teduglutide eligibility

Dispense intake and output diaries

Adverse events, concomitant medications and concomitant GI procedures

Physical examination and vital signs, including weight

Height and head circumference

Review intake and output diaries

Record PS and EN prescriptions, and adjust as needed 

Safety laboratory tests

Quality of life measurements 

Antibodies to teduglutide

Pregnancy testing (urine)

Dispense study drug
7.1.3.3
Site Visits during Teduglutide Treatment Period
Subjects will return for clinic visits on cycle weeks 1, 2, 4, 6, 9, 12, 16, 20, and 24/EOT. 
Assessments and procedures at these visits will be performed as outlined in Table 1-3 and as 
described below:

Dispense/review intake and output diaries

Physical examination and vital signs, including weight

Record PS and EN prescriptions, and adjust as needed

Safety laboratory tests 

Urine pregnancy testing for FOCBP (CxW4, CxW9, CxW12, CxW16, CxW20, 
CxW24)
For non-commercial use only


Shire
CONFIDENTIAL
Page 41
Protocol SHP633-304
08 April 2016

Study drug dispensation (except for CxW24)

Adverse events, concomitant medications and concomitant GI procedures
In addition, at CxW12 and CxW24 Visits ONLY, the following procedures will be performed:

Height and head circumference

Antibodies to teduglutide

Fecal occult blood testing (FOBT)

GI-specific testing, including colonoscopy or sigmoidoscopy as indicated 

Quality of life measurements 
At CxW24 ONLY, a serum sample is collected and stored for future analysis. This sample will 
not be used for genetic testing and lack of collection will not constitute a protocol deviation.
7.1.3.4
Phone Visits 
Phone visits are required approximately 1 week after adjustments in PS during the teduglutide 
treatment period. Phone visit assessments and procedures are outlined in Table 1-3 and described 
below:

Review intake and output diaries

Safety laboratory tests (clinical chemistry and urinalysis)

Record PS and EN prescriptions, and adjust as needed

Obtain AEs, concomitant medications, and concomitant GI procedures  

Evaluate escape criteria
7.1.4
Teduglutide Follow-up Period
The safety follow-up period for this protocol is 4 weeks (Weeks 25 – 28 of the cycle). Phone 
visits will occur on cycle weeks 25, 26, and 27 for all subjects. Phone visit assessments and 
procedures at weeks 25-27 will be the same as for telephone visits performed during the 
teduglutide treatment period. In addition, subjects will be evaluated for follow-up period escape 
criteria. If escape criteria are met at any time during the follow-up period, the subject may 
proceed directly to another pre-treatment visit at the investigator’s discretion. 
At cycle week 28 (CxW28), subjects will return to the study site. In addition to the assessments 
performed at weeks 25-27, the following procedures will be performed at CxW28 ONLY:

Physical examination and vital signs, including weight

Antibodies to teduglutide

Pregnancy testing (urine)

Evaluate escape criteria
7.1.4.1
Study Completion/Early Termination Visit (EOS/ET Visit) 
All subjects will return to the study site for the end of study/early termination visit (EOS/ET). 
Assessments and procedures at this visit will be performed as outlined in Table 1-1 and as 
For non-commercial use only


Shire
CONFIDENTIAL
Page 42
Protocol SHP633-304
08 April 2016
described here. If a subject discontinues the study prematurely, the assessments for the EOS/ET 
Visit are to be performed as completely as possible.

Adverse events, concomitant medications and concomitant GI procedures  

Physical examination and vital signs, including weight

Height and head circumference

Review intake and output diaries

Record PS and EN prescriptions, and adjust as needed

Safety laboratory tests 

Fecal occult blood testing, as indicated

Gastrointestinal-specific testing, including colonoscopy or sigmoidoscopy as 
indicated. 

Quality of life measurements 

Antibodies to teduglutide

Pregnancy testing, as needed
7.2
Study Evaluations and Procedures
7.2.1
Demographics, Medical History, and SBS History
Demographics, medical history, and SBS history will be obtained at screening. Medical history 
for purposes of this extension study will consist of the following:

Adverse events that were ongoing at the time of completion of TED-C14-006

Events that occurred during the period between completion of TED-C14-006 and 
informed consent to SHP-633-304

Gestational age at birth and parental heights. 
This medical history information will supplement the medical history information collected at 
the start of the TED-C14-006 core study. If the subject has any changes to the SBS history 
collected at the baseline visit of the TED-C14-006 study, that information (updated SBS history) 
will be collected.
7.2.2
Physical Examination
Physical examinations will be performed according to the study schedules. Any new clinically 
significant findings noted during physical examinations should be recorded on the appropriate 
AE page of the eCRF. 
7.2.3
Vital Signs, Body Weight, Height, Head Circumference and Body Mass 
Index (BMI)
Vital signs will be measured according to the study schedules. Measurements will include 
systolic and diastolic blood pressure (mmHg), pulse (beats per minute), and body temperature 
(°C/°F). Blood pressure should be determined by cuff (using the same method, the same arm, 
and in the same position throughout the study).
For non-commercial use only


Shire
CONFIDENTIAL
Page 43
Protocol SHP633-304
08 April 2016
Body weight will also be recorded in the eCRF; subjects should be weighed on the same scale at 
each study visit. Height (or length) and head circumference (for subjects ≤36 months of age) will 
be measured at selected visits. A height z-score, weight z-score, BMI, and BMI z-score will be 
calculated by the sponsor using the site-provided height and weight data collected at each site 
visit
New clinically significant vital sign abnormalities should be recorded on the appropriate AE 
page of the eCRF.
7.2.4
Clinical Laboratory Tests
Safety laboratory tests to be performed at site visits consist of clinical chemistry, hematology, 
and urinalysis and will be performed as outlined in the study plan (Table 1-1, Table 1-2, and 
Table 1-3) Scheduled laboratory testing will be processed by a central lab. All laboratory assays 
will be performed according to the central laboratory’s normal procedures. Reference ranges are 
to be supplied by the laboratory. The investigator should assess out-of-range clinical laboratory 
values for clinical significance, indicating if the value(s) is/are not clinically significant or 
clinically significant. Abnormal clinical laboratory values, which are unexpected or not 
explained by the subject’s clinical condition, may, at the discretion of the investigator or sponsor, 
be repeated as soon as possible until confirmed, explained, or resolved. 
During the teduglutide treatment period, subjects will also have safety labs within approximately 
5-7 days after a PS adjustment. Safety labs performed after PS adjustment and between site visits 
will consist of clinical chemistry and urinalysis and may be processed by the central laboratory 
or a local laboratory. Local lab results will not be entered in the eCRFs; however, if the local lab 
results indicate any new clinically significant changes, they must be reported as an adverse event 
(see Section 8.1). For pediatric subjects in diapers, urine specimen collection should be 
attempted as part of the safety labs, but lack of urinalysis will not constitute a protocol deviation.
New clinically significant labs should be reported as AEs.
The following clinical laboratory assessments will be performed according to the study 
schedules: 
For non-commercial use only


Shire
CONFIDENTIAL
Page 44
Protocol SHP633-304
08 April 2016
Table 7-1 List of Laboratory Tests 
Hematology:

Hematocrit 

Hemoglobin 

Platelet count

Red blood cell count 

Red blood cell morphology, if needed

White blood cell count with differential
Coagulation:
Prothrombin time/International normalized ratio
Urinalysis: 

Blood

Glucose

Leucocytes

Microscopic analysis

pH and osmolality

Protein

Sodium

Specific gravity

Pregnancy tests
(females of childbearing 
potential):
o
Serum β-HCG (screening)
o
Urine β-HCG (all other visits)
Biochemistry:

Albumin 

Alkaline phosphatase 

Alanine aminotransferase 

Amylase

Aspartate aminotransferase 

Bicarbonate

Bilirubin (total and indirect)

Blood urea nitrogen 

Calcium (total)

Chloride

Cholesterol

C-reactive protein 

Creatinine

Estimated Glomerular Filtration Rate 

(Schwartz formula)

Gamma-glutamyl transferase 

Glucose

Lipase

Magnesium

Phosphorus

Potassium 

Sodium 

Triglycerides

Uric acid
7.2.5
Serum Sampling
Serum samples will be collected and stored for future analysis at the following times: 

During Teduglutide treatment period: at the pretreatment and CxW24 (EOT) visits.

During NTT: Approximately every 24 weeks. 
The serum sample will not be used for genetic testing. Lack of collection will not constitute a 
protocol deviation.
The sponsor, sponsor’s representatives, biorepositories, and any specialty laboratories will be 
blinded to the subject’s identity. The sample and/or extracted material will otherwise be stored 
for up to 15 years from the end of the study after which time it will be destroyed. Upon written 
request, subjects will be permitted to withdraw their sample from the analysis and have their 
sample and/or extracted material destroyed. Any results already generated from the samples will 
not be removed from any analyses that have already been performed.
For non-commercial use only


Shire
CONFIDENTIAL
Page 45
Protocol SHP633-304
08 April 2016
7.2.6
Pregnancy Testing
A serum pregnancy test is performed on all FOCBP at the teduglutide pre-treatment visit. Urine 
pregnancy tests will be administered at all other visits according to the study schedules, or if 
pregnancy is suspected, or as specified per protocol upon withdrawal of the subject from the 
study.
7.2.7
Antibody Testing
Blood samples will be drawn for the analysis of positive/specific antibodies to teduglutide 
according to the Schedule of Assessments (Table 1-1, Table 1-2, and Table 1-3). Blood samples 
for antibodies may be drawn from a central line or from peripheral access. The sample drawn on 
CxD1 must be drawn prior to administration of the first dose of teduglutide.  Once the subject 
has started teduglutide treatment, samples must be drawn at least 14 hours after dosing. Subjects 
who test positive/specific for antibodies to teduglutide will also be tested for neutralizing 
antibody. Subjects who have been previously treated with teduglutide, and who test 
positive/specific for antibodies to teduglutide, will have follow-up blood draws for 
positive/specific antibodies to teduglutide every 12 weeks while on study until a negative result 
is obtained.
7.2.8
Volume of Blood
Efforts will be made to minimize the amount of blood drawn from all pediatric subjects enrolled 
in this study. The volumes of blood to be drawn from each subject will vary depending on 
clinical status. Approximate volumes of blood to be drawn from each subject annually are shown 
in the following table.
Table 7-1: Approximate Volume of Blood to be Drawn from Each Subject Annually 
Assessment
Sample 
Volume (mL)
No. Samples per two 28-week 
Teduglutide Cycles
Total 
Volume (mL)
Subjects Receiving Teduglutide Treatment 
Safety
Biochemistry and -hCGa
2.5
24
60
Hematology
2
24
48
Coagulation Parameters
1
2
2
Antibodies
2
8
16
Serum storage samples
3
4
12
Total mL per 2, 28-week Treatment Cycles (Approximate Annual Volume):
138
Subjects Not Receiving Teduglutide Treatmentb
Assessment
Sample 
Volume (mL)
No. Samples per 4 NTT Visits
Total 
Volume (mL)
Safety
Biochemistry
2.5
4
10
Hematology
2
4
8
Serum storage samples
3
2
6
Total mL per 4 “No Teduglutide Treatment” Visits 48-week period:
24
Abbreviations: β-hCG=beta-human chorionic gonadotropin
a β-hCG testing will only be administered to females who are eligible for teduglutide treatment.
b Subjects not receiving TED treatment, but who were exposed to it previously and tested positive for anti-TED antibodies will 
require blood samples for antibody testing every 12 weeks until they test negative.
For non-commercial use only


Shire
CONFIDENTIAL
Page 46
Protocol SHP633-304
08 April 2016
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment. When more than 1 blood assessment is to be done at the time 
point/period, if they require the same type of tube, the assessments should be combined. Blood 
volume estimates do not include safety labs performed after PS adjustment, and anti-teduglutide 
antibody testing during no-teduglutide treatment.
7.2.9
Gastrointestinal-specific Testing
7.2.9.1
Fecal Occult Blood Testing
Fecal occult blood testing must be performed on all subjects at the pre-treatment visit, week 12, 
and week 24 of the teduglutide cycle. During NTT periods, FOBT must be performed on 
teduglutide-exposed subjects (subjects who have received teduglutide any time in the past and 
are therefore not teduglutide-naïve) on a roughly annual basis (approximately every 48-60 
weeks). Actions to be taken in response to a positive FOBT are described below.
7.2.9.2
Colonoscopy
Teduglutide-naïve subjects age 12 and older will undergo colonoscopy at the pre-treatment visit 
if one has not been performed within 1 year. 
Subjects of any age with newly positive FOBT results at the pre-treatment visit for which a 
readily detectable cause cannot be identified (eg, anal fissure) will undergo a colonoscopy prior 
to receiving teduglutide. If newly positive FOBT results (for which a readily detectable cause 
cannot be identified) are obtained at the end of a teduglutide treatment cycle (CxW24/EOT), 
colonoscopy will be performed. The need for colonoscopy in response to positive FOBTs at any 
other point during the study, or to re-evaluate persistently positive FOBTs is at the discretion of 
the investigator. 
Teduglutide-exposed subjects who have received the equivalent of 2 treatment cycles (48 weeks 
of study drug exposure) will undergo colonoscopy. While receiving additional teduglutide 
treatment, subjects will undergo colonoscopy at 5 year intervals or more often as needed. 
Upper endoscopy may be performed along with any colonoscopy at the investigator’s discretion. 
If a polyp is found, adherence to current polyp follow-up guidelines is recommended. Subjects 
with unresected GI polyps, polyposis conditions, pre-malignant change or malignancy in the GI 
tract will be excluded from teduglutide treatment.
7.2.10
Nutritional Support
Nutritional support includes PS, EN, and other food and fluids. Advances in EN and/or 
reductions to PS will be based on clinical status, including weight, linear growth, hydration 
status, and safety laboratory results. Intake and output diaries will include data to be considered 
in the adjustment of each subject’s nutritional support. Guidelines for nutritional support 
management and weaning algorithms are provided in Appendix 1.
7.2.11
Intake Diary
Intake diaries will be used to collect and evaluate each subject’s nutritional support. The 
subject/parent/guardian will complete the appropriate fields of the PS and enteral nutrition 
(formula) sections of the intake diary 2 weeks prior to ALL scheduled site visits. During the 24-
week teduglutide treatment period, the intake diary will also be completed for 1 week following 
For non-commercial use only


Shire
CONFIDENTIAL
Page 47
Protocol SHP633-304
08 April 2016
PS adjustments. The intake diary will also be completed daily during the 4-week follow-up 
period. The following data will be captured in the intake diaries:

Parenteral support volume and infusion duration

Enteral nutrition (formula) volume

Site personnel will determine the actual PS and EN daily calories based on diary 
entries.
7.2.12
Output Diary
Urine and stool output should be recorded in the output diary over a 48-hour period of PS and 
EN stability before every clinic visit; in addition, output should be recorded for subjects that are 
in a teduglutide treatment cycle within 1 week of implementing a change in the PS prescription, 
regardless of previous teduglutide exposure.
Urine data:

Toilet-trained subjects (who do not wear diapers)

Measure and record all urine output in mL or cc. The subject or parent will perform 
dipstick specific gravity tests on the first urine produced after the daily infusions of 
PS.
Nontoilet-trained subjects (who wear diapers)

Measure and record the weight of all urine-only diapers. Urine volume will be 
calculated using the following formula: 1 g (scale weight) = 1 mL or 1 cc
At the discretion of the investigator, the parent may be asked to collect the first void after the 
daily PS infusion to measure specific gravity.
Stool data (includes diapers with mixed urine and stool):

Toilet-trained subjects WHO DO NOT WEAR DIAPERS

Record the occurrence of each bowel movement and score the stool consistency 
using the Bristol Stool Form Scale (see Output diary)

Nontoilet-trained subjects WHO WEAR DIAPERS

Record the weight of diapers containing stool (including diapers with mixed urine 
and stool) as stool output and score the stool consistency using the Bristol Stool 
Form Scale (see Output diary). Stool volume will be calculated using the formula: 
1 g (scale weight)=1 mL or 1 cc
All ostomy output volume should be recorded. Ostomy output will not be scored using the 
Bristol scale.
All diaries will be reviewed by the investigator or their designee at each clinic and telephone 
contact to assess clinical status and opportunity for PS reduction and advance in feeds.
7.2.13
Health-related Quality of Life Assessments
Throughout the study, health-related quality of life assessments will be performed using the 
PedsQL Generic Core Scales. Each PedsQL age-appropriate form takes less than 4 minutes to 
For non-commercial use only


Shire
CONFIDENTIAL
Page 48
Protocol SHP633-304
08 April 2016
complete. The scales include self-reports for pediatric subjects and adolescents aged 5 to 
18 years and proxy-reports from parents of pediatric subjects aged 2 to 18 years. 
Field trials have shown that the internal consistency reliability of the PedsQL was excellent, with 
alphas for the generic core scales in both self- and proxy-report greater than the 0.70 standard, 
and alphas for the full 23-item scale approaching 0.90 for self- and proxy-report. Missing data 
were minimal. Item response distributions were across the full scale range, with no floor effects, 
and minimal ceiling effects. 
The validity of the PedsQL Generic Core Scales was demonstrated through known group 
comparisons, and correlations with other measures of disease burden. The PedsQL self- and 
proxy-report distinguished between pediatric subjects with and without a chronic health 
condition, and within the group of pediatric subjects with a chronic condition, between those 
who did or did not have an overnight hospital visit in the last 12 months. Further, both child self-
report and parent proxy-report correlated significantly with the number of days the child was too 
ill to pursue normal activities, needed someone to care for him or her, missed school in the last 
month, the number of days the parent missed from work in the last month, and parent-report of 
problems pursuing their normal work routine and concentrating at work. The PedsQL Generic 
Core Scales are also responsive to clinical change, as demonstrated in field trials.
7.2.13.1
Pediatric Quality of Life Generic Core Scale (PedsQL™), Acute version
The PedsQL Generic Core Scale is designed to measures health-related quality of life (HRQoL) 
in pediatric subjects and adolescents (2-18 years of age). The developmentally appropriate 
PedsQL Generic Core Scale will be completed by either the parent or legal guardian and subject 
as indicated in Table 7-2 at the time points as outlined in Table 1-1, Table 1-2 and Table 1-3.
Table 7-2: Developmentally Appropriate PedsQL™Generic Core Scales
Report
Completed by
Parent Report for Toddlers (ages 2-4)
Parent or Legal Guardian
Child Self Report and Parent Proxy-Report for Young Pediatric subjects 
(ages 5-7)
Subject and Parent or Legal Guardian
Child Self Report and Parent Proxy-Report for Pediatric subjects (ages 
8-12)
Subject and Parent or Legal Guardian
Child Self Report and Parent Proxy-Report for Teens (ages 13-18)
Subject and Parent or Legal Guardian
Abbreviations: PedsQL=Pediatric Quality of Life Inventory
The Parent Report for Toddlers (ages 2-4) of the PedsQL Generic Core Scale is composed of 21 
items comprising 4 dimensions as follows: 1) Physical Functioning (8 items), 2) Emotional 
Functioning (5 items), 3) Social Functioning (5 items), 4) School Functioning (3 items). 
The Child and Parent Reports of the PedsQL Generic Core Scale for Young Pediatric subjects 
(ages 5-7), Pediatric subjects (ages 8-12), and Teens (ages 13-18) are composed of 23 items 
comprising 4 dimensions as follows: 1) Physical Functioning (8 items), 2) Emotional 
Functioning (5 items), 3) Social Functioning (5 items), 4) School Functioning (5 items).
For non-commercial use only


Shire
CONFIDENTIAL
Page 49
Protocol SHP633-304
08 April 2016
7.2.13.2
Pediatric Quality of Life Family Impact Module (PedsQL™), Acute 
version
The PedsQL Family Impact Module is a parent-report multidimensional instrument that will be 
completed by the parent or legal guardian, as outlined in Table 1-1, Table 1-2, and Table 1-3.
The PedsQL Family Impact Module is a specific module of the PedsQL that is used to measure 
the impact of pediatric chronic health conditions on parents and the family (Varni et al. 2004). 
The 36-item PedsQL Family Impact Module consists of 6 scales measuring parent self-reported 
functioning as follows: 1) Physical Functioning (6 items), 2) Emotional Functioning (5 items), 3) 
Social Functioning (4 items), 4) Cognitive Functioning (5 items; worries about treatment and 
disease), 5) Communication (3 items), 6) Worry (5 items). Two additional scales measure parent-
reported family functioning as follows: 1) Daily Activities (3 items), and 2) Family Relationships 
(5 items). The PedsQL Family Impact Module should take the parent or legal guardian 
approximately 5 to 10 minutes to complete.
7.2.13.3
PedsQL Gastrointestinal Symptoms Module (PedsQL™), Acute version
The PedsQL Gastrointestinal Symptom Module is a disease-specific 58-item module, comprised 
of 10 different symptom scales that assess gastrointestinal symptom-related quality of life: food 
and drink limits, trouble swallowing, heartburn and reflux, nausea and vomiting, gas and 
bloating, constipation, blood in poop, and diarrhea. The PedsQL Gastrointestinal Symptoms 
Module was designed to allow the selection and scoring of individual scales from the Module. 
The scales of Food and Drink Limits (6 items) and Diarrhea (7 items) were identified as 
clinically relevant and appropriate for the symptoms experienced in this pediatric study 
population, and therefore, are the only scales used in this study. The scales will be completed by 
either the parent or legal guardian and subject as indicated in Table 7-2 at the time points 
outlined in Table 1-1, Table 1-2, and Table 1-3.
For non-commercial use only


Shire
CONFIDENTIAL
Page 50
Protocol SHP633-304
08 April 2016
8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.4. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, 
then each symptom should be listed individually. All AEs should be captured on the appropriate 
AE pages in the eCRF and in source documents. In addition to untoward AEs, unexpected 
benefits outside the investigational product indication should also be captured on the AE eCRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
For non-commercial use only


Shire
CONFIDENTIAL
Page 51
Protocol SHP633-304
08 April 2016
Note that the severity of AEs that constitute dose interruption criteria will also be evaluated 
using the National Cancer Institute’s (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) grading criteria (Table 8-1).
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of 
the investigational product is compelling and/or follows a known or 
suspected response pattern to that product, and the event cannot be 
explained by the subject’s medical condition, other therapies, or 
accident.
Not Related
The event can be readily explained by other factors such as the 
subject’s underlying medical condition, concomitant therapy, or 
accident and no plausible temporal or biologic relationship exists 
between the investigational product and the event.
AEs that are related to study drug that are not resolved at EOT will be followed until the event 
resolves or stabilizes, as judged by the investigator.
Laboratory values, vital signs, and clinical findings at the scheduled physical examinations must 
be reported as AEs if the investigator considers the finding to be a clinically significant change 
from the baseline. 
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study in the eCRF. Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved with Sequelae

Recovering/Resolving

Unknown
For non-commercial use only


Shire
CONFIDENTIAL
Page 52
Protocol SHP633-304
08 April 2016
8.1.4
Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE.
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory or vital sign can represent an AE if the change is 
clinically relevant or if, during the study, a shift of a parameter is observed from a normal value 
to an abnormal value, or a further worsening of an already abnormal value. When evaluating 
such changes, the extent of deviation from the reference range, the duration until return to the 
reference range, either while continuing treatment or after the end of treatment with the 
investigational product, and the range of variation of the respective parameter within its 
reference range, must be taken into consideration.
If, during the study, there are abnormal clinical laboratory values or vital signs which were not 
present at the beginning of the study, further investigations should be performed until the values 
return to within the reference range or until a plausible explanation (eg, concomitant disease) is 
found for the abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory or vital sign is clinically significant and 
therefore represents an AE.
8.1.6
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.4.
Any report of pregnancy for any female study participant must be reported within 24 hours to the
Shire Global Pharmacovigilance and Risk Management Department using the Shire 
Investigational and Marketed Products Pregnancy Report Form. A copy of the Shire 
Investigational and Marketed Products Pregnancy Report Form (and any applicable follow-up 
reports) must also be sent to the Shire Medical Monitor using the details specified in the 
emergency contact information section of the protocol. In the event a subject becomes pregnant 
during the study, teduglutide administration must be discontinued immediately. 
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days post partum.
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Study Adverse Event Form 
for Serious Adverse Events (SAEs) and Non-serious AEs as Required by the Protocol. Note: An 
elective abortion is not considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Adverse Event Form for SAEs and 
Non-serious AEs as Required by the Protocol as well as the Shire Investigational and Marketed 
Products Pregnancy Report Form. The test date of the first positive serum/urine -HCG test or 
will determine the pregnancy onset date.
For non-commercial use only


Shire
CONFIDENTIAL
Page 53
Protocol SHP633-304
08 April 2016
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) 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 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used 
for a non-medical purpose (eg, to alter one’s state of consciousness or get high) in a 
manner that may be detrimental to the individual and/or society.

Misuse – Intentional use of investigational product other than as directed or indicated 
at any dose (Note: this includes a situation where the investigational product is not 
used as directed at the dose prescribed by the protocol).

Overdose – Administration of a dose greater than the allocated dose of the study 
medication or at a frequency greater than the dosing interval specified by the protocol.

Medication Error – An error made in prescribing, dispensing, administration, and/or 
use of an investigational product. For studies, medication errors are reportable to the 
sponsor only as defined below.

Cases of subjects missing doses of the investigational product are not considered 
reportable as medication errors.

Medication errors should be collected/reported for all products under 
investigation.

The administration and/or use of an expired investigational product should be 
considered as a reportable medication error. 
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally-authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator brochure which the sponsor 
has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Pharmacovigilance and Risk Management Department and the Shire Medical Monitor within 24 
hours of the first awareness of the event. Note: The 24-hour reporting requirement for SAEs does 
not apply to reports of abuse, misuse, overdose, or medication errors (see Section 8.1.7) unless 
they result in an SAE.
All Adverse Events of Special Interest, as defined in Section 8.3, must be reported by the 
investigator to the Shire Global Pharmacovigilance and Risk Management Department and the 
Shire Medical Monitor within 24 hours of the first awareness of the event even if the event does 
not fulfill seriousness criterion.
For non-commercial use only


Shire
CONFIDENTIAL
Page 54
Protocol SHP633-304
08 April 2016
The investigator must complete, sign, and date the Shire Clinical Study Adverse Event Form for 
SAEs and Non-serious AEs as Required by Protocol, and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested). Fax or e-mail the completed form to the Shire Global 
Pharmacovigilance and Risk Management Department. A copy of the completed Shire Clinical 
Study Adverse Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as 
Required by Protocol (and any applicable follow-up reports) must also be sent to the Shire 
medical monitor or designee using the details specified in the emergency contact information 
section of the protocol.
8.2.3
Serious Adverse Event Definition
A SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose: 

Results in death

Is life-threatening. Note: The term 'life-threatening' in the definition of "serious" refers to 
an event in which the subject was at risk of death at the time of the event; it does not refer 
to an event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
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).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: 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 subject and may 
require medical or surgical intervention to prevent 1 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; or the development of drug dependency or 
drug abuse. 
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.4, and must be reported 
to the Shire Global Pharmacovigilance and Risk Management Department and the Shire Medical 
Monitor within 24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
For non-commercial use only


Shire
CONFIDENTIAL
Page 55
Protocol SHP633-304
08 April 2016
Pharmacovigilance and Risk Management Department within 24 hours of the first awareness of 
the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death.
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting 
The Sponsor and/or Clinical Contract Research Organization (CRO) is responsible for notifying 
the relevant regulatory authorities, and US central Institutional Review Boards (IRBs)/EU central 
ethics committees (ECs), of related, unexpected SAEs.
In addition, the Clinical CRO is responsible for notifying active sites of all related, unexpected 
SAEs occurring during all interventional studies across the SHP633 program.
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
8.3
Adverse Events of Special Interest
An AE of special interest is an AE (serious or nonserious) of scientific and medical concern 
specific to the sponsor’s product or program and for which ongoing monitoring and immediate 
notification by the investigator to the sponsor is required.
The AEs of special interest that require expedited regulatory reporting include the following:

Growth of pre-existing polyps of the colon

Benign neoplasia of the GI tract including the hepatobiliary system

Tumor-promoting ability (eg, benign and/or malignant neoplasia of any kind, not 
limited to those of the GI or hepatobiliary system)
For non-commercial use only


Shire
CONFIDENTIAL
Page 56
Protocol SHP633-304
08 April 2016
For AEs of special interest, the sponsor must be informed within 24 hours of first awareness as 
per the SAE notification instructions described in Section 8.2.2 even if the event does not fulfill 
the seriousness criteria.
8.4
Dose Interruption and Permanent Discontinuation
The investigator is responsible for contacting the sponsor/designee when the subject’s 
teduglutide dosing regimen is interrupted. Attempts should be made to contact the 
sponsor/designee prior to dose interruption. Reasons for dosage interruptions may include but are 
not limited to hospitalization, incidents of certain AEs, SAEs considered to be related to the 
study drug, a lapse in investigational product delivery, etc.
Study drug must be permanently discontinued if any of the following events occur:

Pregnancy

Severe hypersensitivity, such as anaphylaxis determined by the investigator to be 
related to study drug. This does not include anti-teduglutide antibodies, mild injection 
site reactions or mild symptoms that according to the investigator do not pose a 
significant risk to the subject.

An AE listed in (Table 8-1) that is of NCI CTCAE severity Grade 3 or 4 and 
considered to be related to study drug administration

Confirmed drug-induced liver injury (DILI) related to teduglutide (See Section 8.4.2)
8.4.1
Dose Interruption Criteria Based on Known or Possible Risks of 
Teduglutide
The investigational product may be discontinued if the subject has an AE listed in Table 8-1 that 
is of severity ≥Grade 3 per the NCI CTCAE. All such AEs should be discussed with Shire’s 
medical monitor as soon as possible. Teduglutide administration must be permanently 
discontinued if the AE is considered related to the investigational product. The length of the dose 
interruption, and whether teduglutide administration resumes or is discontinued, depends on the 
clinical situation.
Investigators and the Data Monitoring Committee (DMC) should be guided by the descriptions 
of Grade 3 and 4 events, as they relate to known and possible risks associated with the 
administration of teduglutide. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 57
Protocol SHP633-304
08 April 2016
Table 8-1: CTCAE Criteria for Adverse Events that May Lead to Dose Interruption
Adverse Events
Grade 3 Description
Grade 4 Description
Gastrointestinal Disorders
Colorectal polyps
Severe or medically significant but not 
immediately life threatening;
hospitalization or prolongation of 
existing hospitalization indicated; 
disabling; limiting self-care activities of 
daily living
Life-threatening consequences; urgent 
intervention indicated
Intestinal Obstruction
Hospitalization indicated; elective 
operative intervention indicated; limiting 
self-care activities of daily living; 
disabling
Life-threatening consequences; urgent 
operative intervention indicated
Gallbladder and Bile Duct Disease
Cholecystitis
Severe symptoms; radiologic,
endoscopic or elective operative 
intervention indicated
Life-threatening consequences; urgent 
operative intervention indicated
Gallbladder perforation
Not Applicable
Life-threatening consequences; urgent 
intervention indicated
Gallbladder obstruction
Symptomatic and severely altered 
gastrointestinal function; tube feeding, 
total parenteral nutrition or 
hospitalization indicated; nonemergent 
operative intervention indicated
Life-threatening consequences; urgent 
operative intervention indicated
Gallbladder infection
Intravenous antibiotic, antifungal, or 
antiviral intervention indicated; 
radiologic, endoscopic, or operative 
intervention indicated
Life-threatening consequences; urgent 
intervention indicated
Adverse Events
Grade 3 Description
Grade 4 Description
Alkaline Phosphatase 
increased
>5.0 to 20.0x ULN
>20.0x ULN
Blood bilirubin increased
>3.0 to 10.0x ULN
>10.0x ULN
Bile duct stenosis
Severely altered gastrointestinal function; 
radiologic, endoscopic or elective 
operative intervention indicated
Life-threatening consequences; urgent 
operative intervention indicated
Pancreatic Disease
Pancreatitis
Severe pain; vomiting; medical 
intervention indicated (eg, analgesia, 
nutritional support)
Life-threatening consequences; urgent 
intervention indicated
Pancreatic duct stenosis
Severely altered gastrointestinal function; 
tube feeding or hospitalization indicated; 
elective operative intervention indicated
Life-threatening consequences; urgent 
operative intervention indicated
Pancreas infection
Intravenous antibiotic, antifungal, or 
antiviral intervention indicated; 
radiologic or operative intervention 
indicated
Life-threatening consequences; urgent 
intervention indicated
Serum amylase increaseda
>2.0 to 5.0x ULN
>5.0x ULN
For non-commercial use only


Shire
CONFIDENTIAL
Page 58
Protocol SHP633-304
08 April 2016
Table 8-1: CTCAE Criteria for Adverse Events that May Lead to Dose Interruption
Lipase increaseda
>2.0 to 5.0x ULN
>5.0x ULN
Cardiovascular Disease
Heart failure
Severe with symptoms at rest or with 
minimal activity or exertion; intervention 
indicated
Life-threatening consequences; urgent 
intervention indicated (eg, continuous 
intravenous therapy or mechanical 
hemodynamic support)
Source: Common Terminology Criteria for Adverse Events, version 4.03, 14 June 2010
ULN=upper limit of normal
a In the setting of clinically acute and symptomatic pancreatitis 
8.4.2
Dose Interruption Criteria Based on Drug-Induced Liver Injury
Teduglutide administration for an individual subject may need to be interrupted if the subject has 
clinical and laboratory evidence of potential DILI, in the absence of an alternative explanation, 
as identified by the following criteria:

ALT or AST >8x ULN

ALT or AST >5x ULN and >2x baseline value for more than 2 weeks

(ALT or AST >3x ULN and >2x baseline value) and (total bilirubin >2x ULN or 
INR>1.5)

ALT or AST >3x ULN and >2x baseline value with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(>5%)
All laboratory values suggestive of potentially new DILI should be repeated and verified within 
3 days. International normalized ratio should be measured with this set of verification laboratory 
assessments and an inquiry should be made as to the presence of clinical symptoms consistent 
with new liver injury. The subject should be followed closely to determine the trajectory of the 
laboratory abnormalities and to evaluate the cause of liver injury. This evaluation may include, 
as clinically indicated, consideration of sepsis, acute viral hepatitis (eg, hepatitis A 
immunoglobulin [IgM], hepatitis B surface antigen, hepatitis C antibodies, cytomegalovirus IgM, 
Epstein-Barr virus antibody panel), hepatobiliary obstruction (ultrasound), autoimmune hepatitis 
(anti-nuclear, anti-smooth muscle, anti-actin, or anti-liver kidney microsomal antibodies), 
intestinal failure associated liver disease, cardiovascular causes such as ischemic hepatitis, and 
concomitant hepatotoxic treatments.
Additional evaluations may be performed at the discretion of the investigator in consultation 
with the Shire medical monitor.
Teduglutide administration must be permanently discontinued if DILI is confirmed and deemed 
related to study drug.
For non-commercial use only


Shire
CONFIDENTIAL
Page 59
Protocol SHP633-304
08 April 2016
8.5
Early Termination of the Clinical Study
The DMC may recommend stopping the study if:

≥2 subjects being administered investigational product develop the same event listed 
in Table 8-1 of severity CTCAE Grade 3 
or

1 subject develops an event listed in Table 8-1 of severity CTCAE Grade 4 which is 
attributable to investigational product or is not reasonably related to the underlying 
disease process.
For non-commercial use only


Shire
CONFIDENTIAL
Page 60
Protocol SHP633-304
08 April 2016
9
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
in the eCRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered in the eCRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. Unscheduled safety follow up assessments (conducted after 
EOS) are not required to be collected.
9.2
Clinical Data Management 
Data are to be entered into a clinical database as specified in the CRO’s data management 
process. Quality control and data validation procedures are applied to ensure the validity and 
accuracy of the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Statistical Analysis Process 
The study will be analyzed by the sponsor or its agent. All statistical analyses will be performed 
using SAS® (SAS Institute, Cary, NC, USA) version 9.3 or higher.
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. 
9.4
Planned Interim Analysis, and Data Monitoring Committee 
An interim analysis is planned when 6 months of safety data have been collected. 
A DMC will be involved in the management of this study. The DMC members will review the 
data approximately every 3 months during the study treatment period (date of the first subject’s 
first dose to date of the last subject’s last dose). The DMC review will include all cumulative 
safety data (ie, AEs, laboratory assessments, physical examinations, etc.) from study assessments 
through each cutoff period. Further details regarding the DMC can be found in the DMC charter, 
which will be available prior to the administration of investigational product. 
The DMC for this study will be conducted in accordance with the FDA Guidance for Clinical 
Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees 
(March 2006).
The DMC will be an external, independent board comprised of physicians with relevant training. 
The DMC will be restricted to individuals free of significant conflicts of interest, including, but 
For non-commercial use only


Shire
CONFIDENTIAL
Page 61
Protocol SHP633-304
08 April 2016
not limited to, financial, scientific, or regulatory in nature. The DMC will be governed by a 
Charter agreed to by members of the Board and the sponsor. Members of the Board may not be 
study investigators or be employed at the same institution as a study investigator, individuals 
employed by the sponsor, independent contractors hired by the sponsor, or members of 
regulatory agencies. The DMC may make recommendations to the sponsor regarding study 
aspects including stopping, modifying or continuing the study; however, the sponsor will have 
the final responsibility to determine whether the study should be modified or temporarily or 
permanently stopped. 
9.5
Sample Size Calculation and Power Considerations 
The number of subjects in this study is not based on statistical power considerations as this is an 
extension study of the core study, TED-C14-006. The maximum number of subjects will be 
determined by the enrollment in TED-C14-006.
9.6
Study Population
The safety population includes all enrolled subjects in the study. Safety population will be used 
for both safety and efficacy analyses.
9.7
Efficacy Analyses 
No claims of statistical significance will be made; however, 95% confidence intervals will be 
provided, if applicable. Continuous variables, including those assessed on a discrete scale, will 
be summarized using descriptive statistics including number of subjects, mean, median, standard 
deviation, maximum, and minimum. For categorical variables, statistical summaries will include 
number of subjects and percentages.
9.7.1
Efficacy Endpoints
The following efficacy/PD endpoints will be measured. For each endpoint, analyses will be 
performed using the Baseline of this extension study at the end of each teduglutide treatment 
period (Week 24 or EOT) and each study visit. In addition, the efficacy/PD endpoints will be 
analyzed using the Baseline of the Core study (TED-C14-006) and the Baseline of each 
treatment cycle. The derivations of the weekly PS volume and 3 baselines will be described in 
the study SAP in detail. 

Reduction in PS volume of at least 20%
• Absolute and relative change in PS volume

Complete weaning off PS

Change in days per week of PS
9.8
Safety Analyses 
9.8.1
Safety Endpoints
The following safety endpoints will be measured. For each endpoint, analyses will be performed 
using the Baseline of this extension study. In addition, the safety endpoints will be analyzed 
using the Baseline of the Core study (TED-C14-006). 
For non-commercial use only


Shire
CONFIDENTIAL
Page 62
Protocol SHP633-304
08 April 2016

Adverse events, including those pertaining to GI symptoms

Vital signs, including temperature, heart rate, blood pressure

Body weight, height (or length), head circumference (up to 36 months of age) trends 
on growth charts, BMI; z-scores will be calculated for height (or length), weight, head 
circumference and BMI

Laboratory safety data (ie, clinical chemistry, hematology, and urinalysis)

Urine output

Stool output 

Antibodies to teduglutide

Gastrointestinal-specific testing (teduglutide treatment eligible subjects only) 
including colonoscopy or sigmoidoscopy, abdominal ultrasound, and FOBT, upper GI 
series with small bowel follow through 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The number of events, incidence, and percentage of AEs will be calculated overall, 
by System Organ Class (SOC) and by preferred term. SAEs will be further summarized by 
severity and relationship to investigational product. Adverse events related to investigational 
product, AEs leading to withdrawal, SAEs, and deaths will be similarly summarized/listed.
Prior and concomitant medications will be coded using the World Health Organization-Drug 
Dictionary (WHO-DD) with regard to drug class and drug name. The number and percentage of 
subjects with specific prior medications will be summarized. Medical history (including 
surgical/procedural history) will be coded using MedDRA. The number and percentage of 
subjects with specific histories will be summarized by system organ class and preferred term. 
For clinical laboratory tests, vital signs, body weight, and fluid balance variables, descriptive 
statistics (mean, median, standard deviation, minimum and maximum values, the number and 
percentage of subjects in specified categories) will be calculated to summarize the observed 
values and change from baseline at each scheduled visit.
The number and percentage of subjects classified as having positive specific or neutralizing 
antibodies to teduglutide will be used to summarize the presence of antibodies. 
Additional safety parameters and measures will include change in body weight, height (or 
length) and head circumference (up to 36 months of age). Derived variables will include height 
z-score, weight z-score, BMI, and BMI z-score. Descriptive statistics (mean, median, standard 
deviation, minimum and maximum values, the number and percentage of subjects in specified 
categories) will be calculated to summarize the absolute values and change from baseline at each 
scheduled visit.
9.9
Other Analyses
9.9.1
Health-related Quality of Life Analyses 
The following HEOR endpoints will be measured. For each endpoint, analyses will be performed 
using the Baseline of this extension study. In addition, the HEOR endpoints will be analyzed 
For non-commercial use only


Shire
CONFIDENTIAL
Page 63
Protocol SHP633-304
08 April 2016
using the Baseline of each treatment cycle at approximately 12 week intervals (Weeks 12 and 24 
of each teduglutide treatment cycle, and every 12 weeks for subjects not on teduglutide).

Change in Pediatric Quality of Life Inventory (PedsQL) score

Change in PedsQL Family Impact Module score

Change in PedsQL Gastrointestinal Symptoms Module Sub-Scales scores: 

Food and Drink Limits

Diarrhea 
For non-commercial use only


Shire
CONFIDENTIAL
Page 64
Protocol SHP633-304
08 April 2016
10
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements. 
The name and address of each third party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996), EU 
Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study. An insurance certificate is supplied to the CRO as necessary. 
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.4
Submission of Summary of Clinical Study Report (CSR) to Competent 
Authorities of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of the end of 
the study completion date for pediatric studies and within 1 year for non-pediatric studies as per 
guidance. The sponsor will provide the ECs with a copy of the same summary.
For non-commercial use only


Shire
CONFIDENTIAL
Page 65
Protocol SHP633-304
08 April 2016
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.
The sponsor will make an EOS declaration to the relevant competent authority as required by 
Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator is appointed to review the final CSR for multicenter 
studies. Agreement with the final CSR is documented by the signed and dated signature of the 
principal investigator (single-site study) or coordinating principal investigator (multicenter 
study), in compliance with Directive 2001/83/EC as amended by Directive 2003/63/EC and ICH 
Guidance E3 (1995). 
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational products, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by international regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
For non-commercial use only


Shire
CONFIDENTIAL
Page 66
Protocol SHP633-304
08 April 2016
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Case Report Forms
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded into eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log.
All data will have separate source documentation; no data will be recorded directly into the 
eCRF.
eCRFs should be approved by the investigator per study specifications and data deliverable 
requirements.
The clinical research associate (CRA)/study monitor will verify the contents against the source 
data per the monitoring plan. If the data are unclear or contradictory, queries are sent for 
corrections or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject diary cards, original clinical laboratory reports, and histology and 
pathology reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor, the respective national, 
local, or foreign regulatory authorities, the IRB/EC, and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF 
entries against the source documents. The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, X-rays etc.). Non-study site personnel will not 
disclose any personal information or personal medical information.
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US Food and Drug 
Administration (FDA) (as well as other US national and local regulatory authorities), the 
European Medicines Agency (EMA), the Medicines and Healthcare products Regulatory 
For non-commercial use only


Shire
CONFIDENTIAL
Page 67
Protocol SHP633-304
08 April 2016
Agency, other regulatory authorities, the sponsor or its representatives, and the IRB/EC for each 
site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent and assent, where 
applicable, from all study subjects prior to any study-related procedures including screening 
assessments. All consent and assent documentation must be in accordance with applicable 
regulations and GCP. Each subject or the subject’s legally-authorized representative, as 
applicable, is requested to sign and date the subject informed consent form or a certified 
translation if applicable, after the subject has received and read (or been read) the written subject 
information and received an explanation of what the study involves, including but not limited to: 
the objectives, potential benefits and risk, inconveniences, and the subject’s rights and 
responsibilities. A copy of the informed consent and assent documentation (ie, a complete set of 
subject information sheets and fully executed signature pages) must be given to the subject or the 
subject’s legally-authorized representative, as applicable. This document may require translation 
into the local language. Signed consent forms must remain in each subject’s study file and must 
be available for verification at any time.
Within the source documents, site personnel should document instruction of and understanding 
by the parent/legally-authorized representative/caregiver of the safe, responsible storage and 
administration of investigational product to the study subject.
The principal investigator provides the sponsor with a copy of the consent form, and assent form 
where applicable, which was reviewed by the IRB/EC and which received their favorable 
opinion/approval. A copy of the IRB/EC’s written favorable opinion/approval of these 
documents must be provided to the sponsor, prior to the start of the study unless it is agreed to 
and documented (abiding by regulatory guidelines and national provisions) prior to study start 
that another party (ie, sponsor or coordinating principal investigator) is responsible for this 
action. Additionally, if the IRB/EC requires modification of the sample subject information and 
consent document provided by the sponsor, the documentation supporting this requirement must 
be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
For non-commercial use only


Shire
CONFIDENTIAL
Page 68
Protocol SHP633-304
08 April 2016
For sites within the EU, the applicant for an EC opinion can be the sponsor, the investigator, or 
for multicenter studies the coordinating principal investigator or sponsor, according to national 
provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the Sponsor (or designee) has received 
written IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; for sites within the EU, this can be done by the sponsor, the investigator or for multicenter 
studies the coordinating principal investigator, according to national provisions. The investigator 
must also keep the local IRB/EC informed of any serious and significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996. A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the Sponsor (or designee).
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
review their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market SHP633; national or local regulatory authorities; and the IRBs/ECs which gave approval 
for the study to proceed. The sponsor and/or its representatives accessing the records and data 
will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject).
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
For non-commercial use only


Shire
CONFIDENTIAL
Page 69
Protocol SHP633-304
08 April 2016
10.5
Study Results / Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2-4 and certain other studies as determined by Shire. The purpose of the 
publication steering committee is to act as a non-commercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
current standards. Participation as an investigator does not confer any rights to authorship of 
publications.
For non-commercial use only


Shire
CONFIDENTIAL
Page 70
Protocol SHP633-304
08 April 2016
11
REFERENCES
Drucker, D. J. & Yusta, B. 2014. Physiology and pharmacology of the enteroendocrine hormone 
glucagon-like peptide-2. Annu Rev Physiol, 76, 561-83.
Khan, F. A., Squires, R. H., Litman, H. J., Balint, J., Carter, B. A., Fisher, J. G., Horslen, S. P., 
Jaksic, T., Kocoshis, S., Martinez, J. A., Mercer, D., Rhee, S., Rudolph, J. A., Soden, J., 
Sudan, D., Superina, R. A., Teitelbaum, D. H., Venick, R., Wales, P. W. & Duggan, C. 
2015. Predictors of Enteral Autonomy in Children with Intestinal Failure: A Multicenter 
Cohort Study. J Pediatr, 167, 29-34.e1.
Mouksassi, M. S., Marier, J. F., Cyran, J. & Vinks, A. A. 2009. Clinical trial simulations in 
pediatric patients using realistic covariates: application to teduglutide, a glucagon-like 
peptide-2 analog in neonates and infants with short-bowel syndrome. Clin Pharmacol 
Ther, 86, 667-71.
O'Keefe, S. J., Buchman, A. L., Fishbein, T. M., Jeejeebhoy, K. N., Jeppesen, P. B. & Shaffer, J. 
2006. Short bowel syndrome and intestinal failure: consensus definitions and overview. 
Clin Gastroenterol Hepatol, 4, 6-10.
Squires, R. H., Duggan, C., Teitelbaum, D. H., Wales, P. W., Balint, J., Venick, R., Rhee, S., 
Sudan, D., Mercer, D., Martinez, J. A., Carter, B. A., Soden, J., Horslen, S., Rudolph, J. 
A., Kocoshis, S., Superina, R., Lawlor, S., Haller, T., Kurs-Lasky, M. & Belle, S. H. 
2012. Natural history of pediatric intestinal failure: initial report from the Pediatric 
Intestinal Failure Consortium. J Pediatr, 161, 723-8.e2.
Tappenden, K. A., Edelman, J. & Joelsson, B. 2013. Teduglutide enhances structural adaptation 
of the small intestinal mucosa in patients with short bowel syndrome. J Clin 
Gastroenterol, 47, 602-7.
Thymann, T., Stoll, B., Mecklenburg, L., Burrin, D. G., Vegge, A., Qvist, N., Eriksen, T., 
Jeppesen, P. B. & Sangild, P. T. 2014. Acute effects of the glucagon-like peptide 2 
analogue, teduglutide, on intestinal adaptation in short bowel syndrome. J Pediatr 
Gastroenterol Nutr, 58, 694-702.
Varni, J. W., Sherman, S. A., Burwinkle, T. M., Dickinson, P. E. & Dixon, P. 2004. The PedsQL 
Family Impact Module: preliminary reliability and validity. Health Qual Life Outcomes,
2, 55.
Wales, P. W., de Silva, N., Kim, J., Lecce, L., To, T. & Moore, A. 2004. Neonatal short bowel 
syndrome: population-based estimates of incidence and mortality rates. J Pediatr Surg,
39, 690-5.
For non-commercial use only


Shire
CONFIDENTIAL
Page 71
Protocol SHP633-304
08 April 2016
12
APPENDICES
For non-commercial use only


Shire
CONFIDENTIAL
Page 72
Protocol SHP633-304
08 April 2016
APPENDIX 1
GUIDELINES FOR NUTRITIONAL SUPPORT MANAGEMENT 
DURING THE STUDY
Nutritional support adjustment in volume and calories should be considered at all planned visits. 
Please consider the following clinical parameters identified as markers for adequate management 
of pediatric SBS. These parameters should also be considered for managing nutritional support 
(PS and/or oral/enteral feeding) in terms of volume and calories during the treatment period. 

Growth trajectory, including weight, height (or length), and head circumference (for pediatric 
subjects up to 36 months of age)

Other clinical evaluations

Normal serum electrolytes

Stable blood urea nitrogen /creatinine levels

Decrease in stool frequency or volume, including mixed output

Stool consistency (ie, Bristol Stool Scale)

Urine specific gravity

General consideration to possible clinical deterioration in SBS

Inability to maintain weight and growth velocity

Diarrhea (≥10 bowel movements per day, ≥80 mL/kg/day from an ostomy, or 
≥75 mL/kg/day mixed output)

Colic/vomiting frequency increased

Electrolyte changes or imbalance

Skin breakdown 

Adjustments should be based on the actual nutritional support in volume and calories 
the subject infuses. Subjects should remain compliant with the nutritional support 
prescription in volume and calories during the study.

Nutritional support constituents may be adjusted at the discretion of the investigator.

During the 48-hour Intake/Output measurement period prior to the subject’s scheduled 
visit, no further changes to the prescribed nutritional support should be made.

If there is a change in EN or other food or fluid intake, the investigator should consider 
this when adjusting the PS/EN support in volume and calories.
For non-commercial use only


Shire
CONFIDENTIAL
Page 73
Protocol SHP633-304
08 April 2016
Figure A-1
Weaning Algorithm for Subjects Who are NOT Toilet Trained and in 
Diapers
For non-commercial use only


Shire
CONFIDENTIAL
Page 74
Protocol SHP633-304
08 April 2016
Figure A-2
Weaning Algorithm for Subjects Who are Toilet Trained and NOT in 
Diapers
For non-commercial use only


Shire
CONFIDENTIAL
Page 75
Protocol SHP633-304
08 April 2016
Figure A-3
Clinical Dehydration Assessment and PS/EN Adjustment
For non-commercial use only


PROTOCOL: SHP633-304
TITLE:
A Prospective, Open-label, Long-term Safety and Efficacy Study of 
Teduglutide in Pediatric Patients with Short Bowel Syndrome Who 
Completed TED-C14-006
DRUG:
Teduglutide
IND:
IND# 058213
EUDRACT NO.:
2016-000849-30
SPONSOR:
Shire Human Genetic Therapies, Inc.
300 Shire Way, Lexington, MA 02421 USA
PROTOCOL 
HISTORY:
Amendment 1: 22 Nov 2016
Original Protocol: 08 April 2016
This document contains confidential and proprietary information of Shire and is disclosed pursuant to 
confidentiality and non-disclosure obligations. This information should be used solely for the purposes for which 
it was provided and should not be copied, shared with, or disclosed to any third party without the express written 
consent of Shire.
For non-commercial use only


CONFIDENTIAL 
Page2 
Version 2 
PROTOCOL SIGNATURE PAGE 
Sponsor's (Shire) Approval 
Signature: 
, MD PhD 
 
Global Clinical Development 
Investigator's Acknowledgement 
I have read this protocol for Shire Study SHP633-304. 
Date: 
Title: A prospective, open label, long-term safety and efficacy study of teduglutide in pediatric 
patients with short bowel syndrome who completed TED-C14-006 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Conference on Harmonization (ICH) guidelines on Good Clinical 
Practice (GCP) and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
inrmediately in writing to the sponsor. 
Investigator Name and Address: 
(please hand print or type) 
Shire
CONFIDENTIAL
Page 2
Protocol SHP633-304
Version 2 / 22 Nov 2016
Signature:
Date:
For non-commercial use only


Shire
CONFIDENTIAL
Page 3
Protocol SHP633-304
Version 2 / 22 Nov 2016
SUMMARY OF CHANGES FROM PREVIOUS VERSION
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 1
Amendment Date
22 Nov 2016
Global
Description of Change and Rationale
Section(s) Affected by Change
Title of the Shire medical monitor has been changed to 
 
for clarity.
Protocol Signature Page
Emergency Contact Information
Clarification has been made that during the no-teduglutide treatment 
period, visits will take place approximately every 12 weeks.
Synopsis
Sections 3.1, 7.1.2
Figure 3-1
The study design flow chart has been edited for clarity.
Synopsis
Figure 3-1
The collection of all actual and prescribed enteral nutrition data has been 
removed to reduce the burden on the subjects and investigators. Enteral 
nutrition data are not required as the efficacy endpoints are limited to 
parenteral support parameters.
Synopsis
Table 1-1, Table 1-2, Table 1-3
Sections 7.1.2, 7.1.3.1, 7.1.3.2, 
7.1.5, 7.2.11.2, 7.2.11.3
Exclusion criterion 11 has been revised to add Smoflipid as other
experimental drugs that are allowed prior and during the study. Like 
glutamine and Omegaven, Smoflipid is not expected to interfere with the 
assessments of safety and efficacy of teduglutide and many subjects may 
already be receiving the treatments off-label as part of standard medical 
therapy.  
Synopsis
Section 4.5
Exclusion criterion 12 and prohibited treatment have been refined: 
exclusion/prohibition of treatment with growth hormone has been 
extended to 3 months for consistency with other teduglutide studies.
Synopsis
Section 4.5
Table 5-1
The language on escape criteria has been corrected for consistency 
within the protocol. 
Synopsis
Section 4.6
Language in efficacy and safety endpoints has been clarified.
Synopsis
Sections 9.7.1, 9.8.1
Completion and review of intake and output diaries have been clarified. 
Table 1-2, Table 1-3
Sections 7.1.3.2, 7.1.5
When the screening and pre-treatment visits are combined, the serum 
pregnancy test required at the pre-treatment visit should be performed at 
the local laboratory instead of the central laboratory. This will ensure 
timely results prior to starting treatment with teduglutide.
Table 1-3
Sections 7.1.3.1, 7.2.6
The requirement for urine specimen collection has been revised so that a
lack of urinalysis will not constitute a protocol deviation for any 
pediatric subjects (not only for subjects wearing diapers).
Table 1-1, Table 1-2, Table 1-3
Section 7.2.4
Clarification has been made that the first no-teduglutide treatment visit 
after the screening visit will occur within 2 to 12 weeks of the screening 
(formerly within 12 weeks of screening).
Synopsis
Table 1-2
Section 7.1.1
Windows have been clarified for visits during the no-teduglutide and 
teduglutide treatment periods.
Table 1-2, Table 1-3
Section 7.1.2
For non-commercial use only


Shire
CONFIDENTIAL
Page 4
Protocol SHP633-304
Version 2 / 22 Nov 2016
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 1
Amendment Date
22 Nov 2016
Global
Description of Change and Rationale
Section(s) Affected by Change
‘Specific’ has been deleted from ‘positive/specific anti-teduglutide 
antibodies’ to eliminate the redundancy. By definition, positive samples 
must be specific (as assessed in the confirmatory assay), or otherwise
considered negative.
Table 1-2
Sections 7.2.7, 9.8.1
Parental height and gestational age at birth have been removed from 
medical history.
Table 1-1 (footnote b)
Section 7.2.1
For consistency within the protocol, sigmoidoscopy has been added as 
the alternate to colonoscopy throughout the protocol. 
Table 1-1, Table 1-2, Table 1-3
Sections 3.1, 7.1.2, 7.2.9.2
Removal of former footnote i on fecal occult blood test for clarity.
Table 1-3
Clarification has been made on circumstances when the CxW28 visit 
may be combined with the next pre-treatment or EOS/ET visit. 
Table 1-3
Section 7.1.4
The text on PS support requirements over time in pediatric subjects with 
SBS has been clarified, and text on intestinal adaptation has been refined.
Section 1.1
Status of current teduglutide approvals for use has been updated.
Section 1.2, 3.1
The term ‘re-challenge’ has been replaced with ‘additional teduglutide 
treatment’ for clarity and consistency with other studies.
Section 3.1
Number of subjects enrolled has been corrected for consistency with 
protocol synopsis.
Section 3.1
Definition of a subject’s completion of the study has been corrected for 
consistency within the protocol.
Section 3.2
Evaluations to be performed when a subject discontinues teduglutide or
when withdraws from the study have been clarified.
Sections 4.8.1, 4.8.2
Withdrawal by parent/guardian has been added as reason for 
discontinuation.
Section 4.8.3
COUMADIN has been changed to warfarin for clarity.
Sections 5.1, 5.1.2
Clarification has been made on handling of study drug, which is for 
single use only and should be used within 3 hours following 
reconstitution.  
Section 6.3.3
The investigator or designee may now dispense the unused study drug 
vials to the same subject if deemed appropriate to ensure sufficient 
supplies between visits. Also, documentation of all dispensed study 
medication has been clarified.
Section 6.4
Clarification has been made that local laboratory results are not required 
to be entered in the eCRFs.
Section 7.2.4
Collection of urine sodium and urine osmolality has been removed.
Section 7.2.4
Clarification has been made that the serum sample will not be collected 
at the pre-treatment visit if the subject met a follow-up period escape 
criterion.
Section 7.2.5
Intake and output diaries (formerly in Sections 7.2.11 and 7.2.12, 
respectively) have been moved under a new Section 7.2.11 ‘Diaries’ for 
clarity, and are now Sections 7.2.11.2 and 7.2.11.3, respectively. 
Sections 7.2.11, 7.2.11.1,  7.2.11.2, 
7.2.11.3
For non-commercial use only


Shire
CONFIDENTIAL
Page 5
Protocol SHP633-304
Version 2 / 22 Nov 2016
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 1
Amendment Date
22 Nov 2016
Global
Description of Change and Rationale
Section(s) Affected by Change
Information on study drug administration diary has been added in 
Section 7.2.11.1. Clarification has been made that only available diary 
data will be reviewed at each clinic and telephone visit.
Performance of dipstick specific gravity tests by the subject at home on 
the first urine produced after the daily infusions of PS has been removed. 
It is now at the discretion of the investigator for all subjects, not just 
those in diapers. This change is to align with standard medical practice.
Section 7.2.11.3
Clarifications have been made to the language on dose interruption.
Sections 8.4, 8.4.1
Unscheduled safety follow up assessments (including visits conducted 
after EOS) are not to be recorded. However, clarification has been made 
that they are to be collected where requested.
Section 9.1
The protocol now refers to the data monitoring committee (DMC) 
Charter for the schedule of DMC reviews.
Section 9.4
Changes have been made to the Health economics and outcomes research
endpoints to include the beginning of each treatment cycle (CxD1) as 
additional baseline. These changes are for clarity and consistency with 
other teduglutide studies.
Synopsis
Section 9.9.1
Minor corrections have been made to the guidelines for nutritional 
support management during the study.
Appendix 2
See Appendix 1 for protocol history, including all amendments.
For non-commercial use only


Shire
CONFIDENTIAL
Page 6
Protocol SHP633-304
Version 2 / 22 Nov 2016
EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Adverse Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as 
Required by Protocol within 24 hours to the Shire Global Pharmacovigilance and Risk 
Management Department. Applicable fax numbers and e-mail address can be found on the form 
(sent under separate cover). A copy of this form must also be sent to the Shire Medical Monitor 
by fax or e-mail using the details below.
, MD PhD
Email: 
Fax: 
For protocol- or safety-related issues during normal business hours (9 am to 5 pm Eastern 
Standard Time), the investigator must contact the Shire Medical Monitor:
, MD PhD, 
Phone: 
Mobile: 
Email: 
Fax: 
For protocol- or safety-related issues outside of normal business hours, the investigator 
must contact Quintiles Medical Support:
, MD, 
Phone: 
 (medical emergencies – US & Canada)
Phone: 
 (medical emergencies – global)
Email: 
For non-commercial use only


Shire
CONFIDENTIAL
Page 7
Protocol SHP633-304
Version 2 / 22 Nov 2016
PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
European Union and Rest of World
Telephone numbers (provided for reference): 
 Shire (USA) 
For non-commercial use only


Shire
CONFIDENTIAL
Page 8
Protocol SHP633-304
Version 2 / 22 Nov 2016
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................3
EMERGENCY CONTACT INFORMATION................................................................................6
PRODUCT QUALITY COMPLAINTS..........................................................................................7
LIST OF TABLES.........................................................................................................................12
LIST OF FIGURES .......................................................................................................................12
LIST OF APPENDICES................................................................................................................12
ABBREVIATIONS .......................................................................................................................13
STUDY SYNOPSIS ......................................................................................................................15
STUDY SCHEDULE(S) ...............................................................................................................20
1
BACKGROUND INFORMATION.......................................................................................25
1.1
Indication and Current Treatment Options...............................................................25
1.2
Product Background.................................................................................................25
1.3
Clinical Studies with Teduglutide in Pediatric subjects...........................................26
2
STUDY OBJECTIVES AND PURPOSE ..............................................................................27
2.1
Rationale for the Study.............................................................................................27
2.2
Study Objectives ......................................................................................................27
2.2.1
Primary Objectives.................................................................................................27
2.2.2
Secondary Objectives.............................................................................................27
3
STUDY DESIGN ...................................................................................................................28
3.1
Study Design and Flow Chart ..................................................................................28
3.2
Duration and Study Completion Definition .............................................................30
4
STUDY POPULATION.........................................................................................................31
4.1
Study Inclusion Eligibility Criteria ..........................................................................31
4.2
Study Exclusion Eligibility Criteria .........................................................................31
4.3
Teduglutide Eligibility Criteria ................................................................................31
4.4
Teduglutide Treatment Inclusion Criteria................................................................31
4.5
Teduglutide Treatment Exclusion Criteria...............................................................32
4.6
Follow-up Period Escape Criteria ............................................................................33
4.7
Reproductive Potential .............................................................................................33
4.7.1
Female Contraception............................................................................................33
4.8
Discontinuation of Subjects .....................................................................................34
4.8.1
Teduglutide Discontinuation..................................................................................34
4.8.2
Study Withdrawal ..................................................................................................34
4.8.3
Reasons for Discontinuation..................................................................................34
4.8.3.1
Subjects ‘Lost to Follow-up’ Prior to Last Scheduled Visit ..................35
For non-commercial use only


Shire
CONFIDENTIAL
Page 9
Protocol SHP633-304
Version 2 / 22 Nov 2016
5
CONCOMITANT TREATMENT..........................................................................................36
5.1
Concomitant Medications and GI Procedures..........................................................36
5.1.1
Permitted Treatment...............................................................................................36
5.1.2
Prohibited Treatment .............................................................................................36
6
INVESTIGATIONAL PRODUCT ........................................................................................37
6.1
Identity of Investigational Product...........................................................................37
6.1.1
Blinding the Treatment Assignment......................................................................37
6.2
Administration of Investigational Product(s)...........................................................37
6.2.1
Interactive Response Technology for Investigational Product Management ........37
6.2.2
Allocation of Subjects to Treatment ......................................................................37
6.2.3
Dosing....................................................................................................................37
6.2.4
Unblinding the Treatment Assignment..................................................................38
6.3
Labeling, Packaging, Storage, and Handling ...........................................................38
6.3.1
Labeling .................................................................................................................38
6.3.2
Packaging...............................................................................................................38
6.3.3
Storage and Handling.............................................................................................39
6.4
Drug Accountability.................................................................................................39
6.5
Subject Compliance..................................................................................................40
7
STUDY PROCEDURES........................................................................................................41
7.1
Study Schedule.........................................................................................................41
7.1.1
Screening................................................................................................................41
7.1.2
Visits for Subjects Not Receiving Teduglutide .....................................................41
7.1.3
Visits for Subjects Receiving Teduglutide ............................................................42
7.1.3.1
Pre-treatment Visit .................................................................................42
7.1.3.2
Teduglutide Treatment Period (CxD1-CxW24).....................................43
7.1.4
Teduglutide Follow-up Period...............................................................................45
7.1.5
Study Completion/Early Termination Visit (EOS/ET Visit).................................45
7.2
Study Evaluations and Procedures ...........................................................................46
7.2.1
Demographics, Medical History, and SBS History ...............................................46
7.2.2
Physical Examination.............................................................................................46
7.2.3
Vital Signs, Body Weight, Height, Head Circumference and Body Mass 
Index (BMI) ...........................................................................................................46
7.2.4
Clinical Laboratory Tests.......................................................................................47
7.2.5
Serum Sampling.....................................................................................................48
7.2.6
Pregnancy Testing..................................................................................................49
7.2.7
Antibody Testing ...................................................................................................49
7.2.8
Volume of Blood....................................................................................................49
7.2.9
Gastrointestinal-specific Testing ...........................................................................50
For non-commercial use only


Shire
CONFIDENTIAL
Page 10
Protocol SHP633-304
Version 2 / 22 Nov 2016
7.2.9.1
Fecal Occult Blood Testing....................................................................50
7.2.9.2
Colonoscopy or Sigmoidoscopy.............................................................50
7.2.10 Nutritional Support ................................................................................................51
7.2.11 Diaries
51
7.2.11.1
Study Drug Administration Diary..........................................................51
7.2.11.2
Intake Diary............................................................................................51
7.2.11.3
Output Diary...........................................................................................51
7.2.12 Health-related Quality of Life Assessments ..........................................................52
7.2.12.1
Pediatric Quality of Life Generic Core Scale (PedsQL™), Acute 
version ....................................................................................................52
7.2.12.2
Pediatric Quality of Life Family Impact Module (PedsQL™), Acute 
version ....................................................................................................53
7.2.12.3
PedsQL Gastrointestinal Symptoms Module (PedsQL™), Acute 
version ....................................................................................................53
8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................54
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................54
8.1.1
Severity Categorization..........................................................................................54
8.1.2
Relationship Categorization...................................................................................55
8.1.3
Outcome Categorization ........................................................................................55
8.1.4
Symptoms of the Disease under Study ..................................................................56
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................56
8.1.6
Pregnancy...............................................................................................................56
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................57
8.2
Serious Adverse Event Procedures ..........................................................................58
8.2.1
Reference Safety Information................................................................................58
8.2.2
Reporting Procedures.............................................................................................58
8.2.3
Serious Adverse Event Definition .........................................................................58
8.2.4
Serious Adverse Event Collection Time Frame.....................................................59
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................59
8.2.6
Fatal Outcome........................................................................................................59
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................60
8.3
Adverse Events of Special Interest...........................................................................60
8.4
Dose Interruption of Individual Subjects .................................................................60
8.4.1
Dose Interruption Criteria Based on Known or Possible Risks of 
Teduglutide ............................................................................................................61
8.4.2
Dose Interruption Criteria Based on Drug-Induced Liver Injury ..........................62
8.5
Early Termination of the Clinical Study ..................................................................63
For non-commercial use only


Shire
CONFIDENTIAL
Page 11
Protocol SHP633-304
Version 2 / 22 Nov 2016
9
DATA MANAGEMENT AND STATISTICAL METHODS...............................................64
9.1
Data Collection.........................................................................................................64
9.2
Clinical Data Management.......................................................................................64
9.3
Statistical Analysis Process......................................................................................64
9.4
Planned Interim Analysis, and Data Monitoring Committee...................................64
9.5
Sample Size Calculation and Power Considerations................................................65
9.6
Study Population ......................................................................................................65
9.7
Efficacy Analyses.....................................................................................................65
9.7.1
Efficacy Endpoints.................................................................................................65
9.8
Safety Analyses........................................................................................................65
9.8.1
Safety Endpoints....................................................................................................65
9.9
Other Analyses .........................................................................................................67
9.9.1
Health-related Quality of Life Analyses................................................................67
10 SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................68
10.1
Sponsor’s Responsibilities .......................................................................................68
10.1.1 Good Clinical Practice Compliance.......................................................................68
10.1.2 Indemnity/Liability and Insurance.........................................................................68
10.1.3 Public Posting of Study Information......................................................................68
10.1.4 Submission of Summary of Clinical Study Report (CSR) to Competent 
Authorities of Member States Concerned and Ethics Committees........................68
10.1.5 Study Suspension, Termination, and Completion..................................................69
10.2
Investigator’s Responsibilities .................................................................................69
10.2.1 Good Clinical Practice Compliance.......................................................................69
10.2.2 Protocol Adherence and Investigator Agreement..................................................69
10.2.3 Documentation and Retention of Records.............................................................70
10.2.3.1
Case Report Forms.................................................................................70
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................70
10.2.3.3
Audit/Inspection.....................................................................................71
10.2.3.4
Financial Disclosure...............................................................................71
10.3
Ethical Considerations..............................................................................................71
10.3.1 Informed Consent...................................................................................................71
10.3.2 Institutional Review Board or Ethics Committee..................................................72
10.4
Privacy and Confidentiality......................................................................................72
10.5
Study Results / Publication Policy ...........................................................................73
11 REFERENCES .......................................................................................................................75
12 APPENDICES ........................................................................................................................76
For non-commercial use only


Shire
CONFIDENTIAL
Page 12
Protocol SHP633-304
Version 2 / 22 Nov 2016
LIST OF TABLES
Table 1-1:
Schedule of Events Required for All Subjects ..............................................20
Table 1-2: 
Schedule of Events for Subjects Not Receiving Teduglutide .......................21
Table 1-3: 
Schedule of Events for Subjects While Receiving Teduglutide....................22
Table 5-1: 
Prohibited Treatment.....................................................................................36
Table 7-1:
Approximate Volume of Blood to be Drawn from Each Subject 
Annually ........................................................................................................49
Table 7-2:
Developmentally Appropriate PedsQL™Generic Core Scales .....................53
Table 8-1:
CTCAE Criteria for Adverse Events that May Lead to Dose 
Interruption....................................................................................................61
LIST OF FIGURES
Figure 3-1:
Study Design Flow Chart ..............................................................................30
LIST OF APPENDICES
Appendix 1
Protocol History.............................................................................................77
Appendix 2
Guidelines for Nutritional Support Management During the Study .............78
For non-commercial use only


Shire
CONFIDENTIAL
Page 13
Protocol SHP633-304
Version 2 / 22 Nov 2016
ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
-HCG
beta-human chorionic gonadotropin
BMI
body mass index
CRA
clinical research associate
CRO
contract research organization
CSR
clinical study report
CTCAE
common terminology criteria for adverse events
DILI
drug-induced livery injury
DMC
data monitoring committee
DPP-4
dipeptidyl peptidase 4
EC
ethics committee
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EN
enteral nutrition
EOS
end of study
EOT
end of treatment
ET
early termination
EU
European Union
FDA
Food and Drug Administration
FOBT
fecal occult blood test
FOCBT
female of child-bearing potential
GCP
Good Clinical Practice
GI
gastrointestinal
GLP-1
glucagon-like peptide 1
GLP-2
glucagon-like peptide 2
HIPAA
Health Insurance Portability and Accountability Act
ICF
informed consent form
ICH
International Conference on Harmonization
IGF-1
insulin-like growth factor 1
IRB
institutional review board
IV
intravenous
For non-commercial use only


Shire
CONFIDENTIAL
Page 14
Protocol SHP633-304
Version 2 / 22 Nov 2016
IWRS
interactive web-based response system
MedDRA
Medical Dictionary for Regulatory Activities
NCI
National Cancer Institute
NDA
new drug application
NTT
no-teduglutide treatment
PDA
patent ductus arteriosus
PedsQL
Pediatric Quality of Life inventory
PS
parenteral support
PT/INR
prothrombin time/international normalized ratio
QD
once daily
SAE
serious adverse event
SAP
statistical analysis plan
SBS
short bowel syndrome
SC
subcutaneous
SOC
standard of care
t1/2
elimination half-life
TESAE
treatment-emergent serious adverse event
UK
United Kingdom
ULN
upper limit of normal
US
United States
WHO-DD
World Health Organization – Drug Dictionary
For non-commercial use only


Shire
CONFIDENTIAL
Page 15
Protocol SHP633-304
Version 2 / 22 Nov 2016
STUDY SYNOPSIS
Protocol number: SHP633-304
Drug: Teduglutide
Title of the study: A Prospective, Open-label, Long-term Safety and Efficacy Study of Teduglutide in Pediatric 
Patients with Short Bowel Syndrome (SBS) Who Completed TED-C14-006
Number of subjects (total and for each treatment arm):
Approximately 34 subjects who completed the TED-C14-006 study, including subjects in the standard of care 
treatment arm, are expected to enroll in this extension study. This study will enroll up to as many subjects as 
complete the TED-C14-006 study.
Investigator(s): Multicenter study
Site(s) and Region(s): 
Approximately 28 investigational sites in North America and Europe will participate in this extension study
Study period (planned):
October 2016 – September 2019
Clinical phase:
3 Extension
Objectives:
Primary: To evaluate the long-term safety and tolerability of teduglutide treatment in pediatric subjects with SBS.
Secondary: To evaluate long-term efficacy of teduglutide treatment in pediatric subjects with SBS.
Rationale:
This is a Phase 3, prospective, open-label, long-term extension study to evaluate the safety and efficacy of 
teduglutide in pediatric subjects with short bowel syndrome (SBS) who completed the TED-C14-006 study (the 
core study). In addition to evaluating the long-term safety and durability of efficacy after 24-weeks of treatment, 
this extension study will evaluate the need for additional teduglutide treatment in these subjects, and will allow 
the study of first-time treatment of teduglutide-naïve subjects who participated in the standard of care (SOC) 
treatment arm in TED-C14-006. 
Investigational product, dose, and mode of administration:
This study will allow repeat doses of teduglutide 0.05 mg/kg subcutaneous (SC) once daily (QD) injection for 
eligible pediatric subjects. There is no active comparator or reference product.
Methodology:
This is a Phase 3, prospective, open-label, long-term extension study to evaluate the safety and efficacy of 
teduglutide in pediatric subjects who completed the TED-C14-006 study (core study).
Once the informed consent (and if applicable, informed assent) have been reviewed and signed, demographics, 
and updates to medical history and short bowel syndrome history will be obtained. Subjects not receiving 
teduglutide treatment (ie, in a no-teduglutide treatment [NTT] period), will be seen approximately every 12 weeks 
for safety, parenteral support (PS) requirements, and quality of life. The first NTT visit after the screening visit 
will occur within 2 to 12 weeks of the screening visit. At any point after screening, including during a NTT 
period, subjects who meet ≥1 teduglutide treatment inclusion criteria, may proceed immediately to the 
pre-treatment visit if the investigator, subject, and parent agree to proceed with teduglutide therapy.
After the pre-treatment visit, subjects who meet ≥1 of the teduglutide treatment inclusion criteria, and meet none 
of the teduglutide treatment exclusion criteria, will start a 28-week cycle, consisting of 24 weeks of teduglutide 
treatment at 0.05 mg/kg SC once daily, followed by a 4-week follow-up period (during which no teduglutide is 
administered) (Figure 3-1). During the 28-week cycle, clinic visits will occur at weeks 1, 2, 4, 6, 9, 12, 16, 20, 24, 
and 28. Phone visits are required approximately 1 week after adjustments in PS during the teduglutide treatment 
period (between weeks 1 and 24), and weekly during the teduglutide follow-up period (between weeks 24 and 
28). Safety and PS requirements will be evaluated at every visit, and quality of life assessments will be made 
approximately every 12 weeks. If a subject has clinical deterioration and meets follow-up period escape criteria 
For non-commercial use only


Shire
CONFIDENTIAL
Page 16
Protocol SHP633-304
Version 2 / 22 Nov 2016
after stopping teduglutide, the subject may "escape" the follow-up period early and proceed immediately to 
another pre-treatment visit. Following completion of the 28-week treatment cycle, the subject will proceed to an
NTT visit within approximately 12 weeks.
At all site visits and telephone contacts, safety will be monitored and nutritional support will be reviewed and
adjusted as needed. To maintain consistency across centers, all attempts should be made to follow the nutritional
support adjustment guidelines (developed with SBS expert input and provided in the protocol) for decisions
regarding PS support reduction and advances in enteral feeds based on weight gain, urine and stool output, and
clinical stability. Departure from the guidelines, however, is not considered a protocol deviation. (Appendix 2).
Study Design Flow Chart 
Figure legend: Safety and efficacy data for subjects not receiving teduglutide treatment are captured approximately every 
12 weeks, but subjects may proceed to the pre-treatment visit at any time in order to assess eligibility for teduglutide 
therapy. Eligible subjects will enter a 28-week teduglutide cycle. During this cycle, subjects will return to the site for 
safety and efficacy assessments at weeks 1, 2, 4, 6, 9, 12, 16, 20, and 24 (solid black lines). Phone visits are required
approximately 1 week after adjustments in PS during the intervening weeks between weeks 2 and 24 (dashed grey 
lines). Subjects discontinue teduglutide at week 24 and enter a 4-week follow-up (no-treatment) period, during which 
phone visits will be performed weekly (solid grey lines). If an escape criterion is met during the follow-up period, 
subjects may proceed directly to another pre-treatment visit.
Study Inclusion Criteria: 
The subject will be considered eligible for the study if they meet all of the study inclusion criteria. Teduglutide 
treatment eligibility does not impact study eligibility.
1.
Subject provides written informed consent (subject, parent or legal guardian and, as appropriate, 
informed assent) to participate in the study before completing any study-related procedures.
2.
Subject completed the TED-C14-006 study (including subjects in the standard of care treatment arm).
3.
Subject understands and is willing and able to fully adhere to study requirements as defined in this 
protocol. 
Study Exclusion Criteria: There are no exclusion criteria for this study.
Teduglutide Eligibility Criteria: Subjects are eligible for teduglutide treatment if at least one (≥1) of the 
teduglutide treatment inclusion criteria, and none of the teduglutide treatment exclusion criteria, are met. In 
addition, the investigator and the subject (and/or parent or legal guardian, as appropriate) must agree to proceed 
with treatment.
Teduglutide Treatment Inclusion Criteria:
1.
Subject is teduglutide-naïve, receiving PS, and unable to significantly reduce PS or advance enteral feeds 
(eg, 10% or less change in PS or advance in feeds) for at least 3 months prior to and during the 
For non-commercial use only


Shire
CONFIDENTIAL
Page 17
Protocol SHP633-304
Version 2 / 22 Nov 2016
teduglutide pre-treatment visit, as assessed by the investigator. Transient instability for events such as 
interruption of central access or treatment for sepsis is allowed if the PS returns to within 10% of 
baseline prior to the event.
2.
Subject was previously treated with teduglutide and at least one of the following criteria is satisfied:
a.
Increasing PS requirements following teduglutide discontinuation.
b.
Decreased PS requirement during prior teduglutide treatment, followed by cessation of 
improvement after teduglutide discontinuation.
c.
Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal tolerated 
enteral nutrition following teduglutide discontinuation.
d.
Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and electrolyte 
intake following teduglutide discontinuation.
e.
Severe diarrhea related to teduglutide discontinuation.
Teduglutide Treatment Exclusion Criteria:
1.
Body weight <10 kg at the pre-treatment visit.
2.
Unresected gastrointestinal (GI) polyp, known polyposis condition, pre-malignant change, or 
malignancy, in the GI tract.
3.
History of cancer in the previous 5 years except surgically curative skin cancers.
4.
Serial transverse enteroplasty or other major intestinal surgery within 3 months preceding the teduglutide 
pre-treatment visit. Insertion of a feeding tube, anastomotic ulcer repair, minor intestinal resections 
≤10 cm, and endoscopic procedures are allowed.
5.
Intestinal or other major surgery planned or scheduled to occur during the 28-week cycle.
6.
Clinically significant intestinal stricture or obstruction.
7.
Clinically significant, active or recurrent pancreatic or biliary disease.
8.
Active, severe, or unstable, clinically significant hepatic impairment or injury, including the following 
laboratory values at the pre-treatment visit:
a.
Total bilirubin ≥2 × upper limit of normal (ULN)
b.
Aspartate aminotransferase (AST) ≥7 × ULN
c.
Alanine aminotransferase (ALT) ≥7 × ULN
9.
Renal dysfunction shown by results of an estimated glomerular filtration rate (eGFR) below 
50 mL/min/1.73 m2 at the pre-treatment visit.
10. Unstable cardiac disease, congenital heart disease or cyanotic disease, with the exception of subjects 
who had undergone ventricular or atrial septal defect repair, or patent ductus arteriosus (PDA) ligation.
11. Participation in a clinical study using an experimental drug (other than glutamine, Omegaven, or 
Smoflipid) within 3 months or 5.5 half-lives of the experimental drug, whichever is longer, prior to the 
pre-treatment visit and for the duration of the 28-week cycle.
12. Treatment with analogs of glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2) (not 
including teduglutide), insulin-like growth factor-1 (IGF-1), or growth hormone, within 3 months
preceding the teduglutide pretreatment visit.
13. Treatment with octreotide or dipeptidyl peptidase 4 (DPP-4) inhibitors within 3 months prior to the pre-
treatment visit.
14. Known or suspected intolerance or hypersensitivity to the investigational product, closely-related 
compounds, or any of the stated ingredients.
15. Known history of alcohol or other substance abuse within 1 year prior to the pre-treatment visit.
16. Pregnant or lactating female subjects.
For non-commercial use only


Shire
CONFIDENTIAL
Page 18
Protocol SHP633-304
Version 2 / 22 Nov 2016
17. Sexually active female subjects of child-bearing potential unwilling to use approved contraception 
during teduglutide treatment and for 30 days after the treatment period.
18. Any condition, disease, illness, or circumstance that in the investigator’s opinion puts the subject at any 
undue risk, prevents completion of the study, or interferes with analysis of the study results.
Follow-up Period Escape Criteria: At the discretion of the investigator, the follow-up period may be interrupted 
and the subject may proceed directly to the pre-treatment visit, if ≥1 of the following criteria is met:
1.
Increasing PS requirements following teduglutide discontinuation
2.
Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal tolerated enteral 
nutrition following teduglutide discontinuation.
3.
Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and electrolyte intake 
following teduglutide discontinuation.
4.
Severe diarrhea related to teduglutide discontinuation.
Maximum duration of subject involvement in the study:
A subject will be considered enrolled in the study once the subject has provided signed consent, and meets all of 
the Study Inclusion Criteria. Subjects may participate in multiple NTT periods and/or multiple 28-week treatment 
cycles. The study will continue for at least 1 year, and until each subject has access (as needed) to teduglutide. 
The subject’s maximum duration of participation is expected to be approximately 3 years. A subject will be 
considered as having completed the study if the subject has not withdrawn early from the study for any reason 
prior to completing End of Study (EOS) visit.

Planned duration of no-teduglutide treatment periods: variable, depending on disease course 

Planned duration of the teduglutide pre-treatment visit: 1 to 21 days

Planned cycle duration: 28 weeks. Each cycle consists of 24 weeks of teduglutide treatment followed 
by a 4-week follow-up period (no treatment)
Endpoints and statistical analysis: 

The safety population will consist of all enrolled subjects. The safety population will be used for both 
safety and efficacy analysis.
Efficacy Endpoints
Efficacy endpoints will be analyzed at the end of each teduglutide treatment period (Week 24 or end of treatment 
[EOT]), and at each study visit, relative to the baseline of the core study (TED-C14-006) and/or first exposure to 
teduglutide. The following efficacy endpoints will be analyzed:

Reduction in PS volume of at least 20%

Absolute and relative change in PS volume

Complete weaning off PS

Change in days per week of PS
Health Economics and Outcomes Research Endpoints 
Health economics and outcomes research endpoints will be analyzed at approximately 12-week intervals 
(Weeks 12 and 24 of each teduglutide treatment cycle, and every 12 weeks for subjects not on teduglutide), 
relative to the study baseline. The beginning of each treatment cycle (CxD1) will be an additional baseline.

Change in Pediatric Quality of Life Inventory (PedsQL) score

Change in PedsQL Family Impact Module score

Change in PedsQL Gastrointestinal Symptoms Module Sub-Scales scores: 

Food and Drink Limits

Diarrhea 
Safety Endpoints 
The following safety endpoints will be analyzed:
For non-commercial use only


Shire
CONFIDENTIAL
Page 19
Protocol SHP633-304
Version 2 / 22 Nov 2016

Adverse events

Vital signs, including temperature, heart rate, blood pressure

Laboratory safety data (ie, clinical chemistry, hematology, and urinalysis)

Urine output

Stool output

Antibodies to teduglutide

Gastrointestinal-specific testing, including fecal occult blood testing and colonoscopy or sigmoidoscopy

Z-scores for weight, height (or length), head circumference (up to 36 months of age), and body mass index
Statistical Methodology for Efficacy Analysis
No claims of statistical significance will be made; however, 95% confidence intervals will be provided, if 
applicable. Continuous variables, including those assessed on a discrete scale, will be summarized using 
descriptive statistics including number of subjects, mean, median, standard deviation , maximum, and minimum. 
For categorical variables, statistical summaries will include number of subjects and percentages.
Statistical Methodology for Safety Analysis 
Safety data, including laboratory tests and vital signs assessments, will be summarized by visit. AEs will also be 
collected and summarized. Descriptive statistics will be calculated for quantitative safety data as well as for the 
difference from baseline, if applicable. Frequency counts will be compiled for classification of qualitative safety 
data.
Sample Size Justification 
As this is an extension study, the maximum number of subjects was determined by enrollment in TED-C14-006.
For non-commercial use only


Shire
CONFIDENTIAL
Page 20
Protocol SHP633-304
Version 2 / 22 Nov 2016
STUDY SCHEDULE(S) 
Table 1-1: Schedule of Events Required for All Subjects 
Period
Screening
End of Study or Early Termination
Scr
EOS/ET
Visit Type
Site
Site
Informed consent/assenta
X
Study eligibility
X
Demographics, Medical historyb, SBS historyc
X
Dispense intake and output diaries
X
Evaluate teduglutide treatment inclusion criteriad
X
Adverse events
X
X
Concomitant medications and GI procedurese
X
X
Physical examination and vital signs, including weight
X
Height and head circumferencef
X
Review intake and output diariesg 
X
Record PS prescription and adjust as neededh
X
Safety laboratory testsi
X
PedsQL Generic Core Scale/PedsQL Family Impact Module/ 
PedsQL Gastrointestinal Symptoms Module Sub-Scales
X
Antibodies to teduglutidej
X
Fecal occult blood testingk
(X)
Colonoscopy or sigmoidoscopyl
(X)
Pregnancy testingm
(X)
FOBT = fecal occult blood testing; FOCBP = female of child-bearing potential; EOS =end of study; ET=early termination; 
GI=gastrointestinal; NTx=no treatment; 
PedsQL=Pediatric Quality of Life Inventory; PS=parenteral support; SBS=Short Bowel Syndrome; Scr =Screening.
Note: (X) denotes conditional requirement for a given assessment if the subject meets certain conditions per protocol.
a Informed Consent (and informed assent, if applicable) must be obtained prior to performing any study-related procedures; consent (and 
informed assent, if applicable) may be obtained anytime during the Week 28 (or EOS) visit for the TED-C14-006 study. Subject will 
have up to 7 days after completion of the TED-C14-006 study to sign consent to participate in the SHP633-304 study.
b Updates to the medical history will be collected, consisting of adverse events that were ongoing at the time of completion of TED-C14-
006, and events that occurred during the period between completion of TED-C14-006 and informed consent to SHP-633-304. 
c If the subject has any changes to the SBS history that had been collected at the baseline of the TED-C14-006, then the updated SBS 
history will be collected.
d Subjects who meet ≥1 teduglutide treatment inclusion criteria, may proceed to the pre-treatment visit if the investigator, subject, and 
parent or legal guardian agrees to proceed with teduglutide therapy (Table 1-3).
e Concomitant GI procedures include (but are not limited to) endoscopy, radiographic studies, GI and liver biopsies and associated 
pathology results.
f Head circumference will be measured in subjects 36 months of age and younger.
g The intake diary should be completed daily for a minimum of 2 weeks prior to the EOS/ET visit. The output diary should be completed 
daily over a 48-hour period of nutritional stability before the EOS/ET visit.
h PS adjustments should be made after review of any available intake and output diaries and the safety lab data according to the guidance 
for nutrition support adjustment provided in Appendix 2. 
i Safety laboratory assessments at site visits will consist of clinical chemistry, hematology, and urinalysis, with results processed by a 
central laboratory. Urine specimen collection should be attempted as part of the safety labs, but lack of urinalysis will not constitute a 
protocol deviation.
j Required for all teduglutide-exposed subjects
k FOBT should be performed on teduglutide-exposed subjects on an annual basis, approximately every 48-60 weeks at a minimum.
l The need for colonoscopy/sigmoidoscopy in response to a positive FOBT during a no-teduglutide treatment period is at the discretion of 
the investigator, but all teduglutide-exposed subjects will undergo colonoscopy/sigmoidoscopy after they have received the equivalent of 
2 treatment cycles (48 weeks of study drug exposure), and subjects who continue to receive teduglutide will undergo 
colonoscopy/sigmoidoscopy at 5 year intervals or more often as needed. See Section 7.2.9 for details.
m Pregnancy testing is required for FOCBP at an ET visit if the subject has not had a pregnancy test at least 30 days after study drug 
discontinuation.
For non-commercial use only


Shire
CONFIDENTIAL
Page 21
Protocol SHP633-304
Version 2 / 22 Nov 2016
Table 1-2: Schedule of Events for Subjects Not Receiving Teduglutide 
Visit Number
NTx
Visit Type
Site
Visit Frequencya
Every 12 weeks 
Window (days)b
±7
Dispense intake and output diaries
X
Evaluate teduglutide treatment inclusion criteriac
X
Adverse events
X
Concomitant medications and GI proceduresd
X
Physical examination and vital signs, including weight
X
Height and head circumferencee
X
Review intake and output diariesf
X
Record PS prescription and adjust as neededg
X
Safety laboratory testsh
X
PedsQL Generic Core Scale/PedsQL Family Impact Module/ 
PedsQL Gastrointestinal Symptoms Module Sub-Scales
X
Antibodies to teduglutidei
(X)
Fecal occult blood testingj
Annually 
Colonoscopy or sigmoidoscopy k
(X)
Serum samplel
Every 24 weeks
FOBT = fecal occult blood testing; NTT = no-teduglutide treatment; PedsQL = Pediatric Quality of Life Inventory; 
PS= parenteral support; TED = teduglutide.
Note: (X) denotes conditional requirement for a given assessment if the subject meets certain conditions per 
protocol.
a The first NTx visit following the screening visit must occur within 2 to 12 weeks of screening.
b Window is relative to the first NTx visit in the current no-teduglutide treatment period.
c Subjects who meet ≥1 teduglutide treatment inclusion criteria, may proceed to the pre-treatment visit if the 
investigator, subject, and parent or guardian agree to proceed with teduglutide therapy (Table 1-3).
d Concomitant GI procedures include (but are not limited to) endoscopy, radiographic studies, GI and liver biopsies 
and associated pathology results.
e Head circumference will be measured in subjects 36 months of age and younger.
f Intake diaries will collect actual PS volume and hours per day, completed daily for a minimum of 2 weeks prior to 
each study visit (see Section 7.2.11.2). Urine and stool output should be recorded in the output diary over a 48-hour 
period of nutritional stability before every clinic visit (see Section 7.2.11.3 for more detail).
g PS adjustments should be made after review of the intake and output diaries and the safety lab data according to 
the guidance for nutrition support adjustment provided in Appendix 2. 
h Safety laboratory assessments at site visits will consist of clinical chemistry, hematology, and urinalysis, with 
results processed by a central laboratory. Urine specimen collection should be attempted as part of the safety labs, 
but lack of urinalysis will not constitute a protocol deviation.
i Subjects who have been treated previously and test positive for teduglutide antibodies should have follow-up 
samples collected every 12 weeks during the study until a negative result is obtained.
j FOBT should be performed on teduglutide-exposed subjects on an annual basis, approximately every 48-60 weeks 
at a minimum.
k The need for colonoscopy/sigmoidoscopy in response to a positive FOBT during a no-teduglutide treatment period 
is at the discretion of the investigator, but all teduglutide-exposed subjects will undergo colonoscopy/sigmoidoscopy
after they have received the equivalent of 2 treatment cycles (48 weeks of study drug exposure) and subjects who 
continue to receive teduglutide will undergo colonoscopy/sigmoidoscopy at 5 year intervals or more often as 
needed. See Section 7.2.9 for details.
l Lack of collection of serum samples will not constitute a protocol deviation.
For non-commercial use only


Shire
CONFIDENTIAL
Page 22
Protocol SHP633-304
Version 2 / 22 Nov 2016
Table 1-3: Schedule of Events for Subjects While Receiving Teduglutide
Period
Pre-
treatment
Teduglutide Treatment
Follow-up
Visit Number
Px
Cx
D1
Cx
W1
Cx
W2
Phone contact is required approximately 1 week after PS adjustment
Cx
W4
Phone contact is required approximately 1 week after PS adjustment
Cx 
W6
Phone contact is required approximately 1 week after PS adjustment
Cx 
W9
Phone contact is required approximately 1 week after PS adjustment
Cx 
W12
Phone contact is required approximately 1 week after PS adjustment
Cx 
W16
Phone contact is required approximately 1 week after PS adjustment
Cx 
W20
Phone contact is required approximately 1 week after PS adjustment
CxW24 
(EOT)
CxW25 
CxW26 
CxW27
CxW28b
Visit Type
Site
Site
Site
Site
Site
Site
Site
Site
Site
Site
Site
Phonea
Site
Cycle Day
-21 to 0
1
8
15
29
43
64
85
113
141
169
176
197
183
190
Window (days)c
-21 to 0
±2
±2
±2
±2
±4
±4
±4
±4
±4
±2
±2
Evaluate teduglutide 
eligibility (inclusion 
and exclusion) criteria
X
Xd
Dispense intake and 
output diaries
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications and GI
procedurese
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination 
and vital signs, 
including weight
X
X
X
X
X
X
X
X
X
X
X
X
Height and head 
circumferencef
X
X
X
X
Review intake and 
output diariesg
X
X
X
X
X
X
X
X
X
X
X
X
X
Record PS Rx and 
adjust as neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety laboratory testsi
Xi
X
X
X
X
X
X
X
X
X
X
(X)
X
PedsQL Generic Core 
Scale/ Family Impact 
Module/ GI 
Symptoms Module 
Sub-Scales
X
X
X
Antibodies to 
teduglutidej
X
X
X
X
Fecal occult blood 
testing
X
X
X
Colonoscopy/
sigmoidoscopyk
(X)
(X)
(X)
Pregnancy testingl
X
X
X
X
X
X
X
X
X
For non-commercial use only


Shire
CONFIDENTIAL
Page 23
Protocol SHP633-304
Version 2 / 22 Nov 2016
Table 1-3: Schedule of Events for Subjects While Receiving Teduglutide
Period
Pre-
treatment
Teduglutide Treatment
Follow-up
Serum samplem
X
X
Evaluate escape 
criterian
X
X
Dispense study drugo
X
X
X
X
X
X
X
X
X
EOS = end of study; EOT = end of treatment; ET = early termination; FOBT = fecal occult blood test; FOCBP = female of child-bearing potential; FU = follow-up; GI = 
gastrointestinal; PedsQL = Pediatric Quality of Life Inventory; PS= parenteral support; SBS = Short Bowel Syndrome; SC = subcutaneous; Scr = Screening; TED = teduglutide; 
Tx = treatment.
Note: (X) denotes conditional requirement for a given assessment if the subject meets certain conditions per protocol.
a Phone visits are required approximately 1 week after adjustments in PS. The assessments to be performed at phone visits are the same as those described for CxW25-27 (except 
for evaluation of escape criteria). 
b The investigator may combine the CxW28 visit with the next pre-treatment visit if at least one escape criterion is met at the CxW28 visit, and the pre-treatment assessments occur 
within 7 days of the CxW28 visit. If a subject is completing the study at the CxW28 visit, the EOS/ET visit (Table 1-1) will take place in lieu of the CxW28 visit.
c Visit windows are relative to the CxD1 visit.
d Eligibility will need to be re-confirmed prior to the first dose in the cycle. Negative urine pregnancy test is required prior to the first dose of teduglutide, but results of other labs 
obtained at the CxD1 visit are not required to determine teduglutide treatment eligibility.
e Concomitant GI procedures include (but are not limited to) endoscopy, radiographic studies, GI and liver biopsies and associated pathology results.
f Head circumference will be measured in subjects 36 months of age and younger.
g Intake diaries will collect actual PS volume and hours per day. Intake diaries should be completed daily for a minimum of 2 weeks immediately prior to each clinic visit (except 
at pre-treatment visit), for 1 week following PS adjustment, and daily during the 4-week follow-up period. Urine and stool output should be recorded in the output diary over a 48-
hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PS prescription. See Section 7.2.11 for more detail.
h PS adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment provided in
Appendix 2.
i Safety laboratory assessments at site visits will consist of clinical chemistry, hematology, and urinalysis, with results processed by a central laboratory. Clinical chemistry and 
urinalysis must also be performed within approximately 5-7 days of any adjustment to the PS prescription. Safety labs performed between clinic visits may be performed locally. 
Unscheduled lab results will not be captured in the eCRFs. If abnormal results are considered an adverse event, an AE form will be completed. Collect PT/INR at the pre-treatment 
visit. Additional collection will occur if a potential drug-induced liver injury signal is observed. Urine specimen collection should be attempted as part of the safety labs, but lack 
of urinalysis will not constitute a protocol deviation.
j Samples collected on CxD1 must be drawn prior to first administration of teduglutide. Samples collected while subjects are receiving teduglutide (CxW12 and CxW24) must be 
drawn at least 14 hours after dosing.
k The teduglutide-naïve subjects age 12 and older will undergo colonoscopy/sigmoidoscopy at the pre-treatment visit if one has not been performed within 1 year. Subjects of any 
age with newly positive FOBT results at the pre-treatment visit for which a readily detectable cause cannot be identified (eg, anal fissure) will undergo a 
colonoscopy/sigmoidoscopy prior to receiving teduglutide. If newly positive FOBT results (for which a readily detectable cause cannot be identified) are obtained at the end of a 
teduglutide treatment cycle (CxW24/EOT), colonoscopy/sigmoidoscopy will be performed. The need for colonoscopy/sigmoidoscopy in response to positive FOBTs at CxW12 is 
at the discretion of the investigator. Teduglutide-exposed subjects who have received the equivalent of 2 treatment cycles (48 weeks of study drug exposure) will undergo 
colonoscopy/sigmoidoscopy. See Section 7.2.9 for details.
l A serum pregnancy test is performed on all FOCBP at the teduglutide pre-treatment visit (when the pre-treatment and screening visits are combined, the serum pregnancy test 
For non-commercial use only


Shire
CONFIDENTIAL
Page 24
Protocol SHP633-304
Version 2 / 22 Nov 2016
Table 1-3: Schedule of Events for Subjects While Receiving Teduglutide
Period
Pre-
treatment
Teduglutide Treatment
Follow-up
should be performed at the local laboratory). Urine pregnancy tests will be administered at all other visits according to the study schedules, or if pregnancy is suspected, or as 
specified per protocol upon withdrawal of the subject from the study.
m Lack of collection of serum samples will not constitute a protocol deviation.
n If escape criteria are met, the subject may proceed directly to another pre-treatment visit at the discretion of the investigator.
o The first SC injection of teduglutide in treatment-naïve subjects will be administered under the supervision of the investigator/designee after which the subject will be observed 
for hypersensitivity reactions for at least 4 hours. The site of administration (arm, thigh, abdomen) of the first teduglutide dose must be specified and recorded in the eCRF. See 
Section 6.2.3 for dose adjustment.
For non-commercial use only


Shire
CONFIDENTIAL
Page 25
Protocol SHP633-304
Version 2 / 22 Nov 2016
1
BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options 
Short bowel syndrome (SBS) is a rare disorder resulting from congenital abnormalities or severe 
intestinal diseases that result in major surgical resections of the small intestine. It is estimated 
that, at most, there are a few hundred pediatric subjects 1 year and older with SBS (Khan et al. 
2015; Wales et al. 2004). Unlike the adult population, the majority of cases of SBS in pediatric 
subjects are due to congenital anomalies or catastrophic events that occur during infancy. 
Although the small intestine is capable of remarkable adaptation, excessive loss of absorptive 
surface area or specialized functions can lead to dependence on parenteral nutrition or 
intravenous (IV) fluids (parenteral support [PS]). Treatment of both pediatric and adult patients 
is focused on achieving adequate intestinal absorption to allow for minimization or 
discontinuation of PS. About 30% of infants with SBS become independent of PS requirements 
within 12 months of the initial insult, and an additional 10% wean off PS within 24 months. 
After this time, linear intestinal growth slows. About 60% of pediatric subjects with SBS are able 
to become independent of PS within 5 years of the initial diagnosis (Khan et al. 2015).
Nevertheless, despite optimal medical management, many pediatric subjects remain dependent 
on PS. Complications of long-term PS include liver disease, catheter-related blood stream 
infections, central line-associated venous thrombosis and dwindling central venous access. 
Sepsis is the leading cause of death in these patients and quality of life is poor (Squires et al. 
2012). Accelerating the adaptive process and achieving enteral autonomy is an urgent goal for all 
patients with SBS who are dependent on PS (Khan et al. 2015; Squires et al. 2012).
Intestinal adaptation is driven by hormonal cues in response to nutrient malabsorption (Drucker 
and Yusta 2014). Chief among these is hormones glucagon-like peptide 2 (GLP-2), which is 
secreted from L-type enteroendocrine cells that reside in the intestinal epithelium in the ileum 
and colon. Resection of these regions may impair the adaptive response by limiting endogenous 
production of GLP-2. 
1.2
Product Background 
Teduglutide is a novel, recombinant analog of naturally occurring human GLP-2 that regulates 
the functional and structural integrity of the cells lining the gastrointestinal (GI) tract. 
Teduglutide is a 33-amino acid peptide that differs from native GLP-2 in the substitution of 
glycine for alanine at the second position at the N-terminus. As a result, teduglutide demonstrates 
resistance to degradation by dipeptidyl peptidase-IV (DPP-4) and therefore maintains a longer 
elimination half-life (t1/2) in adults of approximately 2 hours compared to the native peptide, 
which has a t1/2 of approximately 7 minutes. Teduglutide has been shown in animal studies and 
previous human clinical trials to increase villus height and crypt depth in the intestinal 
epithelium, thereby increasing the absorptive surface area of the intestines (Tappenden et al. 
2013; Thymann et al. 2014). The European Commission granted a centralized marketing 
authorization valid throughout the European Union (EU) for teduglutide (Revestive™) on 30 
August 2012 and a New Drug Application (NDA) for teduglutide (Gattex®) was approved by the 
United States (US) Food and Drug Administration (FDA) on 21 December 2012 for the 
treatment of adult patients with SBS who are dependent on PS. Teduglutide has also been 
approved for use in adult patients with SBS in Canada and Switzerland. On 29 Jun 2016, the 
For non-commercial use only


Shire
CONFIDENTIAL
Page 26
Protocol SHP633-304
Version 2 / 22 Nov 2016
European Commission granted an extension of the Market Authorization for teduglutide 
(REVESTIVE™) for the treatment of patients aged 1 year and above with SBS; patients should be 
stable following a period of intestinal adaptation.
1.3
Clinical Studies with Teduglutide in Pediatric subjects
One Phase 3 study, TED-C13-003, was completed in pediatric SBS subjects in the US and 
United Kingdom (UK). In this study, teduglutide was administered to 3 cohorts of pediatric 
subjects from ages 1-17. Thirty-seven pediatric subjects received teduglutide at doses of 0.0125, 
0.025, or 0.05 mg/kg/day for 12 weeks. Five additional pediatric subjects were enrolled in an 
observational standard of care (SOC) cohort. There were clear dose-dependent effects of 
teduglutide seen at the 0.025 and 0.05 mg/kg/day doses compared to SOC and the 0.0125 
mg/kg/day dose. In the 0.025 mg/kg/day cohort there was a reduction in PS volume at Week 12 
of 37%, including complete independence from PS support in 1 subject, and a reduction of 3.94 
hours per day infusion time. In the 0.05 mg/kg/day cohort there was a reduction in PS volume at 
Week 12 of 39%, including complete independence from PS support in 3 subjects, and a 
reduction of 4.18 hours per day infusion time. Teduglutide was generally safe and well tolerated 
by pediatric subjects in all dosing cohorts. There were no deaths during the study and no 
treatment-emergent serious adverse events (TESAEs) related to teduglutide were reported. No 
discontinuations from study were due to adverse events (AEs).
TED-C14-006 is an ongoing study which includes 2 treatment arms: a teduglutide treatment arm 
and a standard of care treatment arm. Subjects in both arms participate in a 2-week minimum 
screening period, a 24-week treatment period, and a 4-week follow-up period. During the 
screening period, subjects will choose into which arm to enroll. During the 24-week treatment 
period, subjects in the SOC treatment arm will receive standard medical therapy for SBS; while 
those in the teduglutide treatment arm will receive daily subcutaneous (SC) injections of 
teduglutide (study drug) in addition to standard medical therapy. The subjects enrolling in the 
teduglutide treatment arm will be randomized 1:1 in a double-blinded manner into 2 parallel dose 
groups: 0.025 mg/kg/day or 0.05 mg/kg/day of teduglutide administered subcutaneously for 24 
weeks.
Always refer to the latest version of the investigator’s brochure for the overall risk/benefit 
assessment and the most accurate and current information regarding the drug metabolism, 
pharmacokinetics, efficacy and safety of teduglutide (SHP633). 
For non-commercial use only


Shire
CONFIDENTIAL
Page 27
Protocol SHP633-304
Version 2 / 22 Nov 2016
2
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study 
This is a Phase 3, prospective, open-label, long-term extension study to evaluate the safety and 
efficacy of teduglutide in pediatric subjects with SBS who completed the TED-C14-006 study. In 
addition to evaluating the long-term safety and durability of efficacy after 24 weeks of treatment, 
this extension study will evaluate the need for additional teduglutide treatment in these subjects, 
and will allow for the first-time treatment of teduglutide-naïve subjects who participated in the 
SOC treatment arm in TED-C14-006.
2.2
Study Objectives
2.2.1
Primary Objectives
The primary objective of the study is to evaluate the long-term safety and tolerability of 
teduglutide treatment in pediatric subjects with SBS who completed TED-C14-006.
2.2.2
Secondary Objectives
The secondary objective of this study is to evaluate the long-term efficacy of teduglutide 
treatment in pediatric subjects with SBS who completed TED-C14-006.
For non-commercial use only


Shire
CONFIDENTIAL
Page 28
Protocol SHP633-304
Version 2 / 22 Nov 2016
3
STUDY DESIGN
3.1
Study Design and Flow Chart
This is a Phase 3, prospective, open-label, long-term extension study to evaluate the safety and 
efficacy of teduglutide in pediatric subjects who completed the TED-C14-006 study (core study). 
At the time of entry into the TED-C14-006 study, subjects were less than 18 years of age, were 
dependent on parenteral nutrition to provide at least 30% of their caloric or fluid needs, and had 
not been able to significantly reduce PS for at least 3 months prior to enrollment. During the core 
study, pediatric subjects in the teduglutide treatment arm were randomized to 0.025 mg/kg or 
0.05 mg/kg once daily (QD) dosing in a double-blinded manner. The TED-C14-006 study will 
also be referred to as the core study interchangeably throughout this protocol.
Approximately 34 subjects who complete the core study are expected to enroll in this extension 
study. Subjects who previously received teduglutide during TED-C14-006, as well as subjects 
who were in the SOC treatment group, may be eligible to receive teduglutide treatment in this 
extension study. To be eligible, subjects must meet ≥1 of the teduglutide treatment inclusion 
criteria and none of the teduglutide treatment exclusion criteria.
Additional Teduglutide Treatment
Subjects not receiving teduglutide treatment (ie, in a “no-teduglutide treatment period”), will be 
seen approximately every 12 weeks for safety, parenteral support (PS) requirements, and quality 
of life. At any point during a no-teduglutide treatment period, subjects who meet ≥1 teduglutide 
treatment inclusion may proceed directly to the pre-treatment visit if the investigator, subject, 
and parent agree to proceed with teduglutide therapy.
Rationale: Some pediatric subjects may have a durable beneficial effect after 24 weeks of 
teduglutide treatment and thus long-term follow-up without additional teduglutide treatment may 
be appropriate. However, there may be some pediatric subjects who deteriorate or stop 
improving after discontinuation of teduglutide treatment. In these pediatric subjects, additional 
teduglutide treatment may be beneficial. 
Dose Selection 
Analysis suggested that pediatric patients, ages 1 to 17 years old, are likely to require the same 
dose as used in adults, namely 0.05 mg/kg/day (Mouksassi et al. 2009). In this extension study to 
TED-C14-006, repeat doses of teduglutide 0.05 mg/kg QD will be administered to eligible 
pediatric subjects who previously received teduglutide 0.05 or 0.025 mg/kg in Study TED-C14-
006.
Rationale: Teduglutide is approved for adult use in the US and EU, and for pediatric use in the 
EU, at a dose of 0.05 mg/kg SC once daily. The completed 12-week pediatric study (TED-C13-
003) demonstrated that teduglutide dosing at 0.025 and 0.05 mg/kg/day was associated with a 
favorable benefit/risk profile. In addition, population pharmacokinetic modeling and simulations 
were conducted to determine the effective dose to be used in pediatric subjects using data from 
8 adult clinical studies including adult Phase 1 studies and Phases 2/3 studies as well as the 
For non-commercial use only


Shire
CONFIDENTIAL
Page 29
Protocol SHP633-304
Version 2 / 22 Nov 2016
pediatric study (TED- C13- 003) and suggested that the dose in pediatric subjects is likely to be 
same as the dose in adults (O'Keefe et al. 2006). 
Duration of Treatment
The duration of teduglutide treatment in this study mirrors that of the TED-C14-006 study, 
consisting of 24 weeks of teduglutide treatment, followed by a 4-week follow-up period. The 
follow-up period is a mechanism to evaluate whether continued teduglutide is needed. If a 
subject deteriorates during the follow-up period, the subject may be evaluated immediately for 
additional teduglutide treatment. Subjects who clinically deteriorate or stop improving at any 
time after the end of the follow-up period will also be assessed for additional treatment.
Rationale: During the teduglutide treatment cycle, visit frequency is similar to frequencies 
performed in TED-C13-003 and TED-C14-006, to ensure sufficient safety monitoring and 
weaning of PS. During the no-teduglutide treatment, visits occur every 12 weeks, a frequency 
that is consistent with standard medical practices.
Measures and Parameters
Following the review and signing of the informed consent (and informed assent, if applicable), 
screening visit procedures will begin including demographics, and updates to medical history
and SBS history. Subjects who meet ≥1 of the teduglutide treatment inclusion criteria may 
proceed to the pre-treatment visit.
After the pre-treatment visit, subjects who still meet ≥1 of the teduglutide treatment inclusion 
criteria, and meet none of the teduglutide treatment exclusion criteria, will start a 28-week cycle, 
consisting of 24 weeks of teduglutide treatment at 0.05 mg/kg SC once daily, followed by a 4-
week follow-up (no treatment) period (Figure 3-1). During the 28-week cycle, clinic visits will 
occur at weeks 1, 2, 4, 6, 9, 12, 16, 20, 24, and 28. Phone visits are required approximately 
1 week after adjustments in PS during the teduglutide treatment period (between weeks 1-24), 
and weekly during the teduglutide follow-up period (between weeks 24 and 28).
Safety and PS requirements will be evaluated on a weekly basis, and quality of life assessments 
will be made approximately every 12 weeks. At all site visits and telephone contacts, safety will 
be monitored and nutritional support will be reviewed and adjusted as needed. To maintain 
consistency across centers, all attempts should be made to follow the nutritional support 
adjustment guidelines (developed with SBS expert input and provided in the protocol) for 
decisions regarding PS reduction and advances in enteral feeds based on weight gain, urine and 
stool output, and clinical stability. Departure from the guidelines, however, is not considered a 
protocol deviation (Appendix 2).
Rationale: Measures of long term safety will include adverse events, growth parameters and 
anti-drug antibodies. Measure of long term efficacy will include durability of effect as measured 
by reduction in PS and improvement in pediatric quality of life measures (PedsQL, PedsQL 
Family Impact Module). A reduction in PS volume of at least 20% at end of treatment (EOT) was 
used as the primary endpoint in pivotal phase 3 adult clinical trials and the completed phase 3 
pediatric study (TED-C13-003), and will be used as an endpoint in this extension study. In 
previous clinical studies, a reduction of this magnitude was associated with a reduction in the 
For non-commercial use only


Shire
CONFIDENTIAL
Page 30
Protocol SHP633-304
Version 2 / 22 Nov 2016
number of days per week of PS, and increases in enteral intake. Reduction in volume and time of 
PS due to improved enteral absorption may provide a pediatric subject with opportunities for 
more age-appropriate activities including oral rehabilitation. Quality of life assessments will be 
performed in this study to quantitate this effect.
Teduglutide has been found to have a targeted intestinotrophic effect. Taking into account the 
patient population and the pharmacologic effect of teduglutide, GI-specific screening tests, 
including fecal occult blood testing and colonoscopy/sigmoidoscopy, which are commonly part 
of the routine care of these subjects, will be performed to ensure safety. This study captures long-
term safety data on polyps and other colonic mucosal changes in teduglutide-exposed subjects 
using the surveillance strategy proposed in Section 7.2.9. 
Figure 3-1:
Study Design Flow Chart
Figure legend: Safety and efficacy data for subjects not receiving teduglutide treatment are captured approximately every 
12 weeks, but subjects may proceed to the pre-treatment visit at any time in order to assess eligibility for teduglutide therapy. 
Eligible subjects will enter a 28-week teduglutide cycle. During this cycle, subjects will return to the site for safety and efficacy 
assessments at weeks 1, 2, 4, 6, 9, 12, 16, 20, and 24 (solid black lines). Phone visits are required approximately 1 week after 
adjustments in PS during the intervening weeks between weeks 2 and 24 (dashed grey lines). Subjects discontinue teduglutide at 
week 24 and enter a 4-week follow-up (no-treatment) period, during which phone visits will be performed weekly (solid grey 
lines). If an escape criterion is met during the follow-up period, subjects may proceed directly to another pre-treatment visit.
3.2
Duration and Study Completion Definition
A subject will be considered enrolled in the study once the subject has provided signed consent, 
and meets all of the Inclusion Criteria. The study will continue for at least 1 year and until each 
subject has access, as needed, to teduglutide. The subject’s maximum duration of participation is 
expected to be approximately 3 years. The study will be completed in approximately 40 months.
A subject will be considered as having completed the study if the subject has not withdrawn 
early from the study for any reason prior to completing the End of Study (EOS) visit.
The study completion date is defined as the date the final subject, across all sites, completes their 
final protocol-defined assessment. Please note that this includes the follow-up visit or contact 
(last safety contact), whichever is later. The study completion date will be used to ascertain 
timing for study results posting and reporting.
For non-commercial use only


Shire
CONFIDENTIAL
Page 31
Protocol SHP633-304
Version 2 / 22 Nov 2016
4
STUDY POPULATION
Each subject must review and sign the informed consent (and informed assent, if applicable) 
before any study-related procedures specified in the protocol are performed. Teduglutide 
treatment eligibility does not impact study eligibility.
4.1
Study Inclusion Eligibility Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1. Subject provides written informed consent (subject, parent or legal guardian and, as 
appropriate, subject informed assent) to participate in the study before completing any 
study-related procedures. 
2. Subject completed the TED-C14-006 study (including subjects in the standard of care 
treatment arm).
3. Subject understands and is willing and able to fully adhere to study requirements as 
defined in this protocol.
4.2
Study Exclusion Eligibility Criteria
There are no exclusion criteria for this study.
4.3
Teduglutide Eligibility Criteria
Subjects are eligible for teduglutide treatment if at least 1 (≥1) of the teduglutide treatment 
inclusion criteria, and none of the teduglutide treatment exclusion criteria are met. In addition, 
the investigator and the subject (and/or parent or legal guardian, as appropriate) must agree to 
proceed with treatment.
4.4
Teduglutide Treatment Inclusion Criteria
1. Subject is teduglutide-naïve, receiving PS, and unable to significantly reduce PS or 
advance enteral feeds (eg, 10% or less change in PS or advance in feeds) for at least 
3 months prior to and during the teduglutide pre-treatment visit, as assessed by the 
investigator. Transient instability for events such as interruption of central access or 
treatment for sepsis is allowed if the PS returns to within 10% of baseline prior to the 
event.
2. Subject was previously treated with teduglutide and at least 1 of the following criteria is 
satisfied:
a.
Increasing PS requirements following teduglutide discontinuation.
b. Decreased PS requirement during prior teduglutide treatment, followed by 
cessation of improvement after teduglutide discontinuation.
c.
Deteriorating nutritional status eg, weight loss or growth failure) despite 
maximal tolerated enteral nutrition following teduglutide discontinuation.
d. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid 
and electrolyte intake following teduglutide discontinuation.
For non-commercial use only


Shire
CONFIDENTIAL
Page 32
Protocol SHP633-304
Version 2 / 22 Nov 2016
e.
Severe diarrhea related to teduglutide discontinuation.
4.5
Teduglutide Treatment Exclusion Criteria
1. Body weight <10 kg at the pre-treatment visit.
2. Unresected GI polyp, known polyposis condition, pre-malignant change, or malignancy, 
in the GI tract
3. History of cancer in the previous 5 years except surgically curative skin cancers
4. Serial transverse enteroplasty or other major intestinal surgery within 3 months 
preceding the teduglutide pre-treatment visit. Insertion of a feeding tube, anastomotic 
ulcer repair, minor intestinal resections ≤10 cm, and endoscopic procedures are allowed.
5. Intestinal or other major surgery planned or scheduled to occur during the 28-week cycle
6. Clinically significant intestinal stricture or obstruction
7. Clinically significant, active or recurrent pancreatic or biliary disease
8. Active, severe, or unstable, clinically significant hepatic impairment or injury, including 
the following laboratory values at the pre-treatment visit:
a.
Total bilirubin ≥2 × upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥7 × ULN
c.
Alanine aminotransferase (ALT) ≥7 × ULN
9. Renal dysfunction shown by results of an estimated glomerular filtration rate (eGFR) 
below 50 mL/min/1.73 m2 at the pre-treatment visit
10. Unstable cardiac disease, congenital heart disease or cyanotic disease, with the exception 
of subjects who had undergone ventricular or atrial septal defect repair, or patent ductus 
arteriosus (PDA) ligation
11. Participation in a clinical study using an experimental drug (other than glutamine, 
Omegaven, or Smoflipid) within 3 months or 5.5 half-lives of the experimental drug, 
whichever is longer, prior to the pre-treatment visit and for the duration of the 28-week 
cycle
12. Treatment with analogs of glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 
(GLP-2) (not including teduglutide), insulin-like growth factor-1 (IGF-1), or growth 
hormone, within 3 months preceding the teduglutide pretreatment visit.
13. Treatment with octreotide or dipeptidyl peptidase 4 (DPP-4) inhibitors within 3 months 
prior to the pre-treatment visit
14. Known or suspected intolerance or hypersensitivity to the investigational product, 
closely-related compounds, or any of the stated ingredients
15. Known history of alcohol or other substance abuse within 1 year prior to the pre-
treatment visit
16. Pregnant or lactating female subjects 
17. Sexually active female subjects of child-bearing potential unwilling to use approved 
contraception during teduglutide treatment and for 30 days after the treatment period 
For non-commercial use only


Shire
CONFIDENTIAL
Page 33
Protocol SHP633-304
Version 2 / 22 Nov 2016
18. Any condition, disease, illness, or circumstance that in the investigator’s opinion puts 
the subject at any undue risk, prevents completion of the study, or interferes with 
analysis of the study results.
4.6
Follow-up Period Escape Criteria
At the discretion of the investigator, the follow-up period may be interrupted and the subject may 
proceed directly to the pre-treatment visit, if ≥1 of the following criteria is met:
1. Increasing PS requirements following teduglutide discontinuation.
2. Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal 
tolerated enteral nutrition following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation.
4. Severe diarrhea related to teduglutide discontinuation.
4.7
Reproductive Potential
4.7.1
Female Contraception
To be eligible for treatment with teduglutide, sexually active females of child-bearing potential 
must use an acceptable form of contraception throughout the study period and for 30 days 
following the last dose of investigational product. If hormonal contraceptives are used, they 
should be administered according to the package insert. Females of child-bearing potential who 
are not currently sexually active must agree to use acceptable contraception, as defined below, if 
they become sexually active during the period of the study and 30 days following the last dose of 
investigational product. 
To be eligible for treatment with teduglutide, female pediatric subjects and adolescent subjects 
should be either:

Pre-menarchal and either Tanner Stage 1 or less than age 9 years, or

Females of child-bearing potential (FOCBP) with a negative serum beta-human chorionic 
gonadotropin (-HCG) pregnancy test at the teduglutide pre-treatment visit. Females of 
child-bearing potential must agree to abstain from sexual activity that could result in 
pregnancy or agree to use acceptable methods of contraception.
Acceptable methods of contraception are:

Abstinence

Intrauterine devices plus condoms

Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or foam)

Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring), stabilized for at 
least 30 days prior to the pre-treatment visit, plus condoms. Note: if subject becomes 
For non-commercial use only


Shire
CONFIDENTIAL
Page 34
Protocol SHP633-304
Version 2 / 22 Nov 2016
sexually active during the study, they should use one of the other acceptable methods 
noted above in addition to the hormonal contraceptive until it has been stabilized for 
30 days.
4.8
Discontinuation of Subjects 
4.8.1
Teduglutide Discontinuation
If the investigational product is discontinued prematurely during a teduglutide treatment cycle
and the subject wishes to remain in the study, the evaluations listed for the EOT visit are to be 
performed. A 4-week follow-up period will ensue, consisting of weekly telephone visits 
(CxW25-27) and the week 28 clinic visit (CxW28). The subject would then enter a 
no-teduglutide treatment (NTT) period and could be evaluated for subsequent teduglutide 
treatment eligibility according to the study schedules. Comments (spontaneous or elicited) or 
complaints made by the subject must be recorded in the source documents. The reason for 
permanent treatment discontinuation, dates of investigational product administered (including 
last date of treatment), and amount of investigational product taken must be recorded in the 
electronic case report form (eCRF) and source documents, as described in Section 4.8.3. The 
investigator is encouraged to discuss withdrawal of a subject from investigational product with 
the medical monitor, when possible.
4.8.2
Study Withdrawal
At any time during the study, the investigator or sponsor may withdraw a subject, or a subject 
may withdraw from the study, for any reason, without prejudice to their future medical care by 
the physician or at the institution.
If a subject withdraws from the study during a teduglutide cycle, the evaluations listed for the 
EOT visit are to be performed as completely as possible. Whenever possible, the subject will 
then be asked to return 4 weeks later for the early termination (ET) visit, and will be contacted 
weekly by phone during the interim period between EOT and ET for safety follow-up.
If a subject withdraws from the study during a NTT period, the evaluations listed for the ET visit 
are to be performed as soon and completely as possible. 
Subjects who withdraw from the study will not be replaced.
4.8.3
Reasons for Discontinuation
The reason(s) for permanent discontinuation of treatment and/or withdrawal from the study must 
be determined by the investigator, and recorded in the subject’s medical record and in the eCRF. 
If a subject is withdrawn for more than 1 reason, each reason should be documented in the source 
document, and the most clinically relevant reason should be entered in the eCRF.
Reasons for discontinuation include, but are not limited to:
Adverse event 
Protocol deviation
For non-commercial use only


Shire
CONFIDENTIAL
Page 35
Protocol SHP633-304
Version 2 / 22 Nov 2016
Lack of efficacy 
Physician decision 
Withdrawal by subject 
Withdrawal by parent/guardian
Lost to follow-up
Pregnancy (Discontinuation of treatment only) 
Death 
Other 
4.8.3.1
Subjects ‘Lost to Follow-up’ Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact (office visit or telephone contact). At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that they 
return to the site for final safety evaluations, and return any unused investigational product.
For non-commercial use only


Shire
CONFIDENTIAL
Page 36
Protocol SHP633-304
Version 2 / 22 Nov 2016
5
CONCOMITANT TREATMENT
5.1
Concomitant Medications and GI Procedures
Concomitant treatment refers to all treatment taken between the dates of informed consent and 
EOS, inclusive. Concomitant treatment information must be recorded on the appropriate eCRF 
page. Concomitant treatments will be assessed at each site visit, and include all non-study 
treatments (medications, herbal treatments, vitamins, invasive and diagnostic procedures). 
Concomitant GI procedures include (but are not limited to) endoscopy, radiographic studies, GI 
and liver biopsies and associated pathology results. Concomitant treatment information must be 
recorded on the appropriate eCRF page. Details of medication changes and/or dosages will be 
recorded on the eCRF.
The mechanism of action of teduglutide may increase absorption of drugs (eg, motility 
medication including narcotics and opioids used for the management of SBS, warfarin, 
psychotropics, metronidazole, and digoxin). Accordingly, due consideration should be given to 
modifying concomitant medication regimens. Down-titration of concomitant medications should 
be considered when drugs, especially those with a narrow therapeutic range, are prescribed at 
dosages that are higher than usual.
5.1.1
Permitted Treatment
Standard medical therapy for SBS should be continued.
5.1.2
Prohibited Treatment
The mechanism of action of teduglutide may increase enteral absorption of drugs (eg, motility 
medication including narcotics and opioids used for the management of SBS, warfarin, 
psychotropics, metronidazole, digoxin), so consideration should be given to modifying 
concomitant enteral medication regimens. Down-titration of concomitant enteral medications 
should be considered when drugs, especially those with a narrow therapeutic range, are given at 
dosages that are higher than usual.
The following medications are prohibited during teduglutide treatment and within the provided 
timeframe prior to the pre-treatment visit:
Table 5-1: Prohibited Treatment
Prior Therapy
Time Restriction Prior to 
the Pre-Treatment Visit
Native/synthetic glucagon-like peptide-2 (not-including teduglutide)
Any
Glucagon-like peptide-1 analog or human growth hormone
3 months
Octreotide or dipeptidyl peptidase 4 inhibitors
3 months
Biological therapy (eg, antitumor necrosis factor)
6 months
For non-commercial use only


Shire
CONFIDENTIAL
Page 37
Protocol SHP633-304
Version 2 / 22 Nov 2016
6
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product 
The test product is teduglutide, which will be provided in sterile, single-use 3 mL vials 
containing 5 mg or 1.25 mg teduglutide as a white lyophilized powder to be reconstituted before
use with 0.5 mL sterile water for injection. In addition to the active ingredient (teduglutide), each 
vial of teduglutide contains L-histidine, mannitol, monobasic sodium phosphate monohydrate, 
and dibasic sodium phosphate as excipients. Additional information is provided in the current 
SHP633 investigator’s brochure.
6.1.1
Blinding the Treatment Assignment
Not applicable for this open-label study.
6.2
Administration of Investigational Product(s)
6.2.1
Interactive Response Technology for Investigational Product Management
An interactive web-based response system (IWRS) will be used for screening and enrolling 
subjects, recording subject visits, investigational product supply dispensation and management, 
inventory management and supply ordering, investigational product expiration tracking and 
management, and return of investigational product. Please refer to the Study Manual for 
additional details regarding the IWRS. 
The IWRS will also be used for creating, tracking, and confirming investigational product 
shipments. A user manual with specific functions and instructions for the IWRS will be provided 
to the site, and site personnel will receive training.
6.2.2
Allocation of Subjects to Treatment 
This is an open-label study. Subjects will retain their assigned subject number from the 
TED-C14-006 study. Assessment of need for teduglutide treatment should be guided by the 
teduglutide treatment inclusion criteria. If the investigator, subject, and/or parent/guardian agree 
to proceed with treatment, a formal evaluation of teduglutide inclusion and exclusion criteria will 
be performed at the pre-treatment visit (Table 1-3). 
6.2.3
Dosing
If teduglutide treatment eligibility is established at the pre-treatment visit and again, confirmed at 
the CxD1 visit, the subject will start a teduglutide treatment period, consisting of 24 weeks of 
teduglutide treatment at 0.05 mg/kg SC once daily. The initial dose will be calculated based on 
body weight measured at the teduglutide pre-treatment visit, and adjusted as needed, based on 
body weight measured at Week 12 (CxW12). No other adjustments to dose will be made during 
the teduglutide treatment period, unless discussed with the sponsor’s medical monitor. 
Following reconstitution, teduglutide will be administered by SC injection QD into 1 of the 
4 quadrants of the abdomen (in subjects without a stoma) or into either the thigh or arm. For 
subjects with a stoma, the quadrant of the abdomen containing the stoma should not be used. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 38
Protocol SHP633-304
Version 2 / 22 Nov 2016
Teduglutide should be used as soon as possible after reconstitution, but no more than 3 hours 
later.
The subject should be dosed at approximately the same time each day. Consecutive doses should 
be separated by at least 12 hours. Each day, the injection site should be rotated.
The first SC injection in teduglutide-naïve subjects should be administered under the supervision 
of the investigator or designee and the subject observed for hypersensitivity reactions for at least 
4 hours during their initial dosing visit. The site of administration (arm, thigh, and abdomen) of 
the first teduglutide dose must be specified and recorded in the eCRF. 
Detailed instructions for reconstitution and injection of the investigational product can be found 
in the Instructions for Use. 
Following each 24-week teduglutide treatment period, subjects will enter a 4-week follow-up 
period. During the follow-up, the investigator will assess the subject via weekly telephone visits. 
At any time during the follow-up period, if escape criteria are met, the subject may proceed 
directly to another Pre-Treatment visit to assess treatment eligibility for another cycle 
(Section 4.6). Following the completion of the 4-week follow-up, the subject will continue in the 
study off teduglutide. Additional 28-week cycles may be repeated if treatment eligibility is 
established each time. 
6.2.4
Unblinding the Treatment Assignment
Not applicable for this open-label study.
6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling 
Labels containing study information and pack identification will be applied to the investigational 
product(s) container. 
The study drug will be packaged, labeled, and shipped to the study site by the sponsor or 
designee. Kits containing 7 vials of study drug will be supplied and these will be labeled in 
accordance with applicable regulatory requirements. Sterile water for injection syringes will be 
provided separately and will be labeled in accordance with the applicable regulatory 
requirements.
All study drug used in this study will be manufactured, tested, labeled, and released according to 
current legal requirements and Good Manufacturing Practice.
6.3.2
Packaging
Investigational product is packaged in the following conditions:
Teduglutide will be provided in a sterile, single-use, glass vial as a lyophilized powder, to be 
reconstituted with 0.5 mL sterile water for injection provided as the diluent in a prefilled syringe.
For non-commercial use only


Shire
CONFIDENTIAL
Page 39
Protocol SHP633-304
Version 2 / 22 Nov 2016
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
6.3.3
Storage and Handling
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.
Study drug must be kept in a locked area with access restricted to specific study personnel. Study 
drug will be stored refrigerated at a temperature between 2 to 8°C (35.6 to 46.4°F) until 
dispensed to a subject. Once dispensed to a subject, the study drug can be stored refrigerated or 
up to a controlled room temperature (acceptable range of 2 to 25°C, or 35.6 to 77°F). 
Parent/guardian will be instructed to keep the subject’s study drug and sterile water diluent at 
controlled room temperature. If there are concerns that the controlled room temperature cannot 
be maintained, the study drug may be refrigerated. The study drug is for single use only, and 
should be used within 3 hours following reconstitution.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (ie, certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
Investigational products are distributed by the pharmacy or nominated member of the study 
team. The pharmacist/nominated team member will enter the unique subject identifier on the 
investigational product bottle/carton labels, as they are distributed. 
6.4
Drug Accountability 
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. The 
investigator is to keep a current record of the inventory and dispensation of all clinical supplies. 
This record will be made available to the sponsor’s site monitor for the purpose of accounting for 
For non-commercial use only


Shire
CONFIDENTIAL
Page 40
Protocol SHP633-304
Version 2 / 22 Nov 2016
all clinical supplies. Any discrepancy or deficiency will be recorded and will include an 
explanation. All supplies sent to the investigator must be accounted for and in no case will 
clinical supplies be used in any unauthorized situation.
The investigator has overall responsibility for administering/dispensing investigational product. 
Where permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator. 
This delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will dispense the investigational product only to subjects eligible 
for teduglutide treatment following the procedures set out in the study protocol. All dispensed 
study medication will be documented in the interactive response technology system and/or other 
investigational product record (eg, investigation product accountability form). The investigator is 
responsible for assuring the retrieval of all study supplies from subjects.
All used and unused study drug vials must be returned by the subjects and/or parent/guardian, 
and will be retained at the site. If deemed appropriate, the investigator or his/her designee may 
dispense the unused study drug vials to the same subject. All original containers, whether empty 
or containing study drug will be returned to the pharmacy. Returned study drugs will NOT be 
relabeled or reassigned for use by other subjects. Contents of the study drug containers will not 
be combined. All used and unused vials must be returned to the distribution center according to 
the sponsor’s instruction. No vial/kit may be destroyed on site without approval by the sponsor. 
Please see the Pharmacy Manual for additional information.
6.5
Subject Compliance
Subjects will be instructed to bring their unused investigational product and empty/used 
investigational product packaging to every visit. Drug accountability will be assessed at the 
container/packaging level for unused investigational product that is contained within the original 
tamper-evident sealed container (eg, bottles, trays, vials) or at the individual count level for 
opened containers/packaging. The pharmacist/nominated person will record details on the drug 
accountability form.
Of those subjects eligible for teduglutide treatment, subjects who have received 80% of the 
planned doses administered will be assessed as being compliant with the study protocol.
For non-commercial use only


Shire
CONFIDENTIAL
Page 41
Protocol SHP633-304
Version 2 / 22 Nov 2016
7
STUDY PROCEDURES
7.1
Study Schedule
Detailed study procedures and assessments to be performed for subjects throughout the study are 
outlined in the Schedule of Assessments (Table 1-1, Table 1-2, and Table 1-3) and must be 
referred to in conjunction with the instructions provided in this section. 
7.1.1
Screening 
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent (and assent, as applicable) 
from the subject. A subject will have up to 7 days, after completion of the TED-C14-006 study, 
to sign consent to participate in the SHP633-304 study. The first visit after screening must occur 
within 12 weeks of screening for a pre-treatment visit, and within 2 to 12 weeks of screening for 
an NTx visit.
The screening visit (Scr) assessments and procedures, beginning with informed consent, will be 
performed as outlined in Table 1-1, and as detailed below:
Informed consent, and informed assent (if applicable), is obtained
Study eligibility is determined. A screen failure is a subject who has given informed 
consent and failed to meet the Study Inclusion Eligibility Criteria. Subjects cannot be 
rescreened once they have been designated as a screen failure. 
Demographics, updates to medical history and SBS history
Intake and output diaries are dispensed
Evaluate teduglutide treatment inclusion criteria 
Adverse events, concomitant medications and concomitant GI procedures
7.1.2
Visits for Subjects Not Receiving Teduglutide
While outside of the 28-week teduglutide-treatment cycle, subjects will be followed 
approximately every 12 weeks for safety and efficacy assessments. No-teduglutide treatment 
visits are numbered sequentially (NT1, NT2, etc.), even if interrupted by the treatment cycles. 
The visit window (±7 days) is relative to the first NTx visit in the current NTT period.
Assessments will be performed as outlined in Table 1-2 and described below.
Intake and output diaries are dispensed
Evaluate teduglutide treatment inclusion criteria
Adverse events, concomitant medications and concomitant GI procedures
Physical examination and vital signs, including weight
For non-commercial use only


Shire
CONFIDENTIAL
Page 42
Protocol SHP633-304
Version 2 / 22 Nov 2016
Height and head circumference
Review intake and output diaries
Record PS prescription and adjust as needed
Safety Laboratory Tests (ie, clinical chemistry, hematology, and urinalysis)
PedsQL Generic Core Scale/PedsQL Family Impact Module/ PedsQL Gastrointestinal 
Symptoms Module Sub-Scales
Antibodies to teduglutide, if and when required
Fecal occult blood testing, as indicated (Section 7.2.9.1)
Colonoscopy/sigmoidoscopy, as indicated (see Section 7.2.9.2)
Serum sample, as indicated
Teduglutide treatment may be considered at any time during the NTT period. If the investigator 
and the subject (and parent or legal guardian, as appropriate) agrees to proceed with treatment if 
the subject is eligible, the subject may proceed to the pre-treatment visit immediately to 
determine eligibility.
7.1.3
Visits for Subjects Receiving Teduglutide
7.1.3.1
Pre-treatment Visit
Subjects who meet at least 1 of the teduglutide treatment inclusion criteria during the screening 
visit or during the NTT period may proceed to the pre-treatment visit immediately if the 
investigator, subject and parent agree to proceed with teduglutide therapy. Similarly, subjects 
who meet escape criteria during the teduglutide follow-up period may proceed to the 
pre-treatment visit immediately.
The pre-treatment visit may also be combined with screening visit, and if the pre-treatment 
visit assessments occur within 7 days of the TED-C14-006 EOS visit (Week 28), both sets of 
assessments can be combined. A subject must have 2 weeks of intake diary data collected, prior 
to the first dose administration (CxD1) during any teduglutide treatment cycle. In general, pre-
treatment assessments may occur over a period of up to 21 days. The teduglutide pre-treatment 
visit (Px) assessments and procedures will be performed as in Table 1-3 and as described below:
Evaluate teduglutide eligibility (treatment inclusion/exclusion criteria) 
Dispense intake and output diaries
Adverse events, concomitant medications and concomitant GI procedures
Fecal occult blood testing 
Gastrointestinal-specific testing, including colonoscopy or sigmoidoscopy as indicated
For non-commercial use only


Shire
CONFIDENTIAL
Page 43
Protocol SHP633-304
Version 2 / 22 Nov 2016
Physical examination and vital signs, including weight
Height and head circumference
Review intake and output diaries
Record PS prescription and adjust as needed.
Safety Laboratory Tests 
(In addition to clinical chemistry, hematology, and urinalysis, labs at this visit include 
prothrombin time [PT] international normalized ratio [INR]. Subsequent prothrombin 
time/international normalized ratio (PT/INR) measurement is only required to evaluate 
for suspected drug-induced liver injury [DILI]). 
Serum pregnancy testing (when the pre-treatment and screening visits are combined, 
the serum pregnancy test should be performed at the local laboratory)
Serum sample 
7.1.3.2
Teduglutide Treatment Period (CxD1-CxW24)
The open-label teduglutide treatment period will comprise 24 weeks, during which all 
assessments and procedures listed for Visits CxD1-CxW24 in Table 1-3 shall be completed. 
Cycles are numbered sequentially, such that the first visit of the first cycle is C1D1, and the first 
visit of the second cycle is C2D1, etc. Visit windows are calculated based upon the date of first 
investigational product administration (Visit CxD1). 
VISIT CXD1
Assessments and procedures at this visit will be performed as outlined Table 1-3 and as 
described below. 
Two weeks of intake diary data are required before drug is administered at CxD1.
Confirm teduglutide treatment eligibility
Dispense intake and output diaries
Adverse events, concomitant medications and concomitant GI procedures
Physical examination and vital signs, including weight
Height and head circumference
Review intake and output diaries
Record PS prescription and adjust as needed 
Safety laboratory tests
For non-commercial use only


Shire
CONFIDENTIAL
Page 44
Protocol SHP633-304
Version 2 / 22 Nov 2016
Quality of life measurements 
Antibodies to teduglutide
Pregnancy testing (urine)
Dispense study drug
SITE VISITS DURING TEDUGLUTIDE TREATMENT PERIOD
Subjects will return for clinic visits on cycle weeks 1, 2, 4, 6, 9, 12, 16, 20, and 24/EOT. 
Assessments and procedures at these visits will be performed as outlined in Table 1-3 and as 
described below:
Dispense/review intake and output diaries (every effort should be made to complete 
2 weeks of intake diary entries prior to each clinic visit and to complete 48 hours of 
output diary entries during a period of nutritional stability prior to each clinic visit)
Physical examination and vital signs, including weight
Record PS prescription and adjust as needed
Safety laboratory tests 
Urine pregnancy testing for FOCBP (CxW4, CxW9, CxW12, CxW16, CxW20, 
CxW24)
Study drug dispensation (except for CxW24)
Adverse events, concomitant medications and concomitant GI procedures
In addition, at CxW12 and CxW24 Visits ONLY, the following procedures will be performed:
Height and head circumference
Antibodies to teduglutide
Fecal occult blood testing (FOBT)
GI-specific testing, including colonoscopy or sigmoidoscopy as indicated 
Quality of life measurements 
At CxW24 ONLY, a serum sample is collected and stored for future analysis. This sample will 
not be used for genetic testing and lack of collection will not constitute a protocol deviation.
PHONE VISITS 
Phone visits are required approximately 1 week after adjustments in PS during the teduglutide 
treatment period. Phone visit assessments and procedures are outlined in Table 1-3 and described 
below:
For non-commercial use only


Shire
CONFIDENTIAL
Page 45
Protocol SHP633-304
Version 2 / 22 Nov 2016
Review intake and output diaries
Safety laboratory tests (clinical chemistry and urinalysis)
Record PS prescription and adjust as needed
Obtain AEs, concomitant medications, and concomitant GI procedures  
Evaluate escape criteria
7.1.4
Teduglutide Follow-up Period
The safety follow-up period for this protocol is 4 weeks (Weeks 25 – 28 of the cycle). Phone 
visits will occur on cycle weeks 25, 26, and 27 for all subjects. Phone visit assessments and 
procedures at weeks 25-27 will be the same as for telephone visits performed during the 
teduglutide treatment period. In addition, subjects will be evaluated for follow-up period escape 
criteria. If escape criteria are met at any time during the follow-up period, the subject may 
proceed directly to another pre-treatment visit at the investigator’s discretion. The investigator 
may combine the CxW28 visit with the next pre-treatment visit if at least one escape criterion is 
met at the CxW28 visit, and the pre-treatment assessments occur within 7 days of the CxW28 
visit. If a subject is completing the study at the CxW28 visit, the EOS/ET visit (Section 7.1.5)
will take place in lieu of the CxW28 visit. Otherwise, following completion of the 28-week 
treatment cycle, the subject will proceed to an NTT visit within approximately 12 weeks.
At cycle week 28 (CxW28), subjects will return to the study site. In addition to the assessments 
performed at weeks 25-27, the following procedures will be performed at CxW28 ONLY:
Dispense intake and output diaries 
Physical examination and vital signs, including weight
Antibodies to teduglutide
Pregnancy testing (urine)
Evaluate escape criteria
7.1.5
Study Completion/Early Termination Visit (EOS/ET Visit) 
All subjects will return to the study site for the end of study/early termination visit (EOS/ET). 
Assessments and procedures at this visit will be performed as outlined in Table 1-1 and as 
described here. If a subject discontinues the study prematurely, the assessments for the EOS/ET 
Visit are to be performed as completely as possible (see Section 4.8.2).
Adverse events, concomitant medications and concomitant GI procedures  
Physical examination and vital signs, including weight
Height and head circumference
For non-commercial use only


Shire
CONFIDENTIAL
Page 46
Protocol SHP633-304
Version 2 / 22 Nov 2016
Review intake and output diaries (the intake diary should be completed daily for a 
minimum of 2 weeks prior to the EOS/ET visit. The output diary should be completed 
daily over a 48-hour period of nutritional stability before the EOS/ET visit)
Record PS prescription and adjust as needed
Safety laboratory tests 
Fecal occult blood testing, as indicated
Gastrointestinal-specific testing, including colonoscopy or sigmoidoscopy as 
indicated. 
Quality of life measurements 
Antibodies to teduglutide
Pregnancy testing, as needed
7.2
Study Evaluations and Procedures
7.2.1
Demographics, Medical History, and SBS History
Demographics, medical history, and SBS history will be obtained at screening. Medical history 
for purposes of this extension study will consist of the following:
Adverse events that were ongoing at the time of completion of TED-C14-006
Events that occurred during the period between completion of TED-C14-006 and 
informed consent to SHP-633-304 
This medical history information will supplement the medical history information collected at 
the start of the TED-C14-006 core study. If the subject has any changes to the SBS history 
collected at the baseline visit of the TED-C14-006 study, that information (updated SBS history) 
will be collected.
7.2.2
Physical Examination
Physical examinations will be performed according to the study schedules. Any new clinically 
significant findings noted during physical examinations should be recorded on the appropriate 
AE page of the eCRF. 
7.2.3
Vital Signs, Body Weight, Height, Head Circumference and Body Mass 
Index (BMI)
Vital signs will be measured according to the study schedules. Measurements will include 
systolic and diastolic blood pressure (mmHg), pulse (beats per minute), and body temperature 
(°C/°F). Blood pressure should be determined by cuff (using the same method, the same arm, 
and in the same position throughout the study).
For non-commercial use only


Shire
CONFIDENTIAL
Page 47
Protocol SHP633-304
Version 2 / 22 Nov 2016
Body weight will also be recorded in the eCRF; subjects should be weighed on the same scale at 
each study visit. Height (or length) and head circumference (for subjects ≤36 months of age) will 
be measured at selected visits. A height z-score, weight z-score, BMI, and BMI z-score will be 
calculated by the sponsor using the site-provided height and weight data collected at each site 
visit
New clinically significant vital sign abnormalities should be recorded on the appropriate AE 
page of the eCRF.
7.2.4
Clinical Laboratory Tests
Safety laboratory tests to be performed at site visits consist of clinical chemistry, hematology, 
and urinalysis and will be performed as outlined in the study plan (Table 1-1, Table 1-2, and 
Table 1-3) Scheduled laboratory testing will be processed by a central lab. All laboratory assays 
will be performed according to the central laboratory’s normal procedures. Reference ranges are 
to be supplied by the laboratory. The investigator should assess out-of-range clinical laboratory 
values for clinical significance, indicating if the value(s) is/are not clinically significant or 
clinically significant. Abnormal clinical laboratory values, which are unexpected or not 
explained by the subject’s clinical condition, may, at the discretion of the investigator or sponsor, 
be repeated as soon as possible until confirmed, explained, or resolved. 
During the teduglutide treatment period, subjects will also have safety labs within approximately 
5-7 days after a PS adjustment. Safety labs performed after PS adjustment and between site visits 
will consist of clinical chemistry and urinalysis and may be processed by the central laboratory 
or a local laboratory. Local lab results are not required to be entered in the eCRFs; however, if 
the local lab results indicate any new clinically significant changes, they must be reported as an 
adverse event (see Section 8.1). Urine specimen collection should be attempted as part of the 
safety labs, but lack of urinalysis will not constitute a protocol deviation.
New clinically significant labs should be reported as AEs.
The following clinical laboratory assessments will be performed according to the study 
schedules: 
For non-commercial use only


Shire
CONFIDENTIAL
Page 48
Protocol SHP633-304
Version 2 / 22 Nov 2016
Table 7-1 List of Laboratory Tests 
Hematology:

Hematocrit 

Hemoglobin 

Platelet count

Red blood cell count 

Red blood cell morphology, if needed

White blood cell count with differential
Coagulation:
Prothrombin time/International normalized ratio
Urinalysis: 

Blood

Glucose

Leukocytes

Microscopic analysis

pH 

Protein

Specific gravity
Pregnancy tests (females of childbearing potential):
o
Serum β-HCG (screening)
o
Urine β-HCG (all other visits)
Biochemistry:

Albumin 

Alkaline phosphatase 

Alanine aminotransferase 

Amylase

Aspartate aminotransferase 

Bicarbonate

Bilirubin (total and indirect)

Blood urea nitrogen 

Calcium (total)

Chloride

Cholesterol

C-reactive protein 

Creatinine

Estimated Glomerular Filtration Rate
(Schwartz formula)

Gamma-glutamyl transferase 

Glucose

Lipase

Magnesium

Phosphorus

Potassium 

Sodium 

Triglycerides

Uric acid
7.2.5
Serum Sampling
Serum samples will be collected and stored for future analysis at the following times: 
At the pre-treatment visit. If the subject met a follow-up period escape criterion, the 
serum sample will not be collected at the pre-treatment visit
At the CxW24 (EOT) visit
During NTT: Approximately every 24 weeks
The serum sample will not be used for genetic testing. Lack of collection will not constitute a 
protocol deviation.
The sponsor, sponsor’s representatives, biorepositories, and any specialty laboratories will be 
blinded to the subject’s identity. The sample and/or extracted material will otherwise be stored 
for up to 15 years from the end of the study after which time it will be destroyed. Upon written 
request, subjects will be permitted to withdraw their sample from the analysis and have their 
For non-commercial use only


Shire
CONFIDENTIAL
Page 49
Protocol SHP633-304
Version 2 / 22 Nov 2016
sample and/or extracted material destroyed. Any results already generated from the samples will 
not be removed from any analyses that have already been performed.
7.2.6
Pregnancy Testing
A serum pregnancy test is performed on all FOCBP at the teduglutide pre-treatment visit (when 
the pre-treatment and screening visits are combined, the serum pregnancy test should be 
performed at the local laboratory). Urine pregnancy tests will be administered at all other visits 
according to the study schedules, or if pregnancy is suspected, or as specified per protocol upon 
withdrawal of the subject from the study.
7.2.7
Antibody Testing
Blood samples will be drawn for the analysis of antibodies to teduglutide according to the 
Schedule of Assessments (Table 1-1, Table 1-2, and Table 1-3). Blood samples for antibodies 
may be drawn from a central line or from peripheral access. The sample drawn on CxD1 must be 
drawn prior to administration of the first dose of teduglutide. Once the subject has started 
teduglutide treatment, samples must be drawn at least 14 hours after dosing. Subjects who test 
positive for antibodies to teduglutide will also be tested for neutralizing antibody. Subjects who 
have been previously treated with teduglutide, and who test positive for antibodies to 
teduglutide, will have follow-up blood draws for antibodies to teduglutide every 12 weeks while 
on study until a negative result is obtained.
7.2.8
Volume of Blood
Efforts will be made to minimize the amount of blood drawn from all pediatric subjects enrolled 
in this study. The volumes of blood to be drawn from each subject will vary depending on 
clinical status. Approximate volumes of blood to be drawn from each subject annually are shown 
in Table 7-1.
Table 7-1: Approximate Volume of Blood to be Drawn from Each Subject Annually 
Assessment
Sample 
Volume (mL)
No. Samples per two 28-week 
Teduglutide Cycles
Total 
Volume (mL)
Subjects Receiving Teduglutide Treatment 
Safety
Biochemistry and -hCGa
2.5
24
60
Hematology
2
24
48
Coagulation Parameters
1
2
2
Antibodies
2
8
16
Serum storage samples
3
4
12
Total mL per 2, 28-week Treatment Cycles (Approximate Annual Volume):
138
Subjects Not Receiving Teduglutide Treatmentb
Assessment
Sample 
Volume (mL)
No. Samples per 4 NTT Visits
Total 
Volume (mL)
Safety
Biochemistry
2.5
4
10
Hematology
2
4
8
Serum storage samples
3
2
6
Total mL per 4 “No-Teduglutide Treatment” Visits 48-week period:
24
For non-commercial use only


Shire
CONFIDENTIAL
Page 50
Protocol SHP633-304
Version 2 / 22 Nov 2016
Table 7-1: Approximate Volume of Blood to be Drawn from Each Subject Annually 
Assessment
Sample 
Volume (mL)
No. Samples per two 28-week 
Teduglutide Cycles
Total 
Volume (mL)
Abbreviations: β-hCG=beta-human chorionic gonadotropin; NTT=no-teduglutide treatment
a β-hCG testing will only be administered to females who are eligible for teduglutide treatment.
b Subjects not receiving teduglutide treatment, but who were exposed to it previously and tested positive for anti-teduglutide 
antibodies will require blood samples for antibody testing every 12 weeks until they test negative.
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment. When more than 1 blood assessment is to be done at the time 
point/period, if they require the same type of tube, the assessments should be combined. Blood 
volume estimates do not include safety labs performed after PS adjustment, and anti-teduglutide 
antibody testing during no-teduglutide treatment.
7.2.9
Gastrointestinal-specific Testing
7.2.9.1
Fecal Occult Blood Testing
Fecal occult blood testing must be performed on all subjects at the pre-treatment visit, week 12, 
and week 24 of the teduglutide cycle. During NTT periods, FOBT must be performed on 
teduglutide-exposed subjects (subjects who have received teduglutide any time in the past and 
are therefore not teduglutide-naïve) on a roughly annual basis (approximately every 48-60 
weeks). Actions to be taken in response to a positive FOBT are described below.
7.2.9.2
Colonoscopy or Sigmoidoscopy
Teduglutide-naïve subjects age 12 and older will undergo colonoscopy or sigmoidoscopy at the 
pre-treatment visit if one has not been performed within 1 year. 
Subjects of any age with newly positive FOBT results at the pre-treatment visit for which a 
readily detectable cause cannot be identified (eg, anal fissure) will undergo a colonoscopy or 
sigmoidoscopy prior to receiving teduglutide. If newly positive FOBT results (for which a 
readily detectable cause cannot be identified) are obtained at the end of a teduglutide treatment 
cycle (CxW24/EOT), colonoscopy or sigmoidoscopy will be performed. The need for 
colonoscopy or sigmoidoscopy in response to positive FOBTs at any other point during the 
study, or to re-evaluate persistently positive FOBTs is at the discretion of the investigator. 
Teduglutide-exposed subjects who have received the equivalent of 2 treatment cycles (48 weeks 
of study drug exposure) will undergo colonoscopy or sigmoidoscopy. While receiving additional 
teduglutide treatment, subjects will undergo colonoscopy or sigmoidoscopy at 5 year intervals or 
more often as needed. 
Upper endoscopy may be performed along with any colonoscopy or sigmoidoscopy at the 
investigator’s discretion. If a polyp is found, adherence to current polyp follow-up guidelines is 
recommended. Subjects with unresected GI polyps, polyposis conditions, pre-malignant change 
or malignancy in the GI tract will be excluded from teduglutide treatment.
For non-commercial use only


Shire
CONFIDENTIAL
Page 51
Protocol SHP633-304
Version 2 / 22 Nov 2016
7.2.10
Nutritional Support
Nutritional support includes PS, enteral nutrition, and other food and fluids. Advances in enteral 
nutrition and/or reductions to PS will be based on clinical status, including weight, linear growth, 
hydration status, and safety laboratory results. Intake and output diaries will include data to be 
considered in the adjustment of each subject’s nutritional support. Guidelines for nutritional 
support management and weaning algorithms are provided in Appendix 2.
7.2.11
Diaries
7.2.11.1
Study Drug Administration Diary
A study drug administration diary will record administration of teduglutide. This diary should be 
completed by the subject (or parent/legal guardian, as applicable) daily during the teduglutide 
treatment period (between visits CxD1 and CxW24).
7.2.11.2
Intake Diary
Intake diaries will be used to collect and evaluate each subject’s nutritional support. The 
subject/parent/guardian will complete the appropriate fields of the PS section of the intake diary 
2 weeks prior to ALL scheduled site visits (except at pre-treatment visit). During the 24-week 
teduglutide treatment period, the intake diary will also be completed for 1 week following PS 
adjustments. The intake diary will also be completed daily during the 4-week follow-up period. 
The following data will be captured in the intake diaries:
Parenteral support volume and infusion duration
Site personnel will determine the actual PS daily calories based on diary entries.
All available diary data will be reviewed by the investigator or their designee at each clinic and 
telephone visit to assess clinical status and opportunity for PS reduction and advance in feeds.
7.2.11.3
Output Diary
Urine and stool output should be recorded in the output diary over a 48-hour period of nutritional 
stability before every clinic visit; in addition, output should be recorded for subjects that are in a 
teduglutide treatment cycle within 1 week of implementing a change in the PS prescription, 
regardless of previous teduglutide exposure.
Urine data:
Toilet-trained subjects (who do not wear diapers)
Measure and record all urine output in mL or cc
Nontoilet-trained subjects (who wear diapers)
Measure and record the weight of all urine-only diapers. Urine volume will be 
calculated using the following formula: 1 g (scale weight) = 1 mL or 1 cc
At the discretion of the investigator, the parent may be asked to collect the first void 
after the daily PS infusion to measure specific gravity
For non-commercial use only


Shire
CONFIDENTIAL
Page 52
Protocol SHP633-304
Version 2 / 22 Nov 2016
Stool data (includes diapers with mixed urine and stool):
Toilet-trained subjects (who do not wear diapers)
Record the occurrence of each bowel movement and score the stool consistency using 
the Bristol Stool Form Scale (see Output diary)
Nontoilet-trained subjects (who wear diapers)
Record the weight of diapers containing stool (including diapers with mixed urine and 
stool) as stool output and score the stool consistency using the Bristol Stool Form 
Scale (see Output diary). Stool volume will be calculated using the formula: 1 g (scale 
weight) = 1 mL or 1 cc
All ostomy output volume should be recorded. Ostomy output will not be scored using the 
Bristol scale.
All available diary data will be reviewed by the investigator or their designee at each clinic and 
telephone visit to assess clinical status and opportunity for PS reduction and advance in feeds.
7.2.12
Health-related Quality of Life Assessments
Throughout the study, health-related quality of life assessments will be performed using the 
PedsQL Generic Core Scales. Each PedsQL age-appropriate form takes less than 4 minutes to 
complete. The scales include self-reports for pediatric subjects and adolescents aged 5 to 
18 years and proxy-reports from parents of pediatric subjects aged 2 to 18 years. 
Field trials have shown that the internal consistency reliability of the PedsQL was excellent, with 
alphas for the generic core scales in both self- and proxy-report greater than the 0.70 standard,
and alphas for the full 23-item scale approaching 0.90 for self- and proxy-report. Missing data 
were minimal. Item response distributions were across the full scale range, with no floor effects, 
and minimal ceiling effects. 
The validity of the PedsQL Generic Core Scales was demonstrated through known group 
comparisons, and correlations with other measures of disease burden. The PedsQL self- and 
proxy-report distinguished between pediatric subjects with and without a chronic health 
condition, and within the group of pediatric subjects with a chronic condition, between those 
who did or did not have an overnight hospital visit in the last 12 months. Further, both child self-
report and parent proxy-report correlated significantly with the number of days the child was too 
ill to pursue normal activities, needed someone to care for him or her, missed school in the last 
month, the number of days the parent missed from work in the last month, and parent-report of 
problems pursuing their normal work routine and concentrating at work. The PedsQL Generic 
Core Scales are also responsive to clinical change, as demonstrated in field trials.
7.2.12.1
Pediatric Quality of Life Generic Core Scale (PedsQL™), Acute version
The PedsQL Generic Core Scale is designed to measures health-related quality of life (HRQoL) 
in pediatric subjects and adolescents (2-18 years of age). The developmentally appropriate 
PedsQL Generic Core Scale will be completed by either the parent or legal guardian and subject 
as indicated in Table 7-2 at the time points as outlined in Table 1-1, Table 1-2, and Table 1-3.
For non-commercial use only


Shire
CONFIDENTIAL
Page 53
Protocol SHP633-304
Version 2 / 22 Nov 2016
Table 7-2: Developmentally Appropriate PedsQL™Generic Core Scales
Report
Completed by
Parent Report for Toddlers (ages 2-4)
Parent or Legal Guardian
Child Self Report and Parent Proxy-Report for Young Pediatric subjects 
(ages 5-7)
Subject and Parent or Legal Guardian
Child Self Report and Parent Proxy-Report for Pediatric subjects 
(ages 8-12)
Subject and Parent or Legal Guardian
Child Self Report and Parent Proxy-Report for Teens (ages 13-18)
Subject and Parent or Legal Guardian
Abbreviations: PedsQL=Pediatric Quality of Life Inventory
The Parent Report for Toddlers (ages 2-4) of the PedsQL Generic Core Scale is composed of 
21 items comprising 4 dimensions as follows: 1) Physical Functioning (8 items), 2) Emotional 
Functioning (5 items), 3) Social Functioning (5 items), 4) School Functioning (3 items). 
The Child and Parent Reports of the PedsQL Generic Core Scale for Young Pediatric subjects 
(ages 5-7), Pediatric subjects (ages 8-12), and Teens (ages 13-18) are composed of 23 items 
comprising 4 dimensions as follows: 1) Physical Functioning (8 items), 2) Emotional 
Functioning (5 items), 3) Social Functioning (5 items), 4) School Functioning (5 items).
7.2.12.2
Pediatric Quality of Life Family Impact Module (PedsQL™), Acute version
The PedsQL Family Impact Module is a parent-report multidimensional instrument that will be 
completed by the parent or legal guardian, as outlined in Table 1-1, Table 1-2, and Table 1-3.
The PedsQL Family Impact Module is a specific module of the PedsQL that is used to measure 
the impact of pediatric chronic health conditions on parents and the family (Varni et al. 2004). 
The 36-item PedsQL Family Impact Module consists of 6 scales measuring parent self-reported 
functioning as follows: 1) Physical Functioning (6 items), 2) Emotional Functioning (5 items), 
3) Social Functioning (4 items), 4) Cognitive Functioning (5 items; worries about treatment and 
disease), 5) Communication (3 items), 6) Worry (5 items). Two additional scales measure parent-
reported family functioning as follows: 1) Daily Activities (3 items), and 2) Family Relationships 
(5 items). The PedsQL Family Impact Module should take the parent or legal guardian 
approximately 5 to 10 minutes to complete.
7.2.12.3
PedsQL Gastrointestinal Symptoms Module (PedsQL™), Acute version
The PedsQL Gastrointestinal Symptom Module is a disease-specific 58-item module, comprised 
of 10 different symptom scales that assess gastrointestinal symptom-related quality of life: food 
and drink limits, trouble swallowing, heartburn and reflux, nausea and vomiting, gas and 
bloating, constipation, blood in poop, and diarrhea. The PedsQL Gastrointestinal Symptoms 
Module was designed to allow the selection and scoring of individual scales from the Module. 
The scales of Food and Drink Limits (6 items) and Diarrhea (7 items) were identified as 
clinically relevant and appropriate for the symptoms experienced in this pediatric study 
population, and therefore, are the only scales used in this study. The scales will be completed by 
either the parent or legal guardian and subject as indicated in Table 7-2 at the time points 
outlined in Table 1-1, Table 1-2, and Table 1-3.
For non-commercial use only


Shire
CONFIDENTIAL
Page 54
Protocol SHP633-304
Version 2 / 22 Nov 2016
8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.4. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, 
then each symptom should be listed individually. All AEs should be captured on the appropriate 
AE pages in the eCRF and in source documents. In addition to untoward AEs, unexpected 
benefits outside the investigational product indication should also be captured on the AE eCRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
For non-commercial use only


Shire
CONFIDENTIAL
Page 55
Protocol SHP633-304
Version 2 / 22 Nov 2016
Note that the severity of AEs that constitute dose interruption criteria will also be evaluated 
using the National Cancer Institute’s (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) grading criteria (Table 8-1).
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of 
the investigational product is compelling and/or follows a known or 
suspected response pattern to that product, and the event cannot be 
explained by the subject’s medical condition, other therapies, or 
accident.
Not Related
The event can be readily explained by other factors such as the 
subject’s underlying medical condition, concomitant therapy, or 
accident and no plausible temporal or biologic relationship exists 
between the investigational product and the event.
AEs that are related to study drug that are not resolved at EOT will be followed until the event 
resolves or stabilizes, as judged by the investigator.
Laboratory values, vital signs, and clinical findings at the scheduled physical examinations must 
be reported as AEs if the investigator considers the finding to be a clinically significant change 
from the baseline. 
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study in the eCRF. Outcomes are 
as follows:
Fatal
Not Recovered/Not Resolved
Recovered/Resolved
Recovered/Resolved with Sequelae
For non-commercial use only


Shire
CONFIDENTIAL
Page 56
Protocol SHP633-304
Version 2 / 22 Nov 2016
Recovering/Resolving
Unknown
8.1.4
Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE.
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory or vital sign can represent an AE if the change is 
clinically relevant or if, during the study, a shift of a parameter is observed from a normal value 
to an abnormal value, or a further worsening of an already abnormal value. When evaluating 
such changes, the extent of deviation from the reference range, the duration until return to the 
reference range, either while continuing treatment or after the end of treatment with the 
investigational product, and the range of variation of the respective parameter within its 
reference range, must be taken into consideration.
If, during the study, there are abnormal clinical laboratory values or vital signs which were not 
present at the beginning of the study, further investigations should be performed until the values 
return to within the reference range or until a plausible explanation (eg, concomitant disease) is 
found for the abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory or vital sign is clinically significant and 
therefore represents an AE.
8.1.6
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.4.
Any report of pregnancy for any female study participant must be reported within 24 hours to the 
Shire Global Pharmacovigilance and Risk Management Department using the Shire 
Investigational and Marketed Products Pregnancy Report Form. A copy of the Shire 
Investigational and Marketed Products Pregnancy Report Form (and any applicable follow-up 
reports) must also be sent to the Shire Medical Monitor using the details specified in the 
emergency contact information section of the protocol. In the event a subject becomes pregnant 
during the study, teduglutide administration must be discontinued immediately. 
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days post partum.
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Study Adverse Event Form 
For non-commercial use only


Shire
CONFIDENTIAL
Page 57
Protocol SHP633-304
Version 2 / 22 Nov 2016
for Serious Adverse Events (SAEs) and Non-serious AEs as Required by the Protocol. Note: An 
elective abortion is not considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Adverse Event Form for SAEs and 
Non-serious AEs as Required by the Protocol as well as the Shire Investigational and Marketed 
Products Pregnancy Report Form. The test date of the first positive serum/urine -HCG test or 
will determine the pregnancy onset date.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) 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 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.
Abuse – Persistent or sporadic intentional intake of investigational product when used 
for a non-medical purpose (eg, to alter one’s state of consciousness or get high) in a 
manner that may be detrimental to the individual and/or society.
Misuse – Intentional use of investigational product other than as directed or indicated 
at any dose (Note: this includes a situation where the investigational product is not 
used as directed at the dose prescribed by the protocol).
Overdose – Administration of a dose greater than the allocated dose of the study 
medication or at a frequency greater than the dosing interval specified by the protocol.
Medication Error – An error made in prescribing, dispensing, administration, and/or 
use of an investigational product. For studies, medication errors are reportable to the 
sponsor only as defined below.
Cases of subjects missing doses of the investigational product are not 
considered 
reportable as medication errors.
Medication errors should be collected/reported for all products under 
investigation.
The administration and/or use of an expired investigational product should 
be 
considered as a reportable medication error. 
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally-authorized representative/caregiver.
For non-commercial use only


Shire
CONFIDENTIAL
Page 58
Protocol SHP633-304
Version 2 / 22 Nov 2016
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator brochure which the sponsor 
has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Pharmacovigilance and Risk Management Department and the Shire Medical Monitor within 24 
hours of the first awareness of the event. Note: The 24-hour reporting requirement for SAEs does 
not apply to reports of abuse, misuse, overdose, or medication errors (see Section 8.1.7) unless 
they result in an SAE.
All Adverse Events of Special Interest, as defined in Section 8.3, must be reported by the 
investigator to the Shire Global Pharmacovigilance and Risk Management Department and the 
Shire Medical Monitor within 24 hours of the first awareness of the event even if the event does 
not fulfill seriousness criterion.
The investigator must complete, sign, and date the Shire Clinical Study Adverse Event Form for 
SAEs and Non-serious AEs as Required by Protocol, and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested). Fax or e-mail the completed form to the Shire Global 
Pharmacovigilance and Risk Management Department. A copy of the completed Shire Clinical 
Study Adverse Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as 
Required by Protocol (and any applicable follow-up reports) must also be sent to the Shire 
medical monitor or designee using the details specified in the emergency contact information
section of the protocol.
8.2.3
Serious Adverse Event Definition
A SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose: 

Results in death

Is life-threatening. Note: The term 'life-threatening' in the definition of "serious" refers to 
an event in which the subject was at risk of death at the time of the event; it does not refer 
to an event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
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).
For non-commercial use only


Shire
CONFIDENTIAL
Page 59
Protocol SHP633-304
Version 2 / 22 Nov 2016

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: 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 subject and may 
require medical or surgical intervention to prevent 1 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; or the development of drug dependency or 
drug abuse. 
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.4, and must be reported 
to the Shire Global Pharmacovigilance and Risk Management Department and the Shire Medical 
Monitor within 24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Pharmacovigilance and Risk Management Department within 24 hours of the first awareness of 
the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death.
For non-commercial use only


Shire
CONFIDENTIAL
Page 60
Protocol SHP633-304
Version 2 / 22 Nov 2016
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting 
The Sponsor and/or Clinical Contract Research Organization (CRO) is responsible for notifying 
the relevant regulatory authorities, and US central Institutional Review Boards (IRBs)/EU central 
ethics committees (ECs), of related, unexpected SAEs.
In addition, the Clinical CRO is responsible for notifying active sites of all related, unexpected 
SAEs occurring during all interventional studies across the SHP633 program.
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
8.3
Adverse Events of Special Interest
An AE of special interest is an AE (serious or nonserious) of scientific and medical concern 
specific to the sponsor’s product or program and for which ongoing monitoring and immediate 
notification by the investigator to the sponsor is required.
The AEs of special interest that require expedited regulatory reporting include the following:

Growth of pre-existing polyps of the colon

Benign neoplasia of the GI tract including the hepatobiliary system

Tumor-promoting ability (eg, benign and/or malignant neoplasia of any kind, not limited 
to those of the GI or hepatobiliary system)
For AEs of special interest, the sponsor must be informed within 24 hours of first awareness as 
per the SAE notification instructions described in Section 8.2.2 even if the event does not fulfill 
the seriousness criteria.
8.4
Dose Interruption of Individual Subjects
The investigator is responsible for contacting the sponsor/designee when the subject’s 
teduglutide dosing regimen is interrupted. Attempts should be made to contact the 
sponsor/designee prior to dose interruption. Reasons for dosage interruptions may include but are 
not limited to hospitalization, AEs, a lapse in investigational product delivery, etc.
Study drug must be discontinued if any of the following events occur:

Pregnancy

Severe hypersensitivity, such as anaphylaxis determined by the investigator to be related 
to study drug. This does not include the presence of anti-teduglutide antibodies, mild
injection site reactions or mild symptoms that according to the investigator do not pose a 
significant risk to the subject.
For non-commercial use only


Shire
CONFIDENTIAL
Page 61
Protocol SHP633-304
Version 2 / 22 Nov 2016

An AE listed in (Table 8-1) that is of NCI CTCAE severity Grade 3 or 4 and considered 
to be related to study drug administration

Confirmed drug-induced liver injury (DILI) related to teduglutide (see Section 8.4.2)
8.4.1
Dose Interruption Criteria Based on Known or Possible Risks of 
Teduglutide
The investigational product may be discontinued if the subject has an AE listed in Table 8-1 that 
is of severity ≥Grade 3 per the NCI CTCAE. All such AEs should be discussed with Shire’s 
medical monitor or designee as soon as possible. Teduglutide administration must be 
discontinued if the AE is considered related to the investigational product. The length of the dose 
interruption, and whether teduglutide administration resumes or is permanently discontinued, 
depends on the clinical situation.
Investigators and the Data Monitoring Committee (DMC) should be guided by the descriptions 
of Grade 3 and 4 events, as they relate to known and possible risks associated with the 
administration of teduglutide. 
Table 8-1: CTCAE Criteria for Adverse Events that May Lead to Dose Interruption
Adverse Events
Grade 3 Description
Grade 4 Description
Gastrointestinal Disorders
Colorectal polyps
Severe or medically significant but not 
immediately life threatening; 
hospitalization or prolongation of 
existing hospitalization indicated; 
disabling; limiting self-care activities of 
daily living
Life-threatening consequences; urgent 
intervention indicated
Intestinal Obstruction
Hospitalization indicated; elective 
operative intervention indicated; limiting 
self-care activities of daily living; 
disabling
Life-threatening consequences; urgent 
operative intervention indicated
Gallbladder and Bile Duct Disease
Cholecystitis
Severe symptoms; radiologic,
endoscopic or elective operative 
intervention indicated
Life-threatening consequences; urgent 
operative intervention indicated
Gallbladder perforation
Not Applicable
Life-threatening consequences; urgent 
intervention indicated
Gallbladder obstruction
Symptomatic and severely altered 
gastrointestinal function; tube feeding, 
total parenteral nutrition or 
hospitalization indicated; nonemergent 
operative intervention indicated
Life-threatening consequences; urgent 
operative intervention indicated
Gallbladder infection
Intravenous antibiotic, antifungal, or 
antiviral intervention indicated; 
radiologic, endoscopic, or operative 
intervention indicated
Life-threatening consequences; urgent 
intervention indicated
For non-commercial use only


Shire
CONFIDENTIAL
Page 62
Protocol SHP633-304
Version 2 / 22 Nov 2016
Table 8-1: CTCAE Criteria for Adverse Events that May Lead to Dose Interruption
Adverse Events
Grade 3 Description
Grade 4 Description
Alkaline Phosphatase 
increased
>5.0 to 20.0x ULN
>20.0x ULN
Blood bilirubin increased
>3.0 to 10.0x ULN
>10.0x ULN
Bile duct stenosis
Severely altered gastrointestinal function; 
radiologic, endoscopic or elective 
operative intervention indicated
Life-threatening consequences; urgent 
operative intervention indicated
Pancreatic Disease
Pancreatitis
Severe pain; vomiting; medical 
intervention indicated (eg, analgesia, 
nutritional support)
Life-threatening consequences; urgent 
intervention indicated
Pancreatic duct stenosis
Severely altered gastrointestinal function; 
tube feeding or hospitalization indicated; 
elective operative intervention indicated
Life-threatening consequences; urgent 
operative intervention indicated
Pancreas infection
Intravenous antibiotic, antifungal, or 
antiviral intervention indicated; 
radiologic or operative intervention 
indicated
Life-threatening consequences; urgent 
intervention indicated
Serum amylase increaseda
>2.0 to 5.0x ULN
>5.0x ULN
Lipase increaseda
>2.0 to 5.0x ULN
>5.0x ULN
Cardiovascular Disease
Heart failure
Severe with symptoms at rest or with 
minimal activity or exertion; intervention 
indicated
Life-threatening consequences; urgent 
intervention indicated (eg, continuous 
intravenous therapy or mechanical 
hemodynamic support)
Source: Common Terminology Criteria for Adverse Events, version 4.03, 14 June 2010
ULN=upper limit of normal
a In the setting of clinically acute and symptomatic pancreatitis 
8.4.2
Dose Interruption Criteria Based on Drug-Induced Liver Injury
Teduglutide administration for an individual subject may need to be interrupted if the subject has 
clinical and laboratory evidence of potential DILI, in the absence of an alternative explanation, 
as identified by the following criteria:

ALT or AST >8x ULN

ALT or AST >5x ULN and >2x baseline value for more than 2 weeks

(ALT or AST >3x ULN and >2x baseline value) and (total bilirubin >2x ULN or 
INR>1.5)

ALT or AST >3x ULN and >2x baseline value with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
For non-commercial use only


Shire
CONFIDENTIAL
Page 63
Protocol SHP633-304
Version 2 / 22 Nov 2016
All laboratory values suggestive of potentially new DILI should be repeated and verified within 
3 days. International normalized ratio should be measured with this set of verification laboratory 
assessments and an inquiry should be made as to the presence of clinical symptoms consistent 
with new liver injury. The subject should be followed closely to determine the trajectory of the 
laboratory abnormalities and to evaluate the cause of liver injury. This evaluation may include, 
as clinically indicated, consideration of sepsis, acute viral hepatitis (eg, hepatitis A 
immunoglobulin [IgM], hepatitis B surface antigen, hepatitis C antibodies, cytomegalovirus IgM, 
Epstein-Barr virus antibody panel), hepatobiliary obstruction (ultrasound), autoimmune hepatitis 
(anti-nuclear, anti-smooth muscle, anti-actin, or anti-liver kidney microsomal antibodies), 
intestinal failure associated liver disease, cardiovascular causes such as ischemic hepatitis, and 
concomitant hepatotoxic treatments.
Additional evaluations may be performed at the discretion of the investigator in consultation 
with the Shire medical monitor.
Teduglutide administration must be permanently discontinued if DILI is confirmed and deemed 
related to study drug.
8.5
Early Termination of the Clinical Study
The DMC may recommend stopping the study if:

≥2 subjects being administered investigational product develop the same event listed in 
Table 8-1 of severity CTCAE Grade 3 
or

1 subject develops an event listed in Table 8-1 of severity CTCAE Grade 4 which is 
attributable to investigational product or is not reasonably related to the underlying 
disease process.
For non-commercial use only


Shire
CONFIDENTIAL
Page 64
Protocol SHP633-304
Version 2 / 22 Nov 2016
9
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
in the eCRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered in the eCRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. Unscheduled safety follow up assessments (including visits 
conducted after EOS) are not to be collected unless requested.
9.2
Clinical Data Management 
Data are to be entered into a clinical database as specified in the CRO’s data management 
process. Quality control and data validation procedures are applied to ensure the validity and 
accuracy of the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Statistical Analysis Process 
The study will be analyzed by the sponsor or its agent. All statistical analyses will be performed 
using SAS® (SAS Institute, Cary, NC, USA) version 9.3 or higher.
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. 
9.4
Planned Interim Analysis, and Data Monitoring Committee 
An interim analysis is planned when 6 months of safety data have been collected. 
A DMC will be involved in the management of this study. The DMC members will review the 
data approximately every 3 months according to the DMC Charter. The DMC review will 
include all cumulative safety data (ie, AEs, laboratory assessments, physical examinations, etc.) 
from study assessments through each cutoff period. Further details regarding the DMC can be 
found in the DMC charter, which will be available prior to the administration of investigational 
product. 
The DMC for this study will be conducted in accordance with the FDA Guidance for Clinical 
Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees 
(March 2006).
For non-commercial use only


Shire
CONFIDENTIAL
Page 65
Protocol SHP633-304
Version 2 / 22 Nov 2016
The DMC will be an external, independent board comprised of physicians with relevant training. 
The DMC will be restricted to individuals free of significant conflicts of interest, including, but 
not limited to, financial, scientific, or regulatory in nature. The DMC will be governed by a 
Charter agreed to by members of the Board and the sponsor. Members of the Board may not be 
study investigators or be employed at the same institution as a study investigator, individuals 
employed by the sponsor, independent contractors hired by the sponsor, or members of 
regulatory agencies. The DMC may make recommendations to the sponsor regarding study 
aspects including stopping, modifying or continuing the study; however, the sponsor will have 
the final responsibility to determine whether the study should be modified or temporarily or 
permanently stopped. 
9.5
Sample Size Calculation and Power Considerations 
The number of subjects in this study is not based on statistical power considerations as this is an 
extension study of the core study, TED-C14-006. The maximum number of subjects was
determined by the enrollment in TED-C14-006.
9.6
Study Population
The safety population includes all enrolled subjects in the study. Safety population will be used 
for both safety and efficacy analyses.
9.7
Efficacy Analyses 
No claims of statistical significance will be made; however, 95% confidence intervals will be 
provided, if applicable. Continuous variables, including those assessed on a discrete scale, will 
be summarized using descriptive statistics including number of subjects, mean, median, standard 
deviation, maximum, and minimum. For categorical variables, statistical summaries will include 
number of subjects and percentages.
9.7.1
Efficacy Endpoints
Efficacy endpoints will be analyzed at the end of each teduglutide treatment period (Week 24 or 
EOT), and at each study visit, relative to the baseline of the core study (TED-C14-006) and/or 
first exposure to teduglutide. The following efficacy endpoints will be analyzed:

Reduction in PS volume of at least 20%

Absolute and relative change in PS volume

Complete weaning off PS

Change in days per week of PS
9.8
Safety Analyses 
9.8.1
Safety Endpoints
The following safety endpoints will be analyzed:
For non-commercial use only


Shire
CONFIDENTIAL
Page 66
Protocol SHP633-304
Version 2 / 22 Nov 2016

Adverse events

Vital signs, including temperature, heart rate, and blood pressure

Laboratory safety data (ie, clinical chemistry, hematology, and urinalysis)

Urine output

Stool output 

Antibodies to teduglutide

Gastrointestinal-specific testing , including fecal occult blood testing and colonoscopy or 
sigmoidoscopy

Z-scores for weight, height (or length), head circumference (up to 36 months of age), and 
body mass index
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The number of events, incidence, and percentage of AEs will be calculated overall, 
by System Organ Class (SOC) and by preferred term. SAEs will be further summarized by 
severity and relationship to investigational product. Adverse events related to investigational 
product, AEs leading to withdrawal, SAEs, and deaths will be similarly summarized/listed.
Prior and concomitant medications will be coded using the World Health Organization-Drug 
Dictionary (WHO-DD) with regard to drug class and drug name. The number and percentage of 
subjects with specific prior medications will be summarized. Medical history (including 
surgical/procedural history) will be coded using MedDRA. The number and percentage of 
subjects with specific histories will be summarized by system organ class and preferred term. 
For clinical laboratory tests, vital signs, body weight, and fluid balance variables, descriptive 
statistics (mean, median, standard deviation, minimum and maximum values, the number and 
percentage of subjects in specified categories) will be calculated to summarize the observed 
values and change from baseline at each scheduled visit.
The number and percentage of subjects classified as having positive or neutralizing antibodies to 
teduglutide will be used to summarize the presence of antibodies. 
Additional safety parameters and measures will include change in body weight, height (or 
length) and head circumference (up to 36 months of age). Derived variables will include height 
z-score, weight z-score, BMI, and BMI z-score. Descriptive statistics (mean, median, standard 
deviation, minimum and maximum values, the number and percentage of subjects in specified 
categories) will be calculated to summarize the absolute values and change from baseline at each 
scheduled visit.
For non-commercial use only


Shire
CONFIDENTIAL
Page 67
Protocol SHP633-304
Version 2 / 22 Nov 2016
9.9
Other Analyses
9.9.1
Health-related Quality of Life Analyses 
Health economics and outcomes research endpoints will be analyzed at approximately 12-week 
intervals (Weeks 12 and 24 of each teduglutide treatment cycle, and every 12 weeks for subjects
not on teduglutide), relative to the study baseline. The beginning of each treatment cycle (CxD1) 
will be an additional baseline.

Change in Pediatric Quality of Life Inventory (PedsQL) score

Change in PedsQL Family Impact Module score

Change in PedsQL Gastrointestinal Symptoms Module Sub-Scales scores: 

Food and Drink Limits

Diarrhea 
For non-commercial use only


Shire
CONFIDENTIAL
Page 68
Protocol SHP633-304
Version 2 / 22 Nov 2016
10 SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements. 
The name and address of each third party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996), EU 
Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study. An insurance certificate is supplied to the CRO as necessary. 
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.4
Submission of Summary of Clinical Study Report (CSR) to Competent 
Authorities of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of the end of 
For non-commercial use only


Shire
CONFIDENTIAL
Page 69
Protocol SHP633-304
Version 2 / 22 Nov 2016
the study completion date for pediatric studies and within 1 year for non-pediatric studies as per 
guidance. The sponsor will provide the ECs with a copy of the same summary.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.
The sponsor will make an EOS declaration to the relevant competent authority as required by 
Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator is appointed to review the final CSR for multicenter 
studies. Agreement with the final CSR is documented by the signed and dated signature of the 
principal investigator (single-site study) or coordinating principal investigator (multicenter 
study), in compliance with Directive 2001/83/EC as amended by Directive 2003/63/EC and ICH 
Guidance E3 (1995). 
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
For non-commercial use only


Shire
CONFIDENTIAL
Page 70
Protocol SHP633-304
Version 2 / 22 Nov 2016
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational products, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by international regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Case Report Forms
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded into eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log.
All data will have separate source documentation; no data will be recorded directly into the 
eCRF.
eCRFs should be approved by the investigator per study specifications and data deliverable 
requirements.
The clinical research associate (CRA)/study monitor will verify the contents against the source 
data per the monitoring plan. If the data are unclear or contradictory, queries are sent for 
corrections or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject diary cards, original clinical laboratory reports, and histology and 
pathology reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor, the respective national, 
local, or foreign regulatory authorities, the IRB/EC, and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF 
entries against the source documents. The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, X-rays etc.). Non-study site personnel will not 
disclose any personal information or personal medical information.
For non-commercial use only


Shire
CONFIDENTIAL
Page 71
Protocol SHP633-304
Version 2 / 22 Nov 2016
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US Food and Drug 
Administration (FDA) (as well as other US national and local regulatory authorities), the 
European Medicines Agency (EMA), the Medicines and Healthcare products Regulatory 
Agency, other regulatory authorities, the sponsor or its representatives, and the IRB/EC for each 
site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent and assent, where 
applicable, from all study subjects prior to any study-related procedures including screening 
assessments. All consent and assent documentation must be in accordance with applicable 
regulations and GCP. Each subject or the subject’s legally-authorized representative, as 
applicable, is requested to sign and date the subject informed consent form or a certified 
translation if applicable, after the subject has received and read (or been read) the written subject 
information and received an explanation of what the study involves, including but not limited to: 
the objectives, potential benefits and risk, inconveniences, and the subject’s rights and 
responsibilities. A copy of the informed consent and assent documentation (ie, a complete set of 
subject information sheets and fully executed signature pages) must be given to the subject or the 
subject’s legally-authorized representative, as applicable. This document may require translation 
into the local language. Signed consent forms must remain in each subject’s study file and must 
be available for verification at any time.
Within the source documents, site personnel should document instruction of and understanding 
by the parent/legally-authorized representative/caregiver of the safe, responsible storage and 
administration of investigational product to the study subject.
For non-commercial use only


Shire
CONFIDENTIAL
Page 72
Protocol SHP633-304
Version 2 / 22 Nov 2016
The principal investigator provides the sponsor with a copy of the consent form, and assent form 
where applicable, which was reviewed by the IRB/EC and which received their favorable 
opinion/approval. A copy of the IRB/EC’s written favorable opinion/approval of these 
documents must be provided to the sponsor, prior to the start of the study unless it is agreed to 
and documented (abiding by regulatory guidelines and national provisions) prior to study start 
that another party (ie, sponsor or coordinating principal investigator) is responsible for this 
action. Additionally, if the IRB/EC requires modification of the sample subject information and 
consent document provided by the sponsor, the documentation supporting this requirement must 
be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
For sites within the EU, the applicant for an EC opinion can be the sponsor, the investigator, or 
for multicenter studies the coordinating principal investigator or sponsor, according to national 
provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the Sponsor (or designee) has received 
written IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; for sites within the EU, this can be done by the sponsor, the investigator or for multicenter 
studies the coordinating principal investigator, according to national provisions. The investigator 
must also keep the local IRB/EC informed of any serious and significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996. A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the Sponsor (or designee).
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
review their medical records and data collected during the study. These records and data may, in 
For non-commercial use only


Shire
CONFIDENTIAL
Page 73
Protocol SHP633-304
Version 2 / 22 Nov 2016
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market SHP633; national or local regulatory authorities; and the IRBs/ECs which gave approval 
for the study to proceed. The sponsor and/or its representatives accessing the records and data 
will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject).
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results / Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2-4 and certain other studies as determined by Shire. The purpose of the 
publication steering committee is to act as a non-commercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
For non-commercial use only


Shire
CONFIDENTIAL
Page 74
Protocol SHP633-304
Version 2 / 22 Nov 2016
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
current standards. Participation as an investigator does not confer any rights to authorship of 
publications.
For non-commercial use only


Shire
CONFIDENTIAL
Page 75
Protocol SHP633-304
Version 2 / 22 Nov 2016
11 REFERENCES
Drucker, D. J. & Yusta, B. 2014. Physiology and pharmacology of the enteroendocrine hormone 
glucagon-like peptide-2. Annu Rev Physiol, 76, 561-83.
Khan, F. A., Squires, R. H., Litman, H. J., Balint, J., Carter, B. A., Fisher, J. G., Horslen, S. P., 
Jaksic, T., Kocoshis, S., Martinez, J. A., Mercer, D., Rhee, S., Rudolph, J. A., Soden, J., Sudan, 
D., Superina, R. A., Teitelbaum, D. H., Venick, R., Wales, P. W. & Duggan, C. 2015. Predictors 
of Enteral Autonomy in Children with Intestinal Failure: A Multicenter Cohort Study. J Pediatr,
167, 29-34.e1.
Mouksassi, M. S., Marier, J. F., Cyran, J. & Vinks, A. A. 2009. Clinical trial simulations in 
pediatric patients using realistic covariates: application to teduglutide, a glucagon-like peptide-2 
analog in neonates and infants with short-bowel syndrome. Clin Pharmacol Ther, 86, 667-71.
O'Keefe, S. J., Buchman, A. L., Fishbein, T. M., Jeejeebhoy, K. N., Jeppesen, P. B. & Shaffer, J. 
2006. Short bowel syndrome and intestinal failure: consensus definitions and overview. Clin 
Gastroenterol Hepatol, 4, 6-10.
Squires, R. H., Duggan, C., Teitelbaum, D. H., Wales, P. W., Balint, J., Venick, R., Rhee, S., 
Sudan, D., Mercer, D., Martinez, J. A., Carter, B. A., Soden, J., Horslen, S., Rudolph, J. A., 
Kocoshis, S., Superina, R., Lawlor, S., Haller, T., Kurs-Lasky, M. & Belle, S. H. 2012. Natural 
history of pediatric intestinal failure: initial report from the Pediatric Intestinal Failure 
Consortium. J Pediatr, 161, 723-8.e2.
Tappenden, K. A., Edelman, J. & Joelsson, B. 2013. Teduglutide enhances structural adaptation 
of the small intestinal mucosa in patients with short bowel syndrome. J Clin Gastroenterol, 47,
602-7.
Thymann, T., Stoll, B., Mecklenburg, L., Burrin, D. G., Vegge, A., Qvist, N., Eriksen, T., 
Jeppesen, P. B. & Sangild, P. T. 2014. Acute effects of the glucagon-like peptide 2 analogue, 
teduglutide, on intestinal adaptation in short bowel syndrome. J Pediatr Gastroenterol Nutr, 58,
694-702.
Varni, J. W., Sherman, S. A., Burwinkle, T. M., Dickinson, P. E. & Dixon, P. 2004. The PedsQL 
Family Impact Module: preliminary reliability and validity. Health Qual Life Outcomes, 2, 55.
Wales, P. W., de Silva, N., Kim, J., Lecce, L., To, T. & Moore, A. 2004. Neonatal short bowel 
syndrome: population-based estimates of incidence and mortality rates. J Pediatr Surg, 39, 690-
5.
For non-commercial use only


Shire
CONFIDENTIAL
Page 76
Protocol SHP633-304
Version 2 / 22 Nov 2016
12 APPENDICES
For non-commercial use only


Shire
CONFIDENTIAL
Page 77
Protocol SHP633-304
Version 2 / 22 Nov 2016
APPENDIX 1
PROTOCOL HISTORY
Document
Date
Global/Country/Site Specific
Original Protocol
08 April 2016
Global
Amendment 1
22 Nov 2016
Global
For non-commercial use only


Shire
CONFIDENTIAL
Page 78
Protocol SHP633-304
Version 2 / 22 Nov 2016
APPENDIX 2
GUIDELINES FOR NUTRITIONAL SUPPORT MANAGEMENT 
DURING THE STUDY
Nutritional support adjustment in volume and calories should be considered at all planned visits. 
Please consider the following clinical parameters identified as markers for adequate management 
of pediatric SBS. These parameters should also be considered for managing nutritional support 
(PS and/or oral/enteral feeding) in terms of volume and calories during the treatment period. 

Growth trajectory, including weight, height (or length), and head circumference (for pediatric 
subjects up to 36 months of age)

Other clinical evaluations

Serum electrolytes

Blood urea nitrogen /creatinine levels

Changes in stool frequency or volume, including mixed output

Stool consistency (ie, Bristol Stool Scale)

Urine specific gravity

General consideration to possible clinical deterioration in SBS

Inability to maintain weight and growth velocity

Diarrhea (≥10 bowel movements per day, ≥80 mL/kg/day from an ostomy, or 
≥75 mL/kg/day mixed output)

Colic/vomiting frequency increased

Electrolyte changes or imbalance

Skin breakdown 

Adjustments should be based on the actual nutritional support in volume and calories the 
subject infuses. Subjects should remain compliant with the nutritional support prescription in 
volume and calories during the study.

Nutritional support constituents may be adjusted at the discretion of the investigator.

During the 48-hour output measurement period prior to the subject’s scheduled visit, no 
further changes to the prescribed nutritional support should be made.

If there is a change in enteral nutrition (EN) or other food or fluid intake, the investigator 
should consider this when adjusting the PS/EN support in volume and calories.
For non-commercial use only


Shire
CONFIDENTIAL
Page 79
Protocol SHP633-304
Version 2 / 22 Nov 2016
Figure A-1
Weaning Algorithm for Subjects Who are NOT Toilet Trained and in 
Diapers
For non-commercial use only


Shire
CONFIDENTIAL
Page 80
Protocol SHP633-304
Version 2 / 22 Nov 2016
Figure A-2
Weaning Algorithm for Subjects Who are Toilet Trained and NOT in 
Diapers
For non-commercial use only


Shire
CONFIDENTIAL
Page 81
Protocol SHP633-304
Version 2 / 22 Nov 2016
Figure A-3
Clinical Dehydration Assessment and PS/EN Adjustment
For non-commercial use only


PROTOCOL: SHP633-304
TITLE:
A Prospective, Open-label, Long-term Safety and Efficacy Study of 
Teduglutide in Pediatric Patients with Short Bowel Syndrome Who 
Completed TED-C14-006
DRUG:
Teduglutide
IND:
IND# 058213
EUDRACT NO.:
2016-000849-30
SPONSOR:
Shire Human Genetic Therapies, Inc.
300 Shire Way, Lexington, MA 02421 USA
PROTOCOL 
HISTORY:
Amendment 2: 23 Mar 2017
Amendment 1: 22 Nov 2016
Original Protocol: 08 April 2016
This document contains confidential and proprietary information of Shire and is disclosed pursuant to 
confidentiality and non-disclosure obligations. This information should be used solely for the purposes for which 
it was provided and should not be copied, shared with, or disclosed to any third party without the express written 
consent of Shire.
For non-commercial use only


Shire 
CONFIDENTIAL 
Page 2 
SHP633-304 Protocol Amendment 2 
Teduglutide 
 
23 Mar 2017 
PROTOCOL SIGNATURE PAGE 
Sponsor's (Shire) Approval 
' 
;' 
' 
--, 
! Signature: 
1 Date: 
1 
I 
1 
 
: 
. 
1
, MD PhD 
1 
i 
 
1 
l_ Global Clinical Development 
I 
Investigator's Acknowledgement 
I have read this protocol for Shire Study SHP633-304. 
Title: A prospective, open label, long-term safety and efficacy study of teduglutide in pediatric 
patients with short bowel syndrome who completed TED-C14-006 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Conference on Harmonization (ICH) guidelines on Good Clinical 
Practice (GCP) and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Address: 
(please hand print or type) 
For non-commercial use only


Shire
CONFIDENTIAL
Page 3
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
SUMMARY OF CHANGES FROM PREVIOUS VERSION
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 2
Amendment Date
23 Mar 2017
Global
Description of Change and Rationale
Section(s) Affected by Change
Updated emergency contact information
Emergency Contact Information; 
Section 8.1.6; Section 8.2.2; Section 
8.2.4
To allow for approximately 7 days for subjects to transfer from Study 
TED-C14-006 to Study SHP633-304 (instead of up to 7 days).
Table 1-1; Section 7.1.1
A footnote was added at the pre-treatment visit in the Schedule of Events 
for Subjects While Receiving Teduglutide to underscore that, when the 
first pre-treatment visit (P1) follows the screening visit, it must occur 
within 12 weeks of screening.
Table 1-3
Revised the language on abstinence as a contraceptive method for
consistency with the Medicines and Healthcare Products Regulatory 
Agency (MHRA) Clinical Trial Facilitation Group's "Recommendations 
related to contraception and pregnancy testing in clinical trials."
Section 4.7.1
Clarification that ancillary components, in addition to sterile water for 
injection syringes, will also be provided and labeled in accordance with 
the applicable regulatory requirements.
Section 6.3.1
A footnote was added in Table 7-2 to clarify that subjects older than 
18 years of age will continue to use the Child Self Report and Parent 
Proxy-Report for Teens (ages 13-18) when completing the Pediatric 
Quality of Life Generic Core Scale (PEDSQL™).
Section 7.2.12.1 (Table 7-3)
Revised the text on severity categorization to specify that a severe 
treatment-emergent adverse event (TEAE) that might lead to dose 
interruption (Section 8.4.1) or early termination of the study 
(Section 8.5) will also be graded according to the National Cancer 
Institute’s (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) severity grading criteria, in addition to the standard severity 
categorization. These events are no longer limited to only the events 
described in Table 8-1, entitled “CTCAE Criteria for Adverse Events 
that May Lead to Dose Interruption (Prospective Period of Observation 
Only).” Therefore, Table 8-1 has been deleted.
Section 8.1.1; Section 8.4; Section 
8.4.1
Table 8-1 (deleted)
Revised the criteria for early termination of the study: stopping criteria 
were extended to all NCI CTCAE Grade 3 and 4 severity events reported 
as related to the investigational product, and no longer limited to the 
events described in Table 8-1, entitled “CTCAE Criteria for Adverse 
Events that May Lead to Dose Interruption (Prospective Period of 
Observation Only).”
Section 8.5
See Appendix 1 for protocol history, including all amendments.
For non-commercial use only


Shire
CONFIDENTIAL
Page 4
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Adverse Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as 
Required by Protocol within 24 hours to the Shire Global Drug Safety Department. Applicable 
fax numbers and e-mail address can be found on the form (sent under separate cover). A copy of 
this form must also be sent to the Shire Medical Monitor by fax or e-mail using the details 
below.
, MD PhD
Email: 
Fax: 
For protocol- or safety-related issues, the investigator must contact Quintiles Medical 
Support:
Primary contact for North America (NA) and backup contact for European Union (EU)
, MD, 
Mobile: 
US Toll Free number: 
Phone: 
 (medical emergencies – NA)
Email: 
Primary contact for EU and backup contact for NA
, MD, 
Mobile: 
Phone: 
Phone: 
 (medical emergencies – EU)
Email: 
In addition, the investigator may also contact the Shire Medical Monitor:
, MD PhD, 
Phone: 
Mobile: 
Email: 
For non-commercial use only


Shire
CONFIDENTIAL
Page 5
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
European Union and Rest of World
Telephone numbers (provided for reference): 
 Shire (USA) 
For non-commercial use only


Shire
CONFIDENTIAL
Page 6
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................3
EMERGENCY CONTACT INFORMATION................................................................................4
PRODUCT QUALITY COMPLAINTS..........................................................................................5
TABLE OF CONTENTS.................................................................................................................6
LIST OF TABLES.........................................................................................................................10
LIST OF FIGURES .......................................................................................................................10
LIST OF APPENDICES................................................................................................................10
ABBREVIATIONS .......................................................................................................................11
STUDY SYNOPSIS ......................................................................................................................13
STUDY SCHEDULE(S) ...............................................................................................................18
1
BACKGROUND INFORMATION.......................................................................................23
1.1
Indication and Current Treatment Options...............................................................23
1.2
Product Background.................................................................................................23
1.3
Clinical Studies with Teduglutide in Pediatric Subjects ..........................................24
2
STUDY OBJECTIVES AND PURPOSE ..............................................................................25
2.1
Rationale for the Study.............................................................................................25
2.2
Study Objectives ......................................................................................................25
2.2.1
Primary Objectives.................................................................................................25
2.2.2
Secondary Objectives.............................................................................................25
3
STUDY DESIGN ...................................................................................................................26
3.1
Study Design and Flow Chart ..................................................................................26
3.2
Duration and Study Completion Definition .............................................................28
4
STUDY POPULATION.........................................................................................................29
4.1
Study Inclusion Eligibility Criteria ..........................................................................29
4.2
Study Exclusion Eligibility Criteria .........................................................................29
4.3
Teduglutide Eligibility Criteria ................................................................................29
4.4
Teduglutide Treatment Inclusion Criteria................................................................29
4.5
Teduglutide Treatment Exclusion Criteria...............................................................30
4.6
Follow-up Period Escape Criteria ............................................................................31
4.7
Reproductive Potential .............................................................................................31
4.7.1
Female Contraception............................................................................................31
4.8
Discontinuation of Subjects .....................................................................................32
4.8.1
Teduglutide Discontinuation..................................................................................32
4.8.2
Study Withdrawal ..................................................................................................32
4.8.3
Reasons for Discontinuation..................................................................................32
For non-commercial use only


Shire
CONFIDENTIAL
Page 7
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
4.8.3.1
Subjects ‘Lost to Follow-up’ Prior to Last Scheduled Visit ..................33
5
CONCOMITANT TREATMENT..........................................................................................34
5.1
Concomitant Medications and GI Procedures..........................................................34
5.1.1
Permitted Treatment...............................................................................................34
5.1.2
Prohibited Treatment .............................................................................................34
6
INVESTIGATIONAL PRODUCT ........................................................................................35
6.1
Identity of Investigational Product...........................................................................35
6.1.1
Blinding the Treatment Assignment......................................................................35
6.2
Administration of Investigational Product(s)...........................................................35
6.2.1
Interactive Response Technology for Investigational Product Management ........35
6.2.2
Allocation of Subjects to Treatment ......................................................................35
6.2.3
Dosing....................................................................................................................35
6.2.4
Unblinding the Treatment Assignment..................................................................36
6.3
Labeling, Packaging, Storage, and Handling ...........................................................36
6.3.1
Labeling .................................................................................................................36
6.3.2
Packaging...............................................................................................................36
6.3.3
Storage and Handling.............................................................................................36
6.4
Drug Accountability.................................................................................................37
6.5
Subject Compliance..................................................................................................38
7
STUDY PROCEDURES........................................................................................................39
7.1
Study Schedule.........................................................................................................39
7.1.1
Screening................................................................................................................39
7.1.2
Visits for Subjects Not Receiving Teduglutide .....................................................39
7.1.3
Visits for Subjects Receiving Teduglutide ............................................................40
7.1.3.1
Pre-treatment Visit .................................................................................40
7.1.3.2
Teduglutide Treatment Period (CxD1-CxW24).....................................41
7.1.4
Teduglutide Follow-up Period...............................................................................43
7.1.5
Study Completion/Early Termination Visit (EOS/ET Visit).................................43
7.2
Study Evaluations and Procedures ...........................................................................44
7.2.1
Demographics, Medical History, and SBS History ...............................................44
7.2.2
Physical Examination.............................................................................................44
7.2.3
Vital Signs, Body Weight, Height, Head Circumference and Body Mass 
Index (BMI) ...........................................................................................................45
7.2.4
Clinical Laboratory Tests.......................................................................................45
7.2.5
Serum Sampling.....................................................................................................46
7.2.6
Pregnancy Testing..................................................................................................47
7.2.7
Antibody Testing ...................................................................................................47
7.2.8
Volume of Blood....................................................................................................47
For non-commercial use only


Shire
CONFIDENTIAL
Page 8
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
7.2.9
Gastrointestinal-specific Testing ...........................................................................48
7.2.9.1
Fecal Occult Blood Testing....................................................................48
7.2.9.2
Colonoscopy or Sigmoidoscopy.............................................................48
7.2.10 Nutritional Support ................................................................................................48
7.2.11 Diaries.....................................................................................................................49
7.2.11.1
Study Drug Administration Diary..........................................................49
7.2.11.2
Intake Diary............................................................................................49
7.2.11.3
Output Diary...........................................................................................49
7.2.12 Health-related Quality of Life Assessments ..........................................................50
7.2.12.1
Pediatric Quality of Life Generic Core Scale (PedsQL™), Acute 
version ....................................................................................................50
7.2.12.2
Pediatric Quality of Life Family Impact Module (PedsQL™), Acute 
version ....................................................................................................51
7.2.12.3
PedsQL Gastrointestinal Symptoms Module (PedsQL™), Acute 
version ....................................................................................................51
8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................52
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................52
8.1.1
Severity Categorization..........................................................................................52
8.1.2
Relationship Categorization...................................................................................53
8.1.3
Outcome Categorization ........................................................................................53
8.1.4
Symptoms of the Disease under Study ..................................................................54
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................54
8.1.6
Pregnancy...............................................................................................................54
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................55
8.2
Serious Adverse Event Procedures ..........................................................................55
8.2.1
Reference Safety Information................................................................................55
8.2.2
Reporting Procedures.............................................................................................55
8.2.3
Serious Adverse Event Definition .........................................................................56
8.2.4
Serious Adverse Event Collection Time Frame.....................................................57
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................57
8.2.6
Fatal Outcome........................................................................................................57
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................57
8.3
Adverse Events of Special Interest...........................................................................57
8.4
Dose Interruption of Individual Subjects .................................................................58
8.4.1
Dose Interruption Criteria Based on Adverse Event Severity and 
Relationship to Investigational Product.................................................................58
8.4.2
Dose Interruption Criteria Based on Drug-Induced Liver Injury ..........................59
For non-commercial use only


Shire
CONFIDENTIAL
Page 9
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
8.5
Early Termination of the Clinical Study ..................................................................59
9
DATA MANAGEMENT AND STATISTICAL METHODS...............................................60
9.1
Data Collection.........................................................................................................60
9.2
Clinical Data Management.......................................................................................60
9.3
Statistical Analysis Process......................................................................................60
9.4
Planned Interim Analysis, and Data Monitoring Committee...................................60
9.5
Sample Size Calculation and Power Considerations................................................61
9.6
Study Population ......................................................................................................61
9.7
Efficacy Analyses.....................................................................................................61
9.7.1
Efficacy Endpoints.................................................................................................61
9.8
Safety Analyses........................................................................................................61
9.8.1
Safety Endpoints....................................................................................................61
9.9
Other Analyses .........................................................................................................62
9.9.1
Health-related Quality of Life Analyses................................................................62
10 SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................64
10.1
Sponsor’s Responsibilities .......................................................................................64
10.1.1 Good Clinical Practice Compliance.......................................................................64
10.1.2 Indemnity/Liability and Insurance.........................................................................64
10.1.3 Public Posting of Study Information......................................................................64
10.1.4 Submission of Summary of Clinical Study Report (CSR) to Competent 
Authorities of Member States Concerned and Ethics Committees........................64
10.1.5 Study Suspension, Termination, and Completion..................................................65
10.2
Investigator’s Responsibilities .................................................................................65
10.2.1 Good Clinical Practice Compliance.......................................................................65
10.2.2 Protocol Adherence and Investigator Agreement..................................................65
10.2.3 Documentation and Retention of Records.............................................................66
10.2.3.1
Case Report Forms.................................................................................66
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................66
10.2.3.3
Audit/Inspection.....................................................................................66
10.2.3.4
Financial Disclosure...............................................................................67
10.3
Ethical Considerations..............................................................................................67
10.3.1 Informed Consent...................................................................................................67
10.3.2 Institutional Review Board or Ethics Committee..................................................67
10.4
Privacy and Confidentiality......................................................................................68
10.5
Study Results / Publication Policy ...........................................................................69
11 REFERENCES .......................................................................................................................70
12 APPENDICES ........................................................................................................................71
For non-commercial use only


Shire
CONFIDENTIAL
Page 10
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
LIST OF TABLES
Table 1-1:
Schedule of Events Required for All Subjects ..............................................18
Table 1-2: 
Schedule of Events for Subjects Not Receiving Teduglutide .......................19
Table 1-3: 
Schedule of Events for Subjects While Receiving Teduglutide....................20
Table 5-1: 
Prohibited Treatment.....................................................................................34
Table 7-1:
List of Laboratory Tests ................................................................................46
Table 7-2:
Approximate Volume of Blood to be Drawn from Each Subject 
Annually ........................................................................................................47
Table 7-3:
Developmentally Appropriate PedsQL™Generic Core Scales .....................50
LIST OF FIGURES
Figure 3-1:
Study Design Flow Chart ..............................................................................28
LIST OF APPENDICES
Appendix 1
Protocol History.............................................................................................72
Appendix 2
Guidelines for Nutritional Support Management During the Study .............75
For non-commercial use only


Shire
CONFIDENTIAL
Page 11
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
-HCG
beta-human chorionic gonadotropin
BMI
body mass index
CRA
clinical research associate
CRO
contract research organization
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DILI
drug-induced livery injury
DMC
data monitoring committee
DPP-4
dipeptidyl peptidase 4
EC
ethics committee
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EN
enteral nutrition
EOS
end of study
EOT
end of treatment
ET
early termination
EU
European Union
FDA
Food and Drug Administration
FOBT
fecal occult blood test
FOCBP
female of child-bearing potential
GCP
Good Clinical Practice
GI
gastrointestinal
GLP-1
glucagon-like peptide 1
GLP-2
glucagon-like peptide 2
HIPAA
Health Insurance Portability and Accountability Act
ICF
informed consent form
ICH
International Conference on Harmonization
IGF-1
insulin-like growth factor 1
IRB
institutional review board
IV
intravenous
For non-commercial use only


Shire
CONFIDENTIAL
Page 12
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
IWRS
interactive web-based response system
MedDRA
Medical Dictionary for Regulatory Activities
NA 
North America
NCI
National Cancer Institute
NDA
new drug application
NTT
no-teduglutide treatment
PDA
patent ductus arteriosus
PedsQL
Pediatric Quality of Life inventory
PS
parenteral support
PT/INR
prothrombin time/international normalized ratio
QD
once daily
SAE
serious adverse event
SAP
statistical analysis plan
SBS
short bowel syndrome
SC
subcutaneous
SOC
standard of care
t1/2
elimination half-life
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
UK
United Kingdom
ULN
upper limit of normal
US
United States
WHO-DD
World Health Organization – Drug Dictionary
For non-commercial use only


Shire
CONFIDENTIAL
Page 13
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
STUDY SYNOPSIS
Protocol number: SHP633-304
Drug: Teduglutide
Title of the study: A Prospective, Open-label, Long-term Safety and Efficacy Study of Teduglutide in Pediatric 
Patients with Short Bowel Syndrome (SBS) Who Completed TED-C14-006
Number of subjects (total and for each treatment arm):
Approximately 34 subjects who completed the TED-C14-006 study, including subjects in the standard of care 
treatment arm, are expected to enroll in this extension study. This study will enroll up to as many subjects as 
complete the TED-C14-006 study.
Investigator(s): Multicenter study
Site(s) and Region(s): 
Approximately 28 investigational sites in North America and Europe will participate in this extension study
Study period (planned):
October 2016 – September 2019
Clinical phase:
3 Extension
Objectives:
Primary: To evaluate the long-term safety and tolerability of teduglutide treatment in pediatric subjects with SBS.
Secondary: To evaluate long-term efficacy of teduglutide treatment in pediatric subjects with SBS.
Rationale:
This is a Phase 3, prospective, open-label, long-term extension study to evaluate the safety and efficacy of 
teduglutide in pediatric subjects with short bowel syndrome (SBS) who completed the TED-C14-006 study (the 
core study). In addition to evaluating the long-term safety and durability of efficacy after 24-weeks of treatment, 
this extension study will evaluate the need for additional teduglutide treatment in these subjects, and will allow 
the study of first-time treatment of teduglutide-naïve subjects who participated in the standard of care (SOC) 
treatment arm in TED-C14-006. 
Investigational product, dose, and mode of administration:
This study will allow repeat doses of teduglutide 0.05 mg/kg subcutaneous (SC) once daily (QD) injection for 
eligible pediatric subjects. There is no active comparator or reference product.
Methodology:
This is a Phase 3, prospective, open-label, long-term extension study to evaluate the safety and efficacy of 
teduglutide in pediatric subjects who completed the TED-C14-006 study (core study).
Once the informed consent (and if applicable, informed assent) have been reviewed and signed, demographics, 
and updates to medical history and short bowel syndrome history will be obtained. Subjects not receiving 
teduglutide treatment (ie, in a no-teduglutide treatment [NTT] period), will be seen approximately every 12 weeks 
for safety, parenteral support (PS) requirements, and quality of life. The first NTT visit after the screening visit 
will occur within 2 to 12 weeks of the screening visit. At any point after screening, including during a NTT 
period, subjects who meet ≥1 teduglutide treatment inclusion criteria, may proceed immediately to the 
pre-treatment visit if the investigator, subject, and parent agree to proceed with teduglutide therapy.
After the pre-treatment visit, subjects who meet ≥1 of the teduglutide treatment inclusion criteria, and meet none 
of the teduglutide treatment exclusion criteria, will start a 28-week cycle, consisting of 24 weeks of teduglutide 
treatment at 0.05 mg/kg SC once daily, followed by a 4-week follow-up period (during which no teduglutide is 
administered) (Figure 3-1). During the 28-week cycle, clinic visits will occur at weeks 1, 2, 4, 6, 9, 12, 16, 20, 24, 
and 28. Phone visits are required approximately 1 week after adjustments in PS during the teduglutide treatment 
period (between weeks 1 and 24), and weekly during the teduglutide follow-up period (between weeks 24 and 
28). Safety and PS requirements will be evaluated at every visit, and quality of life assessments will be made 
For non-commercial use only


Shire
CONFIDENTIAL
Page 14
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
approximately every 12 weeks. If a subject has clinical deterioration and meets follow-up period escape criteria 
after stopping teduglutide, the subject may "escape" the follow-up period early and proceed immediately to 
another pre-treatment visit. Following completion of the 28-week treatment cycle, the subject will proceed to an
NTT visit within approximately 12 weeks.
At all site visits and telephone contacts, safety will be monitored and nutritional support will be reviewed and
adjusted as needed. To maintain consistency across centers, all attempts should be made to follow the nutritional
support adjustment guidelines (developed with SBS expert input and provided in the protocol) for decisions
regarding PS support reduction and advances in enteral feeds based on weight gain, urine and stool output, and
clinical stability. Departure from the guidelines, however, is not considered a protocol deviation. (Appendix 2).
Study Design Flow Chart 
Figure legend: Safety and efficacy data for subjects not receiving teduglutide treatment are captured approximately every 
12 weeks, but subjects may proceed to the pre-treatment visit at any time in order to assess eligibility for teduglutide 
therapy. Eligible subjects will enter a 28-week teduglutide cycle. During this cycle, subjects will return to the site for 
safety and efficacy assessments at weeks 1, 2, 4, 6, 9, 12, 16, 20, and 24 (solid black lines). Phone visits are required
approximately 1 week after adjustments in PS during the intervening weeks between weeks 2 and 24 (dashed grey 
lines). Subjects discontinue teduglutide at week 24 and enter a 4-week follow-up (no-treatment) period, during which 
phone visits will be performed weekly (solid grey lines). If an escape criterion is met during the follow-up period, 
subjects may proceed directly to another pre-treatment visit.
Study Inclusion Criteria: 
The subject will be considered eligible for the study if they meet all of the study inclusion criteria. Teduglutide 
treatment eligibility does not impact study eligibility.
1.
Subject provides written informed consent (subject, parent or legal guardian and, as appropriate, 
informed assent) to participate in the study before completing any study-related procedures.
2.
Subject completed the TED-C14-006 study (including subjects in the standard of care treatment arm).
3.
Subject understands and is willing and able to fully adhere to study requirements as defined in this 
protocol. 
Study Exclusion Criteria: There are no exclusion criteria for this study.
Teduglutide Eligibility Criteria: Subjects are eligible for teduglutide treatment if at least one (≥1) of the 
teduglutide treatment inclusion criteria, and none of the teduglutide treatment exclusion criteria, are met. In 
addition, the investigator and the subject (and/or parent or legal guardian, as appropriate) must agree to proceed 
with treatment.
Teduglutide Treatment Inclusion Criteria:
1.
Subject is teduglutide-naïve, receiving PS, and unable to significantly reduce PS or advance enteral feeds 
For non-commercial use only


Shire
CONFIDENTIAL
Page 15
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
(eg, 10% or less change in PS or advance in feeds) for at least 3 months prior to and during the 
teduglutide pre-treatment visit, as assessed by the investigator. Transient instability for events such as 
interruption of central access or treatment for sepsis is allowed if the PS returns to within 10% of 
baseline prior to the event.
2.
Subject was previously treated with teduglutide and at least one of the following criteria is satisfied:
a.
Increasing PS requirements following teduglutide discontinuation.
b.
Decreased PS requirement during prior teduglutide treatment, followed by cessation of 
improvement after teduglutide discontinuation.
c.
Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal tolerated 
enteral nutrition following teduglutide discontinuation.
d.
Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and electrolyte 
intake following teduglutide discontinuation.
e.
Severe diarrhea related to teduglutide discontinuation.
Teduglutide Treatment Exclusion Criteria:
1.
Body weight <10 kg at the pre-treatment visit.
2.
Unresected gastrointestinal (GI) polyp, known polyposis condition, pre-malignant change, or 
malignancy, in the GI tract.
3.
History of cancer in the previous 5 years except surgically curative skin cancers.
4.
Serial transverse enteroplasty or other major intestinal surgery within 3 months preceding the teduglutide 
pre-treatment visit. Insertion of a feeding tube, anastomotic ulcer repair, minor intestinal resections 
≤10 cm, and endoscopic procedures are allowed.
5.
Intestinal or other major surgery planned or scheduled to occur during the 28-week cycle.
6.
Clinically significant intestinal stricture or obstruction.
7.
Clinically significant, active or recurrent pancreatic or biliary disease.
8.
Active, severe, or unstable, clinically significant hepatic impairment or injury, including the following 
laboratory values at the pre-treatment visit:
a.
Total bilirubin ≥2 × upper limit of normal (ULN)
b.
Aspartate aminotransferase (AST) ≥7 × ULN
c.
Alanine aminotransferase (ALT) ≥7 × ULN
9.
Renal dysfunction shown by results of an estimated glomerular filtration rate (eGFR) below 
50 mL/min/1.73 m2 at the pre-treatment visit.
10. Unstable cardiac disease, congenital heart disease or cyanotic disease, with the exception of subjects 
who had undergone ventricular or atrial septal defect repair, or patent ductus arteriosus (PDA) ligation.
11. Participation in a clinical study using an experimental drug (other than glutamine, Omegaven, or 
Smoflipid) within 3 months or 5.5 half-lives of the experimental drug, whichever is longer, prior to the 
pre-treatment visit and for the duration of the 28-week cycle.
12. Treatment with analogs of glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2) (not 
including teduglutide), insulin-like growth factor-1 (IGF-1), or growth hormone, within 3 months
preceding the teduglutide pretreatment visit.
13. Treatment with octreotide or dipeptidyl peptidase 4 (DPP-4) inhibitors within 3 months prior to the pre-
treatment visit.
14. Known or suspected intolerance or hypersensitivity to the investigational product, closely-related 
compounds, or any of the stated ingredients.
15. Known history of alcohol or other substance abuse within 1 year prior to the pre-treatment visit.
For non-commercial use only


Shire
CONFIDENTIAL
Page 16
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
16. Pregnant or lactating female subjects.
17. Sexually active female subjects of child-bearing potential unwilling to use approved contraception 
during teduglutide treatment and for 30 days after the treatment period.
18. Any condition, disease, illness, or circumstance that in the investigator’s opinion puts the subject at any 
undue risk, prevents completion of the study, or interferes with analysis of the study results.
Follow-up Period Escape Criteria: At the discretion of the investigator, the follow-up period may be interrupted 
and the subject may proceed directly to the pre-treatment visit, if ≥1 of the following criteria is met:
1.
Increasing PS requirements following teduglutide discontinuation
2.
Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal tolerated enteral 
nutrition following teduglutide discontinuation.
3.
Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and electrolyte intake
following teduglutide discontinuation.
4.
Severe diarrhea related to teduglutide discontinuation.
Maximum duration of subject involvement in the study:
A subject will be considered enrolled in the study once the subject has provided signed consent, and meets all of 
the Study Inclusion Criteria. Subjects may participate in multiple NTT periods and/or multiple 28-week treatment 
cycles. The study will continue for at least 1 year, and until each subject has access (as needed) to teduglutide. 
The subject’s maximum duration of participation is expected to be approximately 3 years. A subject will be 
considered as having completed the study if the subject has not withdrawn early from the study for any reason 
prior to completing End of Study (EOS) visit.

Planned duration of no-teduglutide treatment periods: variable, depending on disease course 

Planned duration of the teduglutide pre-treatment visit: 1 to 21 days

Planned cycle duration: 28 weeks. Each cycle consists of 24 weeks of teduglutide treatment followed 
by a 4-week follow-up period (no treatment)
Endpoints and statistical analysis: 

The safety population will consist of all enrolled subjects. The safety population will be used for both 
safety and efficacy analysis.
Efficacy Endpoints
Efficacy endpoints will be analyzed at the end of each teduglutide treatment period (Week 24 or end of treatment 
[EOT]), and at each study visit, relative to the baseline of the core study (TED-C14-006) and/or first exposure to 
teduglutide. The following efficacy endpoints will be analyzed:

Reduction in PS volume of at least 20%

Absolute and relative change in PS volume

Complete weaning off PS

Change in days per week of PS
Health Economics and Outcomes Research Endpoints 
Health economics and outcomes research endpoints will be analyzed at approximately 12-week intervals 
(Weeks 12 and 24 of each teduglutide treatment cycle, and every 12 weeks for subjects not on teduglutide), 
relative to the study baseline. The beginning of each treatment cycle (CxD1) will be an additional baseline.

Change in Pediatric Quality of Life Inventory (PedsQL) score

Change in PedsQL Family Impact Module score

Change in PedsQL Gastrointestinal Symptoms Module Sub-Scales scores: 

Food and Drink Limits

Diarrhea 
For non-commercial use only


Shire
CONFIDENTIAL
Page 17
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
Safety Endpoints 
The following safety endpoints will be analyzed:

Adverse events

Vital signs, including temperature, heart rate, blood pressure

Laboratory safety data (ie, clinical chemistry, hematology, and urinalysis)

Urine output

Stool output

Antibodies to teduglutide

Gastrointestinal-specific testing, including fecal occult blood testing and colonoscopy or sigmoidoscopy

Z-scores for weight, height (or length), head circumference (up to 36 months of age), and body mass index
Statistical Methodology for Efficacy Analysis
No claims of statistical significance will be made; however, 95% confidence intervals will be provided, if 
applicable. Continuous variables, including those assessed on a discrete scale, will be summarized using 
descriptive statistics including number of subjects, mean, median, standard deviation , maximum, and minimum. 
For categorical variables, statistical summaries will include number of subjects and percentages.
Statistical Methodology for Safety Analysis 
Safety data, including laboratory tests and vital signs assessments, will be summarized by visit. AEs will also be 
collected and summarized. Descriptive statistics will be calculated for quantitative safety data as well as for the 
difference from baseline, if applicable. Frequency counts will be compiled for classification of qualitative safety 
data.
Sample Size Justification 
As this is an extension study, the maximum number of subjects was determined by enrollment in TED-C14-006.
For non-commercial use only


Shire
CONFIDENTIAL
Page 18
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
STUDY SCHEDULE(S) 
Table 1-1: Schedule of Events Required for All Subjects 
Period
Screening
End of Study or Early Termination
Scr
EOS/ET
Visit Type
Site
Site
Informed consent/assenta
X
Study eligibility
X
Demographics, medical historyb, SBS historyc
X
Dispense intake and output diaries
X
Evaluate teduglutide treatment inclusion criteriad
X
Adverse events
X
X
Concomitant medications and GI procedurese
X
X
Physical examination and vital signs, including weight
X
Height and head circumferencef
X
Review intake and output diariesg 
X
Record PS prescription and adjust as neededh
X
Safety laboratory testsi
X
PedsQL Generic Core Scale/PedsQL Family Impact Module/ 
PedsQL Gastrointestinal Symptoms Module Sub-Scales
X
Antibodies to teduglutidej
X
Fecal occult blood testingk
(X)
Colonoscopy or sigmoidoscopyl
(X)
Pregnancy testingm
(X)
FOBT = fecal occult blood testing; FOCBP = female of child-bearing potential; EOS =end of study; ET=early termination; 
GI=gastrointestinal; NTx=no treatment; 
PedsQL=Pediatric Quality of Life Inventory; PS=parenteral support; SBS=Short Bowel Syndrome; Scr =Screening.
Note: (X) denotes conditional requirement for a given assessment if the subject meets certain conditions per protocol.
a Informed Consent (and informed assent, if applicable) must be obtained prior to performing any study-related procedures; consent (and 
informed assent, if applicable) may be obtained anytime during the Week 28 (or EOS) visit for the TED-C14-006 study. Subject will 
have approximately 7 days after completion of the TED-C14-006 study to sign consent to participate in the SHP633-304 study.
b Updates to the medical history will be collected, consisting of adverse events that were ongoing at the time of completion of TED-C14-
006, and events that occurred during the period between completion of TED-C14-006 and informed consent to SHP-633-304. 
c If the subject has any changes to the SBS history that had been collected at the baseline of the TED-C14-006, then the updated SBS 
history will be collected.
d Subjects who meet ≥1 teduglutide treatment inclusion criteria, may proceed to the pre-treatment visit if the investigator, subject, and 
parent or legal guardian agrees to proceed with teduglutide therapy (Table 1-3).
e Concomitant GI procedures include (but are not limited to) endoscopy, radiographic studies, GI and liver biopsies and associated 
pathology results.
f Head circumference will be measured in subjects 36 months of age and younger.
g The intake diary should be completed daily for a minimum of 2 weeks prior to the EOS/ET visit. The output diary should be completed 
daily over a 48-hour period of nutritional stability before the EOS/ET visit.
h PS adjustments should be made after review of any available intake and output diaries and the safety lab data according to the guidance 
for nutrition support adjustment provided in Appendix 2. 
i Safety laboratory assessments at site visits will consist of clinical chemistry, hematology, and urinalysis, with results processed by a 
central laboratory. Urine specimen collection should be attempted as part of the safety labs, but lack of urinalysis will not constitute a 
protocol deviation.
j Required for all teduglutide-exposed subjects
k FOBT should be performed on teduglutide-exposed subjects on an annual basis, approximately every 48-60 weeks at a minimum.
l The need for colonoscopy/sigmoidoscopy in response to a positive FOBT during a no-teduglutide treatment period is at the discretion of 
the investigator, but all teduglutide-exposed subjects will undergo colonoscopy/sigmoidoscopy after they have received the equivalent of 
2 treatment cycles (48 weeks of study drug exposure), and subjects who continue to receive teduglutide will undergo 
colonoscopy/sigmoidoscopy at 5 year intervals or more often as needed. See Section 7.2.9 for details.
m Pregnancy testing is required for FOCBP at an ET visit if the subject has not had a pregnancy test at least 30 days after study drug 
discontinuation.
For non-commercial use only


Shire
CONFIDENTIAL
Page 19
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
Table 1-2: Schedule of Events for Subjects Not Receiving Teduglutide 
Visit Number
NTx
Visit Type
Site
Visit Frequencya
Every 12 weeks 
Window (days)b
±7
Dispense intake and output diaries
X
Evaluate teduglutide treatment inclusion criteriac
X
Adverse events
X
Concomitant medications and GI proceduresd
X
Physical examination and vital signs, including weight
X
Height and head circumferencee
X
Review intake and output diariesf
X
Record PS prescription and adjust as neededg
X
Safety laboratory testsh
X
PedsQL Generic Core Scale/PedsQL Family Impact Module/ 
PedsQL Gastrointestinal Symptoms Module Sub-Scales
X
Antibodies to teduglutidei
(X)
Fecal occult blood testingj
Annually 
Colonoscopy or sigmoidoscopyk
(X)
Serum samplel
Every 24 weeks
FOBT = fecal occult blood testing; NTT = no-teduglutide treatment; PedsQL = Pediatric Quality of Life Inventory; 
PS= parenteral support; TED = teduglutide.
Note: (X) denotes conditional requirement for a given assessment if the subject meets certain conditions per 
protocol.
a The first NTx visit following the screening visit must occur within 2 to 12 weeks of screening.
b Window is relative to the first NTx visit in the current no-teduglutide treatment period.
c Subjects who meet ≥1 teduglutide treatment inclusion criteria, may proceed to the pre-treatment visit if the 
investigator, subject, and parent or guardian agree to proceed with teduglutide therapy (Table 1-3).
d Concomitant GI procedures include (but are not limited to) endoscopy, radiographic studies, GI and liver biopsies 
and associated pathology results.
e Head circumference will be measured in subjects 36 months of age and younger.
f Intake diaries will collect actual PS volume and hours per day, completed daily for a minimum of 2 weeks prior to 
each study visit (see Section 7.2.11.2). Urine and stool output should be recorded in the output diary over a 48-hour 
period of nutritional stability before every clinic visit (see Section 7.2.11.3 for more detail).
g PS adjustments should be made after review of the intake and output diaries and the safety lab data according to 
the guidance for nutrition support adjustment provided in Appendix 2. 
h Safety laboratory assessments at site visits will consist of clinical chemistry, hematology, and urinalysis, with 
results processed by a central laboratory. Urine specimen collection should be attempted as part of the safety labs, 
but lack of urinalysis will not constitute a protocol deviation.
i Subjects who have been treated previously and test positive for teduglutide antibodies should have follow-up 
samples collected every 12 weeks during the study until a negative result is obtained.
j FOBT should be performed on teduglutide-exposed subjects on an annual basis, approximately every 48-60 weeks 
at a minimum.
k The need for colonoscopy/sigmoidoscopy in response to a positive FOBT during a no-teduglutide treatment period 
is at the discretion of the investigator, but all teduglutide-exposed subjects will undergo colonoscopy/sigmoidoscopy
after they have received the equivalent of 2 treatment cycles (48 weeks of study drug exposure) and subjects who 
continue to receive teduglutide will undergo colonoscopy/sigmoidoscopy at 5 year intervals or more often as 
needed. See Section 7.2.9 for details.
l Lack of collection of serum samples will not constitute a protocol deviation.
For non-commercial use only


Shire
CONFIDENTIAL
Page 20
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
Table 1-3: Schedule of Events for Subjects While Receiving Teduglutide
Period
Pre-
treatment
Teduglutide Treatment
Follow-up
Visit Number
Pxa
Cx
D1
Cx
W1
Cx
W2
Phone contact is required approximately 1 week after PS adjustment
Cx
W4
Phone contact is required approximately 1 week after PS adjustment
Cx 
W6
Phone contact is required approximately 1 week after PS adjustment
Cx 
W9
Phone contact is required approximately 1 week after PS adjustment
Cx 
W12
Phone contact is required approximately 1 week after PS adjustment
Cx 
W16
Phone contact is required approximately 1 week after PS adjustment
Cx 
W20
Phone contact is required approximately 1 week after PS adjustment
CxW24 
(EOT)
CxW25 
CxW26 
CxW27
CxW28c
Visit Type
Site
Site
Site
Site
Site
Site
Site
Site
Site
Site
Site
Phoneb
Site
Cycle Day
-21 to 0
1
8
15
29
43
64
85
113
141
169
176
197
183
190
Window (days)d
-21 to 0
±2
±2
±2
±2
±4
±4
±4
±4
±4
±2
±2
Evaluate teduglutide 
eligibility (inclusion 
and exclusion) criteria
X
Xe
Dispense intake and 
output diaries
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications and GI
proceduresf
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination 
and vital signs, 
including weight
X
X
X
X
X
X
X
X
X
X
X
X
Height and head 
circumferenceg
X
X
X
X
Review intake and 
output diariesh
X
X
X
X
X
X
X
X
X
X
X
X
X
Record PS Rx and 
adjust as neededi
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety laboratory testsj
Xj
X
X
X
X
X
X
X
X
X
X
(X)
X
PedsQL Generic Core 
Scale/ Family Impact 
Module/ GI 
Symptoms Module 
Sub-Scales
X
X
X
Antibodies to 
teduglutidek
X
X
X
X
Fecal occult blood 
testing
X
X
X
Colonoscopy/
sigmoidoscopyl
(X)
(X)
(X)
Pregnancy testingm
X
X
X
X
X
X
X
X
X
For non-commercial use only


Shire
CONFIDENTIAL
Page 21
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
Table 1-3: Schedule of Events for Subjects While Receiving Teduglutide
Period
Pre-
treatment
Teduglutide Treatment
Follow-up
Serum samplen
X
X
Evaluate escape 
criteriao
X
X
Dispense study drugp
X
X
X
X
X
X
X
X
X
EOS = end of study; EOT = end of treatment; ET = early termination; FOBT = fecal occult blood test; FOCBP = female of child-bearing potential; FU = follow-up; GI = 
gastrointestinal; PedsQL = Pediatric Quality of Life Inventory; PS= parenteral support; SBS = Short Bowel Syndrome; SC = subcutaneous; Scr = Screening; TED = teduglutide; 
Tx = treatment.
Note: (X) denotes conditional requirement for a given assessment if the subject meets certain conditions per protocol.
a If the first pre-treatment visit (P1) follows the screening visit, it must occur within 12 weeks of screening.
b Phone visits are required approximately 1 week after adjustments in PS. The assessments to be performed at phone visits are the same as those described for CxW25-27 (except 
for evaluation of escape criteria). 
c The investigator may combine the CxW28 visit with the next pre-treatment visit if at least one escape criterion is met at the CxW28 visit, and the pre-treatment assessments occur 
within 7 days of the CxW28 visit. If a subject is completing the study at the CxW28 visit, the EOS/ET visit (Table 1-1) will take place in lieu of the CxW28 visit.
d Visit windows are relative to the CxD1 visit.
e Eligibility will need to be re-confirmed prior to the first dose in the cycle. Negative urine pregnancy test is required prior to the first dose of teduglutide, but results of other labs 
obtained at the CxD1 visit are not required to determine teduglutide treatment eligibility.
f Concomitant GI procedures include (but are not limited to) endoscopy, radiographic studies, GI and liver biopsies and associated pathology results.
g Head circumference will be measured in subjects 36 months of age and younger.
h Intake diaries will collect actual PS volume and hours per day. Intake diaries should be completed daily for a minimum of 2 weeks immediately prior to each clinic visit (except 
at pre-treatment visit), for 1 week following PS adjustment, and daily during the 4-week follow-up period. Urine and stool output should be recorded in the output diary over a 48-
hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PS prescription. See Section 7.2.11 for more detail.
i PS adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment provided in
Appendix 2.
j Safety laboratory assessments at site visits will consist of clinical chemistry, hematology, and urinalysis, with results processed by a central laboratory. Clinical chemistry and 
urinalysis must also be performed within approximately 5-7 days of any adjustment to the PS prescription. Safety labs performed between clinic visits may be performed locally. 
Unscheduled lab results will not be captured in the eCRFs. If abnormal results are considered an adverse event, an AE form will be completed. Collect PT/INR at the pre-treatment 
visit. Additional collection will occur if a potential drug-induced liver injury signal is observed. Urine specimen collection should be attempted as part of the safety labs, but lack 
of urinalysis will not constitute a protocol deviation.
k Samples collected on CxD1 must be drawn prior to first administration of teduglutide. Samples collected while subjects are receiving teduglutide (CxW12 and CxW24) must be 
drawn at least 14 hours after dosing.
l The teduglutide-naïve subjects age 12 and older will undergo colonoscopy/sigmoidoscopy at the pre-treatment visit if one has not been performed within 1 year. Subjects of any 
age with newly positive FOBT results at the pre-treatment visit for which a readily detectable cause cannot be identified (eg, anal fissure) will undergo a 
colonoscopy/sigmoidoscopy prior to receiving teduglutide. If newly positive FOBT results (for which a readily detectable cause cannot be identified) are obtained at the end of a 
teduglutide treatment cycle (CxW24/EOT), colonoscopy/sigmoidoscopy will be performed. The need for colonoscopy/sigmoidoscopy in response to positive FOBTs at CxW12 is 
at the discretion of the investigator. Teduglutide-exposed subjects who have received the equivalent of 2 treatment cycles (48 weeks of study drug exposure) will undergo 
For non-commercial use only


Shire
CONFIDENTIAL
Page 22
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
Table 1-3: Schedule of Events for Subjects While Receiving Teduglutide
Period
Pre-
treatment
Teduglutide Treatment
Follow-up
colonoscopy/sigmoidoscopy. See Section 7.2.9 for details.
m A serum pregnancy test is performed on all FOCBP at the teduglutide pre-treatment visit (when the pre-treatment and screening visits are combined, the serum pregnancy test 
should be performed at the local laboratory). Urine pregnancy tests will be administered at all other visits according to the study schedules, or if pregnancy is suspected, or as 
specified per protocol upon withdrawal of the subject from the study.
n Lack of collection of serum samples will not constitute a protocol deviation.
o If escape criteria are met, the subject may proceed directly to another pre-treatment visit at the discretion of the investigator.
p The first SC injection of teduglutide in treatment-naïve subjects will be administered under the supervision of the investigator/designee after which the subject will be observed 
for hypersensitivity reactions for at least 4 hours. The site of administration (arm, thigh, abdomen) of the first teduglutide dose must be specified and recorded in the eCRF. See 
Section 6.2.3 for dose adjustment.
For non-commercial use only


Shire
CONFIDENTIAL
Page 23
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
1
BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options 
Short bowel syndrome (SBS) is a rare disorder resulting from congenital abnormalities or severe 
intestinal diseases that result in major surgical resections of the small intestine. It is estimated 
that, at most, there are a few hundred pediatric subjects 1 year and older with SBS (Khan et al., 
2015; Wales et al., 2004). Unlike the adult population, the majority of cases of SBS in pediatric 
subjects are due to congenital anomalies or catastrophic events that occur during infancy. 
Although the small intestine is capable of remarkable adaptation, excessive loss of absorptive 
surface area or specialized functions can lead to dependence on parenteral nutrition or 
intravenous (IV) fluids (parenteral support [PS]). Treatment of both pediatric and adult patients 
is focused on achieving adequate intestinal absorption to allow for minimization or 
discontinuation of PS. About 30% of infants with SBS become independent of PS requirements 
within 12 months of the initial insult, and an additional 10% wean off PS within 24 months. 
After this time, linear intestinal growth slows. About 60% of pediatric subjects with SBS are able 
to become independent of PS within 5 years of the initial diagnosis (Khan et al., 2015). 
Nevertheless, despite optimal medical management, many pediatric subjects remain dependent 
on PS. Complications of long-term PS include liver disease, catheter-related blood stream 
infections, central line-associated venous thrombosis and dwindling central venous access. 
Sepsis is the leading cause of death in these patients and quality of life is poor (Squires et al., 
2012). Accelerating the adaptive process and achieving enteral autonomy is an urgent goal for all 
patients with SBS who are dependent on PS (Khan et al., 2015; Squires et al., 2012).
Intestinal adaptation is driven by hormonal cues in response to nutrient malabsorption (Drucker 
and Yusta, 2014). Chief among these is hormones glucagon-like peptide 2 (GLP-2), which is 
secreted from L-type enteroendocrine cells that reside in the intestinal epithelium in the ileum 
and colon. Resection of these regions may impair the adaptive response by limiting endogenous 
production of GLP-2. 
1.2
Product Background 
Teduglutide is a novel, recombinant analog of naturally occurring human GLP-2 that regulates 
the functional and structural integrity of the cells lining the gastrointestinal (GI) tract. 
Teduglutide is a 33-amino acid peptide that differs from native GLP-2 in the substitution of 
glycine for alanine at the second position at the N-terminus. As a result, teduglutide demonstrates 
resistance to degradation by dipeptidyl peptidase-IV (DPP-4) and therefore maintains a longer 
elimination half-life (t1/2) in adults of approximately 2 hours compared to the native peptide, 
which has a t1/2 of approximately 7 minutes. Teduglutide has been shown in animal studies and 
previous human clinical trials to increase villus height and crypt depth in the intestinal 
epithelium, thereby increasing the absorptive surface area of the intestines (Tappenden et al., 
2013; Thymann et al., 2014). The European Commission granted a centralized marketing 
authorization valid throughout the European Union (EU) for teduglutide (Revestive™) on 30 
August 2012 and a New Drug Application (NDA) for teduglutide (Gattex®) was approved by the 
United States (US) Food and Drug Administration (FDA) on 21 December 2012 for the 
treatment of adult patients with SBS who are dependent on PS. Teduglutide has also been 
approved for use in adult patients with SBS in Canada and Switzerland. On 29 Jun 2016, the 
For non-commercial use only


Shire
CONFIDENTIAL
Page 24
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
European Commission granted an extension of the Market Authorization for teduglutide 
(REVESTIVE™) for the treatment of patients aged 1 year and above with SBS; patients should be 
stable following a period of intestinal adaptation.
1.3
Clinical Studies with Teduglutide in Pediatric Subjects
One Phase 3 study, TED-C13-003, was completed in pediatric SBS subjects in the US and 
United Kingdom (UK). In this study, teduglutide was administered to 3 cohorts of pediatric 
subjects from ages 1-17. Thirty-seven pediatric subjects received teduglutide at doses of 0.0125, 
0.025, or 0.05 mg/kg/day for 12 weeks. Five additional pediatric subjects were enrolled in an 
observational standard of care (SOC) cohort. There were clear dose-dependent effects of 
teduglutide seen at the 0.025 and 0.05 mg/kg/day doses compared to SOC and the 0.0125 
mg/kg/day dose. In the 0.025 mg/kg/day cohort there was a reduction in PS volume at Week 12 
of 37%, including complete independence from PS support in 1 subject, and a reduction of 3.94 
hours per day infusion time. In the 0.05 mg/kg/day cohort there was a reduction in PS volume at 
Week 12 of 39%, including complete independence from PS support in 3 subjects, and a 
reduction of 4.18 hours per day infusion time. Teduglutide was generally safe and well tolerated 
by pediatric subjects in all dosing cohorts. There were no deaths during the study and no 
treatment-emergent serious adverse events (TESAEs) related to teduglutide were reported. No 
discontinuations from study were due to adverse events (AEs).
TED-C14-006 is an ongoing study which includes 2 treatment arms: a teduglutide treatment arm 
and a standard of care treatment arm. Subjects in both arms participate in a 2-week minimum 
screening period, a 24-week treatment period, and a 4-week follow-up period. During the 
screening period, subjects will choose into which arm to enroll. During the 24-week treatment 
period, subjects in the SOC treatment arm will receive standard medical therapy for SBS; while 
those in the teduglutide treatment arm will receive daily subcutaneous (SC) injections of 
teduglutide (study drug) in addition to standard medical therapy. The subjects enrolling in the 
teduglutide treatment arm will be randomized 1:1 in a double-blinded manner into 2 parallel dose 
groups: 0.025 mg/kg/day or 0.05 mg/kg/day of teduglutide administered subcutaneously for 24 
weeks.
Always refer to the latest version of the investigator’s brochure for the overall risk/benefit 
assessment and the most accurate and current information regarding the drug metabolism, 
pharmacokinetics, efficacy and safety of teduglutide (SHP633). 
For non-commercial use only


Shire
CONFIDENTIAL
Page 25
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
2
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study 
This is a Phase 3, prospective, open-label, long-term extension study to evaluate the safety and 
efficacy of teduglutide in pediatric subjects with SBS who completed the TED-C14-006 study. In 
addition to evaluating the long-term safety and durability of efficacy after 24 weeks of treatment, 
this extension study will evaluate the need for additional teduglutide treatment in these subjects, 
and will allow for the first-time treatment of teduglutide-naïve subjects who participated in the 
SOC treatment arm in TED-C14-006.
2.2
Study Objectives
2.2.1
Primary Objectives
The primary objective of the study is to evaluate the long-term safety and tolerability of 
teduglutide treatment in pediatric subjects with SBS who completed TED-C14-006.
2.2.2
Secondary Objectives
The secondary objective of this study is to evaluate the long-term efficacy of teduglutide 
treatment in pediatric subjects with SBS who completed TED-C14-006.
For non-commercial use only


Shire
CONFIDENTIAL
Page 26
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
3
STUDY DESIGN
3.1
Study Design and Flow Chart
This is a Phase 3, prospective, open-label, long-term extension study to evaluate the safety and 
efficacy of teduglutide in pediatric subjects who completed the TED-C14-006 study (core study). 
At the time of entry into the TED-C14-006 study, subjects were less than 18 years of age, were 
dependent on parenteral nutrition to provide at least 30% of their caloric or fluid needs, and had 
not been able to significantly reduce PS for at least 3 months prior to enrollment. During the core 
study, pediatric subjects in the teduglutide treatment arm were randomized to 0.025 mg/kg or 
0.05 mg/kg once daily (QD) dosing in a double-blinded manner. The TED-C14-006 study will 
also be referred to as the core study interchangeably throughout this protocol.
Approximately 34 subjects who complete the core study are expected to enroll in this extension 
study. Subjects who previously received teduglutide during TED-C14-006, as well as subjects 
who were in the SOC treatment group, may be eligible to receive teduglutide treatment in this 
extension study. To be eligible, subjects must meet ≥1 of the teduglutide treatment inclusion 
criteria and none of the teduglutide treatment exclusion criteria.
Additional Teduglutide Treatment
Subjects not receiving teduglutide treatment (ie, in a “no-teduglutide treatment period”), will be 
seen approximately every 12 weeks for safety, parenteral support (PS) requirements, and quality 
of life. At any point during a no-teduglutide treatment period, subjects who meet ≥1 teduglutide 
treatment inclusion may proceed directly to the pre-treatment visit if the investigator, subject, 
and parent agree to proceed with teduglutide therapy.
Rationale: Some pediatric subjects may have a durable beneficial effect after 24 weeks of 
teduglutide treatment and thus long-term follow-up without additional teduglutide treatment may 
be appropriate. However, there may be some pediatric subjects who deteriorate or stop 
improving after discontinuation of teduglutide treatment. In these pediatric subjects, additional 
teduglutide treatment may be beneficial. 
Dose Selection 
Analysis suggested that pediatric patients, ages 1 to 17 years old, are likely to require the same 
dose as used in adults, namely 0.05 mg/kg/day (Mouksassi et al., 2009). In this extension study 
to TED-C14-006, repeat doses of teduglutide 0.05 mg/kg QD will be administered to eligible 
pediatric subjects who previously received teduglutide 0.05 or 0.025 mg/kg in Study TED-C14-
006.
Rationale: Teduglutide is approved for adult use in the US and EU, and for pediatric use in the 
EU, at a dose of 0.05 mg/kg SC once daily. The completed 12-week pediatric study (TED-C13-
003) demonstrated that teduglutide dosing at 0.025 and 0.05 mg/kg/day was associated with a 
favorable benefit/risk profile. In addition, population pharmacokinetic modeling and simulations 
were conducted to determine the effective dose to be used in pediatric subjects using data from 
8 adult clinical studies including adult Phase 1 studies and Phases 2/3 studies as well as the 
pediatric study (TED- C13- 003) and suggested that the dose in pediatric subjects is likely to be 
same as the dose in adults (O'Keefe et al., 2006).
For non-commercial use only


Shire
CONFIDENTIAL
Page 27
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
Duration of Treatment
The duration of teduglutide treatment in this study mirrors that of the TED-C14-006 study, 
consisting of 24 weeks of teduglutide treatment, followed by a 4-week follow-up period. The 
follow-up period is a mechanism to evaluate whether continued teduglutide is needed. If a 
subject deteriorates during the follow-up period, the subject may be evaluated immediately for 
additional teduglutide treatment. Subjects who clinically deteriorate or stop improving at any 
time after the end of the follow-up period will also be assessed for additional treatment.
Rationale: During the teduglutide treatment cycle, visit frequency is similar to frequencies 
performed in TED-C13-003 and TED-C14-006, to ensure sufficient safety monitoring and 
weaning of PS. During the no-teduglutide treatment, visits occur every 12 weeks, a frequency 
that is consistent with standard medical practices.
Measures and Parameters
Following the review and signing of the informed consent (and informed assent, if applicable), 
screening visit procedures will begin including demographics, and updates to medical history
and SBS history. Subjects who meet ≥1 of the teduglutide treatment inclusion criteria may 
proceed to the pre-treatment visit.
After the pre-treatment visit, subjects who still meet ≥1 of the teduglutide treatment inclusion 
criteria, and meet none of the teduglutide treatment exclusion criteria, will start a 28-week cycle, 
consisting of 24 weeks of teduglutide treatment at 0.05 mg/kg SC once daily, followed by a 4-
week follow-up (no treatment) period (Figure 3-1). During the 28-week cycle, clinic visits will 
occur at weeks 1, 2, 4, 6, 9, 12, 16, 20, 24, and 28. Phone visits are required approximately 
1 week after adjustments in PS during the teduglutide treatment period (between weeks 1-24), 
and weekly during the teduglutide follow-up period (between weeks 24 and 28).
Safety and PS requirements will be evaluated on a weekly basis, and quality of life assessments 
will be made approximately every 12 weeks. At all site visits and telephone contacts, safety will 
be monitored and nutritional support will be reviewed and adjusted as needed. To maintain 
consistency across centers, all attempts should be made to follow the nutritional support 
adjustment guidelines (developed with SBS expert input and provided in the protocol) for 
decisions regarding PS reduction and advances in enteral feeds based on weight gain, urine and 
stool output, and clinical stability. Departure from the guidelines, however, is not considered a 
protocol deviation (Appendix 2).
Rationale: Measures of long term safety will include adverse events, growth parameters and anti-
drug antibodies. Measure of long term efficacy will include durability of effect as measured by 
reduction in PS and improvement in pediatric quality of life measures (PedsQL, PedsQL Family 
Impact Module). A reduction in PS volume of at least 20% at end of treatment (EOT) was used 
as the primary endpoint in pivotal phase 3 adult clinical trials and the completed phase 3 
pediatric study (TED-C13-003), and will be used as an endpoint in this extension study. In 
previous clinical studies, a reduction of this magnitude was associated with a reduction in the 
number of days per week of PS, and increases in enteral intake. Reduction in volume and time of 
PS due to improved enteral absorption may provide a pediatric subject with opportunities for 
more age-appropriate activities including oral rehabilitation. Quality of life assessments will be 
performed in this study to quantitate this effect.
For non-commercial use only


Shire
CONFIDENTIAL
Page 28
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
Teduglutide has been found to have a targeted intestinotrophic effect. Taking into account the 
patient population and the pharmacologic effect of teduglutide, GI-specific screening tests, 
including fecal occult blood testing and colonoscopy/sigmoidoscopy, which are commonly part 
of the routine care of these subjects, will be performed to ensure safety. This study captures long-
term safety data on polyps and other colonic mucosal changes in teduglutide-exposed subjects 
using the surveillance strategy proposed in Section 7.2.9. 
Figure 3-1:
Study Design Flow Chart
Figure legend: Safety and efficacy data for subjects not receiving teduglutide treatment are captured approximately every 
12 weeks, but subjects may proceed to the pre-treatment visit at any time in order to assess eligibility for teduglutide therapy. 
Eligible subjects will enter a 28-week teduglutide cycle. During this cycle, subjects will return to the site for safety and efficacy 
assessments at weeks 1, 2, 4, 6, 9, 12, 16, 20, and 24 (solid black lines). Phone visits are required approximately 1 week after 
adjustments in PS during the intervening weeks between weeks 2 and 24 (dashed grey lines). Subjects discontinue teduglutide at 
week 24 and enter a 4-week follow-up (no-treatment) period, during which phone visits will be performed weekly (solid grey 
lines). If an escape criterion is met during the follow-up period, subjects may proceed directly to another pre-treatment visit.
3.2
Duration and Study Completion Definition
A subject will be considered enrolled in the study once the subject has provided signed consent, 
and meets all of the Inclusion Criteria. The study will continue for at least 1 year and until each 
subject has access, as needed, to teduglutide. The subject’s maximum duration of participation is 
expected to be approximately 3 years. The study will be completed in approximately 40 months.
A subject will be considered as having completed the study if the subject has not withdrawn 
early from the study for any reason prior to completing the End of Study (EOS) visit.
The study completion date is defined as the date the final subject, across all sites, completes their 
final protocol-defined assessment. Please note that this includes the follow-up visit or contact 
(last safety contact), whichever is later. The study completion date will be used to ascertain 
timing for study results posting and reporting.
For non-commercial use only


Shire
CONFIDENTIAL
Page 29
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
4
STUDY POPULATION
Each subject must review and sign the informed consent (and informed assent, if applicable) 
before any study-related procedures specified in the protocol are performed. Teduglutide 
treatment eligibility does not impact study eligibility.
4.1
Study Inclusion Eligibility Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1. Subject provides written informed consent (subject, parent or legal guardian and, as 
appropriate, subject informed assent) to participate in the study before completing any 
study-related procedures. 
2. Subject completed the TED-C14-006 study (including subjects in the standard of care 
treatment arm).
3. Subject understands and is willing and able to fully adhere to study requirements as 
defined in this protocol.
4.2
Study Exclusion Eligibility Criteria
There are no exclusion criteria for this study.
4.3
Teduglutide Eligibility Criteria
Subjects are eligible for teduglutide treatment if at least 1 (≥1) of the teduglutide treatment 
inclusion criteria, and none of the teduglutide treatment exclusion criteria are met. In addition, 
the investigator and the subject (and/or parent or legal guardian, as appropriate) must agree to 
proceed with treatment.
4.4
Teduglutide Treatment Inclusion Criteria
1. Subject is teduglutide-naïve, receiving PS, and unable to significantly reduce PS or 
advance enteral feeds (eg, 10% or less change in PS or advance in feeds) for at least 
3 months prior to and during the teduglutide pre-treatment visit, as assessed by the 
investigator. Transient instability for events such as interruption of central access or 
treatment for sepsis is allowed if the PS returns to within 10% of baseline prior to the 
event.
2. Subject was previously treated with teduglutide and at least 1 of the following criteria is 
satisfied:
a.
Increasing PS requirements following teduglutide discontinuation.
b. Decreased PS requirement during prior teduglutide treatment, followed by 
cessation of improvement after teduglutide discontinuation.
c.
Deteriorating nutritional status eg, weight loss or growth failure) despite 
maximal tolerated enteral nutrition following teduglutide discontinuation.
d. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid 
and electrolyte intake following teduglutide discontinuation.
e.
Severe diarrhea related to teduglutide discontinuation.
For non-commercial use only


Shire
CONFIDENTIAL
Page 30
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
4.5
Teduglutide Treatment Exclusion Criteria
1. Body weight <10 kg at the pre-treatment visit.
2. Unresected GI polyp, known polyposis condition, pre-malignant change, or malignancy, 
in the GI tract
3. History of cancer in the previous 5 years except surgically curative skin cancers
4. Serial transverse enteroplasty or other major intestinal surgery within 3 months 
preceding the teduglutide pre-treatment visit. Insertion of a feeding tube, anastomotic 
ulcer repair, minor intestinal resections ≤10 cm, and endoscopic procedures are allowed.
5. Intestinal or other major surgery planned or scheduled to occur during the 28-week cycle
6. Clinically significant intestinal stricture or obstruction
7. Clinically significant, active or recurrent pancreatic or biliary disease
8. Active, severe, or unstable, clinically significant hepatic impairment or injury, including 
the following laboratory values at the pre-treatment visit:
a.
Total bilirubin ≥2 × upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥7 × ULN
c.
Alanine aminotransferase (ALT) ≥7 × ULN
9. Renal dysfunction shown by results of an estimated glomerular filtration rate (eGFR) 
below 50 mL/min/1.73 m2 at the pre-treatment visit
10. Unstable cardiac disease, congenital heart disease or cyanotic disease, with the exception 
of subjects who had undergone ventricular or atrial septal defect repair, or patent ductus 
arteriosus (PDA) ligation
11. Participation in a clinical study using an experimental drug (other than glutamine, 
Omegaven, or Smoflipid) within 3 months or 5.5 half-lives of the experimental drug, 
whichever is longer, prior to the pre-treatment visit and for the duration of the 28-week 
cycle
12. Treatment with analogs of glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 
(GLP-2) (not including teduglutide), insulin-like growth factor-1 (IGF-1), or growth 
hormone, within 3 months preceding the teduglutide pretreatment visit.
13. Treatment with octreotide or dipeptidyl peptidase 4 (DPP-4) inhibitors within 3 months 
prior to the pre-treatment visit
14. Known or suspected intolerance or hypersensitivity to the investigational product, 
closely-related compounds, or any of the stated ingredients
15. Known history of alcohol or other substance abuse within 1 year prior to the pre-
treatment visit
16. Pregnant or lactating female subjects 
17. Sexually active female subjects of child-bearing potential unwilling to use approved 
contraception during teduglutide treatment and for 30 days after the treatment period 
For non-commercial use only


Shire
CONFIDENTIAL
Page 31
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
18. Any condition, disease, illness, or circumstance that in the investigator’s opinion puts 
the subject at any undue risk, prevents completion of the study, or interferes with 
analysis of the study results.
4.6
Follow-up Period Escape Criteria
At the discretion of the investigator, the follow-up period may be interrupted and the subject may 
proceed directly to the pre-treatment visit, if ≥1 of the following criteria is met:
1. Increasing PS requirements following teduglutide discontinuation.
2. Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal 
tolerated enteral nutrition following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation.
4. Severe diarrhea related to teduglutide discontinuation.
4.7
Reproductive Potential
4.7.1
Female Contraception
To be eligible for treatment with teduglutide, sexually active females of child-bearing potential 
must use an acceptable form of contraception throughout the study period and for 30 days 
following the last dose of investigational product. If hormonal contraceptives are used, they 
should be administered according to the package insert. Females of child-bearing potential who 
are not currently sexually active must agree to use acceptable contraception, as defined below, if 
they become sexually active during the period of the study and 30 days following the last dose of 
investigational product. 
To be eligible for treatment with teduglutide, female pediatric subjects and adolescent subjects 
should be either:

Pre-menarchal and either Tanner Stage 1 or less than age 9 years, or

Females of child-bearing potential (FOCBP) with a negative serum beta-human chorionic 
gonadotropin (-HCG) pregnancy test at the teduglutide pre-treatment visit. Females of 
child-bearing potential must agree to abstain from sexual activity that could result in 
pregnancy or agree to use acceptable methods of contraception.
Acceptable methods of contraception are:

True abstinence: Abstention of sexual activity that is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
post-ovulation methods] and withdrawal are not acceptable methods of contraception).

Intrauterine devices plus condoms

Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or foam)
For non-commercial use only


Shire
CONFIDENTIAL
Page 32
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017

Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring), stabilized for at 
least 30 days prior to the pre-treatment visit, plus condoms. Note: if subject becomes 
sexually active during the study, they should use one of the other acceptable methods 
noted above in addition to the hormonal contraceptive until it has been stabilized for 
30 days.
4.8
Discontinuation of Subjects 
4.8.1
Teduglutide Discontinuation
If the investigational product is discontinued prematurely during a teduglutide treatment cycle
and the subject wishes to remain in the study, the evaluations listed for the EOT visit are to be 
performed. A 4-week follow-up period will ensue, consisting of weekly telephone visits 
(CxW25-27) and the week 28 clinic visit (CxW28). The subject would then enter a 
no-teduglutide treatment (NTT) period and could be evaluated for subsequent teduglutide 
treatment eligibility according to the study schedules. Comments (spontaneous or elicited) or 
complaints made by the subject must be recorded in the source documents. The reason for 
permanent treatment discontinuation, dates of investigational product administered (including 
last date of treatment), and amount of investigational product taken must be recorded in the 
electronic case report form (eCRF) and source documents, as described in Section 4.8.3. The 
investigator is encouraged to discuss withdrawal of a subject from investigational product with 
the medical monitor, when possible.
4.8.2
Study Withdrawal
At any time during the study, the investigator or sponsor may withdraw a subject, or a subject 
may withdraw from the study, for any reason, without prejudice to their future medical care by 
the physician or at the institution.
If a subject withdraws from the study during a teduglutide cycle, the evaluations listed for the 
EOT visit are to be performed as completely as possible. Whenever possible, the subject will 
then be asked to return 4 weeks later for the early termination (ET) visit, and will be contacted 
weekly by phone during the interim period between EOT and ET for safety follow-up.
If a subject withdraws from the study during a NTT period, the evaluations listed for the ET visit 
are to be performed as soon and completely as possible. 
Subjects who withdraw from the study will not be replaced.
4.8.3
Reasons for Discontinuation
The reason(s) for permanent discontinuation of treatment and/or withdrawal from the study must 
be determined by the investigator, and recorded in the subject’s medical record and in the eCRF. 
If a subject is withdrawn for more than 1 reason, each reason should be documented in the source 
document, and the most clinically relevant reason should be entered in the eCRF.
Reasons for discontinuation include, but are not limited to:

Adverse event 

Protocol deviation
For non-commercial use only


Shire
CONFIDENTIAL
Page 33
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017

Lack of efficacy 

Physician decision 

Withdrawal by subject 

Withdrawal by parent/guardian

Lost to follow-up

Pregnancy (Discontinuation of treatment only) 

Death 

Other 
4.8.3.1
Subjects ‘Lost to Follow-up’ Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact (office visit or telephone contact). At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that they 
return to the site for final safety evaluations, and return any unused investigational product.
For non-commercial use only


Shire
CONFIDENTIAL
Page 34
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
5
CONCOMITANT TREATMENT
5.1
Concomitant Medications and GI Procedures
Concomitant treatment refers to all treatment taken between the dates of informed consent and 
EOS, inclusive. Concomitant treatment information must be recorded on the appropriate eCRF 
page. Concomitant treatments will be assessed at each site visit, and include all non-study 
treatments (medications, herbal treatments, vitamins, invasive and diagnostic procedures). 
Concomitant GI procedures include (but are not limited to) endoscopy, radiographic studies, GI 
and liver biopsies and associated pathology results. Concomitant treatment information must be 
recorded on the appropriate eCRF page. Details of medication changes and/or dosages will be 
recorded on the eCRF.
The mechanism of action of teduglutide may increase absorption of drugs (eg, motility 
medication including narcotics and opioids used for the management of SBS, warfarin, 
psychotropics, metronidazole, and digoxin). Accordingly, due consideration should be given to 
modifying concomitant medication regimens. Down-titration of concomitant medications should 
be considered when drugs, especially those with a narrow therapeutic range, are prescribed at 
dosages that are higher than usual.
5.1.1
Permitted Treatment
Standard medical therapy for SBS should be continued.
5.1.2
Prohibited Treatment
The mechanism of action of teduglutide may increase enteral absorption of drugs (eg, motility 
medication including narcotics and opioids used for the management of SBS, warfarin, 
psychotropics, metronidazole, digoxin), so consideration should be given to modifying 
concomitant enteral medication regimens. Down-titration of concomitant enteral medications 
should be considered when drugs, especially those with a narrow therapeutic range, are given at 
dosages that are higher than usual.
The following medications are prohibited during teduglutide treatment and within the provided 
timeframe prior to the pre-treatment visit:
Table 5-1: Prohibited Treatment
Prior Therapy
Time Restriction Prior to 
the Pre-Treatment Visit
Native/synthetic glucagon-like peptide-2 (not-including teduglutide)
Any
Glucagon-like peptide-1 analog or human growth hormone
3 months
Octreotide or dipeptidyl peptidase 4 inhibitors
3 months
Biological therapy (eg, antitumor necrosis factor)
6 months
For non-commercial use only


Shire
CONFIDENTIAL
Page 35
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
6
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product 
The test product is teduglutide, which will be provided in sterile, single-use 3 mL vials 
containing 5 mg or 1.25 mg teduglutide as a white lyophilized powder to be reconstituted before 
use with 0.5 mL sterile water for injection. In addition to the active ingredient (teduglutide), each 
vial of teduglutide contains L-histidine, mannitol, monobasic sodium phosphate monohydrate, 
and dibasic sodium phosphate as excipients. Additional information is provided in the current 
SHP633 investigator’s brochure.
6.1.1
Blinding the Treatment Assignment
Not applicable for this open-label study.
6.2
Administration of Investigational Product(s)
6.2.1
Interactive Response Technology for Investigational Product Management
An interactive web-based response system (IWRS) will be used for screening and enrolling 
subjects, recording subject visits, investigational product supply dispensation and management, 
inventory management and supply ordering, investigational product expiration tracking and 
management, and return of investigational product. Please refer to the Study Manual for 
additional details regarding the IWRS. 
The IWRS will also be used for creating, tracking, and confirming investigational product 
shipments. A user manual with specific functions and instructions for the IWRS will be provided 
to the site, and site personnel will receive training.
6.2.2
Allocation of Subjects to Treatment 
This is an open-label study. Subjects will retain their assigned subject number from the 
TED-C14-006 study. Assessment of need for teduglutide treatment should be guided by the 
teduglutide treatment inclusion criteria. If the investigator, subject, and/or parent/guardian agree 
to proceed with treatment, a formal evaluation of teduglutide inclusion and exclusion criteria will 
be performed at the pre-treatment visit (Table 1-3). 
6.2.3
Dosing
If teduglutide treatment eligibility is established at the pre-treatment visit and again, confirmed at 
the CxD1 visit, the subject will start a teduglutide treatment period, consisting of 24 weeks of 
teduglutide treatment at 0.05 mg/kg SC once daily. The initial dose will be calculated based on 
body weight measured at the teduglutide pre-treatment visit, and adjusted as needed, based on 
body weight measured at Week 12 (CxW12). No other adjustments to dose will be made during 
the teduglutide treatment period, unless discussed with the sponsor’s medical monitor. 
Following reconstitution, teduglutide will be administered by SC injection QD into 1 of the 
4 quadrants of the abdomen (in subjects without a stoma) or into either the thigh or arm. For 
subjects with a stoma, the quadrant of the abdomen containing the stoma should not be used. 
Teduglutide should be used as soon as possible after reconstitution, but no more than 3 hours 
later.
For non-commercial use only


Shire
CONFIDENTIAL
Page 36
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
The subject should be dosed at approximately the same time each day. Consecutive doses should 
be separated by at least 12 hours. Each day, the injection site should be rotated.
The first SC injection in teduglutide-naïve subjects should be administered under the supervision 
of the investigator or designee and the subject observed for hypersensitivity reactions for at least 
4 hours during their initial dosing visit. The site of administration (arm, thigh, and abdomen) of 
the first teduglutide dose must be specified and recorded in the eCRF. 
Detailed instructions for reconstitution and injection of the investigational product can be found 
in the Instructions for Use. 
Following each 24-week teduglutide treatment period, subjects will enter a 4-week follow-up 
period. During the follow-up, the investigator will assess the subject via weekly telephone visits. 
At any time during the follow-up period, if escape criteria are met, the subject may proceed 
directly to another Pre-Treatment visit to assess treatment eligibility for another cycle 
(Section 4.6). Following the completion of the 4-week follow-up, the subject will continue in the 
study off teduglutide. Additional 28-week cycles may be repeated if treatment eligibility is 
established each time. 
6.2.4
Unblinding the Treatment Assignment
Not applicable for this open-label study.
6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling 
Labels containing study information and pack identification will be applied to the investigational 
product(s) container. 
The study drug will be packaged, labeled, and shipped to the study site by the sponsor or 
designee. Kits containing 7 vials of study drug will be supplied and these will be labeled in 
accordance with applicable regulatory requirements. Sterile water for injection syringes and 
other ancillary components will be provided separately and will be labeled in accordance with 
the applicable regulatory requirements.
All study drug used in this study will be manufactured, tested, labeled, and released according to 
current legal requirements and Good Manufacturing Practice.
6.3.2
Packaging
Investigational product is packaged in the following conditions:
Teduglutide will be provided in a sterile, single-use, glass vial as a lyophilized powder, to be 
reconstituted with 0.5 mL sterile water for injection provided as the diluent in a prefilled syringe.
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
6.3.3
Storage and Handling
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.
For non-commercial use only


Shire
CONFIDENTIAL
Page 37
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
Study drug must be kept in a locked area with access restricted to specific study personnel. Study 
drug will be stored refrigerated at a temperature between 2 to 8°C (35.6 to 46.4°F) until 
dispensed to a subject. Once dispensed to a subject, the study drug can be stored refrigerated or 
up to a controlled room temperature (acceptable range of 2 to 25°C, or 35.6 to 77°F). 
Parent/guardian will be instructed to keep the subject’s study drug and sterile water diluent at 
controlled room temperature. If there are concerns that the controlled room temperature cannot 
be maintained, the study drug may be refrigerated. The study drug is for single use only, and 
should be used within 3 hours following reconstitution.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (ie, certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
Investigational products are distributed by the pharmacy or nominated member of the study 
team. The pharmacist/nominated team member will enter the unique subject identifier on the 
investigational product bottle/carton labels, as they are distributed. 
6.4
Drug Accountability 
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. The 
investigator is to keep a current record of the inventory and dispensation of all clinical supplies. 
This record will be made available to the sponsor’s site monitor for the purpose of accounting for 
all clinical supplies. Any discrepancy or deficiency will be recorded and will include an 
explanation. All supplies sent to the investigator must be accounted for and in no case will 
clinical supplies be used in any unauthorized situation.
The investigator has overall responsibility for administering/dispensing investigational product. 
Where permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator. 
This delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will dispense the investigational product only to subjects eligible 
For non-commercial use only


Shire
CONFIDENTIAL
Page 38
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
for teduglutide treatment following the procedures set out in the study protocol. All dispensed 
study medication will be documented in the interactive response technology system and/or other 
investigational product record (eg, investigation product accountability form). The investigator is 
responsible for assuring the retrieval of all study supplies from subjects.
All used and unused study drug vials must be returned by the subjects and/or parent/guardian, 
and will be retained at the site. If deemed appropriate, the investigator or his/her designee may 
dispense the unused study drug vials to the same subject. All original containers, whether empty 
or containing study drug will be returned to the pharmacy. Returned study drugs will NOT be 
relabeled or reassigned for use by other subjects. Contents of the study drug containers will not 
be combined. All used and unused vials must be returned to the distribution center according to 
the sponsor’s instruction. No vial/kit may be destroyed on site without approval by the sponsor. 
Please see the Pharmacy Manual for additional information.
6.5
Subject Compliance
Subjects will be instructed to bring their unused investigational product and empty/used 
investigational product packaging to every visit. Drug accountability will be assessed at the 
container/packaging level for unused investigational product that is contained within the original 
tamper-evident sealed container (eg, bottles, trays, vials) or at the individual count level for 
opened containers/packaging. The pharmacist/nominated person will record details on the drug 
accountability form.
Of those subjects eligible for teduglutide treatment, subjects who have received 80% of the 
planned doses administered will be assessed as being compliant with the study protocol.
For non-commercial use only


Shire
CONFIDENTIAL
Page 39
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
7
STUDY PROCEDURES
7.1
Study Schedule
Detailed study procedures and assessments to be performed for subjects throughout the study are 
outlined in the Schedule of Assessments (Table 1-1, Table 1-2, and Table 1-3) and must be 
referred to in conjunction with the instructions provided in this section. 
7.1.1
Screening
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent (and assent, as applicable) 
from the subject. A subject will have approximately 7 days, after completion of the TED-C14-
006 study, to sign consent to participate in the SHP633-304 study. The first visit after screening 
must occur within 12 weeks of screening for a pre-treatment visit, and within 2 to 12 weeks of 
screening for an NTx visit.
The screening visit (Scr) assessments and procedures, beginning with informed consent, will be 
performed as outlined in Table 1-1, and as detailed below:

Informed consent, and informed assent (if applicable), is obtained

Study eligibility is determined. A screen failure is a subject who has given informed 
consent and failed to meet the Study Inclusion Eligibility Criteria. Subjects cannot be 
rescreened once they have been designated as a screen failure. 

Demographics, updates to medical history and SBS history

Intake and output diaries are dispensed

Evaluate teduglutide treatment inclusion criteria 

Adverse events, concomitant medications and concomitant GI procedures
7.1.2
Visits for Subjects Not Receiving Teduglutide
While outside of the 28-week teduglutide-treatment cycle, subjects will be followed 
approximately every 12 weeks for safety and efficacy assessments. No-teduglutide treatment 
visits are numbered sequentially (NT1, NT2, etc.), even if interrupted by the treatment cycles. 
The visit window (±7 days) is relative to the first NTx visit in the current NTT period.
Assessments will be performed as outlined in Table 1-2 and described below.

Intake and output diaries are dispensed

Evaluate teduglutide treatment inclusion criteria

Adverse events, concomitant medications and concomitant GI procedures

Physical examination and vital signs, including weight
For non-commercial use only


Shire
CONFIDENTIAL
Page 40
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017

Height and head circumference

Review intake and output diaries

Record PS prescription and adjust as needed

Safety Laboratory Tests (ie, clinical chemistry, hematology, and urinalysis)

PedsQL Generic Core Scale/PedsQL Family Impact Module/ PedsQL Gastrointestinal 
Symptoms Module Sub-Scales

Antibodies to teduglutide, if and when required

Fecal occult blood testing, as indicated (Section 7.2.9.1)

Colonoscopy/sigmoidoscopy, as indicated (see Section 7.2.9.2)

Serum sample, as indicated
Teduglutide treatment may be considered at any time during the NTT period. If the investigator 
and the subject (and parent or legal guardian, as appropriate) agrees to proceed with treatment if 
the subject is eligible, the subject may proceed to the pre-treatment visit immediately to 
determine eligibility.
7.1.3
Visits for Subjects Receiving Teduglutide
7.1.3.1
Pre-treatment Visit
Subjects who meet at least 1 of the teduglutide treatment inclusion criteria during the screening 
visit or during the NTT period may proceed to the pre-treatment visit immediately if the 
investigator, subject and parent agree to proceed with teduglutide therapy. Similarly, subjects 
who meet escape criteria during the teduglutide follow-up period may proceed to the 
pre-treatment visit immediately.
The pre-treatment visit may also be combined with screening visit, and if the pre-treatment 
visit assessments occur within 7 days of the TED-C14-006 EOS visit (Week 28), both sets of 
assessments can be combined. A subject must have 2 weeks of intake diary data collected, prior 
to the first dose administration (CxD1) during any teduglutide treatment cycle. In general, pre-
treatment assessments may occur over a period of up to 21 days. The teduglutide pre-treatment 
visit (Px) assessments and procedures will be performed as in Table 1-3 and as described below:

Evaluate teduglutide eligibility (treatment inclusion/exclusion criteria) 

Dispense intake and output diaries

Adverse events, concomitant medications and concomitant GI procedures

Fecal occult blood testing 
For non-commercial use only


Shire
CONFIDENTIAL
Page 41
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017

Gastrointestinal-specific testing, including colonoscopy or sigmoidoscopy as indicated

Physical examination and vital signs, including weight

Height and head circumference

Review intake and output diaries

Record PS prescription and adjust as needed.

Safety Laboratory Tests 
(In addition to clinical chemistry, hematology, and urinalysis, labs at this visit include 
prothrombin time [PT] international normalized ratio [INR]. Subsequent prothrombin 
time/international normalized ratio (PT/INR) measurement is only required to evaluate 
for suspected drug-induced liver injury [DILI]). 

Serum pregnancy testing (when the pre-treatment and screening visits are combined, the 
serum pregnancy test should be performed at the local laboratory)

Serum sample 
7.1.3.2
Teduglutide Treatment Period (CxD1-CxW24)
The open-label teduglutide treatment period will comprise 24 weeks, during which all 
assessments and procedures listed for Visits CxD1-CxW24 in Table 1-3 shall be completed. 
Cycles are numbered sequentially, such that the first visit of the first cycle is C1D1, and the first 
visit of the second cycle is C2D1, etc. Visit windows are calculated based upon the date of first 
investigational product administration (Visit CxD1). 
Visit CxD1
Assessments and procedures at this visit will be performed as outlined Table 1-3 and as 
described below. 
Two weeks of intake diary data are required before drug is administered at CxD1.

Confirm teduglutide treatment eligibility

Dispense intake and output diaries

Adverse events, concomitant medications and concomitant GI procedures

Physical examination and vital signs, including weight 

Height and head circumference

Review intake and output diaries

Record PS prescription and adjust as needed 
For non-commercial use only


Shire
CONFIDENTIAL
Page 42
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017

Safety laboratory tests

Quality of life measurements 

Antibodies to teduglutide

Pregnancy testing (urine)

Dispense study drug
Site Visits during Teduglutide Treatment Period
Subjects will return for clinic visits on cycle weeks 1, 2, 4, 6, 9, 12, 16, 20, and 24/EOT. 
Assessments and procedures at these visits will be performed as outlined in Table 1-3 and as 
described below:

Dispense/review intake and output diaries (every effort should be made to complete 
2 weeks of intake diary entries prior to each clinic visit and to complete 48 hours of 
output diary entries during a period of nutritional stability prior to each clinic visit)

Physical examination and vital signs, including weight

Record PS prescription and adjust as needed

Safety laboratory tests 

Urine pregnancy testing for FOCBP (CxW4, CxW9, CxW12, CxW16, CxW20, CxW24)

Study drug dispensation (except for CxW24)

Adverse events, concomitant medications and concomitant GI procedures
In addition, at CxW12 and CxW24 Visits ONLY, the following procedures will be performed:

Height and head circumference

Antibodies to teduglutide

Fecal occult blood testing (FOBT)

GI-specific testing, including colonoscopy or sigmoidoscopy as indicated 

Quality of life measurements 
At CxW24 ONLY, a serum sample is collected and stored for future analysis. This sample will 
not be used for genetic testing and lack of collection will not constitute a protocol deviation.
For non-commercial use only


Shire
CONFIDENTIAL
Page 43
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
PHONE VISITS 
Phone visits are required approximately 1 week after adjustments in PS during the teduglutide 
treatment period. Phone visit assessments and procedures are outlined in Table 1-3 and described 
below:

Review intake and output diaries

Safety laboratory tests (clinical chemistry and urinalysis)

Record PS prescription and adjust as needed

Obtain AEs, concomitant medications, and concomitant GI procedures  

Evaluate escape criteria
7.1.4
Teduglutide Follow-up Period
The safety follow-up period for this protocol is 4 weeks (Weeks 25 – 28 of the cycle). Phone 
visits will occur on cycle weeks 25, 26, and 27 for all subjects. Phone visit assessments and 
procedures at weeks 25-27 will be the same as for telephone visits performed during the 
teduglutide treatment period. In addition, subjects will be evaluated for follow-up period escape 
criteria. If escape criteria are met at any time during the follow-up period, the subject may 
proceed directly to another pre-treatment visit at the investigator’s discretion. The investigator 
may combine the CxW28 visit with the next pre-treatment visit if at least one escape criterion is 
met at the CxW28 visit, and the pre-treatment assessments occur within 7 days of the CxW28 
visit. If a subject is completing the study at the CxW28 visit, the EOS/ET visit (Section 7.1.5)
will take place in lieu of the CxW28 visit. Otherwise, following completion of the 28-week 
treatment cycle, the subject will proceed to an NTT visit within approximately 12 weeks.
At cycle week 28 (CxW28), subjects will return to the study site. In addition to the assessments 
performed at weeks 25-27, the following procedures will be performed at CxW28 ONLY:

Dispense intake and output diaries 

Physical examination and vital signs, including weight

Antibodies to teduglutide

Pregnancy testing (urine)

Evaluate escape criteria
7.1.5
Study Completion/Early Termination Visit (EOS/ET Visit) 
All subjects will return to the study site for the end of study/early termination visit (EOS/ET). 
Assessments and procedures at this visit will be performed as outlined in Table 1-1 and as 
described here. If a subject discontinues the study prematurely, the assessments for the EOS/ET 
Visit are to be performed as completely as possible (see Section 4.8.2).
For non-commercial use only


Shire
CONFIDENTIAL
Page 44
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017

Adverse events, concomitant medications and concomitant GI procedures  

Physical examination and vital signs, including weight

Height and head circumference

Review intake and output diaries (the intake diary should be completed daily for a 
minimum of 2 weeks prior to the EOS/ET visit. The output diary should be completed 
daily over a 48-hour period of nutritional stability before the EOS/ET visit)

Record PS prescription and adjust as needed

Safety laboratory tests 

Fecal occult blood testing, as indicated

Gastrointestinal-specific testing, including colonoscopy or sigmoidoscopy as indicated. 

Quality of life measurements 

Antibodies to teduglutide

Pregnancy testing, as needed
7.2
Study Evaluations and Procedures
7.2.1
Demographics, Medical History, and SBS History
Demographics, medical history, and SBS history will be obtained at screening. Medical history 
for purposes of this extension study will consist of the following:

Adverse events that were ongoing at the time of completion of TED-C14-006

Events that occurred during the period between completion of TED-C14-006 and 
informed consent to SHP-633-304 
This medical history information will supplement the medical history information collected at 
the start of the TED-C14-006 core study. If the subject has any changes to the SBS history 
collected at the baseline visit of the TED-C14-006 study, that information (updated SBS history) 
will be collected.
7.2.2
Physical Examination
Physical examinations will be performed according to the study schedules. Any new clinically 
significant findings noted during physical examinations should be recorded on the appropriate 
AE page of the eCRF. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 45
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
7.2.3
Vital Signs, Body Weight, Height, Head Circumference and Body Mass 
Index (BMI)
Vital signs will be measured according to the study schedules. Measurements will include 
systolic and diastolic blood pressure (mmHg), pulse (beats per minute), and body temperature 
(°C/°F). Blood pressure should be determined by cuff (using the same method, the same arm, 
and in the same position throughout the study).
Body weight will also be recorded in the eCRF; subjects should be weighed on the same scale at 
each study visit. Height (or length) and head circumference (for subjects ≤36 months of age) will 
be measured at selected visits. A height z-score, weight z-score, BMI, and BMI z-score will be 
calculated by the sponsor using the site-provided height and weight data collected at each site 
visit
New clinically significant vital sign abnormalities should be recorded on the appropriate AE 
page of the eCRF.
7.2.4
Clinical Laboratory Tests
Safety laboratory tests to be performed at site visits consist of clinical chemistry, hematology, 
and urinalysis and will be performed as outlined in the study plan (Table 1-1, Table 1-2, and 
Table 1-3) Scheduled laboratory testing will be processed by a central lab. All laboratory assays 
will be performed according to the central laboratory’s normal procedures. Reference ranges are 
to be supplied by the laboratory. The investigator should assess out-of-range clinical laboratory 
values for clinical significance, indicating if the value(s) is/are not clinically significant or 
clinically significant. Abnormal clinical laboratory values, which are unexpected or not 
explained by the subject’s clinical condition, may, at the discretion of the investigator or sponsor, 
be repeated as soon as possible until confirmed, explained, or resolved. 
During the teduglutide treatment period, subjects will also have safety labs within approximately 
5-7 days after a PS adjustment. Safety labs performed after PS adjustment and between site visits 
will consist of clinical chemistry and urinalysis and may be processed by the central laboratory 
or a local laboratory. Local lab results are not required to be entered in the eCRFs; however, if 
the local lab results indicate any new clinically significant changes, they must be reported as an 
adverse event (see Section 8.1). Urine specimen collection should be attempted as part of the 
safety labs, but lack of urinalysis will not constitute a protocol deviation.
New clinically significant labs should be reported as AEs.
The following clinical laboratory assessments will be performed according to the study 
schedules: 
For non-commercial use only


Shire
CONFIDENTIAL
Page 46
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
Table 7-1: List of Laboratory Tests 
Hematology:

Hematocrit 

Hemoglobin 

Platelet count

Red blood cell count 

Red blood cell morphology, if needed

White blood cell count with differential
Coagulation:
Prothrombin time/International normalized ratio
Urinalysis: 

Blood

Glucose

Leukocytes

Microscopic analysis

pH 

Protein

Specific gravity
Pregnancy tests (females of childbearing potential):
o
Serum β-HCG (screening)
o
Urine β-HCG (all other visits)
Biochemistry:

Albumin 

Alkaline phosphatase 

Alanine aminotransferase 

Amylase

Aspartate aminotransferase 

Bicarbonate

Bilirubin (total and indirect)

Blood urea nitrogen 

Calcium (total)

Chloride

Cholesterol

C-reactive protein 

Creatinine

Estimated Glomerular Filtration Rate
(Schwartz formula)

Gamma-glutamyl transferase 

Glucose

Lipase

Magnesium

Phosphorus

Potassium 

Sodium 

Triglycerides

Uric acid
7.2.5
Serum Sampling
Serum samples will be collected and stored for future analysis at the following times: 

At the pre-treatment visit. If the subject met a follow-up period escape criterion, the 
serum sample will not be collected at the pre-treatment visit

At the CxW24 (EOT) visit

During NTT: Approximately every 24 weeks
The serum sample will not be used for genetic testing. Lack of collection will not constitute a 
protocol deviation.
The sponsor, sponsor’s representatives, biorepositories, and any specialty laboratories will be 
blinded to the subject’s identity. The sample and/or extracted material will otherwise be stored 
for up to 15 years from the end of the study after which time it will be destroyed. Upon written 
request, subjects will be permitted to withdraw their sample from the analysis and have their 
For non-commercial use only


Shire
CONFIDENTIAL
Page 47
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
sample and/or extracted material destroyed. Any results already generated from the samples will 
not be removed from any analyses that have already been performed.
7.2.6
Pregnancy Testing
A serum pregnancy test is performed on all FOCBP at the teduglutide pre-treatment visit (when 
the pre-treatment and screening visits are combined, the serum pregnancy test should be 
performed at the local laboratory). Urine pregnancy tests will be administered at all other visits 
according to the study schedules, or if pregnancy is suspected, or as specified per protocol upon 
withdrawal of the subject from the study.
7.2.7
Antibody Testing
Blood samples will be drawn for the analysis of antibodies to teduglutide according to the 
Schedule of Assessments (Table 1-1, Table 1-2, and Table 1-3). Blood samples for antibodies 
may be drawn from a central line or from peripheral access. The sample drawn on CxD1 must be 
drawn prior to administration of the first dose of teduglutide. Once the subject has started 
teduglutide treatment, samples must be drawn at least 14 hours after dosing. Subjects who test 
positive for antibodies to teduglutide will also be tested for neutralizing antibody. Subjects who 
have been previously treated with teduglutide, and who test positive for antibodies to 
teduglutide, will have follow-up blood draws for antibodies to teduglutide every 12 weeks while 
on study until a negative result is obtained.
7.2.8
Volume of Blood
Efforts will be made to minimize the amount of blood drawn from all pediatric subjects enrolled 
in this study. The volumes of blood to be drawn from each subject will vary depending on 
clinical status. Approximate volumes of blood to be drawn from each subject annually are shown 
in Table 7-2.
Table 7-2: Approximate Volume of Blood to be Drawn from Each Subject Annually 
Assessment
Sample 
Volume (mL)
No. Samples per two 28-week 
Teduglutide Cycles
Total 
Volume (mL)
Subjects Receiving Teduglutide Treatment 
Safety
Biochemistry and -hCGa
2.5
24
60
Hematology
2
24
48
Coagulation Parameters
1
2
2
Antibodies
2
8
16
Serum storage samples
3
4
12
Total mL per 2, 28-week Treatment Cycles (Approximate Annual Volume):
138
Subjects Not Receiving Teduglutide Treatmentb
Assessment
Sample 
Volume (mL)
No. Samples per 4 NTT Visits
Total 
Volume (mL)
Safety
Biochemistry
2.5
4
10
Hematology
2
4
8
Serum storage samples
3
2
6
Total mL per 4 “No-Teduglutide Treatment” Visits 48-week period:
24
Abbreviations: β-hCG=beta-human chorionic gonadotropin; NTT=no-teduglutide treatment
a β-hCG testing will only be administered to females who are eligible for teduglutide treatment.
For non-commercial use only


Shire
CONFIDENTIAL
Page 48
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
Table 7-2: Approximate Volume of Blood to be Drawn from Each Subject Annually 
Assessment
Sample 
Volume (mL)
No. Samples per two 28-week 
Teduglutide Cycles
Total 
Volume (mL)
b Subjects not receiving teduglutide treatment, but who were exposed to it previously and tested positive for anti-teduglutide 
antibodies will require blood samples for antibody testing every 12 weeks until they test negative.
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment. When more than 1 blood assessment is to be done at the time 
point/period, if they require the same type of tube, the assessments should be combined. Blood 
volume estimates do not include safety labs performed after PS adjustment, and anti-teduglutide 
antibody testing during no-teduglutide treatment.
7.2.9
Gastrointestinal-specific Testing
7.2.9.1
Fecal Occult Blood Testing
Fecal occult blood testing must be performed on all subjects at the pre-treatment visit, week 12, 
and week 24 of the teduglutide cycle. During NTT periods, FOBT must be performed on 
teduglutide-exposed subjects (subjects who have received teduglutide any time in the past and 
are therefore not teduglutide-naïve) on a roughly annual basis (approximately every 48-60 
weeks). Actions to be taken in response to a positive FOBT are described below.
7.2.9.2
Colonoscopy or Sigmoidoscopy
Teduglutide-naïve subjects age 12 and older will undergo colonoscopy or sigmoidoscopy at the 
pre-treatment visit if one has not been performed within 1 year. 
Subjects of any age with newly positive FOBT results at the pre-treatment visit for which a 
readily detectable cause cannot be identified (eg, anal fissure) will undergo a colonoscopy or 
sigmoidoscopy prior to receiving teduglutide. If newly positive FOBT results (for which a 
readily detectable cause cannot be identified) are obtained at the end of a teduglutide treatment 
cycle (CxW24/EOT), colonoscopy or sigmoidoscopy will be performed. The need for 
colonoscopy or sigmoidoscopy in response to positive FOBTs at any other point during the 
study, or to re-evaluate persistently positive FOBTs is at the discretion of the investigator. 
Teduglutide-exposed subjects who have received the equivalent of 2 treatment cycles (48 weeks 
of study drug exposure) will undergo colonoscopy or sigmoidoscopy. While receiving additional 
teduglutide treatment, subjects will undergo colonoscopy or sigmoidoscopy at 5 year intervals or 
more often as needed. 
Upper endoscopy may be performed along with any colonoscopy or sigmoidoscopy at the 
investigator’s discretion. If a polyp is found, adherence to current polyp follow-up guidelines is 
recommended. Subjects with unresected GI polyps, polyposis conditions, pre-malignant change 
or malignancy in the GI tract will be excluded from teduglutide treatment.
7.2.10
Nutritional Support
Nutritional support includes PS, enteral nutrition, and other food and fluids. Advances in enteral 
nutrition and/or reductions to PS will be based on clinical status, including weight, linear growth, 
hydration status, and safety laboratory results. Intake and output diaries will include data to be 
For non-commercial use only


Shire
CONFIDENTIAL
Page 49
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
considered in the adjustment of each subject’s nutritional support. Guidelines for nutritional 
support management and weaning algorithms are provided in Appendix 2.
7.2.11
Diaries
7.2.11.1
Study Drug Administration Diary
A study drug administration diary will record administration of teduglutide. This diary should be 
completed by the subject (or parent/legal guardian, as applicable) daily during the teduglutide 
treatment period (between visits CxD1 and CxW24).
7.2.11.2
Intake Diary
Intake diaries will be used to collect and evaluate each subject’s nutritional support. The 
subject/parent/guardian will complete the appropriate fields of the PS section of the intake diary 
2 weeks prior to ALL scheduled site visits (except at pre-treatment visit). During the 24-week 
teduglutide treatment period, the intake diary will also be completed for 1 week following PS 
adjustments. The intake diary will also be completed daily during the 4-week follow-up period. 
The following data will be captured in the intake diaries:

Parenteral support volume and infusion duration

Site personnel will determine the actual PS daily calories based on diary entries.
All available diary data will be reviewed by the investigator or their designee at each clinic and 
telephone visit to assess clinical status and opportunity for PS reduction and advance in feeds.
7.2.11.3
Output Diary
Urine and stool output should be recorded in the output diary over a 48-hour period of nutritional 
stability before every clinic visit; in addition, output should be recorded for subjects that are in a 
teduglutide treatment cycle within 1 week of implementing a change in the PS prescription, 
regardless of previous teduglutide exposure.
Urine data:

Toilet-trained subjects (who do not wear diapers)
Measure and record all urine output in mL or cc

Nontoilet-trained subjects (who wear diapers)
Measure and record the weight of all urine-only diapers. Urine volume will be calculated 
using the following formula: 1 g (scale weight) = 1 mL or 1 cc

At the discretion of the investigator, the parent may be asked to collect the first void after 
the daily PS infusion to measure specific gravity
Stool data (includes diapers with mixed urine and stool):

Toilet-trained subjects (who do not wear diapers)
Record the occurrence of each bowel movement and score the stool consistency using the 
Bristol Stool Form Scale (see Output diary)
For non-commercial use only


Shire
CONFIDENTIAL
Page 50
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017

Nontoilet-trained subjects (who wear diapers)
Record the weight of diapers containing stool (including diapers with mixed urine and 
stool) as stool output and score the stool consistency using the Bristol Stool Form Scale 
(see Output diary). Stool volume will be calculated using the formula: 1 g (scale weight)
= 1 mL or 1 cc
All ostomy output volume should be recorded. Ostomy output will not be scored using the 
Bristol scale.
All available diary data will be reviewed by the investigator or their designee at each clinic and 
telephone visit to assess clinical status and opportunity for PS reduction and advance in feeds.
7.2.12
Health-related Quality of Life Assessments
Throughout the study, health-related quality of life assessments will be performed using the 
PedsQL Generic Core Scales. Each PedsQL age-appropriate form takes less than 4 minutes to 
complete. The scales include self-reports for pediatric subjects and adolescents aged 5 to 
18 years and proxy-reports from parents of pediatric subjects aged 2 to 18 years. 
Field trials have shown that the internal consistency reliability of the PedsQL was excellent, with 
alphas for the generic core scales in both self- and proxy-report greater than the 0.70 standard, 
and alphas for the full 23-item scale approaching 0.90 for self- and proxy-report. Missing data 
were minimal. Item response distributions were across the full scale range, with no floor effects, 
and minimal ceiling effects. 
The validity of the PedsQL Generic Core Scales was demonstrated through known group 
comparisons, and correlations with other measures of disease burden. The PedsQL self- and 
proxy-report distinguished between pediatric subjects with and without a chronic health 
condition, and within the group of pediatric subjects with a chronic condition, between those 
who did or did not have an overnight hospital visit in the last 12 months. Further, both child self-
report and parent proxy-report correlated significantly with the number of days the child was too 
ill to pursue normal activities, needed someone to care for him or her, missed school in the last 
month, the number of days the parent missed from work in the last month, and parent-report of 
problems pursuing their normal work routine and concentrating at work. The PedsQL Generic 
Core Scales are also responsive to clinical change, as demonstrated in field trials.
7.2.12.1
Pediatric Quality of Life Generic Core Scale (PedsQL™), Acute version
The PedsQL Generic Core Scale is designed to measures health-related quality of life (HRQoL) 
in pediatric subjects and adolescents (2-18 years of age). The developmentally appropriate 
PedsQL Generic Core Scale will be completed by either the parent or legal guardian and subject 
as indicated in Table 7-3 at the time points as outlined in Table 1-1, Table 1-2, and Table 1-3.
Table 7-3: Developmentally Appropriate PedsQL™Generic Core Scales
Report
Completed by
Parent Report for Toddlers (ages 2-4)
Parent or Legal Guardian
Child Self Report and Parent Proxy-Report for Young Pediatric subjects 
(ages 5-7)
Subject and Parent or Legal Guardian
For non-commercial use only


Shire
CONFIDENTIAL
Page 51
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
Table 7-3: Developmentally Appropriate PedsQL™Generic Core Scales
Report
Completed by
Child Self Report and Parent Proxy-Report for Pediatric subjects 
(ages 8-12)
Subject and Parent or Legal Guardian
Child Self Report and Parent Proxy-Report for Teens (ages 13-18)a
Subject and Parent or Legal Guardian
Abbreviations: PedsQL=Pediatric Quality of Life Inventory
a The Child Self Report and Parent Proxy-Report for Teens (ages 13-18) will also be completed for subjects older 
than 18 years of age
The Parent Report for Toddlers (ages 2-4) of the PedsQL Generic Core Scale is composed of 
21 items comprising 4 dimensions as follows: 1) Physical Functioning (8 items), 2) Emotional 
Functioning (5 items), 3) Social Functioning (5 items), 4) School Functioning (3 items). 
The Child and Parent Reports of the PedsQL Generic Core Scale for Young Pediatric subjects 
(ages 5-7), Pediatric subjects (ages 8-12), and Teens (ages 13-18) are composed of 23 items 
comprising 4 dimensions as follows: 1) Physical Functioning (8 items), 2) Emotional 
Functioning (5 items), 3) Social Functioning (5 items), 4) School Functioning (5 items).
7.2.12.2
Pediatric Quality of Life Family Impact Module (PedsQL™), Acute 
version
The PedsQL Family Impact Module is a parent-report multidimensional instrument that will be 
completed by the parent or legal guardian, as outlined in Table 1-1, Table 1-2, and Table 1-3.
The PedsQL Family Impact Module is a specific module of the PedsQL that is used to measure 
the impact of pediatric chronic health conditions on parents and the family (Varni et al., 2004). 
The 36-item PedsQL Family Impact Module consists of 6 scales measuring parent self-reported 
functioning as follows: 1) Physical Functioning (6 items), 2) Emotional Functioning (5 items), 
3) Social Functioning (4 items), 4) Cognitive Functioning (5 items; worries about treatment and 
disease), 5) Communication (3 items), 6) Worry (5 items). Two additional scales measure parent-
reported family functioning as follows: 1) Daily Activities (3 items), and 2) Family Relationships 
(5 items). The PedsQL Family Impact Module should take the parent or legal guardian 
approximately 5 to 10 minutes to complete.
7.2.12.3
PedsQL Gastrointestinal Symptoms Module (PedsQL™), Acute version
The PedsQL Gastrointestinal Symptom Module is a disease-specific 58-item module, comprised 
of 10 different symptom scales that assess gastrointestinal symptom-related quality of life: food 
and drink limits, trouble swallowing, heartburn and reflux, nausea and vomiting, gas and 
bloating, constipation, blood in poop, and diarrhea. The PedsQL Gastrointestinal Symptoms 
Module was designed to allow the selection and scoring of individual scales from the Module. 
The scales of Food and Drink Limits (6 items) and Diarrhea (7 items) were identified as 
clinically relevant and appropriate for the symptoms experienced in this pediatric study 
population, and therefore, are the only scales used in this study. The scales will be completed by 
either the parent or legal guardian and subject as indicated in Table 7-3 at the time points 
outlined in Table 1-1, Table 1-2, and Table 1-3.
For non-commercial use only


Shire
CONFIDENTIAL
Page 52
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.4. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, 
then each symptom should be listed individually. All AEs should be captured on the appropriate 
AE pages in the eCRF and in source documents. In addition to untoward AEs, unexpected 
benefits outside the investigational product indication should also be captured on the AE eCRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
For non-commercial use only


Shire
CONFIDENTIAL
Page 53
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
In consideration of whether a treatment-emergent adverse event (TEAE) might lead to dose 
interruption (Section 8.4.1) or early termination of the study (Section 8.5), severe TEAEs will 
also be graded according to the National Cancer Institute’s (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) severity grading criteria (US Department of Health and Human 
Services et al., 2010).
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of 
the investigational product is compelling and/or follows a known or 
suspected response pattern to that product, and the event cannot be 
explained by the subject’s medical condition, other therapies, or 
accident.
Not Related
The event can be readily explained by other factors such as the 
subject’s underlying medical condition, concomitant therapy, or 
accident and no plausible temporal or biologic relationship exists 
between the investigational product and the event.
AEs that are related to study drug that are not resolved at EOT will be followed until the event 
resolves or stabilizes, as judged by the investigator.
Laboratory values, vital signs, and clinical findings at the scheduled physical examinations must 
be reported as AEs if the investigator considers the finding to be a clinically significant change 
from the baseline. 
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study in the eCRF. Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved with Sequelae 
For non-commercial use only


Shire
CONFIDENTIAL
Page 54
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017

Recovering/Resolving

Unknown
8.1.4
Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE.
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory or vital sign can represent an AE if the change is 
clinically relevant or if, during the study, a shift of a parameter is observed from a normal value 
to an abnormal value, or a further worsening of an already abnormal value. When evaluating 
such changes, the extent of deviation from the reference range, the duration until return to the 
reference range, either while continuing treatment or after the end of treatment with the 
investigational product, and the range of variation of the respective parameter within its 
reference range, must be taken into consideration.
If, during the study, there are abnormal clinical laboratory values or vital signs which were not 
present at the beginning of the study, further investigations should be performed until the values 
return to within the reference range or until a plausible explanation (eg, concomitant disease) is 
found for the abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory or vital sign is clinically significant and 
therefore represents an AE.
8.1.6
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.4.
Any report of pregnancy for any female study participant must be reported within 24 hours to the 
Shire Global Drug Safety Department using the Shire Investigational and Marketed Products 
Pregnancy Report Form. A copy of the Shire Investigational and Marketed Products Pregnancy 
Report Form (and any applicable follow-up reports) must also be sent to the Shire Medical 
Monitor using the details specified in the emergency contact information section of the protocol. 
In the event a subject becomes pregnant during the study, teduglutide administration must be 
discontinued immediately. 
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days post partum.
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Study Adverse Event Form 
for Serious Adverse Events (SAEs) and Non-serious AEs as Required by the Protocol. Note: An 
elective abortion is not considered an SAE.
For non-commercial use only


Shire
CONFIDENTIAL
Page 55
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Adverse Event Form for SAEs and 
Non-serious AEs as Required by the Protocol as well as the Shire Investigational and Marketed 
Products Pregnancy Report Form. The test date of the first positive serum/urine -HCG test or 
will determine the pregnancy onset date.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) 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 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for 
a non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner 
that may be detrimental to the individual and/or society.

Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol).

Overdose – Administration of a dose greater than the allocated dose of the study 
medication or at a frequency greater than the dosing interval specified by the protocol.

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product. For studies, medication errors are reportable to the sponsor 
only as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error. 
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally-authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator brochure which the sponsor 
has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Drug Safety Department and the Shire Medical Monitor within 24 hours of the first awareness of 
For non-commercial use only


Shire
CONFIDENTIAL
Page 56
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
the event. Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, 
misuse, overdose, or medication errors (see Section 8.1.7) unless they result in an SAE.
All Adverse Events of Special Interest, as defined in Section 8.3, must be reported by the 
investigator to the Shire Global Drug Safety Department and the Shire Medical Monitor within 
24 hours of the first awareness of the event even if the event does not fulfill seriousness criterion.
The investigator must complete, sign, and date the Shire Clinical Study Adverse Event Form for 
SAEs and Non-serious AEs as Required by Protocol, and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested). Fax or e-mail the completed form to the Shire Global Drug Safety 
Department. A copy of the completed Shire Clinical Study Adverse Event Form for Serious 
Adverse Events (SAEs) and Non-serious AEs as Required by Protocol (and any applicable 
follow-up reports) must also be sent to the Shire medical monitor or designee using the details 
specified in the emergency contact information section of the protocol.
8.2.3
Serious Adverse Event Definition
A SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose: 

Results in death

Is life-threatening. Note: The term 'life-threatening' in the definition of "serious" refers to 
an event in which the subject was at risk of death at the time of the event; it does not refer 
to an event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
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).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: 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 subject and may 
require medical or surgical intervention to prevent 1 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; or the development of drug dependency or 
drug abuse. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 57
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.4, and must be reported 
to the Shire Global Drug Safety Department and the Shire Medical Monitor within 24 hours of 
the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Drug Safety Department within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death.
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting 
The Sponsor and/or Clinical Contract Research Organization (CRO) is responsible for notifying 
the relevant regulatory authorities, and US central Institutional Review Boards (IRBs)/EU central 
ethics committees (ECs), of related, unexpected SAEs.
In addition, the Clinical CRO is responsible for notifying active sites of all related, unexpected 
SAEs occurring during all interventional studies across the SHP633 program.
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
8.3
Adverse Events of Special Interest
An AE of special interest is an AE (serious or nonserious) of scientific and medical concern 
specific to the sponsor’s product or program and for which ongoing monitoring and immediate 
notification by the investigator to the sponsor is required.
For non-commercial use only


Shire
CONFIDENTIAL
Page 58
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
The AEs of special interest that require expedited regulatory reporting include the following:

Growth of pre-existing polyps of the colon

Benign neoplasia of the GI tract including the hepatobiliary system

Tumor-promoting ability (eg, benign and/or malignant neoplasia of any kind, not limited 
to those of the GI or hepatobiliary system)
For AEs of special interest, the sponsor must be informed within 24 hours of first awareness as 
per the SAE notification instructions described in Section 8.2.2 even if the event does not fulfill 
the seriousness criteria.
8.4
Dose Interruption of Individual Subjects
The investigator is responsible for contacting the sponsor/designee when the subject’s 
teduglutide dosing regimen is interrupted. Attempts should be made to contact the 
sponsor/designee prior to dose interruption. Reasons for dosage interruptions may include but are 
not limited to hospitalization, AEs, a lapse in investigational product delivery, etc.
Study drug must be discontinued if any of the following events occur:

Pregnancy

Severe hypersensitivity, such as anaphylaxis determined by the investigator to be related 
to study drug. This does not include the presence of anti-teduglutide antibodies, mild 
injection site reactions or mild symptoms that according to the investigator do not pose a 
significant risk to the subject.

An AE that is of NCI CTCAE severity Grade 3 or 4 and considered to be related to study 
drug administration

Confirmed drug-induced liver injury (DILI) related to teduglutide (see Section 8.4.2)
8.4.1
Dose Interruption Criteria Based on Adverse Event Severity and 
Relationship to Investigational Product
The investigational product must be discontinued if the subject experienced an AE that is of 
severity ≥Grade 3 per the NCI CTCAE and is reported as related to the investigational product. 
In consideration of whether a TEAE might lead to dose interruption, severe TEAEs will also be 
graded according to the NCI CTCAE severity grading criteria (US Department of Health and 
Human Services et al., 2010). All such TEAEs should be discussed with the Shire Medical 
Monitor or designee as soon as possible. The length of the dose interruption, and whether 
teduglutide administration resumes or is permanently discontinued, depends on the clinical 
situation.
For non-commercial use only


Shire
CONFIDENTIAL
Page 59
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
8.4.2
Dose Interruption Criteria Based on Drug-Induced Liver Injury
Teduglutide administration for an individual subject may need to be interrupted if the subject has 
clinical and laboratory evidence of potential DILI, in the absence of an alternative explanation, 
as identified by the following criteria:

ALT or AST >8x ULN

ALT or AST >5x ULN and >2x baseline value for more than 2 weeks

(ALT or AST >3x ULN and >2x baseline value) and (total bilirubin >2x ULN or 
INR>1.5)

ALT or AST >3x ULN and >2x baseline value with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
All laboratory values suggestive of potentially new DILI should be repeated and verified within 
3 days. International normalized ratio should be measured with this set of verification laboratory 
assessments and an inquiry should be made as to the presence of clinical symptoms consistent 
with new liver injury. The subject should be followed closely to determine the trajectory of the 
laboratory abnormalities and to evaluate the cause of liver injury. This evaluation may include, 
as clinically indicated, consideration of sepsis, acute viral hepatitis (eg, hepatitis A 
immunoglobulin [IgM], hepatitis B surface antigen, hepatitis C antibodies, cytomegalovirus IgM, 
Epstein-Barr virus antibody panel), hepatobiliary obstruction (ultrasound), autoimmune hepatitis 
(anti-nuclear, anti-smooth muscle, anti-actin, or anti-liver kidney microsomal antibodies), 
intestinal failure associated liver disease, cardiovascular causes such as ischemic hepatitis, and 
concomitant hepatotoxic treatments.
Additional evaluations may be performed at the discretion of the investigator in consultation 
with the Shire medical monitor.
Teduglutide administration must be permanently discontinued if DILI is confirmed and deemed 
related to study drug.
8.5
Early Termination of the Clinical Study
The DMC may recommend stopping the study if any of the following conditions are met:

≥2 subjects develop the same event of CTCAE severity Grade 3 that is reported as related 
to the investigational product
or

1 subject develops an event of CTCAE severity Grade 4 that is reported as related to the 
investigational product.
For non-commercial use only


Shire
CONFIDENTIAL
Page 60
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
9
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
in the eCRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered in the eCRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. Unscheduled safety follow up assessments (including visits 
conducted after EOS) are not to be collected unless requested.
9.2
Clinical Data Management 
Data are to be entered into a clinical database as specified in the CRO’s data management 
process. Quality control and data validation procedures are applied to ensure the validity and 
accuracy of the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Statistical Analysis Process 
The study will be analyzed by the sponsor or its agent. All statistical analyses will be performed 
using SAS® (SAS Institute, Cary, NC, USA) version 9.3 or higher.
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. 
9.4
Planned Interim Analysis, and Data Monitoring Committee 
An interim analysis is planned when 6 months of safety data have been collected. 
A DMC will be involved in the management of this study. The DMC members will review the 
data approximately every 3 months according to the DMC Charter. The DMC review will 
include all cumulative safety data (ie, AEs, laboratory assessments, physical examinations, etc.) 
from study assessments through each cutoff period. Further details regarding the DMC can be 
found in the DMC charter, which will be available prior to the administration of investigational 
product. 
The DMC for this study will be conducted in accordance with the FDA Guidance for Clinical 
Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees 
(March 2006).
The DMC will be an external, independent board comprised of physicians with relevant training. 
The DMC will be restricted to individuals free of significant conflicts of interest, including, but 
For non-commercial use only


Shire
CONFIDENTIAL
Page 61
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
not limited to, financial, scientific, or regulatory in nature. The DMC will be governed by a 
Charter agreed to by members of the Board and the sponsor. Members of the Board may not be 
study investigators or be employed at the same institution as a study investigator, individuals 
employed by the sponsor, independent contractors hired by the sponsor, or members of 
regulatory agencies. The DMC may make recommendations to the sponsor regarding study 
aspects including stopping, modifying or continuing the study; however, the sponsor will have 
the final responsibility to determine whether the study should be modified or temporarily or 
permanently stopped. 
9.5
Sample Size Calculation and Power Considerations 
The number of subjects in this study is not based on statistical power considerations as this is an 
extension study of the core study, TED-C14-006. The maximum number of subjects was
determined by the enrollment in TED-C14-006.
9.6
Study Population
The safety population includes all enrolled subjects in the study. Safety population will be used 
for both safety and efficacy analyses.
9.7
Efficacy Analyses 
No claims of statistical significance will be made; however, 95% confidence intervals will be 
provided, if applicable. Continuous variables, including those assessed on a discrete scale, will 
be summarized using descriptive statistics including number of subjects, mean, median, standard 
deviation, maximum, and minimum. For categorical variables, statistical summaries will include 
number of subjects and percentages.
9.7.1
Efficacy Endpoints
Efficacy endpoints will be analyzed at the end of each teduglutide treatment period (Week 24 or 
EOT), and at each study visit, relative to the baseline of the core study (TED-C14-006) and/or 
first exposure to teduglutide. The following efficacy endpoints will be analyzed:

Reduction in PS volume of at least 20%

Absolute and relative change in PS volume

Complete weaning off PS

Change in days per week of PS
9.8
Safety Analyses 
9.8.1
Safety Endpoints
The following safety endpoints will be analyzed:

Adverse events

Vital signs, including temperature, heart rate, and blood pressure
For non-commercial use only


Shire
CONFIDENTIAL
Page 62
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017

Laboratory safety data (ie, clinical chemistry, hematology, and urinalysis)

Urine output

Stool output 

Antibodies to teduglutide

Gastrointestinal-specific testing , including fecal occult blood testing and colonoscopy or 
sigmoidoscopy

Z-scores for weight, height (or length), head circumference (up to 36 months of age), and 
body mass index
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The number of events, incidence, and percentage of AEs will be calculated overall, 
by System Organ Class (SOC) and by preferred term. SAEs will be further summarized by 
severity and relationship to investigational product. Adverse events related to investigational 
product, AEs leading to withdrawal, SAEs, and deaths will be similarly summarized/listed.
Prior and concomitant medications will be coded using the World Health Organization-Drug 
Dictionary (WHO-DD) with regard to drug class and drug name. The number and percentage of 
subjects with specific prior medications will be summarized. Medical history (including 
surgical/procedural history) will be coded using MedDRA. The number and percentage of 
subjects with specific histories will be summarized by system organ class and preferred term. 
For clinical laboratory tests, vital signs, body weight, and fluid balance variables, descriptive 
statistics (mean, median, standard deviation, minimum and maximum values, the number and 
percentage of subjects in specified categories) will be calculated to summarize the observed 
values and change from baseline at each scheduled visit.
The number and percentage of subjects classified as having positive or neutralizing antibodies to 
teduglutide will be used to summarize the presence of antibodies. 
Additional safety parameters and measures will include change in body weight, height (or 
length) and head circumference (up to 36 months of age). Derived variables will include height 
z-score, weight z-score, BMI, and BMI z-score. Descriptive statistics (mean, median, standard 
deviation, minimum and maximum values, the number and percentage of subjects in specified 
categories) will be calculated to summarize the absolute values and change from baseline at each 
scheduled visit.
9.9
Other Analyses
9.9.1
Health-related Quality of Life Analyses 
Health economics and outcomes research endpoints will be analyzed at approximately 12-week 
intervals (Weeks 12 and 24 of each teduglutide treatment cycle, and every 12 weeks for subjects 
not on teduglutide), relative to the study baseline. The beginning of each treatment cycle (CxD1) 
will be an additional baseline.

Change in Pediatric Quality of Life Inventory (PedsQL) score
For non-commercial use only


Shire
CONFIDENTIAL
Page 63
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017

Change in PedsQL Family Impact Module score

Change in PedsQL Gastrointestinal Symptoms Module Sub-Scales scores: 

Food and Drink Limits

Diarrhea 
For non-commercial use only


Shire
CONFIDENTIAL
Page 64
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
10
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements. 
The name and address of each third party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996), EU 
Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study. An insurance certificate is supplied to the CRO as necessary. 
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.4
Submission of Summary of Clinical Study Report (CSR) to Competent 
Authorities of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of the end of 
the study completion date for pediatric studies and within 1 year for non-pediatric studies as per 
guidance. The sponsor will provide the ECs with a copy of the same summary.
For non-commercial use only


Shire
CONFIDENTIAL
Page 65
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.
The sponsor will make an EOS declaration to the relevant competent authority as required by 
Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator is appointed to review the final CSR for multicenter 
studies. Agreement with the final CSR is documented by the signed and dated signature of the 
principal investigator (single-site study) or coordinating principal investigator (multicenter 
study), in compliance with Directive 2001/83/EC as amended by Directive 2003/63/EC and ICH 
Guidance E3 (1995). 
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational products, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by international regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
For non-commercial use only


Shire
CONFIDENTIAL
Page 66
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Case Report Forms
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded into eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log.
All data will have separate source documentation; no data will be recorded directly into the 
eCRF.
eCRFs should be approved by the investigator per study specifications and data deliverable 
requirements.
The clinical research associate (CRA)/study monitor will verify the contents against the source 
data per the monitoring plan. If the data are unclear or contradictory, queries are sent for 
corrections or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject diary cards, original clinical laboratory reports, and histology and 
pathology reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor, the respective national, 
local, or foreign regulatory authorities, the IRB/EC, and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF 
entries against the source documents. The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local
regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, X-rays etc.). Non-study site personnel will not 
disclose any personal information or personal medical information.
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US Food and Drug 
Administration (FDA) (as well as other US national and local regulatory authorities), the 
European Medicines Agency (EMA), the Medicines and Healthcare products Regulatory 
For non-commercial use only


Shire
CONFIDENTIAL
Page 67
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
Agency, other regulatory authorities, the sponsor or its representatives, and the IRB/EC for each 
site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent and assent, where 
applicable, from all study subjects prior to any study-related procedures including screening 
assessments. All consent and assent documentation must be in accordance with applicable 
regulations and GCP. Each subject or the subject’s legally-authorized representative, as 
applicable, is requested to sign and date the subject informed consent form or a certified 
translation if applicable, after the subject has received and read (or been read) the written subject 
information and received an explanation of what the study involves, including but not limited to: 
the objectives, potential benefits and risk, inconveniences, and the subject’s rights and 
responsibilities. A copy of the informed consent and assent documentation (ie, a complete set of 
subject information sheets and fully executed signature pages) must be given to the subject or the 
subject’s legally-authorized representative, as applicable. This document may require translation 
into the local language. Signed consent forms must remain in each subject’s study file and must 
be available for verification at any time.
Within the source documents, site personnel should document instruction of and understanding 
by the parent/legally-authorized representative/caregiver of the safe, responsible storage and 
administration of investigational product to the study subject.
The principal investigator provides the sponsor with a copy of the consent form, and assent form 
where applicable, which was reviewed by the IRB/EC and which received their favorable 
opinion/approval. A copy of the IRB/EC’s written favorable opinion/approval of these 
documents must be provided to the sponsor, prior to the start of the study unless it is agreed to 
and documented (abiding by regulatory guidelines and national provisions) prior to study start 
that another party (ie, sponsor or coordinating principal investigator) is responsible for this 
action. Additionally, if the IRB/EC requires modification of the sample subject information and 
consent document provided by the sponsor, the documentation supporting this requirement must 
be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
For non-commercial use only


Shire
CONFIDENTIAL
Page 68
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
For sites within the EU, the applicant for an EC opinion can be the sponsor, the investigator, or 
for multicenter studies the coordinating principal investigator or sponsor, according to national 
provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the Sponsor (or designee) has received 
written IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; for sites within the EU, this can be done by the sponsor, the investigator or for multicenter 
studies the coordinating principal investigator, according to national provisions. The investigator 
must also keep the local IRB/EC informed of any serious and significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996. A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the Sponsor (or designee).
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
review their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market SHP633; national or local regulatory authorities; and the IRBs/ECs which gave approval 
for the study to proceed. The sponsor and/or its representatives accessing the records and data 
will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject).
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
For non-commercial use only


Shire
CONFIDENTIAL
Page 69
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
10.5
Study Results / Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2-4 and certain other studies as determined by Shire. The purpose of the 
publication steering committee is to act as a non-commercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
current standards. Participation as an investigator does not confer any rights to authorship of 
publications.
For non-commercial use only


Shire
CONFIDENTIAL
Page 70
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
11
REFERENCES
Drucker, D. J. & Yusta, B. 2014. Physiology and pharmacology of the enteroendocrine hormone 
glucagon-like peptide-2. Annu Rev Physiol, 76, 561-83.
Khan, F. A., Squires, R. H., Litman, H. J., Balint, J., Carter, B. A., Fisher, J. G., Horslen, S. P., 
Jaksic, T., Kocoshis, S., Martinez, J. A., Mercer, D., Rhee, S., Rudolph, J. A., Soden, J., Sudan, 
D., Superina, R. A., Teitelbaum, D. H., Venick, R., Wales, P. W. & Duggan, C. 2015. Predictors 
of Enteral Autonomy in Children with Intestinal Failure: A Multicenter Cohort Study. J Pediatr,
167, 29-34.e1.
Mouksassi, M. S., Marier, J. F., Cyran, J. & Vinks, A. A. 2009. Clinical trial simulations in 
pediatric patients using realistic covariates: application to teduglutide, a glucagon-like peptide-2 
analog in neonates and infants with short-bowel syndrome. Clin Pharmacol Ther, 86, 667-71.
O'Keefe, S. J., Buchman, A. L., Fishbein, T. M., Jeejeebhoy, K. N., Jeppesen, P. B. & Shaffer, J. 
2006. Short bowel syndrome and intestinal failure: consensus definitions and overview. Clin 
Gastroenterol Hepatol, 4, 6-10.
Squires, R. H., Duggan, C., Teitelbaum, D. H., Wales, P. W., Balint, J., Venick, R., Rhee, S., 
Sudan, D., Mercer, D., Martinez, J. A., Carter, B. A., Soden, J., Horslen, S., Rudolph, J. A., 
Kocoshis, S., Superina, R., Lawlor, S., Haller, T., Kurs-Lasky, M. & Belle, S. H. 2012. Natural 
history of pediatric intestinal failure: initial report from the Pediatric Intestinal Failure 
Consortium. J Pediatr, 161, 723-8.e2.
Tappenden, K. A., Edelman, J. & Joelsson, B. 2013. Teduglutide enhances structural adaptation 
of the small intestinal mucosa in patients with short bowel syndrome. J Clin Gastroenterol, 47,
602-7.
Thymann, T., Stoll, B., Mecklenburg, L., Burrin, D. G., Vegge, A., Qvist, N., Eriksen, T., 
Jeppesen, P. B. & Sangild, P. T. 2014. Acute effects of the glucagon-like peptide 2 analogue, 
teduglutide, on intestinal adaptation in short bowel syndrome. J Pediatr Gastroenterol Nutr, 58,
694-702.
US Department of Health and Human Services, National Institutes of Health & National Cancer 
Institute 2010. Common Terminology Criteria for Adverse Events (CTCAE).
Varni, J. W., Sherman, S. A., Burwinkle, T. M., Dickinson, P. E. & Dixon, P. 2004. The PedsQL 
Family Impact Module: preliminary reliability and validity. Health Qual Life Outcomes, 2, 55.
Wales, P. W., de Silva, N., Kim, J., Lecce, L., To, T. & Moore, A. 2004. Neonatal short bowel 
syndrome: population-based estimates of incidence and mortality rates. J Pediatr Surg, 39, 690-
5.
For non-commercial use only


Shire
CONFIDENTIAL
Page 71
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
12
APPENDICES
For non-commercial use only


Shire
CONFIDENTIAL
Page 72
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
APPENDIX 1
PROTOCOL HISTORY
Document
Date
Global/Country/Site Specific
Original Protocol
08 April 2016
Global
Amendment 1
22 Nov 2016
Global
Amendment 2
23 Mar 2017
Global
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 1
Amendment Date
22 Nov 2016
Global
Description of Change and Rationale
Section(s) Affected by Change
Title of the Shire medical monitor has been changed to 
 
for clarity.
Protocol Signature Page
Emergency Contact Information
Clarification has been made that during the no-teduglutide treatment 
period, visits will take place approximately every 12 weeks.
Synopsis
Sections 3.1, 7.1.2
Figure 3-1
The study design flow chart has been edited for clarity.
Synopsis
Figure 3-1
The collection of all actual and prescribed enteral nutrition data has been 
removed to reduce the burden on the subjects and investigators. Enteral 
nutrition data are not required as the efficacy endpoints are limited to 
parenteral support parameters.
Synopsis
Table 1-1, Table 1-2, Table 1-3
Sections 7.1.2, 7.1.3.1, 7.1.3.2, 7.1.5,
7.2.11.2, 7.2.11.3
Exclusion criterion 11 has been revised to add Smoflipid as other 
experimental drugs that are allowed prior and during the study. Like 
glutamine and Omegaven, Smoflipid is not expected to interfere with the 
assessments of safety and efficacy of teduglutide and many subjects may 
already be receiving the treatments off-label as part of standard medical 
therapy.  
Synopsis
Section 4.5
Exclusion criterion 12 and prohibited treatment have been refined: 
exclusion/prohibition of treatment with growth hormone has been 
extended to 3 months for consistency with other teduglutide studies.
Synopsis
Section 4.5
Table 5-1
The language on escape criteria has been corrected for consistency within 
the protocol. 
Synopsis
Section 4.6
Language in efficacy and safety endpoints has been clarified.
Synopsis
Sections 9.7.1, 9.8.1
Completion and review of intake and output diaries have been clarified. 
Table 1-2, Table 1-3
Sections 7.1.3.2, 7.1.5
When the screening and pre-treatment visits are combined, the serum 
pregnancy test required at the pre-treatment visit should be performed at 
the local laboratory instead of the central laboratory. This will ensure 
timely results prior to starting treatment with teduglutide.
Table 1-3
Sections 7.1.3.1, 7.2.6
The requirement for urine specimen collection has been revised so that a
lack of urinalysis will not constitute a protocol deviation for any pediatric 
Table 1-1, Table 1-2, Table 1-3
Section 7.2.4
For non-commercial use only


Shire
CONFIDENTIAL
Page 73
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 1
Amendment Date
22 Nov 2016
Global
Description of Change and Rationale
Section(s) Affected by Change
subjects (not only for subjects wearing diapers).
Clarification has been made that the first no-teduglutide treatment visit 
after the screening visit will occur within 2 to 12 weeks of the screening 
(formerly within 12 weeks of screening).
Synopsis
Table 1-2
Section 7.1.1
Windows have been clarified for visits during the no-teduglutide and 
teduglutide treatment periods.
Table 1-2, Table 1-3
Section 7.1.2
‘Specific’ has been deleted from ‘positive/specific anti-teduglutide 
antibodies’ to eliminate the redundancy. By definition, positive samples 
must be specific (as assessed in the confirmatory assay), or otherwise
considered negative.
Table 1-2
Sections 7.2.7, 9.8.1
Parental height and gestational age at birth have been removed from 
medical history.
Table 1-1 (footnote b)
Section 7.2.1
For consistency within the protocol, sigmoidoscopy has been added as the 
alternate to colonoscopy throughout the protocol. 
Table 1-1, Table 1-2, Table 1-3
Sections 3.1, 7.1.2, 7.2.9.2
Removal of former footnote i on fecal occult blood test for clarity.
Table 1-3
Clarification has been made on circumstances when the CxW28 visit may 
be combined with the next pre-treatment or EOS/ET visit. 
Table 1-3
Section 7.1.4
The text on PS support requirements over time in pediatric subjects with 
SBS has been clarified, and text on intestinal adaptation has been refined.
Section 1.1
Status of current teduglutide approvals for use has been updated.
Section 1.2, 3.1
The term ‘re-challenge’ has been replaced with ‘additional teduglutide 
treatment’ for clarity and consistency with other studies.
Section 3.1
Number of subjects enrolled has been corrected for consistency with 
protocol synopsis.
Section 3.1
Definition of a subject’s completion of the study has been corrected for 
consistency within the protocol.
Section 3.2
Evaluations to be performed when a subject discontinues teduglutide or 
when withdraws from the study have been clarified.
Sections 4.8.1, 4.8.2
Withdrawal by parent/guardian has been added as reason for 
discontinuation.
Section 4.8.3
COUMADIN has been changed to warfarin for clarity.
Sections 5.1, 5.1.2
Clarification has been made on handling of study drug, which is for single 
use only and should be used within 3 hours following reconstitution.  
Section 6.3.3
The investigator or designee may now dispense the unused study drug 
vials to the same subject if deemed appropriate to ensure sufficient 
supplies between visits. Also, documentation of all dispensed study 
medication has been clarified.
Section 6.4
Clarification has been made that local laboratory results are not required to 
be entered in the eCRFs.
Section 7.2.4
Collection of urine sodium and urine osmolality has been removed.
Section 7.2.4
For non-commercial use only


Shire
CONFIDENTIAL
Page 74
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 1
Amendment Date
22 Nov 2016
Global
Description of Change and Rationale
Section(s) Affected by Change
Clarification has been made that the serum sample will not be collected at 
the pre-treatment visit if the subject met a follow-up period escape 
criterion.
Section 7.2.5
Intake and output diaries (formerly in Sections 7.2.11 and 7.2.12, 
respectively) have been moved under a new Section 7.2.11 ‘Diaries’ for 
clarity, and are now Sections 7.2.11.2 and 7.2.11.3, respectively. 
Information on study drug administration diary has been added in Section
7.2.11.1. Clarification has been made that only available diary data will be 
reviewed at each clinic and telephone visit.
Sections 7.2.11, 7.2.11.1,  7.2.11.2, 
7.2.11.3 
Performance of dipstick specific gravity tests by the subject at home on the 
first urine produced after the daily infusions of PS has been removed. It is 
now at the discretion of the investigator for all subjects, not just those in 
diapers. This change is to align with standard medical practice.
Section 7.2.11.3
Clarifications have been made to the language on dose interruption.
Sections 8.4, 8.4.1
Unscheduled safety follow up assessments (including visits conducted 
after EOS) are not to be recorded. However, clarification has been made 
that they are to be collected where requested.
Section 9.1
The protocol now refers to the data monitoring committee (DMC) Charter 
for the schedule of DMC reviews.
Section 9.4
Changes have been made to the Health economics and outcomes research
endpoints to include the beginning of each treatment cycle (CxD1) as 
additional baseline. These changes are for clarity and consistency with 
other teduglutide studies.
Synopsis
Section 9.9.1
Minor corrections have been made to the guidelines for nutritional support 
management during the study.
Appendix 2
For non-commercial use only


Shire
CONFIDENTIAL
Page 75
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
APPENDIX 2
GUIDELINES FOR NUTRITIONAL SUPPORT MANAGEMENT 
DURING THE STUDY
Nutritional support adjustment in volume and calories should be considered at all planned visits. 
Please consider the following clinical parameters identified as markers for adequate management 
of pediatric SBS. These parameters should also be considered for managing nutritional support 
(PS and/or oral/enteral feeding) in terms of volume and calories during the treatment period. 

Growth trajectory, including weight, height (or length), and head circumference (for pediatric 
subjects up to 36 months of age)

Other clinical evaluations

Serum electrolytes

Blood urea nitrogen /creatinine levels

Changes in stool frequency or volume, including mixed output

Stool consistency (ie, Bristol Stool Scale)

Urine specific gravity

General consideration to possible clinical deterioration in SBS

Inability to maintain weight and growth velocity

Diarrhea (≥10 bowel movements per day, ≥80 mL/kg/day from an ostomy, or 
≥75 mL/kg/day mixed output)

Colic/vomiting frequency increased

Electrolyte changes or imbalance

Skin breakdown 

Adjustments should be based on the actual nutritional support in volume and calories the 
subject infuses. Subjects should remain compliant with the nutritional support prescription in 
volume and calories during the study.

Nutritional support constituents may be adjusted at the discretion of the investigator.

During the 48-hour output measurement period prior to the subject’s scheduled visit, no 
further changes to the prescribed nutritional support should be made.

If there is a change in enteral nutrition (EN) or other food or fluid intake, the investigator 
should consider this when adjusting the PS/EN support in volume and calories.
For non-commercial use only


Shire
CONFIDENTIAL
Page 76
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
Figure A-1
Weaning Algorithm for Subjects Who are NOT Toilet Trained and in 
Diapers
For non-commercial use only


Shire
CONFIDENTIAL
Page 77
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
Figure A-2
Weaning Algorithm for Subjects Who are Toilet Trained and NOT in 
Diapers
For non-commercial use only


Shire
CONFIDENTIAL
Page 78
SHP633-304 Protocol Amendment 2
Teduglutide
23 Mar 2017
Figure A-3
Clinical Dehydration Assessment and PS/EN Adjustment
For non-commercial use only


PROTOCOL: SHP633-304
TITLE:
A Prospective, Open-label, Long-term Safety and Efficacy Study of 
Teduglutide in Pediatric Patients with Short Bowel Syndrome Who 
Completed TED-C14-006 or SHP633-301
DRUG:
Teduglutide
IND:
IND# 058213
EUDRACT NO.:
2016-000849-30
SPONSOR:
Shire Human Genetic Therapies, Inc.
300 Shire Way, Lexington, MA 02421 USA
PROTOCOL 
HISTORY:
Amendment 3: 16 May 2018
Amendment 2: 23 Mar 2017
Amendment 1: 22 Nov 2016
Original Protocol: 08 April 2016
This document contains confidential and proprietary information of Shire and is disclosed pursuant to 
confidentiality and non-disclosure obligations. This information should be used solely for the purposes for which 
it was provided and should not be copied, shared with, or disclosed to any third party without the express written 
consent of Shire.
For non-commercial use only


Shire 
CONFIDENTIAL 
Page2 
SHP633-304 Protocol Amendment 3 
Teduglutide 
16May2018 
PROTOCOL SIGNATURE PAGE 
Sponsor's (Shire) Approval 
Signature: 
i Date: 
-
I 
, MD PhD 
 
Global Clinical Development 
Investigator's Acknowledgement 
I have read this protocol for Shire Study SHP633-304. 
Title: A prospective, open label, long-term safety and efficacy study ofteduglutide in pediatric 
patients with short bowel syndrome who completed TED-C14-006 or SHP633-301 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review ofthe study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Conference on Harmonization (ICH) guidelines on Good Clinical 
Practice (GCP) and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Address: 
(please hand print or type) 
For non-commercial use only


Shire
CONFIDENTIAL
Page 3
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
SUMMARY OF CHANGES FROM PREVIOUS VERSION
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 3
Amendment Date
16 May 2018
Global
Description of Change and Rationale
Section(s) Affected by Change
The primary contact for EU and backup contact for NA was updated to 
.
Emergency Contact Information
To allow the enrollment of subjects who completed SHP633-301 where 
SHP633-301 was registered and approved by the local Health Authorities. 
The study title and eligibility criteria have been modified to accommodate 
younger children completing SHP633-301. 
SHP633-304 will evaluate long-term safety and efficacy in subjects who 
completed SHP633-301 and will provide a mechanism for subjects who 
complete SHP633-301 to receive additional teduglutide treatment if 
clinically indicated.  
Synopsis; Table 1-1; Section 2; 
Section 3.1; Section 4.1; 
Section 4.5; Section 6.2.2; 
Section 7.1.1; Section 7.1.3.1; 
Section 7.2.1; Section 9.5; 
Section 9.7.1
To minimize risk to subjects, a new escape criterion was added, allowing 
those who had escaped during the follow-up period of a previous 
teduglutide treatment to omit the follow-up period during subsequent 
teduglutide treatment cycles. 
For subjects who previously escaped the follow-up period, CxW24 
assessments can be combined with the next pretreatment visit assessments.
Synopsis; Table 1-3;  Figure 3-1; 
Section 3.1; Section 4.6; 
Section 6.2.3; Section 7.1.3.1; 
Section 7.1.3.2; Section 7.1.4; 
Section 7.2.5
Added the recording of parenteral support prescription at screening.  
Table 1-1
Clarified language that all concomitant procedures are to be captured, not 
just gastrointestinal procedures.
Table 1-1; Table 1-2; Table 1-3, 
Section 5.1; Section 7.1.1; Section 
7.1.2; Section 7.1.3.1; 
Section 7.1.3.2; Section 7.1.5
Updated the information on the clinical studies with teduglutide in pediatric 
subjects to include the results of TED-C14-006 and a description of the 
additional core study, SHP633-301. 
Section 1.3
Added new PK simulation data to further support dosing. 
Section 3.1
Deleted text that was duplicated in other sentences of sections.
Section 5.1
Deleted biological therapy (eg, antitumor necrosis factor) from the table of 
prohibited treatments as it was included in error.
Table 5-1
Clarified that compliance with study drug is calculated from subject diaries
Section 6.5
Added direct bilirubin to the list of laboratory tests.
Table 7-1
Specified that blood pressure should be collected in the same extremity 
rather than in the same arm as blood pressure is not collected using the arm 
in small children.
Section 7.2.3
Specified that saved serum samples should be omitted for subjects 
weighing less than 10 kg and whenever local blood volume limitations are 
exceeded.
Section 7.2.8
Clarified that if a child is under 2 years of age or unable to complete a 
quality of life questionnaire (due to developmental delay or other illness) it 
will not constitute a protocol deviation.
Section 7.2.12
For non-commercial use only


Shire
CONFIDENTIAL
Page 4
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
Specified that an interim analysis is planned when 6 months of safety data 
have been collected for subjects entering from TED-C14-006. Additional 
interim analyses may be conducted as needed.
Section 9.4
Minor editorial changes and corrections to typographical errors (which do 
not modify content and/or intent of the original document) were made.
Throughout protocol
See Appendix 1 for protocol history, including all amendments.
For non-commercial use only


Shire
CONFIDENTIAL
Page 5
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Adverse Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as 
Required by Protocol within 24 hours to the Shire Global Drug Safety Department. Applicable 
fax numbers and e-mail address can be found on the form (sent under separate cover). A copy of 
this form must also be sent to the Shire Medical Monitor by fax or e-mail using the details 
below.
, MD PhD
Email: 
Fax: 
For protocol- or safety-related issues, the investigator must contact Quintiles Medical 
Support:
Primary contact for North America (NA) and backup contact for European Union (EU)
, MD, 
Mobile: 
US Toll Free number: 
Phone: 
 (medical emergencies – NA)
Email: 
Primary contact for EU and backup contact for NA
, MD, 
Mobile: 
Phone: 
Phone: 
 (medical emergencies – EU)
Email: 
In addition, the investigator may also contact the Shire Medical Monitor:
, MD PhD, 
Phone: 
Mobile: 
Email: 
For non-commercial use only


Shire
CONFIDENTIAL
Page 6
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
European Union and Rest of World
Telephone numbers (provided for reference): 
 Shire (USA) 
For non-commercial use only


Shire
CONFIDENTIAL
Page 7
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................3
EMERGENCY CONTACT INFORMATION................................................................................5
PRODUCT QUALITY COMPLAINTS..........................................................................................6
TABLE OF CONTENTS.................................................................................................................7
LIST OF TABLES.........................................................................................................................11
LIST OF FIGURES .......................................................................................................................11
LIST OF APPENDICES................................................................................................................11
ABBREVIATIONS .......................................................................................................................12
STUDY SYNOPSIS ......................................................................................................................14
STUDY SCHEDULE(S) ...............................................................................................................19
1
BACKGROUND INFORMATION.......................................................................................24
1.1
Indication and Current Treatment Options...............................................................24
1.2
Product Background.................................................................................................24
1.3
Clinical Studies with Teduglutide in Pediatric Subjects ..........................................25
2
STUDY OBJECTIVES AND PURPOSE ..............................................................................27
2.1
Rationale for the Study.............................................................................................27
2.2
Study Objectives ......................................................................................................27
2.2.1
Primary Objectives.................................................................................................27
2.2.2
Secondary Objectives.............................................................................................27
3
STUDY DESIGN ...................................................................................................................28
3.1
Study Design and Flow Chart ..................................................................................28
3.2
Duration and Study Completion Definition .............................................................31
4
STUDY POPULATION.........................................................................................................32
4.1
Study Inclusion Eligibility Criteria ..........................................................................32
4.2
Study Exclusion Eligibility Criteria .........................................................................32
4.3
Teduglutide Eligibility Criteria ................................................................................32
4.4
Teduglutide Treatment Inclusion Criteria................................................................32
4.5
Teduglutide Treatment Exclusion Criteria...............................................................33
4.6
Follow-up Period Escape Criteria ............................................................................34
4.7
Reproductive Potential .............................................................................................34
4.7.1
Female Contraception............................................................................................34
4.8
Discontinuation of Subjects .....................................................................................35
4.8.1
Teduglutide Discontinuation..................................................................................35
4.8.2
Study Withdrawal ..................................................................................................35
4.8.3
Reasons for Discontinuation..................................................................................35
For non-commercial use only


Shire
CONFIDENTIAL
Page 8
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
4.8.3.1
Subjects ‘Lost to Follow-up’ Prior to Last Scheduled Visit ..................36
5
CONCOMITANT TREATMENT..........................................................................................37
5.1
Concomitant Medications and Procedures...............................................................37
5.1.1
Permitted Treatment...............................................................................................37
5.1.2
Prohibited Treatment .............................................................................................37
6
INVESTIGATIONAL PRODUCT ........................................................................................38
6.1
Identity of Investigational Product...........................................................................38
6.1.1
Blinding the Treatment Assignment......................................................................38
6.2
Administration of Investigational Product(s)...........................................................38
6.2.1
Interactive Response Technology for Investigational Product Management ........38
6.2.2
Allocation of Subjects to Treatment ......................................................................38
6.2.3
Dosing....................................................................................................................38
6.2.4
Unblinding the Treatment Assignment..................................................................39
6.3
Labeling, Packaging, Storage, and Handling ...........................................................39
6.3.1
Labeling .................................................................................................................39
6.3.2
Packaging...............................................................................................................39
6.3.3
Storage and Handling.............................................................................................40
6.4
Drug Accountability.................................................................................................40
6.5
Subject Compliance..................................................................................................41
7
STUDY PROCEDURES........................................................................................................42
7.1
Study Schedule.........................................................................................................42
7.1.1
Screening................................................................................................................42
7.1.2
Visits for Subjects Not Receiving Teduglutide .....................................................42
7.1.3
Visits for Subjects Receiving Teduglutide ............................................................43
7.1.3.1
Pre-treatment Visit .................................................................................43
7.1.3.2
Teduglutide Treatment Period (CxD1-CxW24).....................................44
7.1.4
Teduglutide Follow-up Period...............................................................................46
7.1.5
Study Completion/Early Termination Visit (EOS/ET Visit).................................47
7.2
Study Evaluations and Procedures ...........................................................................47
7.2.1
Demographics, Medical History, and SBS History ...............................................47
7.2.2
Physical Examination.............................................................................................48
7.2.3
Vital Signs, Body Weight, Height, Head Circumference and Body Mass 
Index ......................................................................................................................48
7.2.4
Clinical Laboratory Tests.......................................................................................48
7.2.5
Serum Sampling.....................................................................................................49
7.2.6
Pregnancy Testing..................................................................................................50
7.2.7
Antibody Testing ...................................................................................................50
7.2.8
Volume of Blood....................................................................................................50
For non-commercial use only


Shire
CONFIDENTIAL
Page 9
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
7.2.9
Gastrointestinal-specific Testing ...........................................................................51
7.2.9.1
Fecal Occult Blood Testing....................................................................51
7.2.9.2
Colonoscopy or Sigmoidoscopy.............................................................51
7.2.10 Nutritional Support ................................................................................................51
7.2.11 Diaries
................................................................................................................52
7.2.11.1
Study Drug Administration Diary..........................................................52
7.2.11.2
Intake Diary............................................................................................52
7.2.11.3
Output Diary...........................................................................................52
7.2.12 Health-related Quality of Life Assessments ..........................................................53
7.2.12.1
Pediatric Quality of Life Generic Core Scale (PedsQL™), Acute 
version ....................................................................................................53
7.2.12.2
Pediatric Quality of Life Family Impact Module (PedsQL™), Acute 
version ....................................................................................................54
7.2.12.3
PedsQL Gastrointestinal Symptoms Module (PedsQL™), Acute 
version ....................................................................................................54
8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................55
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................55
8.1.1
Severity Categorization..........................................................................................55
8.1.2
Relationship Categorization...................................................................................56
8.1.3
Outcome Categorization ........................................................................................56
8.1.4
Symptoms of the Disease under Study ..................................................................57
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................57
8.1.6
Pregnancy...............................................................................................................57
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................58
8.2
Serious Adverse Event Procedures ..........................................................................58
8.2.1
Reference Safety Information................................................................................58
8.2.2
Reporting Procedures.............................................................................................58
8.2.3
Serious Adverse Event Definition .........................................................................59
8.2.4
Serious Adverse Event Collection Time Frame.....................................................59
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................60
8.2.6
Fatal Outcome........................................................................................................60
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................60
8.3
Adverse Events of Special Interest...........................................................................60
8.4
Dose Interruption of Individual Subjects .................................................................61
8.4.1
Dose Interruption Criteria Based on Adverse Event Severity and 
Relationship to Investigational Product.................................................................61
8.4.2
Dose Interruption Criteria Based on Drug-Induced Liver Injury ..........................62
For non-commercial use only


Shire
CONFIDENTIAL
Page 10
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
8.5
Early Termination of the Clinical Study ..................................................................62
9
DATA MANAGEMENT AND STATISTICAL METHODS...............................................63
9.1
Data Collection.........................................................................................................63
9.2
Clinical Data Management.......................................................................................63
9.3
Statistical Analysis Process......................................................................................63
9.4
Planned Interim Analysis, and Data Monitoring Committee...................................63
9.5
Sample Size Calculation and Power Considerations................................................64
9.6
Study Population ......................................................................................................64
9.7
Efficacy Analyses.....................................................................................................64
9.7.1
Efficacy Endpoints.................................................................................................64
9.8
Safety Analyses........................................................................................................64
9.8.1
Safety Endpoints....................................................................................................64
9.9
Other Analyses .........................................................................................................66
9.9.1
Health-related Quality of Life Analyses................................................................66
10 SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................67
10.1
Sponsor’s Responsibilities .......................................................................................67
10.1.1 Good Clinical Practice Compliance.......................................................................67
10.1.2 Indemnity/Liability and Insurance.........................................................................67
10.1.3 Public Posting of Study Information......................................................................67
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................67
10.1.5 Study Suspension, Termination, and Completion..................................................68
10.2
Investigator’s Responsibilities .................................................................................68
10.2.1 Good Clinical Practice Compliance.......................................................................68
10.2.2 Protocol Adherence and Investigator Agreement..................................................68
10.2.3 Documentation and Retention of Records.............................................................69
10.2.3.1
Case Report Forms.................................................................................69
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................69
10.2.3.3
Audit/Inspection.....................................................................................69
10.2.3.4
Financial Disclosure...............................................................................70
10.3
Ethical Considerations..............................................................................................70
10.3.1 Informed Consent...................................................................................................70
10.3.2 Institutional Review Board or Ethics Committee..................................................70
10.4
Privacy and Confidentiality......................................................................................71
10.5
Study Results / Publication Policy ...........................................................................72
11 REFERENCES .......................................................................................................................73
12 APPENDICES ........................................................................................................................74
For non-commercial use only


Shire
CONFIDENTIAL
Page 11
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
LIST OF TABLES
Table 1-1:
Schedule of Events Required for All Subjects ..............................................19
Table 1-2: 
Schedule of Events for Subjects Not Receiving Teduglutide .......................20
Table 1-3: 
Schedule of Events for Subjects While Receiving Teduglutide....................21
Table 5-1: 
Prohibited Treatment.....................................................................................37
Table 7-1:
List of Laboratory Tests ................................................................................49
Table 7-2:
Approximate Volume of Blood to be Drawn from Each Subject 
Annually ........................................................................................................50
Table 7-3:
Developmentally Appropriate PedsQL™Generic Core Scales .....................54
LIST OF FIGURES
Figure 3-1:
Study Design Flow Chart ..............................................................................31
LIST OF APPENDICES
Appendix 1
Protocol History.............................................................................................75
Appendix 2
Guidelines for Nutritional Support Management During the Study .............79
For non-commercial use only


Shire
CONFIDENTIAL
Page 12
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
-HCG
beta-human chorionic gonadotropin
BMI
body mass index
CRA
clinical research associate
CRO
contract research organization
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DILI
drug-induced livery injury
DMC
data monitoring committee
DPP-4
dipeptidyl peptidase 4
EC
ethics committee
eCRF
electronic case report form
EMA
European Medicines Agency
EN
enteral nutrition
EOS
end of study
EOT
end of treatment
ET
early termination
EU
European Union
FDA
Food and Drug Administration
FOBT
fecal occult blood test
FOCBP
female of child-bearing potential
GCP
Good Clinical Practice
GI
gastrointestinal
GLP-1
glucagon-like peptide 1
GLP-2
glucagon-like peptide 2
HIPAA
Health Insurance Portability and Accountability Act
ICF
informed consent form
ICH
International Conference on Harmonization
IGF-1
insulin-like growth factor 1
IRB
institutional review board
IV
intravenous
IWRS
interactive web-based response system
For non-commercial use only


Shire
CONFIDENTIAL
Page 13
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
MedDRA
Medical Dictionary for Regulatory Activities
NA 
North America
NCI
National Cancer Institute
NDA
new drug application
NTT
no-teduglutide treatment
PedsQL
Pediatric Quality of Life inventory
PS
parenteral support
PT/INR
prothrombin time/international normalized ratio
QD
once daily
SAE
serious adverse event
SAP
statistical analysis plan
SBS
short bowel syndrome
SC
subcutaneous
SOC
standard of care
t1/2
elimination half-life
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
UK
United Kingdom
ULN
upper limit of normal
US
United States
WHO-DD
World Health Organization – Drug Dictionary
For non-commercial use only


Shire
CONFIDENTIAL
Page 14
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
STUDY SYNOPSIS
Protocol number: SHP633-304
Drug: Teduglutide
Title of the study: A Prospective, Open-label, Long-term Safety and Efficacy Study of Teduglutide in Pediatric 
Patients with Short Bowel Syndrome (SBS) Who Completed TED-C14-006 or SHP633-301
Number of subjects (total and for each treatment arm):
Approximately 65 subjects who completed the TED-C14-006 or SHP633-301 studies, including subjects in the 
standard of care treatment arms, are expected to enroll in this extension study. This study will enroll up to as 
many subjects as complete the TED-C14-006 and SHP633-301 studies.
Investigator(s): Multicenter study
Site(s) and Region(s): 
Approximately 28 investigational sites in North America and Europe will participate in this extension study
Study period (planned):
October 2016 – September 2019
Clinical phase:
3 Extension
Objectives:
Primary: To evaluate the long-term safety and tolerability of teduglutide treatment in pediatric subjects with SBS.
Secondary: To evaluate long-term efficacy of teduglutide treatment in pediatric subjects with SBS.
Rationale:
This is a Phase 3, prospective, open-label, long-term extension study to evaluate the safety and efficacy of 
teduglutide in pediatric subjects with short bowel syndrome (SBS) who completed either the TED-C14-006 or 
SHP633-301 studies (the core studies). In addition to evaluating the long-term safety and durability of efficacy 
after 24-weeks of treatment, this extension study will evaluate the need for additional teduglutide treatment in 
these subjects, and will allow the study of first-time treatment of teduglutide-naïve subjects who participated in 
the standard of care (SOC) treatment arms in TED-C14-006 or SHP633-301. 
Investigational product, dose, and mode of administration:
This study will allow repeat doses of teduglutide 0.05 mg/kg subcutaneous (SC) once daily (QD) injection for 
eligible pediatric subjects. There is no active comparator or reference product.
Methodology:
This is a Phase 3, prospective, open-label, long-term extension study to evaluate the safety and efficacy of 
teduglutide in pediatric subjects who completed the TED-C14-006 or SHP633-301 studies (core studies).
Once the informed consent (and if applicable, informed assent) have been reviewed and signed, demographics, 
and updates to medical history and short bowel syndrome history will be obtained. Subjects not receiving 
teduglutide treatment (ie, in a no-teduglutide treatment [NTT] period), will be seen approximately every 12 weeks 
for safety, parenteral support (PS) requirements, and quality of life. The first NTT visit after the screening visit 
will occur within 2 to 12 weeks of the screening visit. At any point after screening, including during a NTT 
period, subjects who meet ≥1 teduglutide treatment inclusion criteria, may proceed immediately to the 
pretreatment visit if the investigator, subject, and parent agree to proceed with teduglutide therapy.
After the pretreatment visit, subjects who meet ≥1 of the teduglutide treatment inclusion criteria, and meet none 
of the teduglutide treatment exclusion criteria, will start a 28-week cycle, consisting of 24 weeks of teduglutide 
treatment at 0.05 mg/kg SC once daily, followed by a 4-week follow-up period (during which no teduglutide is 
administered) (Figure 3-1). During the 28-week cycle, clinic visits will occur at weeks 1, 2, 4, 6, 9, 12, 16, 20, 24, 
and 28. Phone visits are required approximately 1 week after adjustments in PS during the teduglutide treatment 
period (between weeks 1 and 24), and weekly during the teduglutide follow-up period (between weeks 24 and 
28). Safety and PS requirements will be evaluated at every visit, and quality of life assessments will be made 
approximately every 12 weeks. If a subject meets 1 of the follow-up period escape criteria between cycle week 24 
For non-commercial use only


Shire
CONFIDENTIAL
Page 15
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
and 28, the subject may "escape" the follow-up period early and proceed immediately to another pretreatment 
visit.  Following completion of the 28-week treatment cycle, the subject will proceed to an NTT visit or another 
pretreatment visit within approximately 12 weeks.
At all site visits and telephone contacts, safety will be monitored and nutritional support will be reviewed and
adjusted as needed. To maintain consistency across centers, all attempts should be made to follow the nutritional
support adjustment guidelines (developed with SBS expert input and provided in the protocol) for decisions
regarding PS support reduction and advances in enteral feeds based on weight gain, urine and stool output, and
clinical stability. Departure from the guidelines, however, is not considered a protocol deviation. (Appendix 2).
Study Design Flow Chart 
Figure legend: Safety and efficacy data for subjects not receiving teduglutide treatment are captured approximately every 
12 weeks, but subjects may proceed to the pretreatment visit at any time in order to assess eligibility for teduglutide 
therapy. Eligible subjects will enter a 28-week teduglutide cycle. During this cycle, subjects will return to the site for 
safety and efficacy assessments at weeks 1, 2, 4, 6, 9, 12, 16, 20, and 24 (solid black lines). Phone visits are required 
approximately 1 week after adjustments in PS during the intervening weeks between weeks 2 and 24 (dashed grey 
lines). Subjects discontinue teduglutide at week 24 and enter a 4-week follow-up (no-treatment) period, during which 
phone visits will be performed weekly (solid grey lines). If an escape criterion is met at week 24 or during the follow-up 
period, subjects may proceed directly to another pretreatment visit.
Study Inclusion Criteria: 
The subject will be considered eligible for the study if they meet all of the study inclusion criteria. Teduglutide 
treatment eligibility does not impact study eligibility.
1.
Subject provides written informed consent (subject, parent or legal guardian and, as appropriate, 
informed assent) to participate in the study before completing any study-related procedures.
2.
Subject completed the TED-C14-006 or SHP633-301 studies (including subjects in the standard of care 
treatment arms). Subjects are considered to have completed SHP633-301 if they completed study 
assessments through week 24.
3.
Subject understands and is willing and able to fully adhere to study requirements as defined in this 
protocol. 
Study Exclusion Criteria: There are no exclusion criteria for this study.
Teduglutide Eligibility Criteria: Subjects are eligible for teduglutide treatment if at least one (≥1) of the 
teduglutide treatment inclusion criteria, and none of the teduglutide treatment exclusion criteria, are met. In 
addition, the investigator and the subject (and/or parent or legal guardian, as appropriate) must agree to proceed 
with treatment.
Teduglutide Treatment Inclusion Criteria:
For non-commercial use only


Shire
CONFIDENTIAL
Page 16
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
1.
Subject is teduglutide-naïve, receiving PS, and unable to significantly reduce PS or advance enteral feeds 
(eg, 10% or less change in PS or advance in feeds) for at least 3 months prior to and during the 
teduglutide pretreatment visit, as assessed by the investigator. Transient instability for events such as 
interruption of central access or treatment for sepsis is allowed if the PS returns to within 10% of 
baseline prior to the event.
2.
Subject was previously treated with teduglutide and at least one of the following criteria is satisfied:
a.
Increasing PS requirements following teduglutide discontinuation.
b.
Decreased PS requirement during prior teduglutide treatment, followed by cessation of 
improvement after teduglutide discontinuation.
c.
Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal tolerated 
enteral nutrition (EN) following teduglutide discontinuation.
d.
Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and electrolyte 
intake following teduglutide discontinuation.
e.
Severe diarrhea related to teduglutide discontinuation.
Teduglutide Treatment Exclusion Criteria:
1.
Body weight <5 kg at the pretreatment visit.
2.
Unresected gastrointestinal (GI) polyp, known polyposis condition, premalignant change, or malignancy, 
in the GI tract.
3.
History of cancer in the previous 5 years except surgically curative skin cancers.
4.
Serial transverse enteroplasty or other major intestinal surgery within 3 months preceding the teduglutide 
pretreatment visit. Insertion of a feeding tube, anastomotic ulcer repair, minor intestinal resections 
≤10 cm, and endoscopic procedures are allowed.
5.
Intestinal or other major surgery planned or scheduled to occur during the 28-week cycle.
6.
Clinically significant intestinal stricture or obstruction.
7.
Clinically significant, active or recurrent pancreatic or biliary disease.
8.
Active, severe, or unstable, clinically significant hepatic impairment or injury, including the following 
laboratory values at the pretreatment visit:
a.
Total bilirubin ≥2 × upper limit of normal (ULN)
b.
Aspartate aminotransferase (AST) ≥7 × ULN
c.
Alanine aminotransferase (ALT) ≥7 × ULN
9.
Renal dysfunction shown by results of an estimated glomerular filtration rate below 50 mL/min/1.73 m2
at the pretreatment visit.
10. Unstable cardiac disease, congenital heart disease or cyanotic disease, with the exception of subjects 
who had undergone ventricular or atrial septal defect repair, or patent ductus arteriosus ligation.
11. Participation in a clinical study using an experimental drug (other than glutamine, Omegaven, or 
Smoflipid) within 3 months or 5.5 half-lives of the experimental drug, whichever is longer, prior to the 
pretreatment visit and for the duration of the 28-week cycle.
12. Treatment with analogs of glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2) (not 
including teduglutide), insulin-like growth factor-1 (IGF-1), or growth hormone, within 3 months 
preceding the teduglutide pretreatment visit.
13. Treatment with octreotide or dipeptidyl peptidase 4 (DPP-4) inhibitors within 3 months prior to the 
pretreatment visit.
14. Known or suspected intolerance or hypersensitivity to the investigational product, closely-related 
compounds, or any of the stated ingredients.
15. Known history of alcohol or other substance abuse within 1 year prior to the pretreatment visit.
For non-commercial use only


Shire
CONFIDENTIAL
Page 17
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
16. Pregnant or lactating female subjects.
17. Sexually active female subjects of child-bearing potential unwilling to use approved contraception 
during teduglutide treatment and for 30 days after the treatment period.
18. Any condition, disease, illness, or circumstance that in the investigator’s opinion puts the subject at any 
undue risk, prevents completion of the study, or interferes with analysis of the study results.
Follow-up Period Escape Criteria: At the discretion of the investigator, the follow-up period may be interrupted 
or omitted and the subject may proceed directly to the pretreatment visit, if ≥1 of the following criteria is met:
1.
Increasing PS requirements following teduglutide discontinuation
2.
Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal tolerated EN
following teduglutide discontinuation.
3.
Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and electrolyte intake 
following teduglutide discontinuation.
4.
Severe diarrhea related to teduglutide discontinuation.
5.
The subject escaped during the follow-up period of SHP633-301 or during the follow-up period of a 
previous teduglutide treatment cycle within SHP633-304.
Maximum duration of subject involvement in the study:
A subject will be considered enrolled in the study once the subject has provided signed consent, and meets all of 
the Study Inclusion Criteria. Subjects may participate in multiple NTT periods and/or multiple 28-week treatment 
cycles. The study will continue for at least 1 year, and until each subject has access (as needed) to teduglutide. 
The subject’s maximum duration of participation is expected to be approximately 3 years. A subject will be 
considered as having completed the study if the subject has not withdrawn early from the study for any reason 
prior to completing End of Study (EOS) visit.

Planned duration of no-teduglutide treatment periods: variable, depending on disease course 

Planned duration of the teduglutide pretreatment visit: 1 to 21 days

Planned cycle duration: 28 weeks. Each cycle consists of 24 weeks of teduglutide treatment followed 
by a 4-week follow-up period (no treatment)
Endpoints and statistical analysis: 

The safety population will consist of all enrolled subjects. The safety population will be used for both 
safety and efficacy analysis.
Efficacy Endpoints
Efficacy endpoints will be analyzed at the end of each teduglutide treatment period (week 24 or end of treatment 
[EOT]), and at each study visit, relative to the baseline of the core study (TED-C14-006 or SHP633-301) and/or 
first exposure to teduglutide. The following efficacy endpoints will be analyzed: 

Reduction in PS volume of at least 20%

Absolute and relative change in PS volume

Complete weaning off PS

Change in days per week of PS
For non-commercial use only


Shire
CONFIDENTIAL
Page 18
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
Health Economics and Outcomes Research Endpoints 
Health economics and outcomes research endpoints will be analyzed at approximately 12-week intervals 
(weeks 12 and 24 of each teduglutide treatment cycle, and every 12 weeks for subjects not on teduglutide), 
relative to the study baseline. The beginning of each treatment cycle (CxD1) will be an additional baseline.

Change in Pediatric Quality of Life Inventory (PedsQL) score

Change in PedsQL Family Impact Module score

Change in PedsQL Gastrointestinal Symptoms Module Sub-Scales scores: 

Food and Drink Limits

Diarrhea 
Safety Endpoints 
The following safety endpoints will be analyzed:

Adverse events

Vital signs, including temperature, heart rate, blood pressure

Laboratory safety data (ie, clinical chemistry, hematology, and urinalysis)

Urine output

Stool output

Antibodies to teduglutide

Gastrointestinal-specific testing, including fecal occult blood testing and colonoscopy or sigmoidoscopy

Z-scores for weight, height (or length), head circumference (up to 36 months of age), and body mass index 
Statistical Methodology for Efficacy Analysis
No claims of statistical significance will be made; however, 95% confidence intervals will be provided, if 
applicable. Continuous variables, including those assessed on a discrete scale, will be summarized using 
descriptive statistics including number of subjects, mean, median, standard deviation , maximum, and minimum. 
For categorical variables, statistical summaries will include number of subjects and percentages.
Statistical Methodology for Safety Analysis 
Safety data, including laboratory tests and vital signs assessments, will be summarized by visit. AEs will also be 
collected and summarized. Descriptive statistics will be calculated for quantitative safety data as well as for the 
difference from baseline, if applicable. Frequency counts will be compiled for classification of qualitative safety 
data.
Sample Size Justification 
As this is an extension study, the maximum number of subjects was determined by enrollment in TED-C14-006 
and SHP633-301.
For non-commercial use only


Shire
CONFIDENTIAL
Page 19
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
STUDY SCHEDULE(S) 
Table 1-1: Schedule of Events Required for All Subjects 
Period
Screening
End of Study or Early Termination
Scr
EOS/ET
Visit Type
Site
Site
Informed consent/assenta
X
Study eligibility
X
Demographics, medical historyb, SBS historyc
X
Dispense intake and output diaries
X
Evaluate teduglutide treatment inclusion criteriad
X
Adverse events
X
X
Concomitant medications and procedures
X
X
Physical examination and vital signs, including weight
X
Height and head circumferencee
X
Review intake and output diariesf
X
Record PS prescription and adjust as neededg
X
X
Safety laboratory testsh
X
PedsQL Generic Core Scale/PedsQL Family Impact Module/ 
PedsQL Gastrointestinal Symptoms Module Sub-Scales
X
Antibodies to teduglutidei
X
Fecal occult blood testingj
(X)
Colonoscopy or sigmoidoscopyk
(X)
Pregnancy testingl
(X)
FOBT = fecal occult blood testing; FOCBP = female of child-bearing potential; EOS =end of study; ET=early termination; 
GI=gastrointestinal; NTx=no treatment; PedsQL=Pediatric Quality of Life Inventory; PS=parenteral support; SBS=Short Bowel 
Syndrome; Scr =Screening.
a Informed Consent (and informed assent, if applicable) must be obtained prior to performing any study-related procedures; 
consent (and informed assent, if applicable) may be obtained anytime during the EOS visit for the TED-C14-006 or SHP633-301 
studies. Subject will have approximately 7 days after completion of the TED-C14-006 or SHP633-301 studies to sign consent to 
participate in the SHP633-304 study.
b Updates to the medical history will be collected, consisting of adverse events that were ongoing at the time of completion of
TED-C14-006 or SHP633-301, and events that occurred during the period between completion of TED-C14-006 or SHP633-301 
and informed consent to SHP-633-304. 
c If the subject has any changes to the SBS history that had been collected at the baseline of the TED-C14-006 or SHP633-301, 
then the updated SBS history will be collected.
d Subjects who meet ≥1 teduglutide treatment inclusion criteria, may proceed to the pretreatment visit if the investigator, subject, 
and parent or legal guardian agrees to proceed with teduglutide therapy (Table 1-3).
e Head circumference will be measured in subjects 36 months of age and younger.
f The intake diary should be completed daily for a minimum of 2 weeks prior to the EOS/ET visit. The output diary should be 
completed daily over a 48-hour period of nutritional stability before the EOS/ET visit.
g PS adjustments should be made after review of any available intake and output diaries and the safety lab data according to the 
guidance for nutrition support adjustment provided in Appendix 2. 
h Safety laboratory assessments at site visits will consist of clinical chemistry, hematology, and urinalysis, with results processed 
by a central laboratory. Urine specimen collection should be attempted as part of the safety labs, but lack of urinalysis will not 
constitute a protocol deviation.
i Required for all teduglutide-exposed subjects
j FOBT should be performed on teduglutide-exposed subjects on an annual basis, approximately every 48-60 weeks at a 
minimum.
k The need for colonoscopy/sigmoidoscopy in response to a positive FOBT during a no-teduglutide treatment period is at the 
discretion of the investigator, but all teduglutide-exposed subjects will undergo colonoscopy/sigmoidoscopy after they have 
received the equivalent of 2 treatment cycles (48 weeks of study drug exposure), and subjects who continue to receive teduglutide 
will undergo colonoscopy/sigmoidoscopy at 5 year intervals or more often as needed. See Section 7.2.9 for details.
l Pregnancy testing is required for FOCBP at an ET visit if the subject has not had a pregnancy test at least 30 days after study 
drug discontinuation.
Note: (X) denotes conditional requirement for a given assessment if the subject meets certain conditions per protocol.
For non-commercial use only


Shire
CONFIDENTIAL
Page 20
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
Table 1-2: Schedule of Events for Subjects Not Receiving Teduglutide 
Visit Number
NTx
Visit Type
Site
Visit Frequencya
Every 12 weeks 
Window (days)b
±7
Dispense intake and output diaries
X
Evaluate teduglutide treatment inclusion criteriac
X
Adverse events
X
Concomitant medications and procedures
X
Physical examination and vital signs, including weight
X
Height and head circumferenced
X
Review intake and output diariese
X
Record PS prescription and adjust as neededf
X
Safety laboratory testsg
X
PedsQL Generic Core Scale/PedsQL Family Impact Module/ 
PedsQL Gastrointestinal Symptoms Module Sub-Scales
X
Antibodies to teduglutideh
(X)
Fecal occult blood testingi
Annually 
Colonoscopy or sigmoidoscopyj
(X)
Serum samplek
Every 24 weeks
FOBT = fecal occult blood testing; NTT = no-teduglutide treatment; PedsQL = Pediatric Quality of Life Inventory; PS= 
parenteral support; TED = teduglutide.
a The first NTx visit following the screening visit must occur within 2 to 12 weeks of screening.
b Window is relative to the first NTx visit in the current no-teduglutide treatment period.
c Subjects who meet ≥1 teduglutide treatment inclusion criteria, may proceed to the pretreatment visit if the investigator, subject, 
and parent or guardian agree to proceed with teduglutide therapy (Table 1-3).
d Head circumference will be measured in subjects 36 months of age and younger.
f Intake diaries will collect actual PS volume and hours per day, completed daily for a minimum of 2 weeks prior to each study 
visit (see Section 7.2.11.2). Urine and stool output should be recorded in the output diary over a 48-hour period of nutritional 
stability before every clinic visit (see Section 7.2.11.3 for more detail).
f PS adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance
for nutrition support adjustment provided in Appendix 2. 
g Safety laboratory assessments at site visits will consist of clinical chemistry, hematology, and urinalysis, with results processed 
by a central laboratory. Urine specimen collection should be attempted as part of the safety labs, but lack of urinalysis will not 
constitute a protocol deviation.
h Subjects who have been treated previously and test positive for teduglutide antibodies should have follow-up samples collected 
every 12 weeks during the study until a negative result is obtained.
iFOBT should be performed on teduglutide-exposed subjects on an annual basis, approximately every 48-60 weeks at a 
minimum.
j The need for colonoscopy/sigmoidoscopy in response to a positive FOBT during a no-teduglutide treatment period is at the 
discretion of the investigator, but all teduglutide-exposed subjects will undergo colonoscopy/sigmoidoscopy after they have 
received the equivalent of 2 treatment cycles (48 weeks of study drug exposure) and subjects who continue to receive teduglutide 
will undergo colonoscopy/sigmoidoscopy at 5 year intervals or more often as needed. See Section 7.2.9 for details.
k Lack of collection of serum samples will not constitute a protocol deviation.
Note: (X) denotes conditional requirement for a given assessment if the subject meets certain conditions per protocol.
For non-commercial use only


Shire
CONFIDENTIAL
Page 21
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
Table 1-3: Schedule of Events for Subjects While Receiving Teduglutide
Period
Pre-
treatment
Teduglutide Treatment
Follow-up
Visit Number
Pxa
Cx
D1
Cx
W1
Cx
W2
Phone contact is required approximately 1 week after PS adjustment
Cx
W4
Phone contact is required approximately 1 week after PS adjustment
Cx 
W6
Phone contact is required approximately 1 week after PS adjustment
Cx 
W9
Phone contact is required approximately 1 week after PS adjustment
Cx 
W12
Phone contact is required approximately 1 week after PS adjustment
Cx 
W16
Phone contact is required approximately 1 week after PS adjustment
Cx 
W20
Phone contact is required approximately 1 week after PS adjustment
CxW24 
(EOT)
CxW25 
CxW26 
CxW27
CxW28c
Visit Type
Site
Site
Site
Site
Site
Site
Site
Site
Site
Site
Site
Phoneb
Site
Cycle Day
-21 to 0
1
8
15
29
43
64
85
113
141
169
176
197
183
190
Window (days)d
-21 to 0
±2
±2
±2
±2
±4
±4
±4
±4
±4
±2
±2
Evaluate teduglutide 
eligibility (inclusion 
and exclusion) criteria
X
Xe
Dispense intake and 
output diaries
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications and 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination 
and vital signs, 
including weight
X
X
X
X
X
X
X
X
X
X
X
X
Height and head 
circumferencef
X
X
X
X
Review intake and 
output diariesg
X
X
X
X
X
X
X
X
X
X
X
X
X
Record PS Rx and 
adjust as neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety laboratory 
testsi
Xi
X
X
X
X
X
X
X
X
X
X
(X)
X
PedsQL Generic Core 
Scale/ Family Impact 
Module/ GI 
Symptoms Module 
Sub-Scales
X
X
X
Antibodies to 
teduglutidej
X
X
X
X
Fecal occult blood 
testing
X
X
X
Colonoscopy/
sigmoidoscopyk
(X)
(X)
(X)
For non-commercial use only


Shire
CONFIDENTIAL
Page 22
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
Table 1-3: Schedule of Events for Subjects While Receiving Teduglutide
Period
Pre-
treatment
Teduglutide Treatment
Follow-up
Pregnancy testingl
X
X
X
X
X
X
X
X
X
Serum samplem
X
X
Evaluate escape 
criterian
Xp
X
X
Dispense study drugo
X
X
X
X
X
X
X
X
X
EOS = end of study; EOT = end of treatment; ET = early termination; FOBT = fecal occult blood test; FOCBP = female of child-bearing potential; FU = follow-up; 
GI = gastrointestinal; PedsQL = Pediatric Quality of Life Inventory; PS= parenteral support; SBS = Short Bowel Syndrome; SC = subcutaneous; Scr = Screening; 
TED = teduglutide; Tx = treatment.
a If the first pretreatment visit (P1) follows the screening visit, it must occur within 12 weeks of screening.
b Phone visits are required approximately 1 week after adjustments in PS. The assessments to be performed at phone visits are the same as those described for CxW25-27 (except 
for evaluation of escape criteria). 
c The investigator may combine the CxW28 visit with the next pretreatment visit if at least one escape criterion is met at the CxW28 visit, and the pretreatment assessments occur 
within 7 days of the CxW28 visit. If a subject is completing the study at the CxW28 visit, the EOS/ET visit (Table 1-1) will take place in lieu of the CxW28 visit.
d Visit windows are relative to the CxD1 visit.
e Eligibility will need to be re-confirmed prior to the first dose in the cycle. Negative urine pregnancy test is required prior to the first dose of teduglutide, but results of other labs 
obtained at the CxD1 visit are not required to determine teduglutide treatment eligibility.
f Head circumference will be measured in subjects 36 months of age and younger.
g Intake diaries will collect actual PS volume and hours per day. Intake diaries should be completed daily for a minimum of 2 weeks immediately prior to each clinic visit (except 
at pretreatment visit), for 1 week following PS adjustment, and daily during the 4-week follow-up period. Urine and stool output should be recorded in the output diary over a 48-
hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PS prescription. See Section 7.2.11 for more detail.
h PS adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment provided in 
Appendix 2.
i Safety laboratory assessments at site visits will consist of clinical chemistry, hematology, and urinalysis, with results processed by a central laboratory. Clinical chemistry and 
urinalysis must also be performed within approximately 5-7 days of any adjustment to the PS prescription. Safety labs performed between clinic visits may be performed locally. 
Unscheduled lab results will not be captured in the eCRFs. If abnormal results are considered an adverse event, an AE form will be completed. Collect PT/INR at the pretreatment 
visit. Additional collection will occur if a potential drug-induced liver injury signal is observed. Urine specimen collection should be attempted as part of the safety labs, but lack 
of urinalysis will not constitute a protocol deviation.
j Samples collected on CxD1 must be drawn prior to first administration of teduglutide. Samples collected while subjects are receiving teduglutide (CxW12 and CxW24) must be 
drawn at least 14 hours after dosing.
k The teduglutide-naïve subjects age 12 and older will undergo colonoscopy/sigmoidoscopy at the pretreatment visit if one has not been performed within 1 year. Subjects of any 
age with newly positive FOBT results at the pretreatment visit for which a readily detectable cause cannot be identified (eg, anal fissure) will undergo a 
colonoscopy/sigmoidoscopy prior to receiving teduglutide. If newly positive FOBT results (for which a readily detectable cause cannot be identified) are obtained at the end of a 
teduglutide treatment cycle (CxW24/EOT), colonoscopy/sigmoidoscopy will be performed. The need for colonoscopy/sigmoidoscopy in response to positive FOBTs at CxW12 is 
at the discretion of the investigator. Teduglutide-exposed subjects who have received the equivalent of 2 treatment cycles (48 weeks of study drug exposure) will undergo 
colonoscopy/sigmoidoscopy. See Section 7.2.9 for details.
l A serum pregnancy test is performed on all FOCBP at the teduglutide pretreatment visit (when the pretreatment and screening visits are combined, the serum pregnancy test 
should be performed at the local laboratory). Urine pregnancy tests will be administered at all other visits according to the study schedules, or if pregnancy is suspected, or as 
specified per protocol upon withdrawal of the subject from the study.
m Lack of collection of serum samples will not constitute a protocol deviation.
For non-commercial use only


Shire
CONFIDENTIAL
Page 23
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
Table 1-3: Schedule of Events for Subjects While Receiving Teduglutide
Period
Pre-
treatment
Teduglutide Treatment
Follow-up
n If escape criteria are met, the subject may proceed directly to another pretreatment visit at the discretion of the investigator.
o The first SC injection of teduglutide in treatment-naïve subjects will be administered under the supervision of the investigator/designee after which the subject will be observed 
for hypersensitivity reactions for at least 4 hours. The site of administration (arm, thigh, abdomen) of the first teduglutide dose must be specified and recorded in the eCRF. See 
Section 6.2.3 for dose adjustment.
p Escape criteria will be assessed for subjects who escaped during the follow-up period of a previous teduglutide treatment cycle at CxW24. The investigator may combine the 
CxW24 visit with the next pretreatment visit if at least 1 escape criterion is met at the CxW24 visit. In order to combine assessments, the pretreatment assessments must occur 
within 7 days of the CxW24 visit. 
Note: (X) denotes conditional requirement for a given assessment if the subject meets certain conditions per protocol.
For non-commercial use only


Shire
CONFIDENTIAL
Page 24
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
1
BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options 
Short bowel syndrome (SBS) is a rare disorder resulting from congenital abnormalities or severe 
intestinal diseases that result in major surgical resections of the small intestine. It is estimated 
that, at most, there are a few hundred pediatric subjects 1 year and older with SBS (Khan et al., 
2015; Wales et al., 2004). Unlike the adult population, the majority of cases of SBS in pediatric 
subjects are due to congenital anomalies or catastrophic events that occur during infancy. 
Although the small intestine is capable of remarkable adaptation, excessive loss of absorptive 
surface area or specialized functions can lead to dependence on parenteral nutrition or 
intravenous (IV) fluids (parenteral support [PS]). Treatment of both pediatric and adult patients 
is focused on achieving adequate intestinal absorption to allow for minimization or 
discontinuation of PS. About 30% of infants with SBS become independent of PS requirements 
within 12 months of the initial insult, and an additional 10% wean off PS within 24 months. 
After this time, linear intestinal growth slows. About 60% of pediatric subjects with SBS are able 
to become independent of PS within 5 years of the initial diagnosis (Khan et al., 2015). 
Nevertheless, despite optimal medical management, many pediatric subjects remain dependent 
on PS. Complications of long-term PS include liver disease, catheter-related blood stream 
infections, central line-associated venous thrombosis and dwindling central venous access. 
Sepsis is the leading cause of death in these patients and quality of life is poor (Squires et al., 
2012). Accelerating the adaptive process and achieving enteral autonomy is an urgent goal for all 
patients with SBS who are dependent on PS (Khan et al., 2015; Squires et al., 2012).
Intestinal adaptation is driven by hormonal cues in response to nutrient malabsorption (Drucker 
and Yusta, 2014). Chief among these is hormones glucagon-like peptide 2 (GLP-2), which is 
secreted from L-type enteroendocrine cells that reside in the intestinal epithelium in the ileum 
and colon. Resection of these regions may impair the adaptive response by limiting endogenous 
production of GLP-2. 
1.2
Product Background 
Teduglutide is a novel, recombinant analog of naturally occurring human GLP-2 that regulates 
the functional and structural integrity of the cells lining the gastrointestinal (GI) tract. 
Teduglutide is a 33-amino acid peptide that differs from native GLP-2 in the substitution of 
glycine for alanine at the second position at the N-terminus. As a result, teduglutide demonstrates 
resistance to degradation by dipeptidyl peptidase-IV (DPP-4) and therefore maintains a longer 
elimination half-life (t1/2) in adults of approximately 2 hours compared to the native peptide, 
which has a t1/2 of approximately 7 minutes. Teduglutide has been shown in animal studies and 
previous human clinical trials to increase villus height and crypt depth in the intestinal 
epithelium, thereby increasing the absorptive surface area of the intestines (Tappenden et al., 
2013; Thymann et al., 2014). The European Commission granted a centralized marketing 
authorization valid throughout the European Union (EU) for teduglutide (Revestive™) on 30 
August 2012 and a New Drug Application (NDA) for teduglutide (Gattex®) was approved by the 
United States (US) Food and Drug Administration (FDA) on 21 December 2012 for the 
treatment of adult patients with SBS who are dependent on PS. Teduglutide has also been 
approved for use in adult patients with SBS in Canada and Switzerland. On 29 Jun 2016, the 
For non-commercial use only


Shire
CONFIDENTIAL
Page 25
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
European Commission granted an extension of the Market Authorization for teduglutide 
(REVESTIVE™) for the treatment of patients aged 1 year and above with SBS; patients should be 
stable following a period of intestinal adaptation.
1.3
Clinical Studies with Teduglutide in Pediatric Subjects
One Phase 3 study, TED-C13-003, was completed in pediatric SBS subjects in the US and 
United Kingdom (UK). In this study, teduglutide was administered to 3 cohorts of pediatric 
subjects from ages 1-17. Thirty-seven pediatric subjects received teduglutide at doses of 0.0125, 
0.025, or 0.05 mg/kg/day for 12 weeks. Five additional pediatric subjects were enrolled in an 
observational standard of care (SOC) cohort. There were clear dose-dependent effects of 
teduglutide seen at the 0.025 and 0.05 mg/kg/day doses compared to SOC and the 0.0125 
mg/kg/day dose. In the 0.025 mg/kg/day cohort there was a reduction in PS volume at week 12 
of 37%, including complete independence from PS support in 1 subject, and a reduction of 
3.94 hours per day infusion time. In the 0.05 mg/kg/day cohort there was a reduction in PS 
volume at week 12 of 39%, including complete independence from PS support in 3 subjects, and 
a reduction of 4.18 hours per day infusion time. Teduglutide was generally safe and well 
tolerated by pediatric subjects in all dosing cohorts. There were no deaths during the study and 
no treatment-emergent serious adverse events (TESAEs) related to teduglutide were reported. No 
discontinuations from study were due to adverse events (AEs).
TED-C14-006 is a recently completed study of pediatric subjects through 17 years which 
included 2 treatment arms: a teduglutide treatment arm and a SOC treatment arm. Subjects in 
both arms participated in a 2-week minimum screening period, a 24-week treatment period, and a 
4-week follow-up period. During the screening period, subjects chose into which arm to enroll. 
During the 24-week treatment period, subjects in the SOC treatment arm received standard 
medical therapy for SBS; while those in the teduglutide treatment arm received daily 
subcutaneous (SC) injections of teduglutide (study drug) in addition to standard medical therapy. 
The subjects enrolling in the teduglutide treatment arm were randomized 1:1 in a double-blinded 
manner into 2 parallel dose groups: 0.025 mg/kg/day or 0.05 mg/kg/day of teduglutide 
administered subcutaneously for 24 weeks.  Compared to the SOC, treatment of pediatric 
subjects with SBS with teduglutide resulted in clinically meaningful reductions in PN/IV 
volume, calories, days per week, and hours per day.  A total 10% of subjects who received 
teduglutide achieved enteral autonomy within 24 weeks despite prior dependence on PN/IV for 
several years.  Teduglutide treatment also resulted in increases in EN volume and caloric intake 
as well as plasma citrulline.  Although the differences in efficacy between the 0.025 and 0.05 
mg/kg dose groups were small, a consistently greater effect was seen in the 0.05 mg/kg dose in 
all efficacy parameters.  The PK properties were well characterized in this population and were 
consistent with the prior 12 week pediatric study.  Teduglutide was generally well tolerated by 
pediatric subjects with SBS.  The safety profile was favorable and consistent with the prior 
pediatric study, the underlying disease, and previous experience with teduglutide in adult 
subjects with SBS.
SHP633-301 is an ongoing study in the United Kingdom, Italy, Finland, and France to evaluate 
the safety, efficacy, and PK of teduglutide treatment in infants 4 to 12 months of age with SBS. 
Like TED-C14-006, this study has a teduglutide treatment arm and a SOC arm. Subjects in both 
arms will participate in a 2-week minimum screening period, a 24-week treatment period, and a 
4-week follow-up period. During the 24-week treatment period, subjects in the SOC treatment 
For non-commercial use only


Shire
CONFIDENTIAL
Page 26
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
arm will receive standard medical therapy for SBS; while those in the teduglutide treatment arm 
will receive daily SC injections of 0.05 mg/kg teduglutide in addition to standard medical 
therapy. Similar to the treatment cycles in SHP633-304, subjects in SHP633-301 may escape 
from the 4-week follow-up period and proceed directly to the SHP633-304 study, if they meet an 
escape criterion specified in the SHP633-301 protocol. It is expected the subjects entering 
SHP633-304 from SHP633-301 will be 11 to 19 months of age when enrolling in SHP633-304. 
Always refer to the latest version of the investigator’s brochure for the overall risk/benefit 
assessment and the most accurate and current information regarding the drug metabolism, 
pharmacokinetics, efficacy and safety of teduglutide (SHP633). 
For non-commercial use only


Shire
CONFIDENTIAL
Page 27
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
2
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study 
This is a Phase 3, prospective, open-label, long-term extension study to evaluate the safety and 
efficacy of teduglutide in pediatric subjects with SBS who completed the TED-C14-006 or 
SHP633-301 studies. In addition to evaluating the long-term safety and durability of efficacy 
after 24 weeks of treatment, this extension study will evaluate the need for additional teduglutide 
treatment in these subjects, and will allow for the first-time treatment of teduglutide-naïve 
subjects who participated in the SOC treatment arms in TED-C14-006 or SHP633-301.
2.2
Study Objectives
2.2.1
Primary Objectives
The primary objective of the study is to evaluate the long-term safety and tolerability of 
teduglutide treatment in pediatric subjects with SBS who completed TED-C14-006 or SHP633-
301. 
2.2.2
Secondary Objectives
The secondary objective of this study is to evaluate the long-term efficacy of teduglutide 
treatment in pediatric subjects with SBS who completed TED-C14-006 or SHP633-301.
For non-commercial use only


Shire
CONFIDENTIAL
Page 28
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
3
STUDY DESIGN
3.1
Study Design and Flow Chart
This is a Phase 3, prospective, open-label, long-term extension study to evaluate the safety and 
efficacy of teduglutide in pediatric subjects who completed the TED-C14-006 or SHP633-301 
studies (the "core studies"). At the time of entry into TED-C14-006, subjects were less than 
18 years of age, were dependent on parenteral nutrition to provide at least 30% of their caloric or 
fluid needs, and had not been able to significantly reduce PS for at least 3 months prior to 
enrollment. During TED-C14-006, some subjects elected to receive standard of care instead of 
teduglutide treatment. Subjects who elected to receive teduglutide were randomized to 
0.025 mg/kg or 0.05 mg/kg once daily (QD) dosing in a double-blinded manner. 
At the time of entry into SHP633-304, subjects were 4 to 12 months corrected gestational age, 
were dependent on parenteral nutrition to provide at least 35% of their caloric or fluid needs, and 
had not been able to significantly reduce PS for at least 1 month prior to enrollment. During 
SHP633-301, subjects were randomized to receive standard of care or teduglutide 0.05 mg/kg SC 
QD. 
Approximately 65 subjects who complete the core studies are expected to enroll in this extension 
study. All subjects who completed either core study, including those who received standard of 
care, may be eligible to enter SHP633-304.  To be eligible to receive teduglutide treatment 
within SHP633-304, subjects must meet ≥1 of the teduglutide treatment inclusion criteria and 
none of the teduglutide treatment exclusion criteria.  
Additional Teduglutide Treatment
Subjects not receiving teduglutide treatment (ie, in a “no-teduglutide treatment period”), will be 
seen approximately every 12 weeks for safety, parenteral support (PS) requirements, and quality 
of life. At any point during a no-teduglutide treatment period, subjects who meet ≥1 teduglutide 
treatment inclusion may proceed directly to the pretreatment visit if the investigator, subject, and 
parent agree to proceed with teduglutide therapy.
Rationale: Some pediatric subjects may have a durable beneficial effect after 24 weeks of 
teduglutide treatment and thus long-term follow-up without additional teduglutide treatment may 
be appropriate. However, there may be some pediatric subjects who deteriorate or stop 
improving after discontinuation of teduglutide treatment. In these pediatric subjects, additional 
teduglutide treatment may be beneficial. 
Dose Selection 
Analysis suggested that pediatric patients, ages 1 to 17 years old, are likely to require the same 
dose as used in adults, namely 0.05 mg/kg/day (Mouksassi et al., 2009). In this extension study, 
all subjects who enter a teduglutide treatment cycle will receive 0.05 mg/kg SC QD.
Rationale: Teduglutide is approved for adult use in the US and EU, and for pediatric use in the 
EU, at a dose of 0.05 mg/kg SC once daily. The completed pediatric studies (TED-C13-003 and 
TED-C14-006) demonstrated that teduglutide dosing at 0.025 and 0.05 mg/kg/day was 
associated with a favorable benefit/risk profile. In addition, population pharmacokinetic 
modeling and simulations were conducted to determine the effective dose to be used in pediatric 
subjects using data from 8 adult clinical studies including adult Phase 1 studies and Phases 2/3 
For non-commercial use only


Shire
CONFIDENTIAL
Page 29
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
studies as well as the pediatric study (TED- C13- 003) and suggested that the dose in pediatric 
subjects is likely to be same as the dose in adults (O'Keefe et al., 2006). 
Further PK simulation was conducted based on the population PK model previously established 
and a virtual population of 1000 pediatric patients created based on Centers for Disease Control 
(CDC) growth charts in the target age group (4 to 12 months) and taking into consideration body 
weights of pediatric patients with SBS enrolled in study TED-C13-003 (approximately 15% 
lower than healthy subjects in the same age group). Monte Carlo simulations for all age groups 
were performed according to the SC dosing regimens of 0.0125, 0.025 and 0.05 mg/kg every 
24 hours. Rich concentration-time profiles were simulated with the customized population PK 
model to derive the exposure metrics area under the concentration curve at steady state (AUCss) 
and maximum concentration at steady state (Cmax,ss). Following 0.05 mg/kg daily SC 
administration, the median Cmax,ss of teduglutide in infants (24.9 ng/mL) was within 20% of that 
observed in the 2 to 4 and 4 to 6 years age groups (26.9 and 29.4 ng/mL, respectively); and 
approximately ~28% lower than that in adult patients with SBS. The clinical package in 
conjunction with Cmax was considered to support teduglutide dose of 0.05 mg/kg since AUCss
was previously shown not to correlate with efficacy. Thus, the 0.05 mg/kg dose is proposed for 
testing in all age groups.
Duration of Treatment
The duration of teduglutide treatment in this study mirrors that of the TED-C14-006 and 
SHP633-301 studies, consisting of 24 weeks of teduglutide treatment, followed by a 4-week 
follow-up period. The follow-up period is a mechanism to evaluate whether continued 
teduglutide is needed. If a subject deteriorates during the follow-up period, the subject may be 
evaluated immediately for additional teduglutide treatment. Subjects who clinically deteriorate or 
stop improving at any time after the end of the follow-up period will also be assessed for 
additional treatment.
Rationale: During the teduglutide treatment cycle, visit frequency is similar to frequencies 
performed in TED-C13-003, TED-C14-006, and SHP633-301 to ensure sufficient safety 
monitoring and weaning of PS. During the no-teduglutide treatment, visits occur every 12 weeks, 
a frequency that is consistent with standard medical practices. To minimize risk to subjects, those 
who have deteriorated quickly after treatment interruption (ie, escaped from a prior follow-up 
period) may be evaluated immediately for eligibility for additional treatment when they reach the 
week 24 visit. 
Measures and Parameters
Following the review and signing of the informed consent (and informed assent, if applicable), 
screening visit procedures will begin including demographics, and updates to medical history 
and SBS history. Subjects who meet ≥1 of the teduglutide treatment inclusion criteria may 
proceed to the pretreatment visit.
After the pretreatment visit, subjects who still meet ≥1 of the teduglutide treatment inclusion 
criteria, and meet none of the teduglutide treatment exclusion criteria, will start a 28-week cycle, 
consisting of 24 weeks of teduglutide treatment at 0.05 mg/kg SC once daily, followed by a 4-
week follow-up (no treatment) period (Figure 3-1). During the 28-week cycle, clinic visits will 
occur at weeks 1, 2, 4, 6, 9, 12, 16, 20, 24, and 28. Phone visits are required approximately 
For non-commercial use only


Shire
CONFIDENTIAL
Page 30
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
1 week after adjustments in PS during the teduglutide treatment period (between weeks 1-24), 
and weekly during the teduglutide follow-up period (between weeks 24 and 28).
Safety and PS requirements will be evaluated on a weekly basis, and quality of life assessments 
will be made approximately every 12 weeks. At all site visits and telephone contacts, safety will 
be monitored and nutritional support will be reviewed and adjusted as needed. To maintain 
consistency across centers, all attempts should be made to follow the nutritional support 
adjustment guidelines (developed with SBS expert input and provided in the protocol) for 
decisions regarding PS reduction and advances in enteral feeds based on weight gain, urine and 
stool output, and clinical stability. Departure from the guidelines, however, is not considered a 
protocol deviation (Appendix 2).
Rationale: Measures of long term safety will include adverse events, growth parameters and anti-
drug antibodies. Measure of long term efficacy will include durability of effect as measured by 
reduction in PS and improvement in pediatric quality of life measures (PedsQL, PedsQL Family 
Impact Module). A reduction in PS volume of at least 20% at end of treatment (EOT) was used 
as the primary endpoint in pivotal phase 3 adult clinical trials and the completed phase 3 
pediatric study (TED-C13-003), and will be used as an endpoint in this extension study. In 
previous clinical studies, a reduction of this magnitude was associated with a reduction in the 
number of days per week of PS, and increases in enteral intake. Reduction in volume and time of 
PS due to improved enteral absorption may provide a pediatric subject with opportunities for 
more age-appropriate activities including oral rehabilitation. Quality of life assessments will be 
performed in this study to quantitate this effect.
Teduglutide has been found to have a targeted intestinotrophic effect. Taking into account the
patient population and the pharmacologic effect of teduglutide, GI-specific screening tests, 
including fecal occult blood testing and colonoscopy/sigmoidoscopy, which are commonly part 
of the routine care of these subjects, will be performed to ensure safety. This study captures long-
term safety data on polyps and other colonic mucosal changes in teduglutide-exposed subjects 
using the surveillance strategy proposed in Section 7.2.9. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 31
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
Figure 3-1:
Study Design Flow Chart
Figure legend: Safety and efficacy data for subjects not receiving teduglutide treatment are captured approximately every 
12 weeks, but subjects may proceed to the pretreatment visit at any time in order to assess eligibility for teduglutide therapy. 
Eligible subjects will enter a 28-week teduglutide cycle. During this cycle, subjects will return to the site for safety and efficacy 
assessments at weeks 1, 2, 4, 6, 9, 12, 16, 20, and 24 (solid black lines). Phone visits are required approximately 1 week after 
adjustments in PS during the intervening weeks between weeks 2 and 24 (dashed grey lines). Subjects discontinue teduglutide at 
week 24 and enter a 4-week follow-up (no-treatment) period, during which phone visits will be performed weekly (solid grey 
lines). If an escape criterion is met at week 24 or during the follow-up period, subjects may proceed directly to another 
pretreatment visit.
3.2
Duration and Study Completion Definition
A subject will be considered enrolled in the study once the subject has provided signed consent, 
and meets all of the Inclusion Criteria. The study will continue for at least 1 year and until each 
subject has access, as needed, to teduglutide. The subject’s maximum duration of participation is 
expected to be approximately 3 years. The study will be completed in approximately 40 months. 
A subject will be considered as having completed the study if the subject has not withdrawn 
early from the study for any reason prior to completing the End of Study (EOS) visit.
The study completion date is defined as the date the final subject, across all sites, completes their 
final protocol-defined assessment. Please note that this includes the follow-up visit or contact 
(last safety contact), whichever is later. The study completion date will be used to ascertain 
timing for study results posting and reporting.
For non-commercial use only


Shire
CONFIDENTIAL
Page 32
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
4
STUDY POPULATION
Each subject must review and sign the informed consent (and informed assent, if applicable) 
before any study-related procedures specified in the protocol are performed. Teduglutide 
treatment eligibility does not impact study eligibility.
4.1
Study Inclusion Eligibility Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1. Subject provides written informed consent (subject, parent or legal guardian and, as 
appropriate, subject informed assent) to participate in the study before completing any 
study-related procedures. 
2. Subject completed the TED-C14-006 or SHP633-301 studies (including subjects in the 
standard of care treatment arms).  Subjects are considered to have completed SHP633-
301 if they completed study assessments through week 24.
3. Subject understands and is willing and able to fully adhere to study requirements as 
defined in this protocol.
4.2
Study Exclusion Eligibility Criteria
There are no exclusion criteria for this study.
4.3
Teduglutide Eligibility Criteria
Subjects are eligible for teduglutide treatment if at least 1 (≥1) of the teduglutide treatment 
inclusion criteria, and none of the teduglutide treatment exclusion criteria are met. In addition, 
the investigator and the subject (and/or parent or legal guardian, as appropriate) must agree to 
proceed with treatment.
4.4
Teduglutide Treatment Inclusion Criteria
1. Subject is teduglutide-naïve, receiving PS, and unable to significantly reduce PS or 
advance enteral feeds (eg, 10% or less change in PS or advance in feeds) for at least 
3 months prior to and during the teduglutide pretreatment visit, as assessed by the 
investigator. Transient instability for events such as interruption of central access or 
treatment for sepsis is allowed if the PS returns to within 10% of baseline prior to the 
event.
2. Subject was previously treated with teduglutide and at least 1 of the following criteria is 
satisfied:
a.
Increasing PS requirements following teduglutide discontinuation.
b. Decreased PS requirement during prior teduglutide treatment, followed by 
cessation of improvement after teduglutide discontinuation.
c.
Deteriorating nutritional status eg, weight loss or growth failure) despite 
maximal tolerated enteral nutrition (EN) following teduglutide discontinuation.
d. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid 
and electrolyte intake following teduglutide discontinuation.
For non-commercial use only


Shire
CONFIDENTIAL
Page 33
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
e.
Severe diarrhea related to teduglutide discontinuation.
4.5
Teduglutide Treatment Exclusion Criteria
1. Body weight <5 kg at the pretreatment visit.
2. Unresected GI polyp, known polyposis condition, premalignant change, or malignancy, 
in the GI tract
3. History of cancer in the previous 5 years except surgically curative skin cancers
4. Serial transverse enteroplasty or other major intestinal surgery within 3 months 
preceding the teduglutide pretreatment visit. Insertion of a feeding tube, anastomotic 
ulcer repair, minor intestinal resections ≤10 cm, and endoscopic procedures are allowed.
5. Intestinal or other major surgery planned or scheduled to occur during the 28-week cycle
6. Clinically significant intestinal stricture or obstruction
7. Clinically significant, active or recurrent pancreatic or biliary disease
8. Active, severe, or unstable, clinically significant hepatic impairment or injury, including 
the following laboratory values at the pretreatment visit:
a.
Total bilirubin ≥2 × upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥7 × ULN
c.
Alanine aminotransferase (ALT) ≥7 × ULN
9. Renal dysfunction shown by results of an estimated glomerular filtration rate below 
50 mL/min/1.73 m2 at the pretreatment visit
10. Unstable cardiac disease, congenital heart disease or cyanotic disease, with the exception 
of subjects who had undergone ventricular or atrial septal defect repair, or patent ductus 
arteriosus ligation
11. Participation in a clinical study using an experimental drug (other than glutamine, 
Omegaven, or Smoflipid) within 3 months or 5.5 half-lives of the experimental drug, 
whichever is longer, prior to the pretreatment visit and for the duration of the 28-week 
cycle
12. Treatment with analogs of glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 
(GLP-2) (not including teduglutide), insulin-like growth factor-1 (IGF-1), or growth 
hormone, within 3 months preceding the teduglutide pretreatment visit.
13. Treatment with octreotide or dipeptidyl peptidase 4 (DPP-4) inhibitors within 3 months 
prior to the pretreatment visit
14. Known or suspected intolerance or hypersensitivity to the investigational product, 
closely-related compounds, or any of the stated ingredients
15. Known history of alcohol or other substance abuse within 1 year prior to the 
pretreatment visit
16. Pregnant or lactating female subjects 
17. Sexually active female subjects of child-bearing potential unwilling to use approved 
contraception during teduglutide treatment and for 30 days after the treatment period 
For non-commercial use only


Shire
CONFIDENTIAL
Page 34
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
18. Any condition, disease, illness, or circumstance that in the investigator’s opinion puts 
the subject at any undue risk, prevents completion of the study, or interferes with 
analysis of the study results.
4.6
Follow-up Period Escape Criteria
At the discretion of the investigator, the follow-up period may be interrupted or omitted and the 
subject may proceed directly to the pretreatment visit, if ≥1 of the following criteria is met:
1. Increasing PS requirements following teduglutide discontinuation.
2. Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation.
4. Severe diarrhea related to teduglutide discontinuation.
5. The subject escaped during the follow-up period of SHP633-301 or during the follow-up 
period of a previous teduglutide treatment cycle within SHP633-304.
4.7
Reproductive Potential
4.7.1
Female Contraception
To be eligible for treatment with teduglutide, sexually active females of child-bearing potential 
must use an acceptable form of contraception throughout the study period and for 30 days 
following the last dose of investigational product. If hormonal contraceptives are used, they 
should be administered according to the package insert. Females of child-bearing potential who 
are not currently sexually active must agree to use acceptable contraception, as defined below, if 
they become sexually active during the period of the study and 30 days following the last dose of 
investigational product. 
To be eligible for treatment with teduglutide, female pediatric subjects and adolescent subjects 
should be either:

Pre-menarchal and either Tanner Stage 1 or less than age 9 years, or

Females of child-bearing potential (FOCBP) with a negative serum beta-human chorionic 
gonadotropin (-HCG) pregnancy test at the teduglutide pretreatment visit. Females of 
child-bearing potential must agree to abstain from sexual activity that could result in 
pregnancy or agree to use acceptable methods of contraception.
Acceptable methods of contraception are:

True abstinence: Abstention of sexual activity that is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
post-ovulation methods] and withdrawal are not acceptable methods of contraception).

Intrauterine devices plus condoms
For non-commercial use only


Shire
CONFIDENTIAL
Page 35
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018

Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or foam)

Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring), stabilized for at 
least 30 days prior to the pretreatment visit, plus condoms. Note: if subject becomes 
sexually active during the study, they should use one of the other acceptable methods 
noted above in addition to the hormonal contraceptive until it has been stabilized for 
30 days.
4.8
Discontinuation of Subjects 
4.8.1
Teduglutide Discontinuation
If the investigational product is discontinued prematurely during a teduglutide treatment cycle 
and the subject wishes to remain in the study, the evaluations listed for the EOT visit are to be 
performed. A 4-week follow-up period will ensue, consisting of weekly telephone visits 
(CxW25-27) and the week 28 clinic visit (CxW28). The subject would then enter a 
no-teduglutide treatment (NTT) period and could be evaluated for subsequent teduglutide 
treatment eligibility according to the study schedules. Comments (spontaneous or elicited) or 
complaints made by the subject must be recorded in the source documents. The reason for 
permanent treatment discontinuation, dates of investigational product administered (including 
last date of treatment), and amount of investigational product taken must be recorded in the 
electronic case report form (eCRF) and source documents, as described in Section 4.8.3. The 
investigator is encouraged to discuss withdrawal of a subject from investigational product with 
the medical monitor, when possible.
4.8.2
Study Withdrawal
At any time during the study, the investigator or sponsor may withdraw a subject, or a subject 
may withdraw from the study, for any reason, without prejudice to their future medical care by 
the physician or at the institution.
If a subject withdraws from the study during a teduglutide cycle, the evaluations listed for the 
EOT visit are to be performed as completely as possible. Whenever possible, the subject will 
then be asked to return 4 weeks later for the early termination (ET) visit, and will be contacted 
weekly by phone during the interim period between EOT and ET for safety follow-up.
If a subject withdraws from the study during a NTT period, the evaluations listed for the ET visit 
are to be performed as soon and completely as possible. 
Subjects who withdraw from the study will not be replaced.
4.8.3
Reasons for Discontinuation
The reason(s) for permanent discontinuation of treatment and/or withdrawal from the study must 
be determined by the investigator, and recorded in the subject’s medical record and in the eCRF. 
If a subject is withdrawn for more than 1 reason, each reason should be documented in the source 
document, and the most clinically relevant reason should be entered in the eCRF.
Reasons for discontinuation include, but are not limited to:
For non-commercial use only


Shire
CONFIDENTIAL
Page 36
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018

Adverse event 

Protocol deviation

Lack of efficacy 

Physician decision 

Withdrawal by subject 

Withdrawal by parent/guardian

Lost to follow-up

Pregnancy (Discontinuation of treatment only) 

Death 

Other 
4.8.3.1
Subjects ‘Lost to Follow-up’ Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact (office visit or telephone contact). At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that they 
return to the site for final safety evaluations, and return any unused investigational product.
For non-commercial use only


Shire
CONFIDENTIAL
Page 37
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
5
CONCOMITANT TREATMENT
5.1
Concomitant Medications and Procedures
Concomitant treatment refers to all treatment taken between the dates of informed consent and 
EOS, inclusive. Concomitant medications and procedures will be assessed at each site visit, and 
include all non-study treatments (medications, herbal treatments, vitamins, invasive and 
diagnostic procedures). Concomitant treatment information must be recorded on the appropriate 
eCRF page. Details of medication changes and/or dosages will be recorded on the eCRF.  
5.1.1
Permitted Treatment
Standard medical therapy for SBS should be continued.
5.1.2
Prohibited Treatment
The mechanism of action of teduglutide may increase enteral absorption of drugs (eg, motility 
medication including narcotics and opioids used for the management of SBS, warfarin, 
psychotropics, metronidazole, digoxin), so consideration should be given to modifying 
concomitant enteral medication regimens. Down-titration of concomitant enteral medications 
should be considered when drugs, especially those with a narrow therapeutic range, are given at 
dosages that are higher than usual.
The following medications are prohibited during teduglutide treatment and within the provided 
timeframe prior to the pretreatment visit:
Table 5-1: Prohibited Treatment
Prior Therapy
Time Restriction Prior to 
the Pretreatment Visit
Native/synthetic glucagon-like peptide-2 (not-including teduglutide)
Any
Glucagon-like peptide-1 analog or human growth hormone
3 months
Octreotide or dipeptidyl peptidase 4 inhibitors
3 months
For non-commercial use only


Shire
CONFIDENTIAL
Page 38
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
6
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product 
The test product is teduglutide, which will be provided in sterile, single-use 3 mL vials 
containing 5 mg or 1.25 mg teduglutide as a white lyophilized powder to be reconstituted before 
use with 0.5 mL sterile water for injection. In addition to the active ingredient (teduglutide), each 
vial of teduglutide contains L-histidine, mannitol, monobasic sodium phosphate monohydrate, 
and dibasic sodium phosphate as excipients. Additional information is provided in the current 
SHP633 investigator’s brochure.
6.1.1
Blinding the Treatment Assignment
Not applicable for this open-label study.
6.2
Administration of Investigational Product(s)
6.2.1
Interactive Response Technology for Investigational Product Management
An interactive web-based response system (IWRS) will be used for screening and enrolling 
subjects, recording subject visits, investigational product supply dispensation and management, 
inventory management and supply ordering, investigational product expiration tracking and 
management, and return of investigational product. Please refer to the Study Manual for 
additional details regarding the IWRS. 
The IWRS will also be used for creating, tracking, and confirming investigational product 
shipments. A user manual with specific functions and instructions for the IWRS will be provided 
to the site, and site personnel will receive training.
6.2.2
Allocation of Subjects to Treatment 
This is an open-label study. Subjects will retain their assigned subject number from the 
TED-C14-006 or SHP633-301 studies. Assessment of need for teduglutide treatment should be 
guided by the teduglutide treatment inclusion criteria. If the investigator, subject, and/or 
parent/guardian agree to proceed with treatment, a formal evaluation of teduglutide inclusion and 
exclusion criteria will be performed at the pretreatment visit (Table 1-3). 
6.2.3
Dosing
If teduglutide treatment eligibility is established at the pretreatment visit and again, confirmed at 
the CxD1 visit, the subject will start a teduglutide treatment period, consisting of 24 weeks of 
teduglutide treatment at 0.05 mg/kg SC once daily. The initial dose will be calculated based on 
body weight measured at the teduglutide pretreatment visit, and adjusted as needed, based on 
body weight measured at week 12 (CxW12). No other adjustments to dose will be made during 
the teduglutide treatment period, unless discussed with the sponsor’s medical monitor. 
Following reconstitution, teduglutide will be administered by SC injection QD into 1 of the 
4 quadrants of the abdomen (in subjects without a stoma) or into either the thigh or arm. For 
subjects with a stoma, the quadrant of the abdomen containing the stoma should not be used. 
Teduglutide should be used as soon as possible after reconstitution, but no more than 3 hours 
later.
For non-commercial use only


Shire
CONFIDENTIAL
Page 39
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
The subject should be dosed at approximately the same time each day. Consecutive doses should 
be separated by at least 12 hours. Each day, the injection site should be rotated.
The first SC injection in teduglutide-naïve subjects should be administered under the supervision 
of the investigator or designee and the subject observed for hypersensitivity reactions for at least 
4 hours during their initial dosing visit. The site of administration (arm, thigh, and abdomen) of 
the first teduglutide dose must be specified and recorded in the eCRF. 
Detailed instructions for reconstitution and injection of the investigational product can be found 
in the Instructions for Use. 
At the end of each 24-week teduglutide treatment period, subjects will be evaluated for the need 
for additional teduglutide treatment. During the 4-week follow-up, the investigator will assess 
the subject via weekly telephone visits. At any time during the follow-up period, if escape 
criteria are met, the subject may proceed directly to another Pre-Treatment visit to assess 
treatment eligibility for another cycle (Section 4.6). Following the completion of the 4-week 
follow-up, the subject will continue in the study off teduglutide until teduglutide treatment 
eligibility criteria are again met. Additional 28-week cycles may be repeated if treatment 
eligibility is established each time. 
6.2.4
Unblinding the Treatment Assignment
Not applicable for this open-label study.
6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling 
Labels containing study information and pack identification will be applied to the investigational 
product(s) container. 
The study drug will be packaged, labeled, and shipped to the study site by the sponsor or 
designee. Kits containing 7 vials of study drug will be supplied and these will be labeled in 
accordance with applicable regulatory requirements. Sterile water for injection syringes and 
other ancillary components will be provided separately and will be labeled in accordance with 
the applicable regulatory requirements.
All study drug used in this study will be manufactured, tested, labeled, and released according to 
current legal requirements and Good Manufacturing Practice.
6.3.2
Packaging
Investigational product is packaged in the following conditions:
Teduglutide will be provided in a sterile, single-use, glass vial as a lyophilized powder, to be 
reconstituted with 0.5 mL sterile water for injection provided as the diluent in a prefilled syringe.
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
For non-commercial use only


Shire
CONFIDENTIAL
Page 40
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
6.3.3
Storage and Handling
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.
Study drug must be kept in a locked area with access restricted to specific study personnel. Study 
drug will be stored refrigerated at a temperature between 2 to 8°C (35.6 to 46.4°F) until 
dispensed to a subject. Once dispensed to a subject, the study drug can be stored refrigerated or 
up to a controlled room temperature (acceptable range of 2 to 25°C, or 35.6 to 77°F). 
Parent/guardian will be instructed to keep the subject’s study drug and sterile water diluent at 
controlled room temperature. If there are concerns that the controlled room temperature cannot 
be maintained, the study drug may be refrigerated. The study drug is for single use only, and 
should be used within 3 hours following reconstitution.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (ie, certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
Investigational products are distributed by the pharmacy or nominated member of the study 
team. The pharmacist/nominated team member will enter the unique subject identifier on the 
investigational product bottle/carton labels, as they are distributed. 
6.4
Drug Accountability 
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. The 
investigator is to keep a current record of the inventory and dispensation of all clinical supplies. 
This record will be made available to the sponsor’s site monitor for the purpose of accounting for 
all clinical supplies. Any discrepancy or deficiency will be recorded and will include an 
explanation. All supplies sent to the investigator must be accounted for and in no case will 
clinical supplies be used in any unauthorized situation.
For non-commercial use only


Shire
CONFIDENTIAL
Page 41
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
The investigator has overall responsibility for administering/dispensing investigational product. 
Where permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator. 
This delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will dispense the investigational product only to subjects eligible 
for teduglutide treatment following the procedures set out in the study protocol. All dispensed 
study medication will be documented in the interactive response technology system and/or other 
investigational product record (eg, investigation product accountability form). The investigator is 
responsible for assuring the retrieval of all study supplies from subjects.
All used and unused study drug vials must be returned by the subjects and/or parent/guardian, 
and will be retained at the site. If deemed appropriate, the investigator or his/her designee may 
dispense the unused study drug vials to the same subject. All original containers, whether empty 
or containing study drug will be returned to the pharmacy. Returned study drugs will NOT be 
relabeled or reassigned for use by other subjects. Contents of the study drug containers will not 
be combined. All used and unused vials must be returned to the distribution center according to 
the sponsor’s instruction. No vial/kit may be destroyed on site without approval by the sponsor. 
Please see the Pharmacy Manual for additional information.
6.5
Subject Compliance
Subjects will be instructed to bring their unused investigational product and empty/used 
investigational product packaging to every visit. Drug accountability will be assessed at the 
container/packaging level for unused investigational product that is contained within the original 
tamper-evident sealed container (eg, bottles, trays, vials) or at the individual count level for 
opened containers/packaging. The pharmacist/nominated person will record details on the drug 
accountability form.
Compliance with study drug is calculated from subject diaries. Of those subjects eligible for 
teduglutide treatment, subjects who have received 80% of the planned doses administered will be 
assessed as being compliant with the study protocol.
For non-commercial use only


Shire
CONFIDENTIAL
Page 42
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
7
STUDY PROCEDURES
7.1
Study Schedule
Detailed study procedures and assessments to be performed for subjects throughout the study are 
outlined in the Schedule of Assessments (Table 1-1, Table 1-2, and Table 1-3) and must be 
referred to in conjunction with the instructions provided in this section. 
7.1.1
Screening 
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent (and assent, as applicable) 
from the subject. A subject will have approximately 7 days, after completion of either the 
TED-C14-006 or SHP633-301 studies, to sign consent to participate in the SHP633-304 study. 
The first visit after screening must occur within 12 weeks of screening for a pretreatment visit, 
and within 2 to 12 weeks of screening for an NTx visit.
The screening visit (Scr) assessments and procedures, beginning with informed consent, will be 
performed as outlined in Table 1-1, and as detailed below:

Informed consent, and informed assent (if applicable), is obtained

Study eligibility is determined. A screen failure is a subject who has given informed 
consent and failed to meet the Study Inclusion Eligibility Criteria. Subjects cannot be 
rescreened once they have been designated as a screen failure. 

Demographics, updates to medical history and SBS history

Intake and output diaries are dispensed

Evaluate teduglutide treatment inclusion criteria 

Adverse events, concomitant medications and concomitant procedures
7.1.2
Visits for Subjects Not Receiving Teduglutide
While outside of the 28-week teduglutide-treatment cycle, subjects will be followed 
approximately every 12 weeks for safety and efficacy assessments. No-teduglutide treatment 
visits are numbered sequentially (NT1, NT2, etc.), even if interrupted by the treatment cycles. 
The visit window (±7 days) is relative to the first NTx visit in the current NTT period. 
Assessments will be performed as outlined in Table 1-2 and described below.

Intake and output diaries are dispensed

Evaluate teduglutide treatment inclusion criteria

Adverse events, concomitant medications and concomitant procedures

Physical examination and vital signs, including weight
For non-commercial use only


Shire
CONFIDENTIAL
Page 43
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018

Height and head circumference

Review intake and output diaries

Record PS prescription and adjust as needed

Safety Laboratory Tests (ie, clinical chemistry, hematology, and urinalysis)

PedsQL Generic Core Scale/PedsQL Family Impact Module/ PedsQL Gastrointestinal 
Symptoms Module Sub-Scales

Antibodies to teduglutide, if and when required

Fecal occult blood testing, as indicated (Section 7.2.9.1)

Colonoscopy/sigmoidoscopy, as indicated (see Section 7.2.9.2)

Serum sample, as indicated
Teduglutide treatment may be considered at any time during the NTT period. If the investigator 
and the subject (and parent or legal guardian, as appropriate) agrees to proceed with treatment if 
the subject is eligible, the subject may proceed to the pretreatment visit immediately to determine 
eligibility. 
7.1.3
Visits for Subjects Receiving Teduglutide
7.1.3.1
Pre-treatment Visit
Subjects who meet at least 1 of the teduglutide treatment inclusion criteria during the screening 
visit or during the NTT period may proceed to the pretreatment visit immediately if the 
investigator, subject and parent agree to proceed with teduglutide therapy. Similarly, subjects 
who meet escape criteria at cycle week 24 or during the teduglutide follow-up period may 
proceed to the pretreatment visit immediately.
The pretreatment visit may also be combined with screening visit, and if the pretreatment visit 
assessments occur within 7 days of the TED-C14-006 or SHP633-301 EOS visit, both sets of 
assessments can be combined. A subject must have 2 weeks of intake diary data collected, prior 
to the first dose administration (CxD1) during any teduglutide treatment cycle. In general, 
pretreatment assessments may occur over a period of up to 21 days. The teduglutide pretreatment 
visit (Px) assessments and procedures will be performed as in Table 1-3 and as described below:

Evaluate teduglutide eligibility (treatment inclusion/exclusion criteria) 

Dispense intake and output diaries

Adverse events, concomitant medications and concomitant procedures

Fecal occult blood testing 
For non-commercial use only


Shire
CONFIDENTIAL
Page 44
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018

Gastrointestinal-specific testing, including colonoscopy or sigmoidoscopy as indicated

Physical examination and vital signs, including weight

Height and head circumference

Review intake and output diaries

Record PS prescription and adjust as needed.

Safety Laboratory Tests 
(In addition to clinical chemistry, hematology, and urinalysis, labs at this visit include 
prothrombin time [PT] international normalized ratio [INR]. Subsequent prothrombin 
time/international normalized ratio [PT/INR] measurement is only required to evaluate 
for suspected drug-induced liver injury [DILI]). 

Serum pregnancy testing, if applicable (when the pretreatment and screening visits are 
combined, the serum pregnancy test should be performed at the local laboratory)

Serum sample 
7.1.3.2
Teduglutide Treatment Period (CxD1-CxW24)
The open-label teduglutide treatment period will comprise 24 weeks, during which all 
assessments and procedures listed for Visits CxD1-CxW24 in Table 1-3 shall be completed. 
Cycles are numbered sequentially, such that the first visit of the first cycle is C1D1, and the first 
visit of the second cycle is C2D1, etc. Visit windows are calculated based upon the date of first 
investigational product administration (Visit CxD1). 
Visit CxD1
Assessments and procedures at this visit will be performed as outlined Table 1-3 and as 
described below. 
Two weeks of intake diary data are required before drug is administered at CxD1.

Confirm teduglutide treatment eligibility

Dispense intake and output diaries

Adverse events, concomitant medications and concomitant procedures

Physical examination and vital signs, including weight 

Height and head circumference

Review intake and output diaries

Record PS prescription and adjust as needed 
For non-commercial use only


Shire
CONFIDENTIAL
Page 45
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018

Safety laboratory tests

Quality of life measurements 

Antibodies to teduglutide

Pregnancy testing (urine), if applicable

Dispense study drug
Site Visits during Teduglutide Treatment Period
Subjects will return for clinic visits on cycle weeks 1, 2, 4, 6, 9, 12, 16, 20, and 24/EOT. 
Assessments and procedures at these visits will be performed as outlined in Table 1-3 and as 
described below:

Dispense/review intake and output diaries (every effort should be made to complete 
2 weeks of intake diary entries prior to each clinic visit and to complete 48 hours of 
output diary entries during a period of nutritional stability prior to each clinic visit)

Physical examination and vital signs, including weight

Record PS prescription and adjust as needed

Safety laboratory tests 

Urine pregnancy testing for FOCBP (CxW4, CxW9, CxW12, CxW16, CxW20, CxW24)

Study drug dispensation (except for CxW24)

Adverse events, concomitant medications and concomitant procedures
In addition, at CxW12 and CxW24 Visits ONLY, the following procedures will be performed:

Height and head circumference

Antibodies to teduglutide

Fecal occult blood testing (FOBT)

GI-specific testing, including colonoscopy or sigmoidoscopy as indicated 

Quality of life measurements 
At CxW24 ONLY, a serum sample is collected and stored for future analysis. This sample will 
not be used for genetic testing and lack of collection will not constitute a protocol deviation.
For non-commercial use only


Shire
CONFIDENTIAL
Page 46
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
Escape criteria are also evaluated at CxW24.  The investigator may combine the CxW24 
assessments with the next pretreatment visit assessments if at least 1 escape criterion is met at the 
CxW24 visit and the pretreatment assessments occur within 7 days of the CxW24 visit.
Phone Visits 
Phone visits are required approximately 1 week after adjustments in PS during the teduglutide 
treatment period. Phone visit assessments and procedures are outlined in Table 1-3 and described 
below:

Review intake and output diaries

Safety laboratory tests (clinical chemistry and urinalysis)

Record PS prescription and adjust as needed

Obtain AEs, concomitant medications, and concomitant procedures  

Evaluate escape criteria
7.1.4
Teduglutide Follow-up Period
The safety follow-up period for this protocol is 4 weeks (weeks 25 – 28 of the cycle). Phone 
visits will occur on cycle weeks 25, 26, and 27 for all subjects. Phone visit assessments and 
procedures at weeks 25-27 will be the same as for telephone visits performed during the 
teduglutide treatment period. In addition, subjects will be evaluated for follow-up period escape 
criteria. If escape criteria are met at any time during the follow-up period, the subject may 
proceed directly to another pretreatment visit at the investigator’s discretion. The investigator 
may combine the CxW24 or CxW28 visits with the next pretreatment visit if at least 1 escape 
criterion is met at the CxW24 or CxW28 visits, and the pretreatment assessments occur within 
7 days of the CxW24 or CxW28 visit. If a subject is completing the study at the CxW28 visit, the 
EOS/ET visit (Section 7.1.5) will take place in lieu of the CxW28 visit. Otherwise, following 
completion of the 28-week treatment cycle, the subject will proceed to an NTT visit within 
approximately 12 weeks.
At cycle week 28 (CxW28), subjects will return to the study site. In addition to the assessments 
performed at weeks 25-27, the following procedures will be performed at CxW28 ONLY:

Dispense intake and output diaries 

Physical examination and vital signs, including weight

Antibodies to teduglutide

Pregnancy testing (urine), if applicable

Evaluate escape criteria
For non-commercial use only


Shire
CONFIDENTIAL
Page 47
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
7.1.5
Study Completion/Early Termination Visit (EOS/ET Visit) 
All subjects will return to the study site for the end of study/early termination visit (EOS/ET). 
Assessments and procedures at this visit will be performed as outlined in Table 1-1 and as 
described here. If a subject discontinues the study prematurely, the assessments for the EOS/ET 
Visit are to be performed as completely as possible (see Section 4.8.2).

Adverse events, concomitant medications and concomitant procedures  

Physical examination and vital signs, including weight

Height and head circumference

Review intake and output diaries (the intake diary should be completed daily for a 
minimum of 2 weeks prior to the EOS/ET visit. The output diary should be completed 
daily over a 48-hour period of nutritional stability before the EOS/ET visit)

Record PS prescription and adjust as needed

Safety laboratory tests 

Fecal occult blood testing, as indicated

Gastrointestinal-specific testing, including colonoscopy or sigmoidoscopy as indicated. 

Quality of life measurements 

Antibodies to teduglutide

Pregnancy testing, as needed
7.2
Study Evaluations and Procedures
7.2.1
Demographics, Medical History, and SBS History
Demographics, medical history, and SBS history will be obtained at screening. Medical history 
for purposes of this extension study will consist of the following:

Adverse events that were ongoing at the time of completion of TED-C14-006 or 
SHP633-301

Events that occurred during the period between completion of TED-C14-006 or SHP633-
301 and informed consent to SHP-633-304 
This medical history information will supplement the medical history information collected at 
the start of the TED-C14-006 or SHP633-301 core studies. If the subject has any changes to the 
SBS history collected at the baseline visit of the TED-C14-006 or SHP633-301 studies, that 
information (updated SBS history) will be collected.
For non-commercial use only


Shire
CONFIDENTIAL
Page 48
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
7.2.2
Physical Examination
Physical examinations will be performed according to the study schedules. Any new clinically 
significant findings noted during physical examinations should be recorded on the appropriate 
AE page of the eCRF. 
7.2.3
Vital Signs, Body Weight, Height, Head Circumference and Body Mass 
Index
Vital signs will be measured according to the study schedules. Measurements will include 
systolic and diastolic blood pressure (mmHg), pulse (beats per minute), and body temperature 
(°C/°F). Blood pressure should be determined by cuff (using the same method, the same 
extremity, and in the same position throughout the study, whenever possible).
Body weight will also be recorded in the eCRF; subjects should be weighed on the same scale at 
each study visit. Height (or length) and head circumference (for subjects ≤36 months of age) will 
be measured at selected visits. A height z-score, weight z-score, BMI, and BMI z-score will be 
calculated by the sponsor using the site-provided height and weight data collected at each site 
visit
New clinically significant vital sign abnormalities should be recorded on the appropriate AE 
page of the eCRF.
7.2.4
Clinical Laboratory Tests
Safety laboratory tests to be performed at site visits consist of clinical chemistry, hematology, 
and urinalysis and will be performed as outlined in the study plan (Table 1-1, Table 1-2, and 
Table 1-3) Scheduled laboratory testing will be processed by a central lab. All laboratory assays 
will be performed according to the central laboratory’s normal procedures. Reference ranges are 
to be supplied by the laboratory. The investigator should assess out-of-range clinical laboratory 
values for clinical significance, indicating if the value(s) is/are not clinically significant or 
clinically significant. Abnormal clinical laboratory values, which are unexpected or not 
explained by the subject’s clinical condition, may, at the discretion of the investigator or sponsor, 
be repeated as soon as possible until confirmed, explained, or resolved. 
During the teduglutide treatment period, subjects will also have safety labs within approximately 
5-7 days after a PS adjustment. Safety labs performed after PS adjustment and between site visits 
will consist of clinical chemistry and urinalysis and may be processed by the central laboratory 
or a local laboratory. Local lab results are not required to be entered in the eCRFs; however, if 
the local lab results indicate any new clinically significant changes, they must be reported as an 
adverse event (see Section 8.1). Urine specimen collection should be attempted as part of the 
safety labs, but lack of urinalysis will not constitute a protocol deviation.
New clinically significant labs should be reported as AEs.
The following clinical laboratory assessments will be performed according to the study 
schedules: 
For non-commercial use only


Shire
CONFIDENTIAL
Page 49
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
Table 7-1: List of Laboratory Tests 
Hematology:

Hematocrit 

Hemoglobin 

Platelet count

Red blood cell count 

Red blood cell morphology, if needed

White blood cell count with differential
Coagulation:
Prothrombin time/International normalized ratio 
Urinalysis: 

Blood

Glucose

Leukocytes

Microscopic analysis

pH 

Protein

Specific gravity
Pregnancy tests (females of childbearing potential):
o
Serum β-HCG (screening)
o
Urine β-HCG (all other visits)
Biochemistry:

Albumin 

Alkaline phosphatase 

Alanine aminotransferase 

Amylase

Aspartate aminotransferase 

Bicarbonate

Bilirubin (total, direct, and indirect)

Blood urea nitrogen 

Calcium (total)

Chloride

Cholesterol

C-reactive protein 

Creatinine

Estimated Glomerular Filtration Rate 
(Schwartz formula)

Gamma-glutamyl transferase 

Glucose

Lipase

Magnesium

Phosphorus

Potassium 

Sodium 

Triglycerides

Uric acid
7.2.5
Serum Sampling
Serum samples will be collected and stored for future analysis at the following times: 

At the pretreatment visit.  If the subject arrived at the pretreatment visit by meeting an 
escape criterion, the serum sample will not be repeated at the pretreatment visit, because 
it will have been collected recently at the CxW24 visit.

At the CxW24 (EOT) visit

During NTT: Approximately every 24 weeks 
The serum sample will not be used for genetic testing. Lack of collection will not constitute a 
protocol deviation.
The sponsor, sponsor’s representatives, biorepositories, and any specialty laboratories will be 
blinded to the subject’s identity. The sample and/or extracted material will otherwise be stored 
for up to 15 years from the end of the study after which time it will be destroyed. Upon written 
request, subjects will be permitted to withdraw their sample from the analysis and have their 
For non-commercial use only


Shire
CONFIDENTIAL
Page 50
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
sample and/or extracted material destroyed. Any results already generated from the samples will 
not be removed from any analyses that have already been performed.
7.2.6
Pregnancy Testing
A serum pregnancy test is performed on all FOCBP at the teduglutide pretreatment visit (when 
the pretreatment and screening visits are combined, the serum pregnancy test should be 
performed at the local laboratory). Urine pregnancy tests will be administered at all other visits 
according to the study schedules, or if pregnancy is suspected, or as specified per protocol upon 
withdrawal of the subject from the study. 
7.2.7
Antibody Testing
Blood samples will be drawn for the analysis of antibodies to teduglutide according to the 
Schedule of Assessments (Table 1-1, Table 1-2, and Table 1-3). Blood samples for antibodies 
may be drawn from a central line or from peripheral access. The sample drawn on CxD1 must be 
drawn prior to administration of the first dose of teduglutide. Once the subject has started 
teduglutide treatment, samples must be drawn at least 14 hours after dosing. Subjects who test 
positive for antibodies to teduglutide will also be tested for neutralizing antibody. Subjects who 
have been previously treated with teduglutide, and who test positive for antibodies to 
teduglutide, will have follow-up blood draws for antibodies to teduglutide every 12 weeks while 
on study until a negative result is obtained.
7.2.8
Volume of Blood
Efforts will be made to minimize the amount of blood drawn from all pediatric subjects enrolled 
in this study. The volumes of blood to be drawn from each subject will vary depending on 
clinical status. Approximate volumes of blood to be drawn from each subject annually are shown 
in Table 7-2.
Table 7-2: Approximate Volume of Blood to be Drawn from Each Subject Annually 
Assessment
Sample 
Volume (mL)
No. Samples per two 28-week 
Teduglutide Cycles
Total 
Volume (mL)
Subjects Receiving Teduglutide Treatment 
Safety
Biochemistry and -hCGa
2.5
24
60
Hematology
2
24
48
Coagulation Parameters
1
2
2
Antibodies
2
8
16
Serum storage samples
3
4
12
Total mL per 2, 28-week Treatment Cycles (Approximate Annual Volume):
138
Subjects Not Receiving Teduglutide Treatmentb
Assessment
Sample 
Volume (mL)
No. Samples per 4 NTT Visits
Total 
Volume (mL)
Safety
Biochemistry
2.5
4
10
Hematology
2
4
8
Serum storage samples
3
2
6
Total mL per 4 “No-Teduglutide Treatment” Visits 48-week period:
24
Abbreviations: β-hCG=beta-human chorionic gonadotropin; NTT=no-teduglutide treatment
a β-hCG testing will only be administered to females who are eligible for teduglutide treatment.
b Subjects not receiving teduglutide treatment, but who were exposed to it previously and tested positive for anti-teduglutide 
antibodies will require blood samples for antibody testing every 12 weeks until they test negative.
For non-commercial use only


Shire
CONFIDENTIAL
Page 51
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment. When more than 1 blood assessment is to be done at the time 
point/period, if they require the same type of tube, the assessments should be combined. Blood 
volume estimates do not include safety labs performed after PS adjustment, and anti-teduglutide 
antibody testing during no-teduglutide treatment.  Saved serum samples should be omitted for 
subjects weighing less than 10 kg and whenever local blood volume limitations are exceeded.
7.2.9
Gastrointestinal-specific Testing
7.2.9.1
Fecal Occult Blood Testing
Fecal occult blood testing must be performed on all subjects at the pretreatment visit, week 12, 
and week 24 of the teduglutide cycle. During NTT periods, FOBT must be performed on 
teduglutide-exposed subjects (subjects who have received teduglutide any time in the past and 
are therefore not teduglutide-naïve) on a roughly annual basis (approximately every 48-60 
weeks). Actions to be taken in response to a positive FOBT are described below.
7.2.9.2
Colonoscopy or Sigmoidoscopy
Teduglutide-naïve subjects age 12 and older will undergo colonoscopy or sigmoidoscopy at the 
pretreatment visit if one has not been performed within 1 year. 
Subjects of any age with newly positive FOBT results at the pretreatment visit for which a 
readily detectable cause cannot be identified (eg, anal fissure) will undergo a colonoscopy or 
sigmoidoscopy prior to receiving teduglutide. If newly positive FOBT results (for which a 
readily detectable cause cannot be identified) are obtained at the end of a teduglutide treatment 
cycle (CxW24/EOT), colonoscopy or sigmoidoscopy will be performed. The need for 
colonoscopy or sigmoidoscopy in response to positive FOBTs at any other point during the 
study, or to re-evaluate persistently positive FOBTs is at the discretion of the investigator. 
Teduglutide-exposed subjects who have received the equivalent of 2 treatment cycles (48 weeks 
of study drug exposure) will undergo colonoscopy or sigmoidoscopy. While receiving additional 
teduglutide treatment, subjects will undergo colonoscopy or sigmoidoscopy at 5 year intervals or 
more often as needed. 
Upper endoscopy may be performed along with any colonoscopy or sigmoidoscopy at the 
investigator’s discretion. If a polyp is found, adherence to current polyp follow-up guidelines is 
recommended. Subjects with unresected GI polyps, polyposis conditions, premalignant change 
or malignancy in the GI tract will be excluded from teduglutide treatment.
7.2.10
Nutritional Support
Nutritional support includes PS, EN, and other food and fluids. Advances in EN and/or 
reductions to PS will be based on clinical status, including weight, linear growth, hydration 
status, and safety laboratory results. Intake and output diaries will include data to be considered 
in the adjustment of each subject’s nutritional support. Guidelines for nutritional support 
management and weaning algorithms are provided in Appendix 2.
For non-commercial use only


Shire
CONFIDENTIAL
Page 52
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
7.2.11
Diaries
7.2.11.1
Study Drug Administration Diary
A study drug administration diary will record administration of teduglutide. This diary should be 
completed by the subject (or parent/legal guardian, as applicable) daily during the teduglutide 
treatment periods (between visits CxD1 and CxW24).
7.2.11.2
Intake Diary
Intake diaries will be used to collect and evaluate each subject’s nutritional support. The 
subject/parent/guardian will complete the appropriate fields of the PS section of the intake diary 
2 weeks prior to ALL scheduled site visits (except at pretreatment visit). During the 24-week 
teduglutide treatment period, the intake diary will also be completed for 1 week following PS 
adjustments. The intake diary will also be completed daily during the 4-week follow-up period.
The following data will be captured in the intake diaries:

Parenteral support volume and infusion duration

Site personnel will determine the actual PS daily calories based on diary entries.
All available diary data will be reviewed by the investigator or their designee at each clinic and 
telephone visit to assess clinical status and opportunity for PS reduction and advance in feeds.
7.2.11.3
Output Diary
Urine and stool output should be recorded in the output diary over a 48-hour period of nutritional 
stability before every clinic visit; in addition, output should be recorded for subjects that are in a 
teduglutide treatment cycle within 1 week of implementing a change in the PS prescription, 
regardless of previous teduglutide exposure.
Urine data:

Toilet-trained subjects (who do not wear diapers)
Measure and record all urine output in mL or cc 

Nontoilet-trained subjects (who wear diapers)
Measure and record the weight of all urine-only diapers. Urine volume will be calculated 
using the following formula: 1 g (scale weight) = 1 mL or 1 cc

At the discretion of the investigator, the parent may be asked to collect the first void after 
the daily PS infusion to measure specific gravity
Stool data (includes diapers with mixed urine and stool):

Toilet-trained subjects (who do not wear diapers)
Record the occurrence of each bowel movement and score the stool consistency using the 
Bristol Stool Form Scale (see Output diary)

Nontoilet-trained subjects (who wear diapers)
Record the weight of diapers containing stool (including diapers with mixed urine and 
stool) as stool output and score the stool consistency using the Bristol Stool Form Scale 
For non-commercial use only


Shire
CONFIDENTIAL
Page 53
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
(see Output diary). Stool volume will be calculated using the formula: 1 g (scale weight) 
= 1 mL or 1 cc
All ostomy output volume should be recorded. Ostomy output will not be scored using the 
Bristol scale.
All available diary data will be reviewed by the investigator or their designee at each clinic and 
telephone visit to assess clinical status and opportunity for PS reduction and advance in feeds.
7.2.12
Health-related Quality of Life Assessments
Throughout the study, health-related quality of life assessments will be performed using the 
PedsQL Generic Core Scales. Each PedsQL age-appropriate form takes less than 4 minutes to 
complete.  The scales include self-reports for pediatric subjects and adolescents aged 5 to 
18 years and proxy-reports from parents of pediatric subjects aged 2 to 18 years.  The PedsQL 
Generic Core Scales will not be performed for subjects younger than 2 years of age.  If a child is 
unable to complete the age-appropriate questionnaire (eg, due to developmental delay or other 
illness) it will not constitute a protocol deviation, but the parent should continue to complete the 
appropriate parent-specific forms.
Field trials have shown that the internal consistency reliability of the PedsQL was excellent, with 
alphas for the generic core scales in both self- and proxy-report greater than the 0.70 standard, 
and alphas for the full 23-item scale approaching 0.90 for self- and proxy-report. Missing data 
were minimal. Item response distributions were across the full scale range, with no floor effects, 
and minimal ceiling effects. 
The validity of the PedsQL Generic Core Scales was demonstrated through known group 
comparisons, and correlations with other measures of disease burden. The PedsQL self- and 
proxy-report distinguished between pediatric subjects with and without a chronic health 
condition, and within the group of pediatric subjects with a chronic condition, between those 
who did or did not have an overnight hospital visit in the last 12 months. Further, both child self-
report and parent proxy-report correlated significantly with the number of days the child was too 
ill to pursue normal activities, needed someone to care for him or her, missed school in the last 
month, the number of days the parent missed from work in the last month, and parent-report of 
problems pursuing their normal work routine and concentrating at work. The PedsQL Generic 
Core Scales are also responsive to clinical change, as demonstrated in field trials.
7.2.12.1
Pediatric Quality of Life Generic Core Scale (PedsQL™), Acute version
The PedsQL Generic Core Scale is designed to measures health-related quality of life (HRQoL) 
in pediatric subjects and adolescents (2-18 years of age). The developmentally appropriate 
PedsQL Generic Core Scale will be completed by either the parent or legal guardian and subject 
as indicated in Table 7-3 at the time points as outlined in Table 1-1, Table 1-2, and Table 1-3.
For non-commercial use only


Shire
CONFIDENTIAL
Page 54
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
Table 7-3: Developmentally Appropriate PedsQL™Generic Core Scales
Report
Completed by
Parent Report for Toddlers (ages 2-4)
Parent or Legal Guardian
Child Self Report and Parent Proxy-Report for Young Pediatric subjects 
(ages 5-7)
Subject and Parent or Legal Guardian
Child Self Report and Parent Proxy-Report for Pediatric subjects 
(ages 8-12)
Subject and Parent or Legal Guardian
Child Self Report and Parent Proxy-Report for Teens (ages 13-18)a
Subject and Parent or Legal Guardian
Abbreviations: PedsQL=Pediatric Quality of Life Inventory
a The Child Self Report and Parent Proxy-Report for Teens (ages 13-18) will also be completed for subjects older 
than 18 years of age
The Parent Report for Toddlers (ages 2-4) of the PedsQL Generic Core Scale is composed of 
21 items comprising 4 dimensions as follows: 1) Physical Functioning (8 items), 2) Emotional 
Functioning (5 items), 3) Social Functioning (5 items), 4) School Functioning (3 items). 
The Child and Parent Reports of the PedsQL Generic Core Scale for Young Pediatric subjects 
(ages 5-7), Pediatric subjects (ages 8-12), and Teens (ages 13-18) are composed of 23 items 
comprising 4 dimensions as follows: 1) Physical Functioning (8 items), 2) Emotional 
Functioning (5 items), 3) Social Functioning (5 items), 4) School Functioning (5 items).
7.2.12.2
Pediatric Quality of Life Family Impact Module (PedsQL™), Acute version
The PedsQL Family Impact Module is a parent-report multidimensional instrument that will be 
completed by the parent or legal guardian, as outlined in Table 1-1, Table 1-2, and Table 1-3.
The PedsQL Family Impact Module is a specific module of the PedsQL that is used to measure 
the impact of pediatric chronic health conditions on parents and the family (Varni et al., 2004). 
The 36-item PedsQL Family Impact Module consists of 6 scales measuring parent self-reported 
functioning as follows: 1) Physical Functioning (6 items), 2) Emotional Functioning (5 items), 
3) Social Functioning (4 items), 4) Cognitive Functioning (5 items; worries about treatment and 
disease), 5) Communication (3 items), 6) Worry (5 items). Two additional scales measure parent-
reported family functioning as follows: 1) Daily Activities (3 items), and 2) Family Relationships 
(5 items). The PedsQL Family Impact Module should take the parent or legal guardian 
approximately 5 to 10 minutes to complete.
7.2.12.3
PedsQL Gastrointestinal Symptoms Module (PedsQL™), Acute version
The PedsQL Gastrointestinal Symptom Module is a disease-specific 58-item module, comprised 
of 10 different symptom scales that assess gastrointestinal symptom-related quality of life: food 
and drink limits, trouble swallowing, heartburn and reflux, nausea and vomiting, gas and 
bloating, constipation, blood in poop, and diarrhea. The PedsQL Gastrointestinal Symptoms 
Module was designed to allow the selection and scoring of individual scales from the Module. 
The scales of Food and Drink Limits (6 items) and Diarrhea (7 items) were identified as 
clinically relevant and appropriate for the symptoms experienced in this pediatric study 
population, and therefore, are the only scales used in this study. The scales will be completed by 
either the parent or legal guardian and subject as indicated in Table 7-3 at the time points 
outlined in Table 1-1, Table 1-2, and Table 1-3.
For non-commercial use only


Shire
CONFIDENTIAL
Page 55
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.4. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, 
then each symptom should be listed individually. All AEs should be captured on the appropriate 
AE pages in the eCRF and in source documents. In addition to untoward AEs, unexpected 
benefits outside the investigational product indication should also be captured on the AE eCRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pretreatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
For non-commercial use only


Shire
CONFIDENTIAL
Page 56
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
In consideration of whether a treatment-emergent adverse event (TEAE) might lead to dose 
interruption (Section 8.4.1) or early termination of the study (Section 8.5), severe TEAEs will 
also be graded according to the National Cancer Institute’s (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) severity grading criteria (US Department of Health and Human 
Services et al., 2010).
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of 
the investigational product is compelling and/or follows a known or 
suspected response pattern to that product, and the event cannot be 
explained by the subject’s medical condition, other therapies, or 
accident.
Not Related
The event can be readily explained by other factors such as the 
subject’s underlying medical condition, concomitant therapy, or 
accident and no plausible temporal or biologic relationship exists 
between the investigational product and the event.
AEs that are related to study drug that are not resolved at EOT will be followed until the event 
resolves or stabilizes, as judged by the investigator.
Laboratory values, vital signs, and clinical findings at the scheduled physical examinations must 
be reported as AEs if the investigator considers the finding to be a clinically significant change 
from the baseline. 
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study in the eCRF. Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved with Sequelae 

Recovering/Resolving
For non-commercial use only


Shire
CONFIDENTIAL
Page 57
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018

Unknown
8.1.4
Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE.
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory or vital sign can represent an AE if the change is 
clinically relevant or if, during the study, a shift of a parameter is observed from a normal value 
to an abnormal value, or a further worsening of an already abnormal value. When evaluating 
such changes, the extent of deviation from the reference range, the duration until return to the 
reference range, either while continuing treatment or after the end of treatment with the 
investigational product, and the range of variation of the respective parameter within its 
reference range, must be taken into consideration.
If, during the study, there are abnormal clinical laboratory values or vital signs which were not 
present at the beginning of the study, further investigations should be performed until the values 
return to within the reference range or until a plausible explanation (eg, concomitant disease) is 
found for the abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory or vital sign is clinically significant and 
therefore represents an AE.
8.1.6
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.4.
Any report of pregnancy for any female study participant must be reported within 24 hours to the 
Shire Global Drug Safety Department using the Shire Investigational and Marketed Products 
Pregnancy Report Form. A copy of the Shire Investigational and Marketed Products Pregnancy 
Report Form (and any applicable follow-up reports) must also be sent to the Shire Medical 
Monitor using the details specified in the emergency contact information section of the protocol. 
In the event a subject becomes pregnant during the study, teduglutide administration must be 
discontinued immediately. 
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days postpartum.
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Study Adverse Event Form 
for Serious Adverse Events and Non-serious AEs as Required by the Protocol. Note: An elective 
abortion is not considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Adverse Event Form for SAEs and 
Non-serious AEs as Required by the Protocol as well as the Shire Investigational and Marketed 
For non-commercial use only


Shire
CONFIDENTIAL
Page 58
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
Products Pregnancy Report Form. The test date of the first positive serum/urine -HCG test or 
will determine the pregnancy onset date.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) 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 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for 
a non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner 
that may be detrimental to the individual and/or society.

Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol).

Overdose – Administration of a dose greater than the allocated dose of the study 
medication or at a frequency greater than the dosing interval specified by the protocol.

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product. For studies, medication errors are reportable to the sponsor 
only as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error. 
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally-authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator brochure which the sponsor 
has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Drug Safety Department and the Shire Medical Monitor within 24 hours of the first awareness of 
the event. Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, 
misuse, overdose, or medication errors (see Section 8.1.7) unless they result in an SAE.
For non-commercial use only


Shire
CONFIDENTIAL
Page 59
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
All Adverse Events of Special Interest, as defined in Section 8.3, must be reported by the 
investigator to the Shire Global Drug Safety Department and the Shire Medical Monitor within 
24 hours of the first awareness of the event even if the event does not fulfill seriousness criterion.
The investigator must complete, sign, and date the Shire Clinical Study Adverse Event Form for 
SAEs and Non-serious AEs as Required by Protocol, and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested). Fax or e-mail the completed form to the Shire Global Drug Safety 
Department. A copy of the completed Shire Clinical Study Adverse Event Form for Serious 
Adverse Events (SAEs) and Non-serious AEs as Required by Protocol (and any applicable 
follow-up reports) must also be sent to the Shire medical monitor or designee using the details 
specified in the emergency contact information section of the protocol.
8.2.3
Serious Adverse Event Definition
A serious adverse event (SAE) is any untoward medical occurrence (whether considered to be 
related to investigational product or not) that at any dose: 

Results in death

Is life-threatening. Note: The term 'life-threatening' in the definition of "serious" refers to 
an event in which the subject was at risk of death at the time of the event; it does not refer 
to an event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
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).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: 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 subject and may 
require medical or surgical intervention to prevent 1 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; or the development of drug dependency or 
drug abuse. 
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.4, and must be reported 
For non-commercial use only


Shire
CONFIDENTIAL
Page 60
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
to the Shire Global Drug Safety Department and the Shire Medical Monitor within 24 hours of 
the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Drug Safety Department within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death.
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting 
The Sponsor and/or Clinical Contract Research Organization (CRO) is responsible for notifying 
the relevant regulatory authorities, and US central Institutional Review Boards (IRBs)/EU central 
ethics committees (ECs), of related, unexpected SAEs.
In addition, the Clinical CRO is responsible for notifying active sites of all related, unexpected 
SAEs occurring during all interventional studies across the SHP633 program.
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
8.3
Adverse Events of Special Interest
An AE of special interest is an AE (serious or nonserious) of scientific and medical concern 
specific to the sponsor’s product or program and for which ongoing monitoring and immediate 
notification by the investigator to the sponsor is required.
The AEs of special interest that require expedited regulatory reporting include the following:

Growth of pre-existing polyps of the colon
For non-commercial use only


Shire
CONFIDENTIAL
Page 61
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018

Benign neoplasia of the GI tract including the hepatobiliary system

Tumor-promoting ability (eg, benign and/or malignant neoplasia of any kind, not limited 
to those of the GI or hepatobiliary system)
For AEs of special interest, the sponsor must be informed within 24 hours of first awareness as 
per the SAE notification instructions described in Section 8.2.2 even if the event does not fulfill 
the seriousness criteria.
8.4
Dose Interruption of Individual Subjects
The investigator is responsible for contacting the sponsor/designee when the subject’s 
teduglutide dosing regimen is interrupted. Attempts should be made to contact the 
sponsor/designee prior to dose interruption. Reasons for dosage interruptions may include but are 
not limited to hospitalization, AEs, a lapse in investigational product delivery, etc.
Study drug must be discontinued if any of the following events occur:

Pregnancy

Severe hypersensitivity, such as anaphylaxis determined by the investigator to be related 
to study drug. This does not include the presence of anti-teduglutide antibodies, mild 
injection site reactions or mild symptoms that according to the investigator do not pose a 
significant risk to the subject.

An AE that is of NCI CTCAE severity Grade 3 or 4 and considered to be related to study 
drug administration

Confirmed DILI related to teduglutide (see Section 8.4.2)
8.4.1
Dose Interruption Criteria Based on Adverse Event Severity and 
Relationship to Investigational Product
The investigational product must be discontinued if the subject experienced an AE that is of 
severity ≥Grade 3 per the NCI CTCAE and is reported as related to the investigational product. 
In consideration of whether a TEAE might lead to dose interruption, severe TEAEs will also be 
graded according to the NCI CTCAE severity grading criteria (US Department of Health and 
Human Services et al., 2010). All such TEAEs should be discussed with the Shire Medical 
Monitor or designee as soon as possible. The length of the dose interruption, and whether 
teduglutide administration resumes or is permanently discontinued, depends on the clinical 
situation. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 62
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
8.4.2
Dose Interruption Criteria Based on Drug-Induced Liver Injury
Teduglutide administration for an individual subject may need to be interrupted if the subject has 
clinical and laboratory evidence of potential DILI, in the absence of an alternative explanation, 
as identified by the following criteria:

ALT or AST >8x ULN

ALT or AST >5x ULN and >2x baseline value for more than 2 weeks

(ALT or AST >3x ULN and >2x baseline value) and (total bilirubin >2x ULN or 
INR>1.5)

ALT or AST >3x ULN and >2x baseline value with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
All laboratory values suggestive of potentially new DILI should be repeated and verified within 
3 days. International normalized ratio should be measured with this set of verification laboratory 
assessments and an inquiry should be made as to the presence of clinical symptoms consistent 
with new liver injury. The subject should be followed closely to determine the trajectory of the 
laboratory abnormalities and to evaluate the cause of liver injury. This evaluation may include, 
as clinically indicated, consideration of sepsis, acute viral hepatitis (eg, hepatitis A 
immunoglobulin [IgM], hepatitis B surface antigen, hepatitis C antibodies, cytomegalovirus IgM, 
Epstein-Barr virus antibody panel), hepatobiliary obstruction (ultrasound), autoimmune hepatitis 
(anti-nuclear, anti-smooth muscle, anti-actin, or anti-liver kidney microsomal antibodies), 
intestinal failure associated liver disease, cardiovascular causes such as ischemic hepatitis, and 
concomitant hepatotoxic treatments.
Additional evaluations may be performed at the discretion of the investigator in consultation 
with the Shire medical monitor.
Teduglutide administration must be permanently discontinued if DILI is confirmed and deemed 
related to study drug.
8.5
Early Termination of the Clinical Study
The data monitoring committee (DMC) may recommend stopping the study if any of the 
following conditions are met:

≥2 subjects develop the same event of CTCAE severity Grade 3 that is reported as related 
to the investigational product
or

1 subject develops an event of CTCAE severity Grade 4 that is reported as related to the 
investigational product.
For non-commercial use only


Shire
CONFIDENTIAL
Page 63
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
9
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
in the eCRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered in the eCRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. Unscheduled safety follow up assessments (including visits 
conducted after EOS) are not to be collected unless requested.
9.2
Clinical Data Management 
Data are to be entered into a clinical database as specified in the CRO’s data management 
process. Quality control and data validation procedures are applied to ensure the validity and 
accuracy of the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Statistical Analysis Process 
The study will be analyzed by the sponsor or its agent. All statistical analyses will be performed 
using SAS® (SAS Institute, Cary, NC, USA) version 9.3 or higher.
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. 
9.4
Planned Interim Analysis, and Data Monitoring Committee 
An interim analysis is planned when 6 months of safety data have been collected for subjects 
entering from TED-C14-006. Additional interim analyses may be conducted as needed.
A DMC will be involved in the management of this study. The DMC members will review the 
data approximately every 3 months according to the DMC Charter. The DMC review will 
include all cumulative safety data (ie, AEs, laboratory assessments, physical examinations, etc.) 
from study assessments through each cutoff period. Further details regarding the DMC can be 
found in the DMC charter, which will be available prior to the administration of investigational 
product. 
The DMC for this study will be conducted in accordance with the FDA Guidance for Clinical 
Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees 
(March 2006).
For non-commercial use only


Shire
CONFIDENTIAL
Page 64
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
The DMC will be an external, independent board comprised of physicians with relevant training. 
The DMC will be restricted to individuals free of significant conflicts of interest, including, but 
not limited to, financial, scientific, or regulatory in nature. The DMC will be governed by a 
Charter agreed to by members of the Board and the sponsor. Members of the Board may not be 
study investigators or be employed at the same institution as a study investigator, individuals 
employed by the sponsor, independent contractors hired by the sponsor, or members of 
regulatory agencies. The DMC may make recommendations to the sponsor regarding study 
aspects including stopping, modifying or continuing the study; however, the sponsor will have 
the final responsibility to determine whether the study should be modified or temporarily or 
permanently stopped. 
9.5
Sample Size Calculation and Power Considerations 
The number of subjects in this study is not based on statistical power considerations as this is an 
extension study of the core studies, TED-C14-006 and SHP633-301. The maximum number of 
subjects was determined by the enrollment in TED-C14-006 and SHP633-301.
9.6
Study Population
The safety population includes all enrolled subjects in the study. Safety population will be used 
for both safety and efficacy analyses.
9.7
Efficacy Analyses 
No claims of statistical significance will be made; however, 95% confidence intervals will be 
provided, if applicable. Continuous variables, including those assessed on a discrete scale, will 
be summarized using descriptive statistics including number of subjects, mean, median, standard 
deviation, maximum, and minimum. For categorical variables, statistical summaries will include 
number of subjects and percentages.
9.7.1
Efficacy Endpoints
Efficacy endpoints will be analyzed at the end of each teduglutide treatment period (week 24 or 
EOT), and at each study visit, relative to the baseline of the core study (TED-C14-006 or 
SHP633-301) and/or first exposure to teduglutide. The following efficacy endpoints will be 
analyzed: 

Reduction in PS volume of at least 20%

Absolute and relative change in PS volume

Complete weaning off PS

Change in days per week of PS
9.8
Safety Analyses 
9.8.1
Safety Endpoints
The following safety endpoints will be analyzed: 
For non-commercial use only


Shire
CONFIDENTIAL
Page 65
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018

Adverse events

Vital signs, including temperature, heart rate, and blood pressure

Laboratory safety data (ie, clinical chemistry, hematology, and urinalysis)

Urine output

Stool output 

Antibodies to teduglutide

Gastrointestinal-specific testing , including fecal occult blood testing and colonoscopy or 
sigmoidoscopy

Z-scores for weight, height (or length), head circumference (up to 36 months of age), and 
BMI
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The number of events, incidence, and percentage of AEs will be calculated overall, 
by System Organ Class (SOC) and by preferred term. SAEs will be further summarized by 
severity and relationship to investigational product. Adverse events related to investigational 
product, AEs leading to withdrawal, SAEs, and deaths will be similarly summarized/listed.
Prior and concomitant medications will be coded using the World Health Organization-Drug 
Dictionary (WHO-DD) with regard to drug class and drug name. The number and percentage of 
subjects with specific prior medications will be summarized. Medical history (including 
surgical/procedural history) will be coded using MedDRA. The number and percentage of 
subjects with specific histories will be summarized by system organ class and preferred term. 
For clinical laboratory tests, vital signs, body weight, and fluid balance variables, descriptive 
statistics (mean, median, standard deviation, minimum and maximum values, the number and 
percentage of subjects in specified categories) will be calculated to summarize the observed 
values and change from baseline at each scheduled visit.
The number and percentage of subjects classified as having positive or neutralizing antibodies to 
teduglutide will be used to summarize the presence of antibodies. 
Additional safety parameters and measures will include change in body weight, height (or 
length) and head circumference (up to 36 months of age). Derived variables will include height 
z-score, weight z-score, BMI, and BMI z-score. Descriptive statistics (mean, median, standard 
deviation, minimum and maximum values, the number and percentage of subjects in specified 
categories) will be calculated to summarize the absolute values and change from baseline at each 
scheduled visit.
For non-commercial use only


Shire
CONFIDENTIAL
Page 66
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
9.9
Other Analyses
9.9.1
Health-related Quality of Life Analyses 
Health economics and outcomes research endpoints will be analyzed at approximately 12-week 
intervals (weeks 12 and 24 of each teduglutide treatment cycle, and every 12 weeks for subjects 
not on teduglutide), relative to the study baseline. The beginning of each treatment cycle (CxD1) 
will be an additional baseline.

Change in Pediatric Quality of Life Inventory (PedsQL) score

Change in PedsQL Family Impact Module score

Change in PedsQL Gastrointestinal Symptoms Module Sub-Scales scores: 

Food and Drink Limits

Diarrhea 
For non-commercial use only


Shire
CONFIDENTIAL
Page 67
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
10
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements. 
The name and address of each third party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH GCP Guideline E6 (1996), EU Directive 2001/20/EC, as 
well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study. An insurance certificate is supplied to the CRO as necessary. 
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of the end of 
the study completion date for pediatric studies and within 1 year for non-pediatric studies as per 
guidance. The sponsor will provide the ECs with a copy of the same summary.
For non-commercial use only


Shire
CONFIDENTIAL
Page 68
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.
The sponsor will make an EOS declaration to the relevant competent authority as required by 
Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator is appointed to review the final CSR for multicenter 
studies. Agreement with the final CSR is documented by the signed and dated signature of the 
principal investigator (single-site study) or coordinating principal investigator (multicenter 
study), in compliance with Directive 2001/83/EC as amended by Directive 2003/63/EC and ICH 
Guidance E3 (1995). 
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational products, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
For non-commercial use only


Shire
CONFIDENTIAL
Page 69
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Case Report Forms
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded into eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log.
All data will have separate source documentation; no data will be recorded directly into the 
eCRF.
eCRFs should be approved by the investigator per study specifications and data deliverable 
requirements.
The clinical research associate (CRA)/study monitor will verify the contents against the source 
data per the monitoring plan. If the data are unclear or contradictory, queries are sent for 
corrections or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject diary cards, original clinical laboratory reports, and histology and 
pathology reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor, the respective national, 
local, or foreign regulatory authorities, the IRB/EC, and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF 
entries against the source documents. The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, X-rays etc.). Non-study site personnel will not 
disclose any personal information or personal medical information.
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the European Medicines Agency (EMA), the 
For non-commercial use only


Shire
CONFIDENTIAL
Page 70
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
Medicines and Healthcare products Regulatory Agency, other regulatory authorities, the sponsor 
or its representatives, and the IRB/EC for each site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent and assent, where 
applicable, from all study subjects prior to any study-related procedures including screening 
assessments. All consent and assent documentation must be in accordance with applicable 
regulations and GCP. Each subject or the subject’s legally-authorized representative, as 
applicable, is requested to sign and date the subject informed consent form or a certified 
translation if applicable, after the subject has received and read (or been read) the written subject 
information and received an explanation of what the study involves, including but not limited to: 
the objectives, potential benefits and risk, inconveniences, and the subject’s rights and 
responsibilities. A copy of the informed consent and assent documentation (ie, a complete set of 
subject information sheets and fully executed signature pages) must be given to the subject or the 
subject’s legally-authorized representative, as applicable. This document may require translation 
into the local language. Signed consent forms must remain in each subject’s study file and must 
be available for verification at any time.
Within the source documents, site personnel should document instruction of and understanding 
by the parent/legally-authorized representative/caregiver of the safe, responsible storage and 
administration of investigational product to the study subject.
The principal investigator provides the sponsor with a copy of the consent form, and assent form 
where applicable, that was reviewed by the IRB/EC and which received their favorable 
opinion/approval. A copy of the IRB/EC’s written favorable opinion/approval of these 
documents must be provided to the sponsor, prior to the start of the study unless it is agreed to 
and documented (abiding by regulatory guidelines and national provisions) prior to study start 
that another party (ie, sponsor or coordinating principal investigator) is responsible for this 
action. Additionally, if the IRB/EC requires modification of the sample subject information and 
consent document provided by the sponsor, the documentation supporting this requirement must 
be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
For non-commercial use only


Shire
CONFIDENTIAL
Page 71
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
For sites within the EU, the applicant for an EC opinion can be the sponsor, the investigator, or 
for multicenter studies the coordinating principal investigator or sponsor, according to national 
provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the Sponsor (or designee) has received 
written IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; for sites within the EU, this can be done by the sponsor, the investigator or for multicenter 
studies the coordinating principal investigator, according to national provisions. The investigator 
must also keep the local IRB/EC informed of any serious and significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996. A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the Sponsor (or designee).
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
review their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market SHP633; national or local regulatory authorities; and the IRBs/ECs which gave approval 
for the study to proceed. The sponsor and/or its representatives accessing the records and data 
will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject).
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
For non-commercial use only


Shire
CONFIDENTIAL
Page 72
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
10.5
Study Results / Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2-4 and certain other studies as determined by Shire. The purpose of the 
publication steering committee is to act as a non-commercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
current standards. Participation as an investigator does not confer any rights to authorship of 
publications.
For non-commercial use only


Shire
CONFIDENTIAL
Page 73
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
11
REFERENCES
Drucker, D. J. & Yusta, B. 2014. Physiology and pharmacology of the enteroendocrine hormone 
glucagon-like peptide-2. Annu Rev Physiol, 76, 561-83.
Khan, F. A., Squires, R. H., Litman, H. J., Balint, J., Carter, B. A., Fisher, J. G., Horslen, S. P., 
Jaksic, T., Kocoshis, S., Martinez, J. A., Mercer, D., Rhee, S., Rudolph, J. A., Soden, J., Sudan, 
D., Superina, R. A., Teitelbaum, D. H., Venick, R., Wales, P. W. & Duggan, C. 2015. Predictors 
of Enteral Autonomy in Children with Intestinal Failure: A Multicenter Cohort Study. J Pediatr,
167, 29-34.e1.
Mouksassi, M. S., Marier, J. F., Cyran, J. & Vinks, A. A. 2009. Clinical trial simulations in 
pediatric patients using realistic covariates: application to teduglutide, a glucagon-like peptide-2 
analog in neonates and infants with short-bowel syndrome. Clin Pharmacol Ther, 86, 667-71.
O'Keefe, S. J., Buchman, A. L., Fishbein, T. M., Jeejeebhoy, K. N., Jeppesen, P. B. & Shaffer, J. 
2006. Short bowel syndrome and intestinal failure: consensus definitions and overview. Clin 
Gastroenterol Hepatol, 4, 6-10.
Squires, R. H., Duggan, C., Teitelbaum, D. H., Wales, P. W., Balint, J., Venick, R., Rhee, S., 
Sudan, D., Mercer, D., Martinez, J. A., Carter, B. A., Soden, J., Horslen, S., Rudolph, J. A., 
Kocoshis, S., Superina, R., Lawlor, S., Haller, T., Kurs-Lasky, M. & Belle, S. H. 2012. Natural 
history of pediatric intestinal failure: initial report from the Pediatric Intestinal Failure 
Consortium. J Pediatr, 161, 723-8.e2.
Tappenden, K. A., Edelman, J. & Joelsson, B. 2013. Teduglutide enhances structural adaptation 
of the small intestinal mucosa in patients with short bowel syndrome. J Clin Gastroenterol, 47,
602-7.
Thymann, T., Stoll, B., Mecklenburg, L., Burrin, D. G., Vegge, A., Qvist, N., Eriksen, T.,
Jeppesen, P. B. & Sangild, P. T. 2014. Acute effects of the glucagon-like peptide 2 analogue, 
teduglutide, on intestinal adaptation in short bowel syndrome. J Pediatr Gastroenterol Nutr, 58,
694-702.
US Department of Health and Human Services, National Institutes of Health & National Cancer 
Institute 2010. Common Terminology Criteria for Adverse Events (CTCAE).
Varni, J. W., Sherman, S. A., Burwinkle, T. M., Dickinson, P. E. & Dixon, P. 2004. The PedsQL 
Family Impact Module: preliminary reliability and validity. Health Qual Life Outcomes, 2, 55.
Wales, P. W., de Silva, N., Kim, J., Lecce, L., To, T. & Moore, A. 2004. Neonatal short bowel 
syndrome: population-based estimates of incidence and mortality rates. J Pediatr Surg, 39, 690-
5.
For non-commercial use only


Shire
CONFIDENTIAL
Page 74
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
12
APPENDICES
For non-commercial use only


Shire
CONFIDENTIAL
Page 75
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
APPENDIX 1
PROTOCOL HISTORY
Document
Date
Global/Country/Site Specific
Original Protocol
08 April 2016
Global
Amendment 1
22 Nov 2016
Global
Amendment 2
23 Mar 2017
Global
Amendment 3
16 May 2018
Global
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 2
Amendment Date
23 Mar 2017
Global
Description of Change and Rationale
Section(s) Affected by Change
Updated emergency contact information
Emergency Contact Information; 
Section 8.1.6; Section 8.2.2; Section 
8.2.4
To allow for approximately 7 days for subjects to transfer from Study 
TED-C14-006 to Study SHP633-304 (instead of up to 7 days).
Table 1-1; Section 7.1.1
A footnote was added at the pretreatment visit in the Schedule of Events 
for Subjects While Receiving Teduglutide to underscore that, when the 
first pretreatment visit (P1) follows the screening visit, it must occur 
within 12 weeks of screening.
Table 1-3
Revised the language on abstinence as a contraceptive method for 
consistency with the Medicines and Healthcare Products Regulatory 
Agency (MHRA) Clinical Trial Facilitation Group's "Recommendations 
related to contraception and pregnancy testing in clinical trials."
Section 4.7.1
Clarification that ancillary components, in addition to sterile water for 
injection syringes, will also be provided and labeled in accordance with 
the applicable regulatory requirements.
Section 6.3.1
A footnote was added in Table 7-2 to clarify that subjects older than 
18 years of age will continue to use the Child Self Report and Parent 
Proxy-Report for Teens (ages 13-18) when completing the Pediatric 
Quality of Life Generic Core Scale (PEDSQL™).
Section 7.2.12.1 (Table 7-3)
Revised the text on severity categorization to specify that a severe 
treatment-emergent adverse event (TEAE) that might lead to dose 
interruption (Section 8.4.1) or early termination of the study 
(Section 8.5) will also be graded according to the National Cancer 
Institute’s (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) severity grading criteria, in addition to the standard severity 
categorization. These events are no longer limited to only the events 
described in Table 8-1, entitled “CTCAE Criteria for Adverse Events 
that May Lead to Dose Interruption (Prospective Period of Observation 
Only).” Therefore, Table 8-1 has been deleted.
Section 8.1.1; Section 8.4; Section 
8.4.1
Table 8-1 (deleted)
For non-commercial use only


Shire
CONFIDENTIAL
Page 76
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
Revised the criteria for early termination of the study: stopping criteria 
were extended to all NCI CTCAE Grade 3 and 4 severity events reported 
as related to the investigational product, and no longer limited to the 
events described in Table 8-1, entitled “CTCAE Criteria for Adverse 
Events that May Lead to Dose Interruption (Prospective Period of 
Observation Only).”
Section 8.5
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 1
Amendment Date
22 Nov 2016
Global
Description of Change and Rationale
Section(s) Affected by Change
Title of the Shire medical monitor has been changed to 
 
for clarity.
Protocol Signature Page
Emergency Contact Information
Clarification has been made that during the no-teduglutide treatment 
period, visits will take place approximately every 12 weeks.
Synopsis
Sections 3.1, 7.1.2
Figure 3-1
The study design flow chart has been edited for clarity.
Synopsis
Figure 3-1
The collection of all actual and prescribed enteral nutrition data has been 
removed to reduce the burden on the subjects and investigators. Enteral 
nutrition data are not required as the efficacy endpoints are limited to 
parenteral support parameters.
Synopsis
Table 1-1, Table 1-2, Table 1-3
Sections 7.1.2, 7.1.3.1, 7.1.3.2, 7.1.5, 
7.2.11.2, 7.2.11.3
Exclusion criterion 11 has been revised to add Smoflipid as other 
experimental drugs that are allowed prior and during the study. Like 
glutamine and Omegaven, Smoflipid is not expected to interfere with the 
assessments of safety and efficacy of teduglutide and many subjects may 
already be receiving the treatments off-label as part of standard medical
therapy.  
Synopsis
Section 4.5
Exclusion criterion 12 and prohibited treatment have been refined: 
exclusion/prohibition of treatment with growth hormone has been 
extended to 3 months for consistency with other teduglutide studies. 
Synopsis
Section 4.5
Table 5-1
The language on escape criteria has been corrected for consistency within 
the protocol. 
Synopsis
Section 4.6
Language in efficacy and safety endpoints has been clarified.
Synopsis
Sections 9.7.1, 9.8.1
Completion and review of intake and output diaries have been clarified. 
Table 1-2, Table 1-3
Sections 7.1.3.2, 7.1.5
When the screening and pretreatment visits are combined, the serum 
pregnancy test required at the pretreatment visit should be performed at 
the local laboratory instead of the central laboratory. This will ensure 
timely results prior to starting treatment with teduglutide.
Table 1-3
Sections 7.1.3.1, 7.2.6
The requirement for urine specimen collection has been revised so that a 
lack of urinalysis will not constitute a protocol deviation for any pediatric 
subjects (not only for subjects wearing diapers).
Table 1-1, Table 1-2, Table 1-3
Section 7.2.4
For non-commercial use only


Shire
CONFIDENTIAL
Page 77
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 1
Amendment Date
22 Nov 2016
Global
Description of Change and Rationale
Section(s) Affected by Change
Clarification has been made that the first no-teduglutide treatment visit 
after the screening visit will occur within 2 to 12 weeks of the screening 
(formerly within 12 weeks of screening).
Synopsis
Table 1-2
Section 7.1.1
Windows have been clarified for visits during the no-teduglutide and 
teduglutide treatment periods.
Table 1-2, Table 1-3
Section 7.1.2
‘Specific’ has been deleted from ‘positive/specific anti-teduglutide 
antibodies’ to eliminate the redundancy. By definition, positive samples 
must be specific (as assessed in the confirmatory assay), or otherwise 
considered negative.
Table 1-2
Sections 7.2.7, 9.8.1
Parental height and gestational age at birth have been removed from 
medical history.
Table 1-1 (footnote b)
Section 7.2.1
For consistency within the protocol, sigmoidoscopy has been added as the 
alternate to colonoscopy throughout the protocol. 
Table 1-1, Table 1-2, Table 1-3
Sections 3.1, 7.1.2, 7.2.9.2
Removal of former footnote i on fecal occult blood test for clarity.
Table 1-3
Clarification has been made on circumstances when the CxW28 visit may 
be combined with the next pretreatment or EOS/ET visit. 
Table 1-3
Section 7.1.4
The text on PS support requirements over time in pediatric subjects with 
SBS has been clarified, and text on intestinal adaptation has been refined.
Section 1.1
Status of current teduglutide approvals for use has been updated.
Section 1.2, 3.1
The term ‘re-challenge’ has been replaced with ‘additional teduglutide 
treatment’ for clarity and consistency with other studies.
Section 3.1
Number of subjects enrolled has been corrected for consistency with 
protocol synopsis.
Section 3.1
Definition of a subject’s completion of the study has been corrected for 
consistency within the protocol.
Section 3.2
Evaluations to be performed when a subject discontinues teduglutide or 
when withdraws from the study have been clarified.
Sections 4.8.1, 4.8.2
Withdrawal by parent/guardian has been added as reason for 
discontinuation.
Section 4.8.3
COUMADIN has been changed to warfarin for clarity.
Sections 5.1, 5.1.2
Clarification has been made on handling of study drug, which is for single 
use only and should be used within 3 hours following reconstitution.  
Section 6.3.3
The investigator or designee may now dispense the unused study drug 
vials to the same subject if deemed appropriate to ensure sufficient 
supplies between visits. Also, documentation of all dispensed study 
medication has been clarified.
Section 6.4
Clarification has been made that local laboratory results are not required to 
be entered in the eCRFs.
Section 7.2.4
Collection of urine sodium and urine osmolality has been removed.
Section 7.2.4
For non-commercial use only


Shire
CONFIDENTIAL
Page 78
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 1
Amendment Date
22 Nov 2016
Global
Description of Change and Rationale
Section(s) Affected by Change
Clarification has been made that the serum sample will not be collected at 
the pretreatment visit if the subject met a follow-up period escape 
criterion.
Section 7.2.5
Intake and output diaries (formerly in Sections 7.2.11 and 7.2.12, 
respectively) have been moved under a new Section 7.2.11 ‘Diaries’ for 
clarity, and are now Sections 7.2.11.2 and 7.2.11.3, respectively. 
Information on study drug administration diary has been added in Section 
7.2.11.1. Clarification has been made that only available diary data will be 
reviewed at each clinic and telephone visit.
Sections 7.2.11, 7.2.11.1,  7.2.11.2, 
7.2.11.3 
Performance of dipstick specific gravity tests by the subject at home on the 
first urine produced after the daily infusions of PS has been removed. It is 
now at the discretion of the investigator for all subjects, not just those in 
diapers. This change is to align with standard medical practice.
Section 7.2.11.3
Clarifications have been made to the language on dose interruption.
Sections 8.4, 8.4.1
Unscheduled safety follow up assessments (including visits conducted 
after EOS) are not to be recorded. However, clarification has been made 
that they are to be collected where requested.
Section 9.1
The protocol now refers to the data monitoring committee (DMC) Charter 
for the schedule of DMC reviews.
Section 9.4
Changes have been made to the Health economics and outcomes research 
endpoints to include the beginning of each treatment cycle (CxD1) as 
additional baseline. These changes are for clarity and consistency with 
other teduglutide studies. 
Synopsis
Section 9.9.1
Minor corrections have been made to the guidelines for nutritional support 
management during the study.
Appendix 2
For non-commercial use only


Shire
CONFIDENTIAL
Page 79
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
APPENDIX 2
GUIDELINES FOR NUTRITIONAL SUPPORT MANAGEMENT 
DURING THE STUDY
Nutritional support adjustment in volume and calories should be considered at all planned visits. 
Please consider the following clinical parameters identified as markers for adequate management 
of pediatric SBS. These parameters should also be considered for managing nutritional support 
(PS and/or oral/enteral feeding) in terms of volume and calories during the treatment period. 

Growth trajectory, including weight, height (or length), and head circumference (for pediatric 
subjects up to 36 months of age)

Other clinical evaluations

Serum electrolytes

Blood urea nitrogen /creatinine levels

Changes in stool frequency or volume, including mixed output

Stool consistency (ie, Bristol Stool Scale)

Urine specific gravity

General consideration to possible clinical deterioration in SBS

Inability to maintain weight and growth velocity

Diarrhea (≥10 bowel movements per day, ≥80 mL/kg/day from an ostomy, or 
≥75 mL/kg/day mixed output)

Colic/vomiting frequency increased

Electrolyte changes or imbalance

Skin breakdown 

Adjustments should be based on the actual nutritional support in volume and calories the 
subject infuses. Subjects should remain compliant with the nutritional support prescription in 
volume and calories during the study.

Nutritional support constituents may be adjusted at the discretion of the investigator.

During the 48-hour output measurement period prior to the subject’s scheduled visit, no 
further changes to the prescribed nutritional support should be made.

If there is a change in EN or other food or fluid intake, the investigator should consider this 
when adjusting the PS/EN support in volume and calories.
For non-commercial use only


Shire
CONFIDENTIAL
Page 80
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
Figure A-1
Weaning Algorithm for Subjects Who are NOT Toilet Trained and in 
Diapers
For non-commercial use only


Shire
CONFIDENTIAL
Page 81
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
Figure A-2
Weaning Algorithm for Subjects Who are Toilet Trained and NOT in 
Diapers
For non-commercial use only


Shire
CONFIDENTIAL
Page 82
SHP633-304 Protocol Amendment 3
Teduglutide
16 May 2018
Figure A-3
Clinical Dehydration Assessment and PS/EN Adjustment
For non-commercial use only


PROTOCOL: SHP633-304
TITLE:
A Prospective, Open-label, Long-term Safety and Efficacy Study of 
Teduglutide in Pediatric Patients with Short Bowel Syndrome Who 
Completed TED-C14-006 or SHP633-301
DRUG:
Teduglutide
IND:
IND# 058213
EUDRACT NO.:
2016-000849-30
SPONSOR:
Shire Human Genetic Therapies, Inc.
300 Shire Way, Lexington, MA 02421 USA
PROTOCOL 
HISTORY:
Amendment 4: 01 Oct 2019
Amendment 3: 16 May 2018
Amendment 2: 23 Mar 2017
Amendment 1: 22 Nov 2016
Original Protocol: 08 Apr 2016
This document contains confidential and proprietary information of Shire and is disclosed pursuant to 
confidentiality and non-disclosure obligations. This information should be used solely for the purposes for which 
it was provided and should not be copied, shared with, or disclosed to any third party without the express written 
consent of Shire.
For non-commercial use only


Shire 
CONFIDENTIAL 
Page2 
SHP633-304 Protocol Amendment 4 
Teduglutide 
01Oct2019 
PROTOCOL SIGNATURE PAGE 
Sponsor's (Shire) Approval 
Signature: 
, 
 
Global Clinical Development 
Investigator's Acknowledgement 
I have read this protocol for Shire Study SHP633-304. 
Title: A prospective, open label, long-term safety and efficacy study of teduglutide in 
pediatric patients with short bowel syndrome who completed TED-Cl4-006 or SHP633-301 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the 
study, without written authorization from the sponsor. It is, however, permissible to provide 
the information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Conference on Harmonization (ICH) guidelines on Good 
Clinical Practice (GCP) and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at 
any time for whatever reason; such a decision will be communicated to me in writing. 
Conversely, should I decide to withdraw from execution of the study I will communicate my 
intention immediately in writing to the sponsor. 
Investigator Name and Address: 
(please hand print or type) 
For non-commercial use only


Shire
CONFIDENTIAL
Page 3
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
SUMMARY OF CHANGES FROM PREVIOUS VERSION
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 4
Amendment Date
01 Oct 2019
Global
Description of Change and Rationale
Section(s) Affected by Change
The name and contact information of the Sponsor
 was 
updated to 
. 
(Administrative letter dated 22 Oct 2018)
The fax number of the Sponsor
 was removed. 
(Administrative letter dated 15 Jan 2019)
Emergency Contact Information
The contact for medical support was updated to reflect Quintiles’ current 
name, IQVIA, and Dr. 
’s email address as 
Emergency Contact Information
Updated the Product Quality Complaints to match the current Sponsor 
standard
Product Quality Complaints
Extended the planned study period to December 2020. 
Synopsis
Clarification of the follow-up period escape criteria and their use in 
combining the CxW24 and pretreatment visits was added.
(Clarification Memo dated 09 Apr 2019) 
Synopsis, Section 4.6
Clarified that AEs will be collected for 4 weeks after the last dose of 
teduglutide in the study even if the EOS/ET occurs within that timeframe.
Table 1-1, Section 7.1.5, Section 8.1
An optional qualitative interview to be conducted by phone and within 
14 days after completion of the end of study/early termination visit was 
added. A single individual telephone interview will be conducted with 
English-speaking parents (or legal guardians) of subjects and subjects aged 
12 years or older who provide informed consent (and if applicable, informed 
assent) to participate in the interview. These interviews will be performed in 
selected countries participating in this trial.
Table 1-1, Section 7.1.6, 
Section 7.2.13, Section 9.9.2,
Appendix 3, Appendix 4
Noted that CRP will not be measured in subjects <10 kg due to blood 
volume limitations.
Table 1-2, Table 1-3, Table 7-1, 
Table 7-2
Noted that stored serum samples should be omitted for subjects weighing 
less than 15 kg and whenever local blood volume limitations are exceeded.
Table 1-2, Table 1-3, Section 7.2.5, 
Table 7-2
Updated the volume of blood to be drawn to be determined by subject 
weight. 
Section 7.2.8
Clarified that serum pregnancy tests will be collected at the teduglutide 
pretreatment visits. 
Table 7-1
Clarified that adverse event collection would include events that were 
reported during the qualitative interviews.
Section 8.1
The definition of an overdose was clarified as the administration of the 
investigational product at a dose or frequency greater than 0.05 mg/kg 
subcutaneous once daily. An overdose occurs if any of the following criteria 
are met: 

More than 0.05 mg/kg is given at any one time

Consecutive doses are spaced less than 12 hours apart

Any more than 0.05 mg/kg given in one day (a day is defined as 
beginning at 12:00 AM and ending at 11:59 PM)
Section 8.1.7
For non-commercial use only


Shire
CONFIDENTIAL
Page 4
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 4
Amendment Date
01 Oct 2019
Global
Description of Change and Rationale
Section(s) Affected by Change
The teduglutide dose interruption criteria were updated to specify events 
leading to an interruption of teduglutide treatment and events leading to a 
permanent discontinuation of teduglutide treatment. 
Investigational product must be interrupted if any of the following events 
occur:

An AE of special interest

An AE that is of NCI CTCAE severity Grade 3 or 4 and related to 
teduglutide

Intestinal obstruction

Biliary obstruction related to teduglutide

Pancreatic duct obstruction related to teduglutide

Heart failure with severe fluid overload related to teduglutide 
Investigational product must be permanently discontinued if any of the 
following events occur:

Pregnancy

Severe hypersensitivity, such as anaphylaxis determined by the 
investigator to be related to study drug. This does not include the 
presence of anti-teduglutide antibodies, mild injection site reactions or 
mild symptoms that according to the investigator do not pose a 
significant risk to the subject.

Confirmed drug-induced liver injury (DILI) related to teduglutide 

Any malignancy
These clarifications were made for consistency with other teduglutide 
studies.
Section 8.4, Section 8.4.1
Minor editorial changes and corrections to typographical errors (which do 
not modify content and/or intent of the original document) were made.
Throughout the protocol
See Appendix 1 for protocol history, including all amendments.
For non-commercial use only


Shire
CONFIDENTIAL
Page 5
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Adverse Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as 
Required by Protocol within 24 hours to the Shire Global Drug Safety Department. Applicable 
fax numbers and e-mail address can be found on the form (sent under separate cover). A copy of 
this form must also be sent to the Sponsor Medical Monitor by e-mail using the details below.
, MD
Email: 
For protocol- or safety-related issues, the investigator must contact IQVIA Medical 
Support:
Primary contact for North America (NA) and backup contact for European Union (EU)
, MD, 
Mobile: 
US Toll Free number: 
Phone: 
 (medical emergencies – NA)
Email: 
Primary contact for EU and backup contact for NA
, MD, 
Mobile: 
Phone: 
Phone: 
 (medical emergencies – EU)
Email: 
In addition, the investigator may also contact the Sponsor Medical Monitor (8:00 to 20:00 
US Eastern Standard Time):
, MD, 
Mobile: 
Email: 
For non-commercial use only


Shire
CONFIDENTIAL
Page 6
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints or non-medical 
complaints to Shire within 24 hours. If requested, defective product(s) will be returned to the 
sponsor for inspection and analysis.
A product quality complaint includes any instances where there is an allegation or report relating 
to Shire licensed or investigational products, received in writing, electronically, or orally, which 
indicates an impact to a product’s strength, identity, safety, purity, or quality, or which suggests 
that the product did not meet the criteria defined in the regulatory applications, licenses, or 
marketing authorizations for the product. Examples of investigational product quality complaints 
include, but are not limited to, the following:
Unit issues

Capsule fill empty or overage

Bottle/vial fill shortage or overage

Capsule/tablet damaged/broken

Syringe/vial cracked/broken

Syringe leakage

Missing components

Product discoloration

Device malfunction
Labeling

Label missing

Leaflet or Instructions For Use 
(IFU) missing 

Label illegible

Incomplete, inaccurate, or 
misleading labeling

Lot number or serial number missing
Packaging

Damaged packaging (eg, secondary, 
primary, bag/pouch)

Tampered seals

Inadequate or faulty closure

Missing components within package
Foreign 
material

Contaminated product

Particulate in bottle/vial

Particulate in packaging
Please report the product quality complaint using the “Product Quality Complaint Data 
Collection Form” via the email address:
Telephone number (provided for reference if needed):
Shire, Lexington, MA (USA)
For instruction on reporting AEs related to product complaints see Section 8.
For non-commercial use only


Shire
CONFIDENTIAL
Page 7
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................3
EMERGENCY CONTACT INFORMATION................................................................................5
PRODUCT QUALITY COMPLAINTS..........................................................................................6
TABLE OF CONTENTS.................................................................................................................7
LIST OF TABLES.........................................................................................................................11
LIST OF FIGURES .......................................................................................................................11
LIST OF APPENDICES................................................................................................................11
ABBREVIATIONS .......................................................................................................................12
STUDY SYNOPSIS ......................................................................................................................14
STUDY SCHEDULE(S) ...............................................................................................................19
1
BACKGROUND INFORMATION.......................................................................................24
1.1
Indication and Current Treatment Options...............................................................24
1.2
Product Background.................................................................................................24
1.3
Clinical Studies with Teduglutide in Pediatric Subjects ..........................................25
2
STUDY OBJECTIVES AND PURPOSE ..............................................................................27
2.1
Rationale for the Study.............................................................................................27
2.2
Study Objectives ......................................................................................................27
2.2.1
Primary Objectives.................................................................................................27
2.2.2
Secondary Objectives.............................................................................................27
3
STUDY DESIGN ...................................................................................................................28
3.1
Study Design and Flow Chart ..................................................................................28
3.2
Duration and Study Completion Definition .............................................................31
4
STUDY POPULATION.........................................................................................................32
4.1
Study Inclusion Eligibility Criteria ..........................................................................32
4.2
Study Exclusion Eligibility Criteria .........................................................................32
4.3
Teduglutide Eligibility Criteria ................................................................................32
4.4
Teduglutide Treatment Inclusion Criteria................................................................32
4.5
Teduglutide Treatment Exclusion Criteria...............................................................33
4.6
Follow-up Period Escape Criteria ............................................................................34
4.7
Reproductive Potential .............................................................................................34
4.7.1
Female Contraception............................................................................................34
4.8
Discontinuation of Subjects .....................................................................................35
4.8.1
Teduglutide Discontinuation..................................................................................35
4.8.2
Study Withdrawal ..................................................................................................35
4.8.3
Reasons for Discontinuation..................................................................................36
For non-commercial use only


Shire
CONFIDENTIAL
Page 8
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
5
CONCOMITANT TREATMENT..........................................................................................37
5.1
Concomitant Medications and Procedures...............................................................37
5.1.1
Permitted Treatment...............................................................................................37
5.1.2
Prohibited Treatment .............................................................................................37
6
INVESTIGATIONAL PRODUCT ........................................................................................38
6.1
Identity of Investigational Product...........................................................................38
6.1.1
Blinding the Treatment Assignment......................................................................38
6.2
Administration of Investigational Product(s)...........................................................38
6.2.1
Interactive Response Technology for Investigational Product Management ........38
6.2.2
Allocation of Subjects to Treatment ......................................................................38
6.2.3
Dosing....................................................................................................................38
6.2.4
Unblinding the Treatment Assignment..................................................................39
6.3
Labeling, Packaging, Storage, and Handling ...........................................................39
6.3.1
Labeling .................................................................................................................39
6.3.2
Packaging...............................................................................................................39
6.3.3
Storage and Handling.............................................................................................40
6.4
Drug Accountability.................................................................................................40
6.5
Subject Compliance..................................................................................................41
7
STUDY PROCEDURES........................................................................................................42
7.1
Study Schedule.........................................................................................................42
7.1.1
Screening................................................................................................................42
7.1.2
Visits for Subjects Not Receiving Teduglutide .....................................................42
7.1.3
Visits for Subjects Receiving Teduglutide ............................................................43
7.1.4
Teduglutide Follow-up Period...............................................................................46
7.1.5
Study Completion/Early Termination Visit (EOS/ET Visit).................................46
7.1.6
Qualitative Interview .............................................................................................47
7.2
Study Evaluations and Procedures ...........................................................................47
7.2.1
Demographics, Medical History, and SBS History ...............................................47
7.2.2
Physical Examination.............................................................................................47
7.2.3
Vital Signs, Body Weight, Height, Head Circumference and Body Mass 
Index ......................................................................................................................47
7.2.4
Clinical Laboratory Tests.......................................................................................48
7.2.5
Serum Sampling.....................................................................................................49
7.2.6
Pregnancy Testing..................................................................................................50
7.2.7
Antibody Testing ...................................................................................................50
7.2.8
Volume of Blood....................................................................................................50
7.2.9
Gastrointestinal-specific Testing ...........................................................................52
7.2.10 Nutritional Support ................................................................................................52
For non-commercial use only


Shire
CONFIDENTIAL
Page 9
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
7.2.11 Diaries.....................................................................................................................53
7.2.12 Health-related Quality of Life Assessments ..........................................................54
7.2.13 Qualitative Interviews............................................................................................56
8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................59
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................59
8.1.1
Severity Categorization..........................................................................................59
8.1.2
Relationship Categorization...................................................................................60
8.1.3
Outcome Categorization ........................................................................................61
8.1.4
Symptoms of the Disease under Study ..................................................................61
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................61
8.1.6
Pregnancy...............................................................................................................61
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................62
8.2
Serious Adverse Event Procedures ..........................................................................63
8.2.1
Reference Safety Information................................................................................63
8.2.2
Reporting Procedures.............................................................................................63
8.2.3
Serious Adverse Event Definition .........................................................................63
8.2.4
Serious Adverse Event Collection Time Frame.....................................................64
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................64
8.2.6
Fatal Outcome........................................................................................................65
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................65
8.3
Adverse Events of Special Interest...........................................................................65
8.4
Dose Interruption of Individual Subjects .................................................................65
8.4.1
Dose Interruption Criteria Based on Adverse Event Severity and 
Relationship to Investigational Product.................................................................66
8.4.2
Dose Interruption Criteria Based on Drug-Induced Liver Injury ..........................67
8.5
Early Termination of the Clinical Study ..................................................................67
9
DATA MANAGEMENT AND STATISTICAL METHODS...............................................68
9.1
Data Collection.........................................................................................................68
9.2
Clinical Data Management.......................................................................................68
9.3
Statistical Analysis Process......................................................................................68
9.4
Planned Interim Analysis, and Data Monitoring Committee...................................68
9.5
Sample Size Calculation and Power Considerations................................................69
9.6
Study Population ......................................................................................................69
9.7
Efficacy Analyses.....................................................................................................69
9.7.1
Efficacy Endpoints.................................................................................................69
9.8
Safety Analyses........................................................................................................70
9.8.1
Safety Endpoints....................................................................................................70
For non-commercial use only


Shire
CONFIDENTIAL
Page 10
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
9.9
Other Analyses .........................................................................................................71
9.9.1
Health-related Quality of Life Analyses................................................................71
9.9.2
Qualitative Interviews............................................................................................71
10 SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................72
10.1
Sponsor’s Responsibilities .......................................................................................72
10.1.1 Good Clinical Practice Compliance.......................................................................72
10.1.2 Indemnity/Liability and Insurance.........................................................................72
10.1.3 Public Posting of Study Information......................................................................72
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................72
10.1.5 Study Suspension, Termination, and Completion..................................................73
10.2
Investigator’s Responsibilities .................................................................................73
10.2.1 Good Clinical Practice Compliance.......................................................................73
10.2.2 Protocol Adherence and Investigator Agreement..................................................73
10.2.3 Documentation and Retention of Records.............................................................74
10.3
Ethical Considerations..............................................................................................75
10.3.1 Informed Consent...................................................................................................75
10.3.2 Institutional Review Board or Ethics Committee..................................................76
10.4
Privacy and Confidentiality......................................................................................76
10.5
Study Results / Publication Policy ...........................................................................77
11 REFERENCES .......................................................................................................................79
For non-commercial use only


Shire
CONFIDENTIAL
Page 11
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
LIST OF TABLES
Table 1-1:
Schedule of Events Required for All Subjects ..............................................19
Table 1-2: 
Schedule of Events for Subjects Not Receiving Teduglutide .......................20
Table 1-3: 
Schedule of Events for Subjects While Receiving Teduglutide....................21
Table 5-1: 
Prohibited Treatment.....................................................................................37
Table 7-1:
List of Laboratory Tests ................................................................................49
Table 7-2:
Approximate Volume of Blood to be Drawn from Each Subject 
Annually ........................................................................................................51
Table 7-3:
Developmentally Appropriate PedsQL™Generic Core Scales .....................55
LIST OF FIGURES
Figure 3-1:
Study Design Flow Chart ..............................................................................31
LIST OF APPENDICES
Appendix 1
Protocol History.............................................................................................80
Appendix 2
Guidelines for Nutritional Support Management During the Study .............85
Appendix 3
Caregiver Interview Guide ............................................................................89
Appendix 4
Pediatric Subject Interview Guide.................................................................94
For non-commercial use only


Shire
CONFIDENTIAL
Page 12
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
ABBREVIATIONS
Abbreviation
Definition
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
-HCG
beta-human chorionic gonadotropin
BMI
body mass index
CRA
clinical research associate
CRO
contract research organization
CSR
clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
DILI
drug-induced livery injury
DMC
data monitoring committee
DPP-4
dipeptidyl peptidase 4
EC
ethics committee
eCRF
electronic case report form
EMA
European Medicines Agency
EN
enteral nutrition
EOS
end of study
EOT
end of treatment
ET
early termination
EU
European Union
FDA
Food and Drug Administration
FOBT
fecal occult blood test
FOCBP
female of child-bearing potential
GCP
Good Clinical Practice
GI
gastrointestinal
GLP-1
glucagon-like peptide 1
GLP-2
glucagon-like peptide 2
HIPAA
Health Insurance Portability and Accountability Act
ICF
informed consent form
ICH
International Conference on Harmonization
IGF-1
insulin-like growth factor 1
IRB
institutional review board
IV
intravenous
For non-commercial use only


Shire
CONFIDENTIAL
Page 13
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
Abbreviation
Definition
IWRS
interactive web-based response system
MedDRA
Medical Dictionary for Regulatory Activities
NA 
North America
NCI
National Cancer Institute
NDA
new drug application
NTT
no-teduglutide treatment
PedsQL
Pediatric Quality of Life inventory
PS
parenteral support
PT/INR
prothrombin time/international normalized ratio
QD
once daily
SAE
serious adverse event
SAP
statistical analysis plan
SBS
short bowel syndrome
SC
subcutaneous
SOC
standard of care
t1/2
elimination half-life
TEAE
treatment-emergent adverse event
TESAE
treatment-emergent serious adverse event
UK
United Kingdom
ULN
upper limit of normal
US
United States
WHO-DD
World Health Organization – Drug Dictionary
For non-commercial use only


Shire
CONFIDENTIAL
Page 14
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
STUDY SYNOPSIS
Protocol number: SHP633-304
Drug: Teduglutide
Title of the study: A Prospective, Open-label, Long-term Safety and Efficacy Study of Teduglutide in Pediatric 
Patients with Short Bowel Syndrome (SBS) Who Completed TED-C14-006 or SHP633-301
Number of subjects (total and for each treatment arm):
Approximately 65 subjects who completed the TED-C14-006 or SHP633-301 studies, including subjects in the 
standard of care treatment arms, are expected to enroll in this extension study. This study will enroll up to as 
many subjects as complete the TED-C14-006 and SHP633-301 studies.
Investigator(s): Multicenter study
Site(s) and Region(s): 
Approximately 28 investigational sites in North America and Europe will participate in this extension study
Study period (planned):
October 2016 – December 2020
Clinical phase:
3 Extension
Objectives:
Primary: To evaluate the long-term safety and tolerability of teduglutide treatment in pediatric subjects with SBS.
Secondary: To evaluate long-term efficacy of teduglutide treatment in pediatric subjects with SBS.
Rationale:
This is a Phase 3, prospective, open-label, long-term extension study to evaluate the safety and efficacy of 
teduglutide in pediatric subjects with short bowel syndrome (SBS) who completed either the TED-C14-006 or 
SHP633-301 studies (the core studies). In addition to evaluating the long-term safety and durability of efficacy 
after 24-weeks of treatment, this extension study will evaluate the need for additional teduglutide treatment in 
these subjects and will allow the study of first-time treatment of teduglutide-naïve subjects who participated in the 
standard of care (SOC) treatment arms in TED-C14-006 or SHP633-301. 
Investigational product, dose, and mode of administration:
This study will allow repeat doses of teduglutide 0.05 mg/kg subcutaneous (SC) once daily (QD) injection for 
eligible pediatric subjects. There is no active comparator or reference product.
Methodology:
This is a Phase 3, prospective, open-label, long-term extension study to evaluate the safety and efficacy of 
teduglutide in pediatric subjects who completed the TED-C14-006 or SHP633-301 studies (core studies).
Once the informed consent (and if applicable, informed assent) have been reviewed and signed, demographics, 
and updates to medical history and short bowel syndrome history will be obtained. Subjects not receiving 
teduglutide treatment (ie, in a no-teduglutide treatment [NTT] period), will be seen approximately every 12 weeks 
for safety, parenteral support (PS) requirements, and quality of life. The first NTT visit after the screening visit 
will occur within 2 to 12 weeks of the screening visit. At any point after screening, including during a NTT 
period, subjects who meet ≥1 teduglutide treatment inclusion criteria, may proceed immediately to the 
pretreatment visit if the investigator, subject, and parent agree to proceed with teduglutide therapy.
After the pretreatment visit, subjects who meet ≥1 of the teduglutide treatment inclusion criteria, and meet none 
of the teduglutide treatment exclusion criteria, will start a 28-week cycle, consisting of 24 weeks of teduglutide 
treatment at 0.05 mg/kg SC once daily, followed by a 4-week follow-up period (during which no teduglutide is 
administered) (Figure 3-1). During the 28-week cycle, clinic visits will occur at weeks 1, 2, 4, 6, 9, 12, 16, 20, 24, 
and 28. Phone visits are required approximately 1 week after adjustments in PS during the teduglutide treatment 
period (between weeks 1 and 24), and weekly during the teduglutide follow-up period (between weeks 24 and 
28). Safety and PS requirements will be evaluated at every visit, and quality of life assessments will be made 
approximately every 12 weeks. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 15
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
If a subject meets 1 of the follow-up period escape criteria between cycle week 24 and 28, the subject may 
"escape" the follow-up period early and proceed immediately to another pretreatment visit. Following completion 
of the 28-week treatment cycle, the subject will proceed to an NTT visit or another pretreatment visit within 
approximately 12 weeks.
At all site visits and telephone contacts, safety will be monitored and nutritional support will be reviewed and
adjusted as needed. To maintain consistency across centers, all attempts should be made to follow the nutritional
support adjustment guidelines (developed with SBS expert input and provided in the protocol) for decisions
regarding PS support reduction and advances in enteral feeds based on weight gain, urine and stool output, and
clinical stability. Departure from the guidelines, however, is not considered a protocol deviation. (Appendix 2).
Study Design Flow Chart 
Figure legend: Safety and efficacy data for subjects not receiving teduglutide treatment are captured approximately every 
12 weeks, but subjects may proceed to the pretreatment visit at any time in order to assess eligibility for teduglutide 
therapy. Eligible subjects will enter a 28-week teduglutide cycle. During this cycle, subjects will return to the site for 
safety and efficacy assessments at weeks 1, 2, 4, 6, 9, 12, 16, 20, and 24 (solid black lines). Phone visits are required 
approximately 1 week after adjustments in PS during the intervening weeks between weeks 2 and 24 (dashed grey 
lines). Subjects discontinue teduglutide at week 24 and enter a 4-week follow-up (no-treatment) period, during which 
phone visits will be performed weekly (solid grey lines). If an escape criterion is met at week 24 or during the follow-up 
period, subjects may proceed directly to another pretreatment visit.
Study Inclusion Criteria: 
The subject will be considered eligible for the study if they meet all of the study inclusion criteria. Teduglutide 
treatment eligibility does not impact study eligibility.
1.
Subject provides written informed consent (subject, parent or legal guardian and, as appropriate, 
informed assent) to participate in the study before completing any study-related procedures.
2.
Subject completed the TED-C14-006 or SHP633-301 studies (including subjects in the standard of care 
treatment arms). Subjects are considered to have completed SHP633-301 if they completed study 
assessments through week 24.
3.
Subject understands and is willing and able to fully adhere to study requirements as defined in this 
protocol. 
Study Exclusion Criteria: There are no exclusion criteria for this study.
Teduglutide Eligibility Criteria: Subjects are eligible for teduglutide treatment if at least one (≥1) of the 
teduglutide treatment inclusion criteria, and none of the teduglutide treatment exclusion criteria, are met. In 
addition, the investigator and the subject (and/or parent or legal guardian, as appropriate) must agree to proceed 
with treatment.
For non-commercial use only


Shire
CONFIDENTIAL
Page 16
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
Teduglutide Treatment Inclusion Criteria:
1.
Subject is teduglutide-naïve, receiving PS, and unable to significantly reduce PS or advance enteral feeds 
(eg, 10% or less change in PS or advance in feeds) for at least 3 months prior to and during the 
teduglutide pretreatment visit, as assessed by the investigator. Transient instability for events such as 
interruption of central access or treatment for sepsis is allowed if the PS returns to within 10% of 
baseline prior to the event.
2.
Subject was previously treated with teduglutide and at least one of the following criteria is satisfied:
a.
Increasing PS requirements following teduglutide discontinuation.
b.
Decreased PS requirement during prior teduglutide treatment, followed by cessation of 
improvement after teduglutide discontinuation.
c.
Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal tolerated 
enteral nutrition (EN) following teduglutide discontinuation.
d.
Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and electrolyte 
intake following teduglutide discontinuation.
e.
Severe diarrhea related to teduglutide discontinuation.
Teduglutide Treatment Exclusion Criteria:
1.
Body weight <5 kg at the pretreatment visit.
2.
Unresected gastrointestinal (GI) polyp, known polyposis condition, premalignant change, or malignancy, 
in the GI tract.
3.
History of cancer in the previous 5 years except surgically curative skin cancers.
4.
Serial transverse enteroplasty or other major intestinal surgery within 3 months preceding the teduglutide 
pretreatment visit. Insertion of a feeding tube, anastomotic ulcer repair, minor intestinal resections 
≤10 cm, and endoscopic procedures are allowed.
5.
Intestinal or other major surgery planned or scheduled to occur during the 28-week cycle.
6.
Clinically significant intestinal stricture or obstruction.
7.
Clinically significant, active or recurrent pancreatic or biliary disease.
8.
Active, severe, or unstable, clinically significant hepatic impairment or injury, including the following 
laboratory values at the pretreatment visit:
a.
Total bilirubin ≥2 × upper limit of normal (ULN)
b.
Aspartate aminotransferase (AST) ≥7 × ULN
c.
Alanine aminotransferase (ALT) ≥7 × ULN
9.
Renal dysfunction shown by results of an estimated glomerular filtration rate below 50 mL/min/1.73 m2
at the pretreatment visit.
10. Unstable cardiac disease, congenital heart disease or cyanotic disease, with the exception of subjects 
who had undergone ventricular or atrial septal defect repair, or patent ductus arteriosus ligation.
11. Participation in a clinical study using an experimental drug (other than glutamine, Omegaven, or 
Smoflipid) within 3 months or 5.5 half-lives of the experimental drug, whichever is longer, prior to the 
pretreatment visit and for the duration of the 28-week cycle.
12. Treatment with analogs of glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2) (not 
including teduglutide), insulin-like growth factor-1 (IGF-1), or growth hormone, within 3 months 
preceding the teduglutide pretreatment visit.
13. Treatment with octreotide or dipeptidyl peptidase 4 (DPP-4) inhibitors within 3 months prior to the 
pretreatment visit.
14. Known or suspected intolerance or hypersensitivity to the investigational product, closely-related 
compounds, or any of the stated ingredients.
For non-commercial use only


Shire
CONFIDENTIAL
Page 17
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
15. Known history of alcohol or other substance abuse within 1 year prior to the pretreatment visit.
16. Pregnant or lactating female subjects.
17. Sexually active female subjects of child-bearing potential unwilling to use approved contraception 
during teduglutide treatment and for 30 days after the treatment period.
18. Any condition, disease, illness, or circumstance that in the investigator’s opinion puts the subject at any 
undue risk, prevents completion of the study, or interferes with analysis of the study results.
Follow-up Period Escape Criteria: At the discretion of the investigator, the follow-up period may be interrupted 
(if the subject meets 1 or more of escape criteria 1 to 4 during the follow-up period) or omitted (if the subject 
meets escape criterion 5 at the CxW24 visit) and the subject may proceed directly to the pretreatment visit, if 
≥1 of the following criteria is met:
1.
Increasing PS requirements following teduglutide discontinuation
2.
Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal tolerated EN 
following teduglutide discontinuation.
3.
Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and electrolyte intake 
following teduglutide discontinuation.
4.
Severe diarrhea related to teduglutide discontinuation.
5.
The subject escaped during the follow-up period of a previous teduglutide treatment cycle within 
SHP633-301 or SHP633-304. In this case, the CxW24 visit may be combined with the next cycle 
pretreatment visit.
Maximum duration of subject involvement in the study:
A subject will be considered enrolled in the study once the subject has provided signed consent and meets all of 
the Study Inclusion Criteria. Subjects may participate in multiple NTT periods and/or multiple 28-week treatment 
cycles. The study will continue for at least 1 year, and until each subject has access (as needed) to teduglutide. 
The subject’s maximum duration of participation is expected to be approximately 3 years. A subject will be 
considered as having completed the study if the subject has not withdrawn early from the study for any reason 
prior to completing End of Study (EOS) visit.

Planned duration of no-teduglutide treatment periods: variable, depending on disease course 

Planned duration of the teduglutide pretreatment visit: 1 to 21 days

Planned cycle duration: 28 weeks. Each cycle consists of 24 weeks of teduglutide treatment followed 
by a 4-week follow-up period (no treatment)
Endpoints and statistical analysis: 

The safety population will consist of all enrolled subjects. The safety population will be used for both 
safety and efficacy analysis.
Efficacy Endpoints
Efficacy endpoints will be analyzed at the end of each teduglutide treatment period (week 24 or end of treatment 
[EOT]), and at each study visit, relative to the baseline of the core study (TED-C14-006 or SHP633-301) and/or 
first exposure to teduglutide. The following efficacy endpoints will be analyzed: 

Reduction in PS volume of at least 20%

Absolute and relative change in PS volume

Complete weaning off PS

Change in days per week of PS
Health Economics and Outcomes Research Endpoints 
Health economics and outcomes research endpoints will be analyzed at approximately 12-week intervals 
(weeks 12 and 24 of each teduglutide treatment cycle, and every 12 weeks for subjects not on teduglutide), 
relative to the study baseline. The beginning of each treatment cycle (CxD1) will be an additional baseline.
For non-commercial use only


Shire
CONFIDENTIAL
Page 18
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019

Change in Pediatric Quality of Life Inventory (PedsQL) score

Change in PedsQL Family Impact Module score

Change in PedsQL Gastrointestinal Symptoms Module Sub-Scales scores: 

Food and Drink Limits

Diarrhea 
Safety Endpoints 
The following safety endpoints will be analyzed:

Adverse events

Vital signs, including temperature, heart rate, blood pressure

Laboratory safety data (ie, clinical chemistry, hematology, and urinalysis)

Urine output

Stool output

Antibodies to teduglutide

Gastrointestinal-specific testing, including fecal occult blood testing and colonoscopy or sigmoidoscopy

Z-scores for weight, height (or length), head circumference (up to 36 months of age), and body mass index 
Statistical Methodology for Efficacy Analysis
No claims of statistical significance will be made; however, 95% confidence intervals will be provided, if 
applicable. Continuous variables, including those assessed on a discrete scale, will be summarized using 
descriptive statistics including number of subjects, mean, median, standard deviation , maximum, and minimum. 
For categorical variables, statistical summaries will include number of subjects and percentages.
Statistical Methodology for Safety Analysis 
Safety data, including laboratory tests and vital signs assessments, will be summarized by visit. AEs will also be 
collected and summarized. Descriptive statistics will be calculated for quantitative safety data as well as for the 
difference from baseline, if applicable. Frequency counts will be compiled for classification of qualitative safety 
data.
Sample Size Justification 
As this is an extension study, the maximum number of subjects was determined by enrollment in TED-C14-006 
and SHP633-301.
For non-commercial use only


Shire
CONFIDENTIAL
Page 19
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
STUDY SCHEDULE(S) 
Table 1-1: Schedule of Events Required for All Subjects 
Period
Screening
End of Study or Early Termination
Scr
EOS/ET
Visit Type
Site
Site
Informed consent/assenta
X
Study eligibility
X
Demographics, medical historyb, SBS historyc
X
Dispense intake and output diaries
X
Evaluate teduglutide treatment inclusion criteriad
X
Adverse events
X
Xn
Concomitant medications and procedures
X
X
Physical examination and vital signs, including weight
X
Height and head circumferencee
X
Review intake and output diariesf 
X
Record PS prescription and adjust as neededg
X
X
Safety laboratory testsh
X
PedsQL Generic Core Scale/PedsQL Family Impact Module/ 
PedsQL Gastrointestinal Symptoms Module Sub-Scales
X
Antibodies to teduglutidei
X
Fecal occult blood testingj
(X)
Colonoscopy or sigmoidoscopyk
(X)
Pregnancy testingl
(X)
Qualitative interviewm
X
FOBT = fecal occult blood testing; FOCBP = female of child-bearing potential; EOS =end of study; ET=early termination; 
GI=gastrointestinal; NTx=no treatment; PedsQL=Pediatric Quality of Life Inventory; PS=parenteral support; SBS=Short Bowel 
Syndrome; Scr =Screening
a Informed Consent (and informed assent, if applicable) must be obtained prior to performing any study-related procedures; 
consent (and informed assent, if applicable) may be obtained anytime during the EOS visit for the TED-C14-006 or SHP633-301 
studies. Subject will have approximately 7 days after completion of the TED-C14-006 or SHP633-301 studies to sign consent to 
participate in the SHP633-304 study.
b Updates to the medical history will be collected, consisting of adverse events that were ongoing at the time of completion of
TED-C14-006 or SHP633-301, and events that occurred during the period between completion of TED-C14-006 or SHP633-301 
and informed consent to SHP-633-304. 
c If the subject has any changes to the SBS history that had been collected at the baseline of the TED-C14-006 or SHP633-301, 
then the updated SBS history will be collected.
d Subjects who meet ≥1 teduglutide treatment inclusion criteria, may proceed to the pretreatment visit if the investigator, subject, 
and parent or legal guardian agrees to proceed with teduglutide therapy (Table 1-3).
e Head circumference will be measured in subjects 36 months of age and younger.
f The intake diary should be completed daily for a minimum of 2 weeks prior to the EOS/ET visit. The output diary should be 
completed daily over a 48-hour period of nutritional stability before the EOS/ET visit.
g PS adjustments should be made after review of any available intake and output diaries and the safety lab data according to the 
guidance for nutrition support adjustment provided in Appendix 2. 
h Safety laboratory assessments at site visits will consist of clinical chemistry, hematology, and urinalysis, with results processed 
by a central laboratory. Urine specimen collection should be attempted as part of the safety labs, but lack of urinalysis will not 
constitute a protocol deviation.
i Required for all teduglutide-exposed subjects
j FOBT should be performed on teduglutide-exposed subjects on an annual basis, approximately every 48-60 weeks at a 
minimum.
k The need for colonoscopy/sigmoidoscopy in response to a positive FOBT during a no-teduglutide treatment period is at the 
discretion of the investigator, but all teduglutide-exposed subjects will undergo colonoscopy/sigmoidoscopy after they have 
received the equivalent of 2 treatment cycles (48 weeks of study drug exposure), and subjects who continue to receive teduglutide 
will undergo colonoscopy/sigmoidoscopy at 5 year intervals or more often as needed. See Section 7.2.9 for details.
l Pregnancy testing is required for FOCBP at an ET visit if the subject has not had a pregnancy test at least 30 days after study 
drug discontinuation.
m Optional interview to be conducted by phone within 14 days after completion of the EOS/ET visit (see Section 7.2.13).
n AEs will be collected for 4 weeks after the last dose of teduglutide in the study even if the EOS/ET occurs within that timeframe.
Note: (X) denotes conditional requirement for a given assessment if the subject meets certain conditions per protocol.
For non-commercial use only


Shire
CONFIDENTIAL
Page 20
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
Table 1-2: Schedule of Events for Subjects Not Receiving Teduglutide 
Visit Number
NTx
Visit Type
Site
Visit Frequencya
Every 12 weeks 
Window (days)b
±7
Dispense intake and output diaries
X
Evaluate teduglutide treatment inclusion criteriac
X
Adverse events
X
Concomitant medications and procedures
X
Physical examination and vital signs, including weight
X
Height and head circumferenced
X
Review intake and output diariese 
X
Record PS prescription and adjust as neededf
X
Safety laboratory testsg
X
PedsQL Generic Core Scale/PedsQL Family Impact Module/ 
PedsQL Gastrointestinal Symptoms Module Sub-Scales
X
Antibodies to teduglutideh
(X)
Fecal occult blood testingi
Annually 
Colonoscopy or sigmoidoscopyj
(X)
Serum samplek
Every 24 weeks
FOBT = fecal occult blood testing; NTT = no-teduglutide treatment; PedsQL = Pediatric Quality of Life Inventory; 
PS= parenteral support; TED = teduglutide
a The first NTx visit following the screening visit must occur within 2 to 12 weeks of screening.
b Window is relative to the first NTx visit in the current no-teduglutide treatment period.
c Subjects who meet ≥1 teduglutide treatment inclusion criteria, may proceed to the pretreatment visit if the investigator, subject, 
and parent or guardian agree to proceed with teduglutide therapy (Table 1-3).
d Head circumference will be measured in subjects 36 months of age and younger.
f Intake diaries will collect actual PS volume and hours per day, completed daily for a minimum of 2 weeks prior to each study 
visit (see Section 7.2.11.2). Urine and stool output should be recorded in the output diary over a 48-hour period of nutritional 
stability before every clinic visit (see Section 7.2.11.3 for more detail).
f PS adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance
for nutrition support adjustment provided in Appendix 2. 
g Safety laboratory assessments at site visits will consist of clinical chemistry, hematology, and urinalysis, with results processed 
by a central laboratory. Urine specimen collection should be attempted as part of the safety labs, but lack of urinalysis will not 
constitute a protocol deviation. CRP will not be measured in subjects <10 kg.
h Subjects who have been treated previously and test positive for teduglutide antibodies should have follow-up samples collected 
every 12 weeks during the study until a negative result is obtained.
i FOBT should be performed on teduglutide-exposed subjects on an annual basis, approximately every 48-60 weeks at a 
minimum.
j The need for colonoscopy/sigmoidoscopy in response to a positive FOBT during a no-teduglutide treatment period is at the 
discretion of the investigator, but all teduglutide-exposed subjects will undergo colonoscopy/sigmoidoscopy after they have 
received the equivalent of 2 treatment cycles (48 weeks of study drug exposure) and subjects who continue to receive teduglutide 
will undergo colonoscopy/sigmoidoscopy at 5 year intervals or more often as needed. See Section 7.2.9 for details.
k Lack of collection of serum samples will not constitute a protocol deviation. Stored serum samples should be omitted for 
subjects weighing less than 15 kg and whenever local blood volume limitations are exceeded.
Note: (X) denotes conditional requirement for a given assessment if the subject meets certain conditions per protocol.
For non-commercial use only


Shire
CONFIDENTIAL
Page 21
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
Table 1-3: Schedule of Events for Subjects While Receiving Teduglutide
Period
Pre-
treatment
Teduglutide Treatment
Follow-up
Visit Number
Pxa
Cx
D1
Cx
W1
Cx
W2
Phone contact is required approximately 1 week after PS adjustment
Cx
W4
Phone contact is required approximately 1 week after PS adjustment
Cx 
W6
Phone contact is required approximately 1 week after PS adjustment
Cx 
W9
Phone contact is required approximately 1 week after PS adjustment
Cx 
W12
Phone contact is required approximately 1 week after PS adjustment
Cx 
W16
Phone contact is required approximately 1 week after PS adjustment
Cx 
W20
Phone contact is required approximately 1 week after PS adjustment
CxW24 
(EOT)
CxW25 
CxW26 
CxW27
CxW28c
Visit Type
Site
Site
Site
Site
Site
Site
Site
Site
Site
Site
Site
Phoneb
Site
Cycle Day
-21 to 0
1
8
15
29
43
64
85
113
141
169
176
197
183
190
Window (days)d
-21 to 0
±2
±2
±2
±2
±4
±4
±4
±4
±4
±2
±2
Evaluate teduglutide 
eligibility (inclusion 
and exclusion) criteria
X
Xe
Dispense intake and 
output diaries
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications and 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination 
and vital signs, 
including weight
X
X
X
X
X
X
X
X
X
X
X
X
Height and head 
circumferencef
X
X
X
X
Review intake and 
output diariesg
X
X
X
X
X
X
X
X
X
X
X
X
X
Record PS Rx and 
adjust as neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety laboratory testsi
Xi
X
X
X
X
X
X
X
X
X
X
(X)
X
PedsQL Generic Core 
Scale/ Family Impact 
Module/ GI 
Symptoms Module 
Sub-Scales
X
X
X
Antibodies to 
teduglutidej
X
X
X
X
Fecal occult blood 
testing
X
X
X
Colonoscopy/
sigmoidoscopyk
(X)
(X)
(X)
Pregnancy testingl
X
X
X
X
X
X
X
X
X
For non-commercial use only


Shire
CONFIDENTIAL
Page 22
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
Table 1-3: Schedule of Events for Subjects While Receiving Teduglutide
Period
Pre-
treatment
Teduglutide Treatment
Follow-up
Serum samplem
X
X
Evaluate escape 
criterian
Xp
X
X
Dispense study drugo
X
X
X
X
X
X
X
X
X
EOS = end of study; EOT = end of treatment; ET = early termination; FOBT = fecal occult blood test; FOCBP = female of child-bearing potential; FU = follow-up; 
GI = gastrointestinal; PedsQL = Pediatric Quality of Life Inventory; PS= parenteral support; SBS = Short Bowel Syndrome; SC = subcutaneous; Scr = Screening; 
TED = teduglutide; Tx = treatment
a If the first pretreatment visit (P1) follows the screening visit, it must occur within 12 weeks of screening.
b Phone visits are required approximately 1 week after adjustments in PS. The assessments to be performed at phone visits are the same as those described for CxW25-27 (except 
for evaluation of escape criteria). 
c The investigator may combine the CxW28 visit with the next pretreatment visit if at least one escape criterion is met at the CxW28 visit, and the pretreatment assessments occur 
within 7 days of the CxW28 visit. If a subject is completing the study at the CxW28 visit, the EOS/ET visit (Table 1-1) will take place in lieu of the CxW28 visit.
d Visit windows are relative to the CxD1 visit.
e Eligibility will need to be re-confirmed prior to the first dose in the cycle. Negative urine pregnancy test is required prior to the first dose of teduglutide, but results of other labs 
obtained at the CxD1 visit are not required to determine teduglutide treatment eligibility.
f Head circumference will be measured in subjects 36 months of age and younger.
g Intake diaries will collect actual PS volume and hours per day. Intake diaries should be completed daily for a minimum of 2 weeks immediately prior to each clinic visit (except 
at pretreatment visit), for 1 week following PS adjustment, and daily during the 4-week follow-up period. Urine and stool output should be recorded in the output diary over a 
48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PS prescription. See Section 7.2.11 for more detail.
h PS adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment provided in 
Appendix 2.
i Safety laboratory assessments at site visits will consist of clinical chemistry, hematology, and urinalysis, with results processed by a central laboratory. Clinical chemistry and 
urinalysis must also be performed within approximately 5-7 days of any adjustment to the PS prescription. Safety labs performed between clinic visits may be performed locally. 
Unscheduled lab results will not be captured in the eCRFs. If abnormal results are considered an adverse event, an AE form will be completed. Collect PT/INR at the pretreatment 
visit. Additional collection will occur if a potential drug-induced liver injury signal is observed. Urine specimen collection should be attempted as part of the safety labs, but lack 
of urinalysis will not constitute a protocol deviation. CRP will not be measured in subjects <10 kg.
j Samples collected on CxD1 must be drawn prior to first administration of teduglutide. Samples collected while subjects are receiving teduglutide (CxW12 and CxW24) must be 
drawn at least 14 hours after dosing.
k The teduglutide-naïve subjects age 12 and older will undergo colonoscopy/sigmoidoscopy at the pretreatment visit if one has not been performed within 1 year. Subjects of any 
age with newly positive FOBT results at the pretreatment visit for which a readily detectable cause cannot be identified (eg, anal fissure) will undergo a 
colonoscopy/sigmoidoscopy prior to receiving teduglutide. If newly positive FOBT results (for which a readily detectable cause cannot be identified) are obtained at the end of a 
teduglutide treatment cycle (CxW24/EOT), colonoscopy/sigmoidoscopy will be performed. The need for colonoscopy/sigmoidoscopy in response to positive FOBTs at CxW12 is 
at the discretion of the investigator. Teduglutide-exposed subjects who have received the equivalent of 2 treatment cycles (48 weeks of study drug exposure) will undergo 
colonoscopy/sigmoidoscopy. See Section 7.2.9 for details.
l A serum pregnancy test is performed on all FOCBP at the teduglutide pretreatment visit (when the pretreatment and screening visits are combined, the serum pregnancy test 
should be performed at the local laboratory). Urine pregnancy tests will be administered at all other visits according to the study schedules, or if pregnancy is suspected, or as 
specified per protocol upon withdrawal of the subject from the study.
m Lack of collection of serum samples will not constitute a protocol deviation. Stored serum samples should be omitted for subjects weighing less than 15 kg and whenever local 
blood volume limitations are exceeded.
For non-commercial use only


Shire
CONFIDENTIAL
Page 23
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
Table 1-3: Schedule of Events for Subjects While Receiving Teduglutide
Period
Pre-
treatment
Teduglutide Treatment
Follow-up
n If escape criteria are met, the subject may proceed directly to another pretreatment visit at the discretion of the investigator.
o The first SC injection of teduglutide in treatment-naïve subjects will be administered under the supervision of the investigator/designee after which the subject will be observed 
for hypersensitivity reactions for at least 4 hours. The site of administration (arm, thigh, abdomen) of the first teduglutide dose must be specified and recorded in the eCRF. See 
Section 6.2.3 for dose adjustment.
p Escape criteria will be assessed for subjects who escaped during the follow-up period of a previous teduglutide treatment cycle at CxW24. The investigator may combine the 
CxW24 visit with the next pretreatment visit if at least 1 escape criterion is met at the CxW24 visit. In order to combine assessments, the pretreatment assessments must occur 
within 7 days of the CxW24 visit. 
Note: (X) denotes conditional requirement for a given assessment if the subject meets certain conditions per protocol.
For non-commercial use only


Shire
CONFIDENTIAL
Page 24
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
1
BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options 
Short bowel syndrome (SBS) is a rare disorder resulting from congenital abnormalities or severe 
intestinal diseases that result in major surgical resections of the small intestine. It is estimated 
that, at most, there are a few hundred pediatric subjects 1 year and older with SBS (Khan et al., 
2015; Wales et al., 2004). Unlike the adult population, the majority of cases of SBS in pediatric 
subjects are due to congenital anomalies or catastrophic events that occur during infancy. 
Although the small intestine is capable of remarkable adaptation, excessive loss of absorptive 
surface area or specialized functions can lead to dependence on parenteral nutrition or 
intravenous (IV) fluids (parenteral support [PS]). Treatment of both pediatric and adult patients 
is focused on achieving adequate intestinal absorption to allow for minimization or 
discontinuation of PS. About 30% of infants with SBS become independent of PS requirements 
within 12 months of the initial insult, and an additional 10% wean off PS within 24 months. 
After this time, linear intestinal growth slows. About 60% of pediatric subjects with SBS are able 
to become independent of PS within 5 years of the initial diagnosis (Khan et al., 2015). 
Nevertheless, despite optimal medical management, many pediatric subjects remain dependent 
on PS. Complications of long-term PS include liver disease, catheter-related blood stream 
infections, central line-associated venous thrombosis and dwindling central venous access. 
Sepsis is the leading cause of death in these patients and quality of life is poor (Squires et al., 
2012). Accelerating the adaptive process and achieving enteral autonomy is an urgent goal for all 
patients with SBS who are dependent on PS (Khan et al., 2015; Squires et al., 2012).
Intestinal adaptation is driven by hormonal cues in response to nutrient malabsorption (Drucker 
and Yusta, 2014). Chief among these is hormones glucagon-like peptide 2 (GLP-2), which is 
secreted from L-type enteroendocrine cells that reside in the intestinal epithelium in the ileum 
and colon. Resection of these regions may impair the adaptive response by limiting endogenous 
production of GLP-2. 
1.2
Product Background 
Teduglutide is a novel, recombinant analog of naturally occurring human GLP-2 that regulates 
the functional and structural integrity of the cells lining the gastrointestinal (GI) tract. 
Teduglutide is a 33-amino acid peptide that differs from native GLP-2 in the substitution of 
glycine for alanine at the second position at the N-terminus. As a result, teduglutide demonstrates 
resistance to degradation by dipeptidyl peptidase-IV (DPP-4) and therefore maintains a longer 
elimination half-life (t1/2) in adults of approximately 2 hours compared to the native peptide, 
which has a t1/2 of approximately 7 minutes. Teduglutide has been shown in animal studies and 
previous human clinical trials to increase villus height and crypt depth in the intestinal 
epithelium, thereby increasing the absorptive surface area of the intestines (Tappenden et al., 
2013; Thymann et al., 2014). The European Commission granted a centralized marketing 
authorization valid throughout the European Union (EU) for teduglutide (Revestive™) on 
30 August 2012 and a New Drug Application (NDA) for teduglutide (Gattex®) was approved by 
the United States (US) Food and Drug Administration (FDA) on 21 December 2012 for the 
treatment of adult patients with SBS who are dependent on PS. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 25
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
Teduglutide has also been approved for use in adult patients with SBS in Canada and 
Switzerland. On 29 Jun 2016, the European Commission granted an extension of the Market 
Authorization for teduglutide (REVESTIVE™) for the treatment of patients aged 1 year and above 
with SBS; patients should be stable following a period of intestinal adaptation.
1.3
Clinical Studies with Teduglutide in Pediatric Subjects
One Phase 3 study, TED-C13-003, was completed in pediatric SBS subjects in the US and 
United Kingdom (UK). In this study, teduglutide was administered to 3 cohorts of pediatric 
subjects from ages 1-17. Thirty-seven pediatric subjects received teduglutide at doses of 
0.0125, 0.025, or 0.05 mg/kg/day for 12 weeks. Five additional pediatric subjects were enrolled 
in an observational standard of care (SOC) cohort. There were clear dose-dependent effects of 
teduglutide seen at the 0.025 and 0.05 mg/kg/day doses compared to SOC and the 
0.0125 mg/kg/day dose. In the 0.025 mg/kg/day cohort there was a reduction in PS volume at 
week 12 of 37%, including complete independence from PS support in 1 subject, and a reduction 
of 3.94 hours per day infusion time. In the 0.05 mg/kg/day cohort there was a reduction in PS 
volume at week 12 of 39%, including complete independence from PS support in 3 subjects, and 
a reduction of 4.18 hours per day infusion time. Teduglutide was generally safe and well 
tolerated by pediatric subjects in all dosing cohorts. There were no deaths during the study and 
no treatment-emergent serious adverse events (TESAEs) related to teduglutide were reported. No 
discontinuations from study were due to adverse events (AEs).
TED-C14-006 is a recently completed study of pediatric subjects through 17 years which 
included 2 treatment arms: a teduglutide treatment arm and a SOC treatment arm. Subjects in 
both arms participated in a 2-week minimum screening period, a 24-week treatment period, and a 
4-week follow-up period. During the screening period, subjects chose into which arm to enroll. 
During the 24-week treatment period, subjects in the SOC treatment arm received standard 
medical therapy for SBS; while those in the teduglutide treatment arm received daily 
subcutaneous (SC) injections of teduglutide (study drug) in addition to standard medical therapy. 
The subjects enrolling in the teduglutide treatment arm were randomized 1:1 in a double-blinded 
manner into 2 parallel dose groups: 0.025 mg/kg/day or 0.05 mg/kg/day of teduglutide 
administered subcutaneously for 24 weeks. Compared to the SOC, treatment of pediatric subjects 
with SBS with teduglutide resulted in clinically meaningful reductions in PN/IV volume, 
calories, days per week, and hours per day. A total 10% of subjects who received teduglutide 
achieved enteral autonomy within 24 weeks despite prior dependence on PN/IV for several 
years. Teduglutide treatment also resulted in increases in EN volume and caloric intake as well 
as plasma citrulline. Although the differences in efficacy between the 0.025 and 0.05 mg/kg dose 
groups were small, a consistently greater effect was seen in the 0.05 mg/kg dose in all efficacy 
parameters. The PK properties were well characterized in this population and were consistent 
with the prior 12 week pediatric study. Teduglutide was generally well tolerated by pediatric 
subjects with SBS. The safety profile was favorable and consistent with the prior pediatric study, 
the underlying disease, and previous experience with teduglutide in adult subjects with SBS.
SHP633-301 is an ongoing study in the United Kingdom, Italy, Finland, and France to evaluate 
the safety, efficacy, and PK of teduglutide treatment in infants 4 to 12 months of age with SBS. 
Like TED-C14-006, this study has a teduglutide treatment arm and a SOC arm. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 26
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
Subjects in both arms will participate in a 2-week minimum screening period, a 24-week 
treatment period, and a 4-week follow-up period. During the 24-week treatment period, subjects 
in the SOC treatment arm will receive standard medical therapy for SBS; while those in the 
teduglutide treatment arm will receive daily SC injections of 0.05 mg/kg teduglutide in addition 
to standard medical therapy. Similar to the treatment cycles in SHP633-304, subjects in 
SHP633-301 may escape from the 4-week follow-up period and proceed directly to the 
SHP633-304 study, if they meet an escape criterion specified in the SHP633-301 protocol. It is 
expected the subjects entering SHP633-304 from SHP633-301 will be 11 to 19 months of age 
when enrolling in SHP633-304. 
Always refer to the latest version of the investigator’s brochure for the overall risk/benefit 
assessment and the most accurate and current information regarding the drug metabolism, 
pharmacokinetics, efficacy and safety of teduglutide (SHP633). 
For non-commercial use only


Shire
CONFIDENTIAL
Page 27
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
2
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study 
This is a Phase 3, prospective, open-label, long-term extension study to evaluate the safety and 
efficacy of teduglutide in pediatric subjects with SBS who completed the TED-C14-006 or 
SHP633-301 studies. In addition to evaluating the long-term safety and durability of efficacy 
after 24 weeks of treatment, this extension study will evaluate the need for additional teduglutide 
treatment in these subjects, and will allow for the first-time treatment of teduglutide-naïve 
subjects who participated in the SOC treatment arms in TED-C14-006 or SHP633-301.
2.2
Study Objectives
2.2.1
Primary Objectives
The primary objective of the study is to evaluate the long-term safety and tolerability of 
teduglutide treatment in pediatric subjects with SBS who completed TED-C14-006 or 
SHP633-301. 
2.2.2
Secondary Objectives
The secondary objective of this study is to evaluate the long-term efficacy of teduglutide 
treatment in pediatric subjects with SBS who completed TED-C14-006 or SHP633-301.
For non-commercial use only


Shire
CONFIDENTIAL
Page 28
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
3
STUDY DESIGN
3.1
Study Design and Flow Chart
This is a Phase 3, prospective, open-label, long-term extension study to evaluate the safety 
and efficacy of teduglutide in pediatric subjects who completed the TED-C14-006 or 
SHP633-301 studies (the "core studies"). At the time of entry into TED-C14-006, subjects were 
less than 18 years of age, were dependent on parenteral nutrition to provide at least 30% of their 
caloric or fluid needs and had not been able to significantly reduce PS for at least 3 months prior 
to enrollment. During TED-C14-006, some subjects elected to receive standard of care instead of 
teduglutide treatment. Subjects who elected to receive teduglutide were randomized to 
0.025 mg/kg or 0.05 mg/kg once daily (QD) dosing in a double-blinded manner. 
At the time of entry into SHP633-304, subjects were 4 to 12 months corrected gestational age, 
were dependent on parenteral nutrition to provide at least 35% of their caloric or fluid needs, and 
had not been able to significantly reduce PS for at least 1 month prior to enrollment. During 
SHP633-301, subjects were randomized to receive standard of care or teduglutide 0.05 mg/kg SC 
QD. 
Approximately 65 subjects who complete the core studies are expected to enroll in this extension 
study. All subjects who completed either core study, including those who received standard of 
care, may be eligible to enter SHP633-304. To be eligible to receive teduglutide treatment within 
SHP633-304, subjects must meet ≥1 of the teduglutide treatment inclusion criteria and none of 
the teduglutide treatment exclusion criteria. 
Additional Teduglutide Treatment
Subjects not receiving teduglutide treatment (ie, in a “no-teduglutide treatment period”), will be 
seen approximately every 12 weeks for safety, parenteral support (PS) requirements, and quality 
of life. At any point during a no-teduglutide treatment period, subjects who meet ≥1 teduglutide 
treatment inclusion may proceed directly to the pretreatment visit if the investigator, subject, and 
parent agree to proceed with teduglutide therapy.
Rationale: Some pediatric subjects may have a durable beneficial effect after 24 weeks of 
teduglutide treatment and thus long-term follow-up without additional teduglutide treatment may 
be appropriate. However, there may be some pediatric subjects who deteriorate or stop 
improving after discontinuation of teduglutide treatment. In these pediatric subjects, additional 
teduglutide treatment may be beneficial. 
Dose Selection 
Analysis suggested that pediatric patients, ages 1 to 17 years old, are likely to require the same 
dose as used in adults, namely 0.05 mg/kg/day (Mouksassi et al., 2009). In this extension study, 
all subjects who enter a teduglutide treatment cycle will receive 0.05 mg/kg SC QD.
For non-commercial use only


Shire
CONFIDENTIAL
Page 29
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
Rationale: Teduglutide is approved for adult use in the US and EU, and for pediatric use in the 
EU, at a dose of 0.05 mg/kg SC once daily. The completed pediatric studies (TED-C13-003 and 
TED-C14-006) demonstrated that teduglutide dosing at 0.025 and 0.05 mg/kg/day was 
associated with a favorable benefit/risk profile. In addition, population pharmacokinetic 
modeling and simulations were conducted to determine the effective dose to be used in 
pediatric subjects using data from 8 adult clinical studies including adult Phase 1 studies and 
Phases 2/3 studies as well as the pediatric study (TED- C13- 003) and suggested that the dose in 
pediatric subjects is likely to be same as the dose in adults (O'Keefe et al., 2006). 
Further PK simulation was conducted based on the population PK model previously established 
and a virtual population of 1000 pediatric patients created based on Centers for Disease Control 
(CDC) growth charts in the target age group (4 to 12 months) and taking into consideration 
body weights of pediatric patients with SBS enrolled in study TED-C13-003 (approximately 
15% lower than healthy subjects in the same age group). Monte Carlo simulations for all age 
groups were performed according to the SC dosing regimens of 0.0125, 0.025 and 0.05 mg/kg 
every 24 hours. Rich concentration-time profiles were simulated with the customized population 
PK model to derive the exposure metrics area under the concentration curve at steady state 
(AUCss) and maximum concentration at steady state (Cmax,ss). Following 0.05 mg/kg daily SC 
administration, the median Cmax,ss of teduglutide in infants (24.9 ng/mL) was within 20% of that 
observed in the 2 to 4 and 4 to 6 years age groups (26.9 and 29.4 ng/mL, respectively); and 
approximately ~28% lower than that in adult patients with SBS. The clinical package in 
conjunction with Cmax was considered to support teduglutide dose of 0.05 mg/kg since AUCss
was previously shown not to correlate with efficacy. Thus, the 0.05 mg/kg dose is proposed for 
testing in all age groups.
Duration of Treatment
The duration of teduglutide treatment in this study mirrors that of the TED-C14-006 and 
SHP633-301 studies, consisting of 24 weeks of teduglutide treatment, followed by a 4-week 
follow-up period. The follow-up period is a mechanism to evaluate whether continued 
teduglutide is needed. If a subject deteriorates during the follow-up period, the subject may be 
evaluated immediately for additional teduglutide treatment. Subjects who clinically deteriorate or 
stop improving at any time after the end of the follow-up period will also be assessed for 
additional treatment.
Rationale: During the teduglutide treatment cycle, visit frequency is similar to frequencies 
performed in TED-C13-003, TED-C14-006, and SHP633-301 to ensure sufficient safety 
monitoring and weaning of PS. During the no-teduglutide treatment, visits occur every 12 weeks, 
a frequency that is consistent with standard medical practices. To minimize risk to subjects, those 
who have deteriorated quickly after treatment interruption (ie, escaped from a prior follow-up 
period) may be evaluated immediately for eligibility for additional treatment when they reach the 
week 24 visit. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 30
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
Measures and Parameters
Following the review and signing of the informed consent (and informed assent, if applicable), 
screening visit procedures will begin including demographics, and updates to medical history 
and SBS history. Subjects who meet ≥1 of the teduglutide treatment inclusion criteria may 
proceed to the pretreatment visit.
After the pretreatment visit, subjects who still meet ≥1 of the teduglutide treatment inclusion 
criteria, and meet none of the teduglutide treatment exclusion criteria, will start a 28-week cycle, 
consisting of 24 weeks of teduglutide treatment at 0.05 mg/kg SC once daily, followed by a 
4-week follow-up (no treatment) period (Figure 3-1). During the 28-week cycle, clinic visits will 
occur at weeks 1, 2, 4, 6, 9, 12, 16, 20, 24, and 28. Phone visits are required approximately 
1 week after adjustments in PS during the teduglutide treatment period (between weeks 1-24), 
and weekly during the teduglutide follow-up period (between weeks 24 and 28).
Safety and PS requirements will be evaluated on a weekly basis, and quality of life assessments 
will be made approximately every 12 weeks. At all site visits and telephone contacts, safety will 
be monitored, and nutritional support will be reviewed and adjusted as needed. To maintain 
consistency across centers, all attempts should be made to follow the nutritional support 
adjustment guidelines (developed with SBS expert input and provided in the protocol) for 
decisions regarding PS reduction and advances in enteral feeds based on weight gain, urine and 
stool output, and clinical stability. Departure from the guidelines, however, is not considered a 
protocol deviation (Appendix 2).
Rationale: Measures of long-term safety will include AEs, growth parameters and anti-drug 
antibodies. Measure of long-term efficacy will include durability of effect as measured by 
reduction in PS and improvement in pediatric quality of life measures (PedsQL, PedsQL Family 
Impact Module). A reduction in PS volume of at least 20% at end of treatment (EOT) was 
used as the primary endpoint in pivotal phase 3 adult clinical trials and the completed 
phase 3 pediatric study (TED-C13-003) and will be used as an endpoint in this extension study. 
In previous clinical studies, a reduction of this magnitude was associated with a reduction in the 
number of days per week of PS and increases in enteral intake. Reduction in volume and time of 
PS due to improved enteral absorption may provide a pediatric subject with opportunities for 
more age-appropriate activities including oral rehabilitation. Quality of life assessments will be 
performed in this study to quantitate this effect.
Teduglutide has been found to have a targeted intestinotrophic effect. Taking into account the 
patient population and the pharmacologic effect of teduglutide, GI-specific screening tests, 
including fecal occult blood testing and colonoscopy/sigmoidoscopy, which are commonly part 
of the routine care of these subjects, will be performed to ensure safety. This study captures 
long-term safety data on polyps and other colonic mucosal changes in teduglutide-exposed 
subjects using the surveillance strategy proposed in Section 7.2.9. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 31
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
Figure 3-1:
Study Design Flow Chart
Figure legend: Safety and efficacy data for subjects not receiving teduglutide treatment are captured approximately every 
12 weeks, but subjects may proceed to the pretreatment visit at any time in order to assess eligibility for teduglutide therapy. 
Eligible subjects will enter a 28-week teduglutide cycle. During this cycle, subjects will return to the site for safety and efficacy 
assessments at weeks 1, 2, 4, 6, 9, 12, 16, 20, and 24 (solid black lines). Phone visits are required approximately 1 week after 
adjustments in PS during the intervening weeks between weeks 2 and 24 (dashed grey lines). Subjects discontinue teduglutide at 
week 24 and enter a 4-week follow-up (no-treatment) period, during which phone visits will be performed weekly (solid grey 
lines). If an escape criterion is met at week 24 or during the follow-up period, subjects may proceed directly to another 
pretreatment visit.
3.2
Duration and Study Completion Definition
A subject will be considered enrolled in the study once the subject has provided signed consent, 
and meets all of the Inclusion Criteria. The study will continue for at least 1 year and until each 
subject has access, as needed, to teduglutide. The subject’s maximum duration of participation is 
expected to be approximately 3 years. The study will be completed in approximately 40 months. 
A subject will be considered as having completed the study if the subject has not withdrawn 
early from the study for any reason prior to completing the End of Study (EOS) visit.
The study completion date is defined as the date the final subject, across all sites, completes their 
final protocol-defined assessment. Please note that this includes the follow-up visit or contact 
(last safety contact), whichever is later. The study completion date will be used to ascertain 
timing for study results posting and reporting.
For non-commercial use only


Shire
CONFIDENTIAL
Page 32
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
4
STUDY POPULATION
Each subject must review and sign the informed consent (and informed assent, if applicable) 
before any study-related procedures specified in the protocol are performed. Teduglutide 
treatment eligibility does not impact study eligibility.
4.1
Study Inclusion Eligibility Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1. Subject provides written informed consent (subject, parent or legal guardian and, as 
appropriate, subject informed assent) to participate in the study before completing any 
study-related procedures. 
2. Subject completed the TED-C14-006 or SHP633-301 studies (including subjects in the 
standard of care treatment arms). Subjects are considered to have completed 
SHP633-301 if they completed study assessments through week 24.
3. Subject understands and is willing and able to fully adhere to study requirements as 
defined in this protocol.
4.2
Study Exclusion Eligibility Criteria
There are no exclusion criteria for this study.
4.3
Teduglutide Eligibility Criteria
Subjects are eligible for teduglutide treatment if at least 1 (≥1) of the teduglutide treatment 
inclusion criteria, and none of the teduglutide treatment exclusion criteria are met. In addition, 
the investigator and the subject (and/or parent or legal guardian, as appropriate) must agree to 
proceed with treatment.
4.4
Teduglutide Treatment Inclusion Criteria
1. Subject is teduglutide-naïve, receiving PS, and unable to significantly reduce PS or 
advance enteral feeds (eg, 10% or less change in PS or advance in feeds) for at least 
3 months prior to and during the teduglutide pretreatment visit, as assessed by the 
investigator. Transient instability for events such as interruption of central access or 
treatment for sepsis is allowed if the PS returns to within 10% of baseline prior to the 
event.
2. Subject was previously treated with teduglutide and at least 1 of the following criteria is 
satisfied:
Increasing PS requirements following teduglutide discontinuation.
a.
Decreased PS requirement during prior teduglutide treatment, followed 
b.
by cessation of improvement after teduglutide discontinuation.
Deteriorating nutritional status eg, weight loss or growth failure) 
c.
despite maximal tolerated enteral nutrition (EN) following teduglutide 
discontinuation.
For non-commercial use only


Shire
CONFIDENTIAL
Page 33
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
Deteriorating fluid or electrolyte status despite maximal tolerated 
d.
enteral fluid and electrolyte intake following teduglutide 
discontinuation.
Severe diarrhea related to teduglutide discontinuation.
e.
4.5
Teduglutide Treatment Exclusion Criteria
1. Body weight <5 kg at the pretreatment visit.
2. Unresected GI polyp, known polyposis condition, premalignant change, or malignancy, 
in the GI tract
3. History of cancer in the previous 5 years except surgically curative skin cancers
4. Serial transverse enteroplasty or other major intestinal surgery within 3 months 
preceding the teduglutide pretreatment visit. Insertion of a feeding tube, anastomotic 
ulcer repair, minor intestinal resections ≤10 cm, and endoscopic procedures are allowed.
5. Intestinal or other major surgery planned or scheduled to occur during the 28-week cycle
6. Clinically significant intestinal stricture or obstruction
7. Clinically significant, active or recurrent pancreatic or biliary disease
8. Active, severe, or unstable, clinically significant hepatic impairment or injury, including 
the following laboratory values at the pretreatment visit:
Total bilirubin ≥2 × upper limit of normal (ULN)
a.
Aspartate aminotransferase (AST) ≥7 × ULN
b.
Alanine aminotransferase (ALT) ≥7 × ULN
c.
9. Renal dysfunction shown by results of an estimated glomerular filtration rate below 
50 mL/min/1.73 m2 at the pretreatment visit
10. Unstable cardiac disease, congenital heart disease or cyanotic disease, with the exception 
of subjects who had undergone ventricular or atrial septal defect repair, or patent ductus 
arteriosus ligation
11. Participation in a clinical study using an experimental drug (other than glutamine, 
Omegaven, or Smoflipid) within 3 months or 5.5 half-lives of the experimental drug, 
whichever is longer, prior to the pretreatment visit and for the duration of the 28-week 
cycle
12. Treatment with analogs of glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 
(GLP-2) (not including teduglutide), insulin-like growth factor-1 (IGF-1), or growth 
hormone, within 3 months preceding the teduglutide pretreatment visit.
13. Treatment with octreotide or dipeptidyl peptidase 4 (DPP-4) inhibitors within 3 months 
prior to the pretreatment visit
14. Known or suspected intolerance or hypersensitivity to the investigational product, 
closely-related compounds, or any of the stated ingredients
For non-commercial use only


Shire
CONFIDENTIAL
Page 34
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
15. Known history of alcohol or other substance abuse within 1 year prior to the 
pretreatment visit
16. Pregnant or lactating female subjects 
17. Sexually active female subjects of child-bearing potential unwilling to use approved 
contraception during teduglutide treatment and for 30 days after the treatment period 
18. Any condition, disease, illness, or circumstance that in the investigator’s opinion puts 
the subject at any undue risk, prevents completion of the study, or interferes with 
analysis of the study results.
4.6
Follow-up Period Escape Criteria
At the discretion of the investigator, the follow-up period may be interrupted (if the subject 
meets 1 or more of escape criteria 1 to 4 during the follow-up period) or omitted (if the subject 
meets escape criterion 5 at the CxW24 visit) and the subject may proceed directly to the 
pretreatment visit, if ≥1 of the following criteria is met:
1. Increasing PS requirements following teduglutide discontinuation.
2. Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation.
4. Severe diarrhea related to teduglutide discontinuation.
5. The subject escaped during the follow-up period of a previous teduglutide treatment 
cycle within SHP633-301 or SHP633-304. In this case, the CxW24 visit may be 
combined with the next cycle pretreatment visit.
4.7
Reproductive Potential
4.7.1
Female Contraception
To be eligible for treatment with teduglutide, sexually active females of child-bearing potential 
must use an acceptable form of contraception throughout the study period and for 30 days 
following the last dose of investigational product. If hormonal contraceptives are used, they 
should be administered according to the package insert. Females of child-bearing potential who 
are not currently sexually active must agree to use acceptable contraception, as defined below, if 
they become sexually active during the period of the study and 30 days following the last dose of 
investigational product. 
To be eligible for treatment with teduglutide, female pediatric subjects and adolescent subjects 
should be either:

Pre-menarchal and either Tanner Stage 1 or less than age 9 years, or

Females of child-bearing potential (FOCBP) with a negative serum beta-human chorionic 
gonadotropin (-HCG) pregnancy test at the teduglutide pretreatment visit. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 35
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
Females of child-bearing potential must agree to abstain from sexual activity that could 
result in pregnancy or agree to use acceptable methods of contraception.
Acceptable methods of contraception are:

True abstinence: Abstention of sexual activity that is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
post-ovulation methods] and withdrawal are not acceptable methods of contraception).

Intrauterine devices plus condoms

Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or foam)

Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring), stabilized for at 
least 30 days prior to the pretreatment visit, plus condoms. Note: if subject becomes 
sexually active during the study, they should use one of the other acceptable methods 
noted above in addition to the hormonal contraceptive until it has been stabilized for 
30 days.
4.8
Discontinuation of Subjects 
4.8.1
Teduglutide Discontinuation
If the investigational product is discontinued prematurely during a teduglutide treatment cycle 
and the subject wishes to remain in the study, the evaluations listed for the EOT visit are to be 
performed. A 4-week follow-up period will ensue, consisting of weekly telephone visits 
(CxW25-27) and the week 28 clinic visit (CxW28). The subject would then enter a 
no-teduglutide treatment (NTT) period and could be evaluated for subsequent teduglutide 
treatment eligibility according to the study schedules. Comments (spontaneous or elicited) or 
complaints made by the subject must be recorded in the source documents. The reason for 
permanent treatment discontinuation, dates of investigational product administered (including 
last date of treatment), and amount of investigational product taken must be recorded in the 
electronic case report form (eCRF) and source documents, as described in Section 4.8.3. The 
investigator is encouraged to discuss withdrawal of a subject from investigational product with 
the medical monitor, when possible.
4.8.2
Study Withdrawal
At any time during the study, the investigator or sponsor may withdraw a subject, or a subject 
may withdraw from the study, for any reason, without prejudice to their future medical care by 
the physician or at the institution.
If a subject withdraws from the study during a teduglutide cycle, the evaluations listed for the 
EOT visit are to be performed as completely as possible. Whenever possible, the subject will 
then be asked to return 4 weeks later for the early termination (ET) visit, and will be contacted 
weekly by phone during the interim period between EOT and ET for safety follow-up.
If a subject withdraws from the study during a NTT period, the evaluations listed for the ET visit 
are to be performed as soon and completely as possible. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 36
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
Subjects who withdraw from the study will not be replaced.
4.8.3
Reasons for Discontinuation
The reason(s) for permanent discontinuation of treatment and/or withdrawal from the study must 
be determined by the investigator, and recorded in the subject’s medical record and in the eCRF. 
If a subject is withdrawn for more than 1 reason, each reason should be documented in the source 
document, and the most clinically relevant reason should be entered in the eCRF.
Reasons for discontinuation include, but are not limited to:

Adverse event 

Protocol deviation

Lack of efficacy 

Physician decision 

Withdrawal by subject 

Withdrawal by parent/guardian

Lost to follow-up

Pregnancy (Discontinuation of treatment only) 

Death 

Other 
4.8.3.1
Subjects ‘Lost to Follow-up’ Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact (office visit or telephone contact). At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that they 
return to the site for final safety evaluations, and return any unused investigational product.
For non-commercial use only


Shire
CONFIDENTIAL
Page 37
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
5
CONCOMITANT TREATMENT
5.1
Concomitant Medications and Procedures
Concomitant treatment refers to all treatment taken between the dates of informed consent and 
EOS, inclusive. Concomitant medications and procedures will be assessed at each site visit, and 
include all non-study treatments (medications, herbal treatments, vitamins, invasive and 
diagnostic procedures). Concomitant treatment information must be recorded on the appropriate 
eCRF page. Details of medication changes and/or dosages will be recorded on the eCRF. 
5.1.1
Permitted Treatment
Standard medical therapy for SBS should be continued.
5.1.2
Prohibited Treatment
The mechanism of action of teduglutide may increase enteral absorption of drugs (eg, motility 
medication including narcotics and opioids used for the management of SBS, warfarin, 
psychotropics, metronidazole, digoxin), so consideration should be given to modifying 
concomitant enteral medication regimens. Down-titration of concomitant enteral medications 
should be considered when drugs, especially those with a narrow therapeutic range, are given at 
dosages that are higher than usual.
The following medications are prohibited during teduglutide treatment and within the provided 
timeframe prior to the pretreatment visit:
Table 5-1: Prohibited Treatment
Prior Therapy
Time Restriction Prior to 
the Pretreatment Visit
Native/synthetic glucagon-like peptide-2 (not-including teduglutide)
Any
Glucagon-like peptide-1 analog or human growth hormone
3 months
Octreotide or dipeptidyl peptidase 4 inhibitors
3 months
For non-commercial use only


Shire
CONFIDENTIAL
Page 38
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
6
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product 
The test product is teduglutide, which will be provided in sterile, single-use 3 mL vials 
containing 5 mg or 1.25 mg teduglutide as a white lyophilized powder to be reconstituted before 
use with 0.5 mL sterile water for injection. In addition to the active ingredient (teduglutide), each 
vial of teduglutide contains L-histidine, mannitol, monobasic sodium phosphate monohydrate, 
and dibasic sodium phosphate as excipients. Additional information is provided in the current 
SHP633 investigator’s brochure.
6.1.1
Blinding the Treatment Assignment
Not applicable for this open-label study.
6.2
Administration of Investigational Product(s)
6.2.1
Interactive Response Technology for Investigational Product Management
An interactive web-based response system (IWRS) will be used for screening and enrolling 
subjects, recording subject visits, investigational product supply dispensation and management, 
inventory management and supply ordering, investigational product expiration tracking and 
management, and return of investigational product. Please refer to the Study Manual for 
additional details regarding the IWRS. 
The IWRS will also be used for creating, tracking, and confirming investigational product 
shipments. A user manual with specific functions and instructions for the IWRS will be provided 
to the site, and site personnel will receive training.
6.2.2
Allocation of Subjects to Treatment 
This is an open-label study. Subjects will retain their assigned subject number from the 
TED-C14-006 or SHP633-301 studies. Assessment of need for teduglutide treatment should be 
guided by the teduglutide treatment inclusion criteria. If the investigator, subject, and/or 
parent/guardian agree to proceed with treatment, a formal evaluation of teduglutide inclusion and 
exclusion criteria will be performed at the pretreatment visit (Table 1-3). 
6.2.3
Dosing
If teduglutide treatment eligibility is established at the pretreatment visit and again, confirmed at 
the CxD1 visit, the subject will start a teduglutide treatment period, consisting of 24 weeks of 
teduglutide treatment at 0.05 mg/kg SC once daily. The initial dose will be calculated based on 
body weight measured at the teduglutide pretreatment visit, and adjusted as needed, based on 
body weight measured at week 12 (CxW12). No other adjustments to dose will be made during 
the teduglutide treatment period, unless discussed with the sponsor’s medical monitor. 
Following reconstitution, teduglutide will be administered by SC injection QD into 1 of the 
4 quadrants of the abdomen (in subjects without a stoma) or into either the thigh or arm. For 
subjects with a stoma, the quadrant of the abdomen containing the stoma should not be used. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 39
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
Teduglutide should be used as soon as possible after reconstitution, but no more than 3 hours 
later.
The subject should be dosed at approximately the same time each day. Consecutive doses should 
be separated by at least 12 hours. Each day, the injection site should be rotated.
The first SC injection in teduglutide-naïve subjects should be administered under the supervision 
of the investigator or designee and the subject observed for hypersensitivity reactions for at least 
4 hours during their initial dosing visit. The site of administration (arm, thigh, and abdomen) of 
the first teduglutide dose must be specified and recorded in the eCRF. 
Detailed instructions for reconstitution and injection of the investigational product can be found 
in the Instructions for Use. 
At the end of each 24-week teduglutide treatment period, subjects will be evaluated for the need 
for additional teduglutide treatment. During the 4-week follow-up, the investigator will assess 
the subject via weekly telephone visits. At any time during the follow-up period, if escape 
criteria are met, the subject may proceed directly to another pretreatment visit to assess treatment 
eligibility for another cycle (Section 4.6). Following the completion of the 4-week follow-up, the 
subject will continue in the study off teduglutide until teduglutide treatment eligibility criteria are 
again met. Additional 28-week cycles may be repeated if treatment eligibility is established each 
time. 
6.2.4
Unblinding the Treatment Assignment
Not applicable for this open-label study.
6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling 
Labels containing study information and pack identification will be applied to the investigational 
product(s) container. 
The study drug will be packaged, labeled, and shipped to the study site by the sponsor or 
designee. Kits containing 7 vials of study drug will be supplied and these will be labeled in 
accordance with applicable regulatory requirements. Sterile water for injection syringes and 
other ancillary components will be provided separately and will be labeled in accordance with 
the applicable regulatory requirements.
All study drug used in this study will be manufactured, tested, labeled, and released according to 
current legal requirements and Good Manufacturing Practice.
6.3.2
Packaging
Investigational product is packaged in the following conditions:
Teduglutide will be provided in a sterile, single-use, glass vial as a lyophilized powder, to be 
reconstituted with 0.5 mL sterile water for injection provided as the diluent in a prefilled syringe.
For non-commercial use only


Shire
CONFIDENTIAL
Page 40
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
6.3.3
Storage and Handling
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.
Study drug must be kept in a locked area with access restricted to specific study personnel. 
Study drug will be stored refrigerated at a temperature between 2 to 8°C (35.6 to 46.4°F) until 
dispensed to a subject. Once dispensed to a subject, the study drug can be stored refrigerated 
or up to a controlled room temperature (acceptable range of 2 to 25°C, or 35.6 to 77°F). 
Parent/guardian will be instructed to keep the subject’s study drug and sterile water diluent at 
controlled room temperature. If there are concerns that the controlled room temperature cannot 
be maintained, the study drug may be refrigerated. The study drug is for single use only, and 
should be used within 3 hours following reconstitution.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (ie, certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
Investigational products are distributed by the pharmacy or nominated member of the study 
team. The pharmacist/nominated team member will enter the unique subject identifier on the 
investigational product bottle/carton labels, as they are distributed. 
6.4
Drug Accountability 
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. The 
investigator is to keep a current record of the inventory and dispensation of all clinical supplies. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 41
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
This record will be made available to the sponsor’s site monitor for the purpose of accounting for 
all clinical supplies. Any discrepancy or deficiency will be recorded and will include an 
explanation. All supplies sent to the investigator must be accounted for and in no case will 
clinical supplies be used in any unauthorized situation.
The investigator has overall responsibility for administering/dispensing investigational product. 
Where permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator. 
This delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will dispense the investigational product only to subjects eligible 
for teduglutide treatment following the procedures set out in the study protocol. All dispensed 
study medication will be documented in the interactive response technology system and/or other 
investigational product record (eg, investigation product accountability form). The investigator is 
responsible for assuring the retrieval of all study supplies from subjects.
All used and unused study drug vials must be returned by the subjects and/or parent/guardian, 
and will be retained at the site. If deemed appropriate, the investigator or his/her designee may 
dispense the unused study drug vials to the same subject. All original containers, whether empty 
or containing study drug will be returned to the pharmacy. Returned study drugs will NOT be 
relabeled or reassigned for use by other subjects. Contents of the study drug containers will not 
be combined. All used and unused vials must be returned to the distribution center according to 
the sponsor’s instruction. No vial/kit may be destroyed on site without approval by the sponsor. 
Please see the Pharmacy Manual for additional information.
6.5
Subject Compliance
Subjects will be instructed to bring their unused investigational product and empty/used 
investigational product packaging to every visit. Drug accountability will be assessed at the 
container/packaging level for unused investigational product that is contained within the original 
tamper-evident sealed container (eg, bottles, trays, vials) or at the individual count level for 
opened containers/packaging. The pharmacist/nominated person will record details on the drug 
accountability form.
Compliance with study drug is calculated from subject diaries. Of those subjects eligible for 
teduglutide treatment, subjects who have received 80% of the planned doses administered will be 
assessed as being compliant with the study protocol.
For non-commercial use only


Shire
CONFIDENTIAL
Page 42
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
7
STUDY PROCEDURES
7.1
Study Schedule
Detailed study procedures and assessments to be performed for subjects throughout the study are 
outlined in the Schedule of Assessments (Table 1-1, Table 1-2, and Table 1-3) and must be 
referred to in conjunction with the instructions provided in this section. 
7.1.1
Screening 
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent (and assent, as applicable) 
from the subject. A subject will have approximately 7 days, after completion of either the 
TED-C14-006 or SHP633-301 studies, to sign consent to participate in the SHP633-304 study. 
The first visit after screening must occur within 12 weeks of screening for a pretreatment visit, 
and within 2 to 12 weeks of screening for an NTx visit.
The screening visit (Scr) assessments and procedures, beginning with informed consent, will be 
performed as outlined in Table 1-1, and as detailed below:

Informed consent, and informed assent (if applicable), is obtained

Study eligibility is determined. A screen failure is a subject who has given informed 
consent and failed to meet the Study Inclusion Eligibility Criteria. Subjects cannot be 
rescreened once they have been designated as a screen failure. 

Demographics, updates to medical history and SBS history

Intake and output diaries are dispensed

Evaluate teduglutide treatment inclusion criteria 

Adverse events, concomitant medications and concomitant procedures
7.1.2
Visits for Subjects Not Receiving Teduglutide
While outside of the 28-week teduglutide-treatment cycle, subjects will be followed 
approximately every 12 weeks for safety and efficacy assessments. No-teduglutide treatment 
visits are numbered sequentially (NT1, NT2, etc.), even if interrupted by the treatment cycles. 
The visit window (±7 days) is relative to the first NTx visit in the current NTT period. 
Assessments will be performed as outlined in Table 1-2 and described below.

Intake and output diaries are dispensed

Evaluate teduglutide treatment inclusion criteria

Adverse events, concomitant medications and concomitant procedures

Physical examination and vital signs, including weight

Height and head circumference

Review intake and output diaries
For non-commercial use only


Shire
CONFIDENTIAL
Page 43
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019

Record PS prescription and adjust as needed

Safety Laboratory Tests (ie, clinical chemistry, hematology, and urinalysis)

PedsQL Generic Core Scale/PedsQL Family Impact Module/ PedsQL Gastrointestinal 
Symptoms Module Sub-Scales

Antibodies to teduglutide, if and when required

Fecal occult blood testing, as indicated (Section 7.2.9.1)

Colonoscopy/sigmoidoscopy, as indicated (see Section 7.2.9.2)

Serum sample, as indicated
Teduglutide treatment may be considered at any time during the NTT period. If the investigator 
and the subject (and parent or legal guardian, as appropriate) agrees to proceed with treatment if 
the subject is eligible, the subject may proceed to the pretreatment visit immediately to determine 
eligibility. 
7.1.3
Visits for Subjects Receiving Teduglutide
7.1.3.1
Pretreatment Visit
Subjects who meet at least 1 of the teduglutide treatment inclusion criteria during the screening 
visit or during the NTT period may proceed to the pretreatment visit immediately if the 
investigator, subject and parent agree to proceed with teduglutide therapy. Similarly, subjects 
who meet escape criteria at cycle week 24 or during the teduglutide follow-up period may 
proceed to the pretreatment visit immediately.
The pretreatment visit may also be combined with screening visit, and if the pretreatment visit 
assessments occur within 7 days of the TED-C14-006 or SHP633-301 EOS visit, both sets of 
assessments can be combined. A subject must have 2 weeks of intake diary data collected, prior 
to the first dose administration (CxD1) during any teduglutide treatment cycle. In general, 
pretreatment assessments may occur over a period of up to 21 days. The teduglutide pretreatment 
visit (Px) assessments and procedures will be performed as in Table 1-3 and as described below:

Evaluate teduglutide eligibility (treatment inclusion/exclusion criteria) 

Dispense intake and output diaries

Adverse events, concomitant medications and concomitant procedures

Fecal occult blood testing 

Gastrointestinal-specific testing, including colonoscopy or sigmoidoscopy as indicated

Physical examination and vital signs, including weight

Height and head circumference

Review intake and output diaries

Record PS prescription and adjust as needed
For non-commercial use only


Shire
CONFIDENTIAL
Page 44
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019

Safety Laboratory Tests 
(In addition to clinical chemistry, hematology, and urinalysis, labs at this visit include 
prothrombin time [PT] international normalized ratio [INR]. Subsequent prothrombin 
time/international normalized ratio [PT/INR] measurement is only required to evaluate 
for suspected drug-induced liver injury [DILI]). 

Serum pregnancy testing, if applicable (when the pretreatment and screening visits are 
combined, the serum pregnancy test should be performed at the local laboratory)

Serum sample 
7.1.3.2
Teduglutide Treatment Period (CxD1-CxW24)
The open-label teduglutide treatment period will comprise 24 weeks, during which all 
assessments and procedures listed for Visits CxD1-CxW24 in Table 1-3 shall be completed. 
Cycles are numbered sequentially, such that the first visit of the first cycle is C1D1, and the first 
visit of the second cycle is C2D1, etc. Visit windows are calculated based upon the date of first 
investigational product administration (Visit CxD1). 
Visit CxD1
Assessments and procedures at this visit will be performed as outlined Table 1-3 and as 
described below. 
Two weeks of intake diary data are required before drug is administered at CxD1.

Confirm teduglutide treatment eligibility

Dispense intake and output diaries

Adverse events, concomitant medications and concomitant procedures

Physical examination and vital signs, including weight 

Height and head circumference

Review intake and output diaries

Record PS prescription and adjust as needed 

Safety laboratory tests

Quality of life measurements 

Antibodies to teduglutide

Pregnancy testing (urine), if applicable

Dispense study drug
For non-commercial use only


Shire
CONFIDENTIAL
Page 45
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
Site Visits during Teduglutide Treatment Period
Subjects will return for clinic visits on cycle weeks 1, 2, 4, 6, 9, 12, 16, 20, and 24/EOT. 
Assessments and procedures at these visits will be performed as outlined in Table 1-3 and as 
described below:

Dispense/review intake and output diaries (every effort should be made to complete 
2 weeks of intake diary entries prior to each clinic visit and to complete 48 hours of 
output diary entries during a period of nutritional stability prior to each clinic visit)

Physical examination and vital signs, including weight

Record PS prescription and adjust as needed

Safety laboratory tests 

Urine pregnancy testing for FOCBP (CxW4, CxW9, CxW12, CxW16, CxW20, CxW24)

Study drug dispensation (except for CxW24)

Adverse events, concomitant medications and concomitant procedures
In addition, at CxW12 and CxW24 Visits ONLY, the following procedures will be performed:

Height and head circumference

Antibodies to teduglutide

Fecal occult blood testing (FOBT)

GI-specific testing, including colonoscopy or sigmoidoscopy as indicated 

Quality of life measurements 
At CxW24 ONLY, a serum sample is collected and stored for future analysis. This sample will 
not be used for genetic testing and lack of collection will not constitute a protocol deviation.
Escape criteria are also evaluated at CxW24. The investigator may combine the CxW24 
assessments with the next pretreatment visit assessments if at least 1 escape criterion is met at the 
CxW24 visit and the pretreatment assessments occur within 7 days of the CxW24 visit.
Phone Visits 
Phone visits are required approximately 1 week after adjustments in PS during the teduglutide 
treatment period. Phone visit assessments and procedures are outlined in Table 1-3 and described 
below:

Review intake and output diaries

Safety laboratory tests (clinical chemistry and urinalysis)

Record PS prescription and adjust as needed
For non-commercial use only


Shire
CONFIDENTIAL
Page 46
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019

Obtain AEs, concomitant medications, and concomitant procedures  

Evaluate escape criteria
7.1.4
Teduglutide Follow-up Period
The safety follow-up period for this protocol is 4 weeks (weeks 25 – 28 of the cycle). Phone 
visits will occur on cycle weeks 25, 26, and 27 for all subjects. Phone visit assessments and 
procedures at weeks 25-27 will be the same as for telephone visits performed during the 
teduglutide treatment period. In addition, subjects will be evaluated for follow-up period escape 
criteria. If escape criteria are met at any time during the follow-up period, the subject may 
proceed directly to another pretreatment visit at the investigator’s discretion. The investigator 
may combine the CxW24 or CxW28 visits with the next pretreatment visit if at least 1 escape 
criterion is met at the CxW24 or CxW28 visits, and the pretreatment assessments occur within 
7 days of the CxW24 or CxW28 visit. If a subject is completing the study at the CxW28 visit, the 
EOS/ET visit (Section 7.1.5) will take place in lieu of the CxW28 visit. Otherwise, following 
completion of the 28-week treatment cycle, the subject will proceed to an NTT visit within 
approximately 12 weeks.
At cycle week 28 (CxW28), subjects will return to the study site. In addition to the assessments 
performed at weeks 25-27, the following procedures will be performed at CxW28 ONLY:

Dispense intake and output diaries 

Physical examination and vital signs, including weight

Antibodies to teduglutide

Pregnancy testing (urine), if applicable

Evaluate escape criteria
7.1.5
Study Completion/Early Termination Visit (EOS/ET Visit) 
All subjects will return to the study site for the end of study/early termination visit (EOS/ET). 
Assessments and procedures at this visit will be performed as outlined in Table 1-1 and as 
described here. If a subject discontinues the study prematurely, the assessments for the EOS/ET 
Visit are to be performed as completely as possible (see Section 4.8.2).

Adverse events - AEs will be collected for 4 weeks after the last dose of teduglutide in 
the study even if the EOS/ET occurs within that timeframe.

Concomitant medications and concomitant procedures  

Physical examination and vital signs, including weight

Height and head circumference

Review intake and output diaries (the intake diary should be completed daily for a 
minimum of 2 weeks prior to the EOS/ET visit. The output diary should be completed 
daily over a 48-hour period of nutritional stability before the EOS/ET visit)
For non-commercial use only


Shire
CONFIDENTIAL
Page 47
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019

Record PS prescription and adjust as needed

Safety laboratory tests 

Fecal occult blood testing, as indicated

Gastrointestinal-specific testing, including colonoscopy or sigmoidoscopy as indicated. 

Quality of life measurements 

Antibodies to teduglutide

Pregnancy testing, as needed
7.1.6
Qualitative Interview
An optional qualitative interview will be conducted by phone and within 14 days after 
completion of the EOS/ET visit (see Section 7.2.13). A single individual telephone interview will 
be conducted with English-speaking parents (or legal guardians) of subjects and subjects aged 
12 years or older and who provide informed consent (and if applicable, informed assent) to 
participate in the interview. These interviews will be performed in selected countries.
7.2
Study Evaluations and Procedures
7.2.1
Demographics, Medical History, and SBS History
Demographics, medical history, and SBS history will be obtained at screening. Medical history 
for purposes of this extension study will consist of the following:

Adverse events that were ongoing at the time of completion of TED-C14-006 or 
SHP633-301

Events that occurred during the period between completion of TED-C14-006 or 
SHP633-301 and informed consent to SHP-633-304 
This medical history information will supplement the medical history information collected at 
the start of the TED-C14-006 or SHP633-301 core studies. If the subject has any changes to the 
SBS history collected at the baseline visit of the TED-C14-006 or SHP633-301 studies, that 
information (updated SBS history) will be collected.
7.2.2
Physical Examination
Physical examinations will be performed according to the study schedules. Any new clinically 
significant findings noted during physical examinations should be recorded on the appropriate 
AE page of the eCRF. 
7.2.3
Vital Signs, Body Weight, Height, Head Circumference and Body Mass 
Index
Vital signs will be measured according to the study schedules. Measurements will include 
systolic and diastolic blood pressure (mmHg), pulse (beats per minute), and body temperature 
(°C/°F). Blood pressure should be determined by cuff (using the same method, the same 
extremity, and in the same position throughout the study, whenever possible).
For non-commercial use only


Shire
CONFIDENTIAL
Page 48
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
Body weight will also be recorded in the eCRF; subjects should be weighed on the same scale at 
each study visit. Height (or length) and head circumference (for subjects ≤36 months of age) will 
be measured at selected visits. A height z-score, weight z-score, BMI, and BMI z-score will be 
calculated by the sponsor using the site-provided height and weight data collected at each site 
visit
New clinically significant vital sign abnormalities should be recorded on the appropriate AE 
page of the eCRF.
7.2.4
Clinical Laboratory Tests
Safety laboratory tests to be performed at site visits consist of clinical chemistry, hematology, 
and urinalysis and will be performed as outlined in the study plan (Table 1-1, Table 1-2, and 
Table 1-3) Scheduled laboratory testing will be processed by a central lab. All laboratory assays 
will be performed according to the central laboratory’s normal procedures. Reference ranges are 
to be supplied by the laboratory. The investigator should assess out-of-range clinical laboratory 
values for clinical significance, indicating if the value(s) is/are not clinically significant or 
clinically significant. Abnormal clinical laboratory values, which are unexpected or not 
explained by the subject’s clinical condition, may, at the discretion of the investigator or sponsor, 
be repeated as soon as possible until confirmed, explained, or resolved. 
During the teduglutide treatment period, subjects will also have safety labs within approximately 
5-7 days after a PS adjustment. Safety labs performed after PS adjustment and between site visits 
will consist of clinical chemistry and urinalysis and may be processed by the central laboratory 
or a local laboratory. Local lab results are not required to be entered in the eCRFs; however, if 
the local lab results indicate any new clinically significant changes, they must be reported as an 
AE (see Section 8.1). Urine specimen collection should be attempted as part of the safety labs, 
but lack of urinalysis will not constitute a protocol deviation.
New clinically significant labs should be reported as AEs.
For non-commercial use only


Shire
CONFIDENTIAL
Page 49
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
The following clinical laboratory assessments will be performed according to the study 
schedules: 
Table 7-1: List of Laboratory Tests 
Hematology:

Hematocrit 

Hemoglobin 

Platelet count

Red blood cell count 

Red blood cell morphology, if needed

White blood cell count with differential
Coagulation:
Prothrombin time/International normalized ratio 
Urinalysis: 

Blood

Glucose

Leukocytes

Microscopic analysis

pH 

Protein

Specific gravity
Pregnancy tests (females of childbearing potential):
o
Serum β-HCG (teduglutide pretreatment visit)
o
Urine β-HCG (all other visits)
Biochemistry:

Albumin 

Alkaline phosphatase 

Alanine aminotransferase 

Amylase

Aspartate aminotransferase 

Bicarbonate

Bilirubin (total, direct, and indirect)

Blood urea nitrogen 

Calcium (total)

Chloride

Cholesterol

C-reactive proteina

Creatinine

Estimated Glomerular Filtration Rate 
(Schwartz formula)

Gamma-glutamyl transferase 

Glucose

Lipase

Magnesium

Phosphorus

Potassium 

Sodium 

Triglycerides

Uric acid
a C-reactive protein will not be measured  in subjects <10 kg.
7.2.5
Serum Sampling
Serum samples will be collected and stored for future analysis at the following times: 

At the pretreatment visit. If the subject arrived at the pretreatment visit by meeting an 
escape criterion, the serum sample will not be repeated at the pretreatment visit, because 
it will have been collected recently at the CxW24 visit.

At the CxW24 (EOT) visit

During NTT: Approximately every 24 weeks 
Stored serum samples should be omitted for subjects weighing less than 15 kg and whenever 
local blood volume limitations are exceeded.
For non-commercial use only


Shire
CONFIDENTIAL
Page 50
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
The serum sample will not be used for genetic testing. Lack of collection will not constitute a 
protocol deviation.
The sponsor, sponsor’s representatives, biorepositories, and any specialty laboratories will be 
blinded to the subject’s identity. The sample and/or extracted material will otherwise be stored 
for up to 15 years from the end of the study after which time it will be destroyed. Upon written 
request, subjects will be permitted to withdraw their sample from the analysis and have their 
sample and/or extracted material destroyed. Any results already generated from the samples will 
not be removed from any analyses that have already been performed.
7.2.6
Pregnancy Testing
A serum pregnancy test is performed on all FOCBP at the teduglutide pretreatment visit (when 
the pretreatment and screening visits are combined, the serum pregnancy test should be 
performed at the local laboratory). Urine pregnancy tests will be administered at all other visits 
according to the study schedules, or if pregnancy is suspected, or as specified per protocol upon 
withdrawal of the subject from the study. 
7.2.7
Antibody Testing
Blood samples will be drawn for the analysis of antibodies to teduglutide according to the 
Schedule of Assessments (Table 1-1, Table 1-2, and Table 1-3). Blood samples for antibodies 
may be drawn from a central line or from peripheral access. The sample drawn on CxD1 must be 
drawn prior to administration of the first dose of teduglutide. Once the subject has started 
teduglutide treatment, samples must be drawn at least 14 hours after dosing. Subjects who test 
positive for antibodies to teduglutide will also be tested for neutralizing antibody. Subjects who 
have been previously treated with teduglutide, and who test positive for antibodies to 
teduglutide, will have follow-up blood draws for antibodies to teduglutide every 12 weeks while 
on study until a negative result is obtained.
7.2.8
Volume of Blood
Efforts will be made to minimize the amount of blood drawn from all pediatric subjects enrolled 
in this study. The volumes of blood to be drawn from each subject will vary depending on 
clinical status and subject weight. Approximate volumes of blood to be drawn from each subject 
annually are shown in Table 7-2.
For non-commercial use only


Shire
CONFIDENTIAL
Page 51
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
Table 7-2: Approximate Volume of Blood to be Drawn from Each Subject Annually
Assessment
Sample 
Volume (mL)
No. Samples per two 28-week 
Teduglutide Cycles
Total 
Volume (mL)
Subjects ≥10 kg Receiving Teduglutide Treatment 
Safety
Biochemistry and -hCGa
2.5
24
60
Hematology
2
24
48
Coagulation Parameters
2
2
4
Antibodies
2
8
16
Serum storage samplesb
3
4
12
Total mL per 2, 28-week Treatment Cycles (Approximate Annual Volume):
140
Subjects <10 kg Receiving Teduglutide Treatment
Safety
Biochemistryc
1
24
24
Hematology
1
24
24
Coagulation Parameters
2
2
4
Antibodies
1
8
8
Total mL per 2, 28-week Treatment Cycles (Approximate Annual Volume):
60
Subjects ≥10 kg Not Receiving Teduglutide Treatmentd
Assessment
Sample 
Volume (mL)
No. Samples per 4 NTT Visits
Total 
Volume (mL)
Safety
Biochemistry
2.5
4
10
Hematology
2
4
8
Serum storage samplesb
3
2
6
Total mL per 4 “No Teduglutide Treatment” Visits 48-week period:
24
Subjects <10 kg Not Receiving Teduglutide Treatmentd,
Assessment
Sample 
Volume (mL)
No. Samples per 4 NTT Visits
Total 
Volume (mL)
Safety
Biochemistryc
1
4
4
Hematology
1
4
4
Total mL per 4 “No Teduglutide Treatment” Visits 48-week period:
8
β-hCG=beta-human chorionic gonadotropin; NTT=no-teduglutide treatment
a β-hCG testing will only be administered to females who are eligible for teduglutide treatment.
b Stored serum samples should be omitted for subjects weighing less than 15 kg and whenever local blood volume limitations are 
exceeded.
c CRP will not be measured in subjects <10 kg.
d Subjects not receiving teduglutide treatment, but who were exposed to it previously and tested positive for anti-teduglutide 
antibodies will require blood samples for antibody testing every 12 weeks until they test negative.
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment. When more than 1 blood assessment is to be done at the time 
point/period, if they require the same type of tube, the assessments should be combined. Blood 
volume estimates do not include safety labs performed after PS adjustment, and anti-teduglutide 
antibody testing during no-teduglutide treatment. Stored serum samples should be omitted for 
subjects weighing less than 15 kg and whenever local blood volume limitations are exceeded. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 52
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
Maximum blood volume at any given visit occurs when the pretreatment and Week 24 visits are 
combined. For subjects <10 kg this is 5.0 mL and for subjects ≥10 kg this is 8.5mL. 
7.2.9
Gastrointestinal-specific Testing
7.2.9.1
Fecal Occult Blood Testing
Fecal occult blood testing must be performed on all subjects at the pretreatment visit, week 12, 
and week 24 of the teduglutide cycle. During NTT periods, FOBT must be performed on 
teduglutide-exposed subjects (subjects who have received teduglutide any time in the past 
and are therefore not teduglutide-naïve) on a roughly annual basis (approximately every 
48-60 weeks). Actions to be taken in response to a positive FOBT are described below.
7.2.9.2
Colonoscopy or Sigmoidoscopy
Teduglutide-naïve subjects age 12 and older will undergo colonoscopy or sigmoidoscopy at the 
pretreatment visit if one has not been performed within 1 year. 
Subjects of any age with newly positive FOBT results at the pretreatment visit for which a 
readily detectable cause cannot be identified (eg, anal fissure) will undergo a colonoscopy or 
sigmoidoscopy prior to receiving teduglutide. If newly positive FOBT results (for which a 
readily detectable cause cannot be identified) are obtained at the end of a teduglutide treatment 
cycle (CxW24/EOT), colonoscopy or sigmoidoscopy will be performed. The need for 
colonoscopy or sigmoidoscopy in response to positive FOBTs at any other point during the 
study, or to re-evaluate persistently positive FOBTs is at the discretion of the investigator. 
Teduglutide-exposed subjects who have received the equivalent of 2 treatment cycles (48 weeks 
of study drug exposure) will undergo colonoscopy or sigmoidoscopy. While receiving additional 
teduglutide treatment, subjects will undergo colonoscopy or sigmoidoscopy at 5 year intervals or 
more often as needed. 
Upper endoscopy may be performed along with any colonoscopy or sigmoidoscopy at the 
investigator’s discretion. If a polyp is found, adherence to current polyp follow-up guidelines is 
recommended. Subjects with unresected GI polyps, polyposis conditions, premalignant change 
or malignancy in the GI tract will be excluded from teduglutide treatment.
7.2.10
Nutritional Support
Nutritional support includes PS, EN, and other food and fluids. Advances in EN and/or 
reductions to PS will be based on clinical status, including weight, linear growth, hydration 
status, and safety laboratory results. Intake and output diaries will include data to be considered 
in the adjustment of each subject’s nutritional support. Guidelines for nutritional support 
management and weaning algorithms are provided in Appendix 2.
For non-commercial use only


Shire
CONFIDENTIAL
Page 53
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
7.2.11
Diaries
7.2.11.1
Study Drug Administration Diary
A study drug administration diary will record administration of teduglutide. This diary should be 
completed by the subject (or parent/legal guardian, as applicable) daily during the teduglutide 
treatment periods (between visits CxD1 and CxW24).
7.2.11.2
Intake Diary
Intake diaries will be used to collect and evaluate each subject’s nutritional support. The 
subject/parent/guardian will complete the appropriate fields of the PS section of the intake diary 
2 weeks prior to ALL scheduled site visits (except at pretreatment visit). During the 24-week 
teduglutide treatment period, the intake diary will also be completed for 1 week following PS 
adjustments. The intake diary will also be completed daily during the 4-week follow-up period. 
The following data will be captured in the intake diaries:

Parenteral support volume and infusion duration

Site personnel will determine the actual PS daily calories based on diary entries.
All available diary data will be reviewed by the investigator or their designee at each clinic and 
telephone visit to assess clinical status and opportunity for PS reduction and advance in feeds.
7.2.11.3
Output Diary
Urine and stool output should be recorded in the output diary over a 48-hour period of nutritional 
stability before every clinic visit; in addition, output should be recorded for subjects that are in a 
teduglutide treatment cycle within 1 week of implementing a change in the PS prescription, 
regardless of previous teduglutide exposure.
Urine data:

Toilet-trained subjects (who do not wear diapers)
Measure and record all urine output in mL or cc 

Nontoilet-trained subjects (who wear diapers)
Measure and record the weight of all urine-only diapers. Urine volume will be calculated 
using the following formula: 1 g (scale weight) = 1 mL or 1 cc

At the discretion of the investigator, the parent may be asked to collect the first void after 
the daily PS infusion to measure specific gravity
Stool data (includes diapers with mixed urine and stool):

Toilet-trained subjects (who do not wear diapers)
Record the occurrence of each bowel movement and score the stool consistency using the 
Bristol Stool Form Scale (see Output diary)
For non-commercial use only


Shire
CONFIDENTIAL
Page 54
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019

Nontoilet-trained subjects (who wear diapers)
Record the weight of diapers containing stool (including diapers with mixed urine and 
stool) as stool output and score the stool consistency using the Bristol Stool Form Scale 
(see Output diary). Stool volume will be calculated using the formula: 1 g (scale weight) 
= 1 mL or 1 cc
All ostomy output volume should be recorded. Ostomy output will not be scored using the 
Bristol scale.
All available diary data will be reviewed by the investigator or their designee at each clinic and 
telephone visit to assess clinical status and opportunity for PS reduction and advance in feeds.
7.2.12
Health-related Quality of Life Assessments
Throughout the study, health-related quality of life assessments will be performed using the 
PedsQL Generic Core Scales. Each PedsQL age-appropriate form takes less than 4 minutes to 
complete. The scales include self-reports for pediatric subjects and adolescents aged 5 to 
18 years and proxy-reports from parents of pediatric subjects aged 2 to 18 years. The PedsQL 
Generic Core Scales will not be performed for subjects younger than 2 years of age. If a child is 
unable to complete the age-appropriate questionnaire (eg, due to developmental delay or other 
illness) it will not constitute a protocol deviation, but the parent should continue to complete the 
appropriate parent-specific forms.
Field trials have shown that the internal consistency reliability of the PedsQL was excellent, with 
alphas for the generic core scales in both self- and proxy-report greater than the 0.70 standard, 
and alphas for the full 23-item scale approaching 0.90 for self- and proxy-report. Missing data 
were minimal. Item response distributions were across the full-scale range, with no floor effects, 
and minimal ceiling effects. 
The validity of the PedsQL Generic Core Scales was demonstrated through known group 
comparisons, and correlations with other measures of disease burden. The PedsQL self- and 
proxy-report distinguished between pediatric subjects with and without a chronic health 
condition, and within the group of pediatric subjects with a chronic condition, between those 
who did or did not have an overnight hospital visit in the last 12 months. Further, both child 
self-report and parent proxy-report correlated significantly with the number of days the child was 
too ill to pursue normal activities, needed someone to care for him or her, missed school in the 
last month, the number of days the parent missed from work in the last month, and parent-report 
of problems pursuing their normal work routine and concentrating at work. The PedsQL Generic 
Core Scales are also responsive to clinical change, as demonstrated in field trials.
7.2.12.1
Pediatric Quality of Life Generic Core Scale (PedsQL™), Acute Version
The PedsQL Generic Core Scale is designed to measures health-related quality of life (HRQoL) 
in pediatric subjects and adolescents (2-18 years of age). The developmentally appropriate 
PedsQL Generic Core Scale will be completed by either the parent or legal guardian and subject 
as indicated in Table 7-3 at the time points as outlined in Table 1-1, Table 1-2, and Table 1-3.
For non-commercial use only


Shire
CONFIDENTIAL
Page 55
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
Table 7-3: Developmentally Appropriate PedsQL™Generic Core Scales
Report
Completed by
Parent Report for Toddlers (ages 2-4)
Parent or Legal Guardian
Child Self Report and Parent Proxy-Report for Young Pediatric subjects 
(ages 5-7)
Subject and Parent or Legal Guardian
Child Self Report and Parent Proxy-Report for Pediatric subjects 
(ages 8-12)
Subject and Parent or Legal Guardian
Child Self Report and Parent Proxy-Report for Teens (ages 13-18)a
Subject and Parent or Legal Guardian
Abbreviations: PedsQL=Pediatric Quality of Life Inventory
a The Child Self Report and Parent Proxy-Report for Teens (ages 13-18) will also be completed for subjects older 
than 18 years of age.
The Parent Report for Toddlers (ages 2-4) of the PedsQL Generic Core Scale is composed of 
21 items comprising 4 dimensions as follows: 1) Physical Functioning (8 items), 2) Emotional 
Functioning (5 items), 3) Social Functioning (5 items), 4) School Functioning (3 items). 
The Child and Parent Reports of the PedsQL Generic Core Scale for Young Pediatric subjects 
(ages 5-7), Pediatric subjects (ages 8-12), and Teens (ages 13-18) are composed of 23 items 
comprising 4 dimensions as follows: 1) Physical Functioning (8 items), 2) Emotional 
Functioning (5 items), 3) Social Functioning (5 items), 4) School Functioning (5 items).
7.2.12.2
Pediatric Quality of Life Family Impact Module (PedsQL™), Acute Version
The PedsQL Family Impact Module is a parent-report multidimensional instrument that will be 
completed by the parent or legal guardian, as outlined in Table 1-1, Table 1-2, and Table 1-3.
The PedsQL Family Impact Module is a specific module of the PedsQL that is used to measure 
the impact of pediatric chronic health conditions on parents and the family (Varni et al., 2004). 
The 36-item PedsQL Family Impact Module consists of 6 scales measuring parent self-reported 
functioning as follows: 1) Physical Functioning (6 items), 2) Emotional Functioning (5 items), 
3) Social Functioning (4 items), 4) Cognitive Functioning (5 items; worries about treatment and 
disease), 5) Communication (3 items), 6) Worry (5 items). Two additional scales measure 
parent-reported family functioning as follows: 1) Daily Activities (3 items), and 2) Family 
Relationships (5 items). The PedsQL Family Impact Module should take the parent or legal 
guardian approximately 5 to 10 minutes to complete.
7.2.12.3
PedsQL Gastrointestinal Symptoms Module (PedsQL™), Acute Version
The PedsQL Gastrointestinal Symptom Module is a disease-specific 58-item module, comprised 
of 10 different symptom scales that assess gastrointestinal symptom-related quality of life: food 
and drink limits, trouble swallowing, heartburn and reflux, nausea and vomiting, gas and 
bloating, constipation, blood in poop, and diarrhea. The PedsQL Gastrointestinal Symptoms 
Module was designed to allow the selection and scoring of individual scales from the Module. 
The scales of Food and Drink Limits (6 items) and Diarrhea (7 items) were identified as 
clinically relevant and appropriate for the symptoms experienced in this pediatric study 
population, and therefore, are the only scales used in this study. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 56
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
The scales will be completed by either the parent or legal guardian and subject as indicated in 
Table 7-3 at the time points outlined in Table 1-1, Table 1-2, and Table 1-3.
7.2.13
Qualitative Interviews
The objective of the qualitative interviews is to elicit the key symptoms and impacts of 
importance associated with SBS as well as the effect of teduglutide in relation to symptoms and 
impact experienced during the clinical study as described by subjects and caregivers in their own 
words. In addition, the interviews with caregivers will elicit concepts on aspects of caregiver 
burden associated with caring for their children with SBS and the impact of teduglutide on the 
caregiver burden experienced during the study. 
The interviews will be offered to English-speaking parents or legal guardians of subjects and 
subjects aged 12 years or older in selected countries. At the qualified subjects’ clinic sites, 
subjects and caregivers will be provided with a description of the qualitative interview and be 
offered the opportunity to participate. Subjects and caregivers who agree to participate will be 
asked to provide written informed consent (for caregiver interviews) and written assent and 
parental permission (for subject interviews) using forms developed specifically for the 
interviews.
The format will be a single individual telephone interview using a semistructured interview 
guide. Each interview will be approximately 45 minutes and will be completed within 14 days
after completion of the EOS/ET visit. Subjects and caregivers will be interviewed individually 
and separately and will be instructed to take the interview at a private setting.
Two interview guides have been developed, one for the caregiver interviews (Appendix 3) and 
one for the subject interviews (Appendix 4). Interview guides for UK sites will be reviewed by a 
native speaker of the local dialect. The guides will begin with a brief overview of the interview 
process and very general questions intended to get the participants talking about their 
experiences (and the impacts of these experiences) associated with SBS prior to entering the 
study. These questions will then be followed by a thorough probing of subject and caregiver 
experience during the study and the importance of the treatment outcomes. Topics included in 
the interview are listed below:

Subjects: SBS-related symptoms and impacts 
o
Symptoms due to SBS
o
Symptoms due to parenteral support
o
Impact of SBS on daily activities, physical functioning and social functioning
o
Impact of parenteral support on daily activities, physical functioning, and social 
functioning
For non-commercial use only


Shire
CONFIDENTIAL
Page 57
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019

Subjects: experience of teduglutide treatment in relation to SBS symptoms and impacts 
during the study
o
Changes of SBS-related symptoms relating to teduglutide
o
Changes of parenteral support-related symptoms relating to teduglutide
o
Changes of daily activities, physical functioning, and social functioning relating to 
teduglutide

Caregivers: 
o
SBS-related symptoms and impacts described as an observer

Symptoms due to SBS 

Symptoms due to parenteral support

Impact of SBS on daily activities, physical functioning, and social functioning

Impact of parenteral support on daily activities, physical functioning, and social 
functioning
o
Changes in SBS-related symptoms and impacts in relation to teduglutide treatment 
during the study described as an observer

Changes of SBS-related symptoms relating to teduglutide 

Changes of parenteral support-related symptoms relating to teduglutide

Changes of daily activities, physical functioning, and social functioning relating 
to teduglutide
o
Description of care provided and impacts on caregivers of pediatric patients with SBS 
requiring parenteral support

Impact on ability to complete activities of daily living

Impact on emotional and social functioning

Financial impact
o
Changes of caregiver impact in relation to teduglutide treatment during the study

Impact on ability to complete activities of daily living

Impact on emotional and social functioning

Financial impact
For non-commercial use only


Shire
CONFIDENTIAL
Page 58
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
To limit bias, the interviewer will begin by asking open-ended questions designed to identify the 
symptoms associated with SBS and their impact, as well as any perceived treatment benefits in 
these areas and the meaningfulness of these changes from the perspective of the parent/legal 
guardian and/or subject. Site personnel will obtain consent, assent, and permission for those 
individuals that agree to participate in the qualitative interviews.
All interviews will be conducted by experienced moderators and will be audio recorded. 
Interviews with subjects and caregivers from UK sites will be conducted by a moderator who is a 
native speaker. The content of the interview will be transcribed, and the audio recording will be 
destroyed to protect patient privacy. All personal information will be removed from the 
transcripts. Using the interview transcripts, dominant trends will be identified in each interview 
and then compared across the results of the other interviews to generate themes or patterns in the 
way subjects and caregivers describe their/their child’s treatment experiences and observations 
during the clinical trial as well as their perceptions of treatment benefit over the trial period. 
Should an interviewer become aware of any potential AE during the telephone interview, the 
interviewer will share the relevant information with the subject’s clinical site staff within 1 day. 
The clinical site will be responsible for follow-up with the subject. The investigator will be 
responsible for determining the clinical significance of the event and the reporting of the event as 
outlined in Section 8.
For non-commercial use only


Shire
CONFIDENTIAL
Page 59
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the 4 weeks following 
the last dose of teduglutide in the study. This includes events occurring during the screening 
phase of the study and the qualitative interviews, regardless of whether or not investigational 
product is administered. Where possible, a diagnosis rather than a list of symptoms should be 
recorded. If a diagnosis has not been made, then each symptom should be listed individually. All 
AEs should be captured on the appropriate AE pages in the eCRF and in source documents. In 
addition to untoward AEs, unexpected benefits outside the investigational product indication 
should also be captured on the AE eCRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pretreatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild:  A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of daily 
living.
Moderate:  A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses no significant 
or permanent risk of harm to the research subject.
For non-commercial use only


Shire
CONFIDENTIAL
Page 60
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
Severe:  A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
In consideration of whether a treatment-emergent adverse event (TEAE) might lead to dose 
interruption (Section 8.4.1) or early termination of the study (Section 8.5), severe TEAEs will 
also be graded according to the National Cancer Institute’s (NCI) Common Terminology Criteria 
for Adverse Events (CTCAE) severity grading criteria (US Department of Health and Human 
Services et al., 2010).
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of 
the investigational product is compelling and/or follows a known or 
suspected response pattern to that product, and the event cannot be 
explained by the subject’s medical condition, other therapies, or 
accident.
Not Related
The event can be readily explained by other factors such as the 
subject’s underlying medical condition, concomitant therapy, or 
accident and no plausible temporal or biologic relationship exists 
between the investigational product and the event.
AEs that are related to study drug that are not resolved at EOT will be followed until the event 
resolves or stabilizes, as judged by the investigator.
Laboratory values, vital signs, and clinical findings at the scheduled physical examinations must 
be reported as AEs if the investigator considers the finding to be a clinically significant change 
from the baseline. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 61
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study in the eCRF. Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved with Sequelae 

Recovering/Resolving

Unknown
8.1.4
Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE.
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory or vital sign can represent an AE if the change is 
clinically relevant or if, during the study, a shift of a parameter is observed from a normal value 
to an abnormal value, or a further worsening of an already abnormal value. When evaluating 
such changes, the extent of deviation from the reference range, the duration until return to the 
reference range, either while continuing treatment or after the end of treatment with the 
investigational product, and the range of variation of the respective parameter within its 
reference range, must be taken into consideration.
If, during the study, there are abnormal clinical laboratory values or vital signs which were not 
present at the beginning of the study, further investigations should be performed until the values 
return to within the reference range or until a plausible explanation (eg, concomitant disease) is 
found for the abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory or vital sign is clinically significant and 
therefore represents an AE.
8.1.6
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.4.
For non-commercial use only


Shire
CONFIDENTIAL
Page 62
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
Any report of pregnancy for any female study participant must be reported within 24 hours to the 
Shire Global Drug Safety Department using the Shire Investigational and Marketed Products 
Pregnancy Report Form. A copy of the Shire Investigational and Marketed Products Pregnancy 
Report Form (and any applicable follow-up reports) must also be sent to the Sponsor Medical 
Monitor using the details specified in the emergency contact information section of the protocol. 
In the event a subject becomes pregnant during the study, teduglutide administration must be 
discontinued immediately. 
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days postpartum.
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Study Adverse Event Form 
for Serious Adverse Events and Non-serious AEs as Required by the Protocol. Note: An elective 
abortion is not considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Adverse Event Form for SAEs and 
Non-serious AEs as Required by the Protocol as well as the Shire Investigational and Marketed 
Products Pregnancy Report Form. The test date of the first positive serum/urine -HCG test or 
will determine the pregnancy onset date.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) 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 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for 
a non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner 
that may be detrimental to the individual and/or society.

Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol).

Overdose – Administration of the investigational product at a dose or frequency greater 
than 0.05 mg/kg subcutaneous once daily. An overdose occurs if any of the following 
criteria are met: 
o
More than 0.05 mg/kg is given at any one time
o
Consecutive doses are spaced less than 12 hours apart
o
Any more than 0.05 mg/kg given in one day (a day is defined as beginning at 
12:00 AM and ending at 11:59 PM)
For non-commercial use only


Shire
CONFIDENTIAL
Page 63
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product. For studies, medication errors are reportable to the sponsor 
only as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error. 
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally-authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator brochure which the sponsor 
has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Drug Safety Department and the Sponsor Medical Monitor within 24 hours of the first awareness 
of the event. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors (see Section 8.1.7) unless they result in an SAE.
All Adverse Events of Special Interest, as defined in Section 8.3, must be reported by the 
investigator to the Shire Global Drug Safety Department and the Sponsor Medical Monitor 
within 24 hours of the first awareness of the event even if the event does not fulfill seriousness 
criterion.
The investigator must complete, sign, and date the Shire Clinical Study Adverse Event Form for 
SAEs and Non-serious AEs as Required by Protocol and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested). Fax or e-mail the completed form to the Shire Global Drug Safety 
Department. A copy of the completed Shire Clinical Study Adverse Event Form for Serious 
Adverse Events (SAEs) and Non-serious AEs as Required by Protocol (and any applicable 
follow-up reports) must also be sent to the Sponsor medical monitor or designee using the details 
specified in the emergency contact information section of the protocol.
8.2.3
Serious Adverse Event Definition
A serious adverse event (SAE) is any untoward medical occurrence (whether considered to be 
related to investigational product or not) that at any dose: 

Results in death
For non-commercial use only


Shire
CONFIDENTIAL
Page 64
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019

Is life-threatening. Note: The term 'life-threatening' in the definition of "serious" refers to 
an event in which the subject was at risk of death at the time of the event; it does not refer 
to an event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
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).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: 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 subject and may 
require medical or surgical intervention to prevent 1 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; or the development of drug dependency or 
drug abuse. 
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.4, and must be reported 
to the Shire Global Drug Safety Department and the Sponsor Medical Monitor within 24 hours 
of the first awareness of the event.
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Drug Safety Department within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
For non-commercial use only


Shire
CONFIDENTIAL
Page 65
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death.
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting 
The Sponsor and/or Clinical Contract Research Organization (CRO) is responsible for notifying 
the relevant regulatory authorities, and US central Institutional Review Boards (IRBs)/EU central 
ethics committees (ECs), of related, unexpected SAEs.
In addition, the Clinical CRO is responsible for notifying active sites of all related, unexpected 
SAEs occurring during all interventional studies across the SHP633 program.
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
8.3
Adverse Events of Special Interest
An AE of special interest is an AE (serious or nonserious) of scientific and medical concern 
specific to the sponsor’s product or program and for which ongoing monitoring and immediate 
notification by the investigator to the sponsor is required.
The AEs of special interest that require expedited regulatory reporting include the following:

Growth of pre-existing polyps of the colon

Benign neoplasia of the GI tract including the hepatobiliary system

Tumor-promoting ability (eg, benign and/or malignant neoplasia of any kind, not limited 
to those of the GI or hepatobiliary system)
For AEs of special interest, the sponsor must be informed within 24 hours of first awareness as 
per the SAE notification instructions described in Section 8.2.2 even if the event does not fulfill 
the seriousness criteria.
8.4
Dose Interruption of Individual Subjects
The investigator is responsible for contacting the sponsor/designee when the subject’s 
teduglutide dosing regimen is interrupted. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 66
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
Attempts should be made to contact the sponsor/designee prior to dose interruption. Reasons for 
dosage interruptions may include but are not limited to hospitalization, AEs, a lapse in 
investigational product delivery, etc. The length of the dose interruption, and whether teduglutide 
administration resumes or is permanently discontinued, depends on the clinical situation.
Investigational product must be interrupted if any of the following events occur:

An AE of special interest (see Section 8.3)

An AE that is of NCI CTCAE severity Grade 3 or 4 and related to teduglutide

Intestinal obstruction

Biliary obstruction related to teduglutide

Pancreatic duct obstruction related to teduglutide

Heart failure with severe fluid overload related to teduglutide
Investigational product must be permanently discontinued if any of the following events occur:

Pregnancy

Severe hypersensitivity, such as anaphylaxis determined by the investigator to be related 
to study drug. This does not include the presence of anti-teduglutide antibodies, mild 
injection site reactions or mild symptoms that according to the investigator do not pose a 
significant risk to the subject.

Confirmed DILI related to teduglutide (see Section 8.4.2)

Any malignancy.
8.4.1
Dose Interruption Criteria Based on Adverse Event Severity and 
Relationship to Investigational Product
The investigational product must be interrupted if the subject experienced an AE that is of 
severity ≥Grade 3 per the NCI CTCAE and is reported as related to the investigational product. 
In consideration of whether a TEAE might lead to dose interruption, severe TEAEs will also be 
graded according to the NCI CTCAE severity grading criteria (US Department of Health and 
Human Services et al., 2010). All such TEAEs should be discussed with the Sponsor Medical 
Monitor or designee as soon as possible. The length of the dose interruption, and whether 
teduglutide administration resumes or is permanently discontinued, depends on the clinical 
situation. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 67
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
8.4.2
Dose Interruption Criteria Based on Drug-Induced Liver Injury
Teduglutide administration for an individual subject may need to be interrupted if the subject has 
clinical and laboratory evidence of potential DILI, in the absence of an alternative explanation, 
as identified by the following criteria:

ALT or AST >8x ULN

ALT or AST >5x ULN and >2x baseline value for more than 2 weeks

(ALT or AST >3x ULN and >2x baseline value) and (total bilirubin >2x ULN or 
INR>1.5)

ALT or AST >3x ULN and >2x baseline value with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
All laboratory values suggestive of potentially new DILI should be repeated and verified within 
3 days. International normalized ratio should be measured with this set of verification laboratory 
assessments and an inquiry should be made as to the presence of clinical symptoms consistent 
with new liver injury. The subject should be followed closely to determine the trajectory of the 
laboratory abnormalities and to evaluate the cause of liver injury. This evaluation may include, 
as clinically indicated, consideration of sepsis, acute viral hepatitis (eg, hepatitis A 
immunoglobulin [IgM], hepatitis B surface antigen, hepatitis C antibodies, cytomegalovirus IgM, 
Epstein-Barr virus antibody panel), hepatobiliary obstruction (ultrasound), autoimmune hepatitis 
(anti-nuclear, anti-smooth muscle, anti-actin, or anti-liver kidney microsomal antibodies), 
intestinal failure associated liver disease, cardiovascular causes such as ischemic hepatitis, and 
concomitant hepatotoxic treatments.
Additional evaluations may be performed at the discretion of the investigator in consultation 
with the Sponsor medical monitor.
Teduglutide administration must be permanently discontinued if DILI is confirmed and deemed 
related to study drug.
8.5
Early Termination of the Clinical Study
The data monitoring committee (DMC) may recommend stopping the study if any of the 
following conditions are met:

≥2 subjects develop the same event of CTCAE severity Grade 3 that is reported as related 
to the investigational product
or

1 subject develops an event of CTCAE severity Grade 4 that is reported as related to the 
investigational product.
For non-commercial use only


Shire
CONFIDENTIAL
Page 68
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
9
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
in the eCRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered in the eCRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. Unscheduled safety follow up assessments (including visits 
conducted after EOS) are not to be collected unless requested.
9.2
Clinical Data Management 
Data are to be entered into a clinical database as specified in the CRO’s data management 
process. Quality control and data validation procedures are applied to ensure the validity and 
accuracy of the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Statistical Analysis Process 
The study will be analyzed by the sponsor or its agent. All statistical analyses will be performed 
using SAS® (SAS Institute, Cary, NC, USA) version 9.3 or higher.
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. 
9.4
Planned Interim Analysis, and Data Monitoring Committee 
An interim analysis is planned when 6 months of safety data have been collected for subjects 
entering from TED-C14-006. Additional interim analyses may be conducted as needed.
A DMC will be involved in the management of this study. The DMC members will review the 
data approximately every 3 months according to the DMC Charter. The DMC review will 
include all cumulative safety data (ie, AEs, laboratory assessments, physical examinations, etc.) 
from study assessments through each cutoff period. Further details regarding the DMC can be 
found in the DMC charter, which will be available prior to the administration of investigational 
product. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 69
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
The DMC for this study will be conducted in accordance with the FDA Guidance for Clinical 
Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees 
(March 2006).
The DMC will be an external, independent board comprised of physicians with relevant training. 
The DMC will be restricted to individuals free of significant conflicts of interest, including, but 
not limited to, financial, scientific, or regulatory in nature. The DMC will be governed by a 
Charter agreed to by members of the Board and the sponsor. Members of the Board may not be 
study investigators or be employed at the same institution as a study investigator, individuals 
employed by the sponsor, independent contractors hired by the sponsor, or members of 
regulatory agencies. The DMC may make recommendations to the sponsor regarding study 
aspects including stopping, modifying or continuing the study; however, the sponsor will have 
the final responsibility to determine whether the study should be modified or temporarily or 
permanently stopped. 
9.5
Sample Size Calculation and Power Considerations 
The number of subjects in this study is not based on statistical power considerations as this is an 
extension study of the core studies, TED-C14-006 and SHP633-301. The maximum number of 
subjects was determined by the enrollment in TED-C14-006 and SHP633-301.
9.6
Study Population
The safety population includes all enrolled subjects in the study. Safety population will be used 
for both safety and efficacy analyses.
9.7
Efficacy Analyses 
No claims of statistical significance will be made; however, 95% confidence intervals will be 
provided, if applicable. Continuous variables, including those assessed on a discrete scale, will 
be summarized using descriptive statistics including number of subjects, mean, median, standard 
deviation, maximum, and minimum. For categorical variables, statistical summaries will include 
number of subjects and percentages.
9.7.1
Efficacy Endpoints
Efficacy endpoints will be analyzed at the end of each teduglutide treatment period (week 24 or 
EOT), and at each study visit, relative to the baseline of the core study (TED-C14-006 or 
SHP633-301) and/or first exposure to teduglutide. The following efficacy endpoints will be 
analyzed: 

Reduction in PS volume of at least 20%

Absolute and relative change in PS volume

Complete weaning off PS

Change in days per week of PS
For non-commercial use only


Shire
CONFIDENTIAL
Page 70
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
9.8
Safety Analyses 
9.8.1
Safety Endpoints
The following safety endpoints will be analyzed: 

Adverse events

Vital signs, including temperature, heart rate, and blood pressure

Laboratory safety data (ie, clinical chemistry, hematology, and urinalysis)

Urine output

Stool output 

Antibodies to teduglutide

Gastrointestinal-specific testing , including fecal occult blood testing and colonoscopy or 
sigmoidoscopy

Z-scores for weight, height (or length), head circumference (up to 36 months of age), and 
BMI 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The number of events, incidence, and percentage of AEs will be calculated overall, 
by System Organ Class (SOC) and by preferred term. SAEs will be further summarized by 
severity and relationship to investigational product. Adverse events related to investigational 
product, AEs leading to withdrawal, SAEs, and deaths will be similarly summarized/listed.
Prior and concomitant medications will be coded using the World Health Organization-Drug 
Dictionary (WHO-DD) with regard to drug class and drug name. The number and percentage of 
subjects with specific prior medications will be summarized. Medical history (including 
surgical/procedural history) will be coded using MedDRA. The number and percentage of 
subjects with specific histories will be summarized by system organ class and preferred term. 
For clinical laboratory tests, vital signs, body weight, and fluid balance variables, descriptive 
statistics (mean, median, standard deviation, minimum and maximum values, the number and 
percentage of subjects in specified categories) will be calculated to summarize the observed 
values and change from baseline at each scheduled visit.
The number and percentage of subjects classified as having positive or neutralizing antibodies to 
teduglutide will be used to summarize the presence of antibodies. 
Additional safety parameters and measures will include change in body weight, height (or 
length) and head circumference (up to 36 months of age). Derived variables will include height 
z-score, weight z-score, BMI, and BMI z-score. Descriptive statistics (mean, median, standard 
deviation, minimum and maximum values, the number and percentage of subjects in specified 
categories) will be calculated to summarize the absolute values and change from baseline at each 
scheduled visit.
For non-commercial use only


Shire
CONFIDENTIAL
Page 71
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
9.9
Other Analyses
9.9.1
Health-related Quality of Life Analyses 
Health economics and outcomes research endpoints will be analyzed at approximately 12-week 
intervals (weeks 12 and 24 of each teduglutide treatment cycle, and every 12 weeks for subjects 
not on teduglutide), relative to the study baseline. The beginning of each treatment cycle (CxD1) 
will be an additional baseline.

Change in Pediatric Quality of Life Inventory (PedsQL) score

Change in PedsQL Family Impact Module score

Change in PedsQL Gastrointestinal Symptoms Module Sub-Scales scores: 
o
Food and Drink Limits
o
Diarrhea 
9.9.2
Qualitative Interviews
A final report will be developed for the qualitative interviews and will be included in the CSR of 
the study.
For non-commercial use only


Shire
CONFIDENTIAL
Page 72
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
10
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements. 
The name and address of each third party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH GCP Guideline E6 (1996), EU Directive 2001/20/EC, as 
well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study. An insurance certificate is supplied to the CRO as necessary. 
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 73
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
This requirement will be fulfilled within 6 months of the end of the study completion date for 
pediatric studies and within 1 year for non-pediatric studies as per guidance. The sponsor will 
provide the ECs with a copy of the same summary.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.
The sponsor will make an EOS declaration to the relevant competent authority as required by 
Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator is appointed to review the final CSR for multicenter 
studies. Agreement with the final CSR is documented by the signed and dated signature of the 
principal investigator (single-site study) or coordinating principal investigator (multicenter 
study), in compliance with Directive 2001/83/EC as amended by Directive 2003/63/EC and ICH 
Guidance E3 (1995). 
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
For non-commercial use only


Shire
CONFIDENTIAL
Page 74
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational products, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Case Report Forms
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded into eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log.
All data will have separate source documentation; no data will be recorded directly into the 
eCRF.
eCRFs should be approved by the investigator per study specifications and data deliverable 
requirements.
The clinical research associate (CRA)/study monitor will verify the contents against the source 
data per the monitoring plan. If the data are unclear or contradictory, queries are sent for 
corrections or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject diary cards, original clinical laboratory reports, and histology and 
pathology reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor, the respective national, 
local, or foreign regulatory authorities, the IRB/EC, and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF 
entries against the source documents. The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, X-rays etc.). Non-study site personnel will not 
disclose any personal information or personal medical information.
For non-commercial use only


Shire
CONFIDENTIAL
Page 75
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the European Medicines Agency (EMA), the 
Medicines and Healthcare products Regulatory Agency, other regulatory authorities, the sponsor 
or its representatives, and the IRB/EC for each site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent and assent, where 
applicable, from all study subjects prior to any study-related procedures including screening 
assessments. All consent and assent documentation must be in accordance with applicable 
regulations and GCP. Each subject or the subject’s legally-authorized representative, as 
applicable, is requested to sign and date the subject informed consent form or a certified 
translation if applicable, after the subject has received and read (or been read) the written subject 
information and received an explanation of what the study involves, including but not limited to: 
the objectives, potential benefits and risk, inconveniences, and the subject’s rights and 
responsibilities. A copy of the informed consent and assent documentation (ie, a complete set of 
subject information sheets and fully executed signature pages) must be given to the subject or the 
subject’s legally-authorized representative, as applicable. This document may require translation 
into the local language. Signed consent forms must remain in each subject’s study file and must 
be available for verification at any time.
Within the source documents, site personnel should document instruction of and understanding 
by the parent/legally-authorized representative/caregiver of the safe, responsible storage and 
administration of investigational product to the study subject.
For non-commercial use only


Shire
CONFIDENTIAL
Page 76
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
The principal investigator provides the sponsor with a copy of the consent form, and assent form 
where applicable, that was reviewed by the IRB/EC and which received their favorable 
opinion/approval. A copy of the IRB/EC’s written favorable opinion/approval of these 
documents must be provided to the sponsor, prior to the start of the study unless it is agreed to 
and documented (abiding by regulatory guidelines and national provisions) prior to study start 
that another party (ie, sponsor or coordinating principal investigator) is responsible for this 
action. Additionally, if the IRB/EC requires modification of the sample subject information and 
consent document provided by the sponsor, the documentation supporting this requirement must 
be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
For sites within the EU, the applicant for an EC opinion can be the sponsor, the investigator, or 
for multicenter studies the coordinating principal investigator or sponsor, according to national 
provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the Sponsor (or designee) has received 
written IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; for sites within the EU, this can be done by the sponsor, the investigator or for multicenter 
studies the coordinating principal investigator, according to national provisions. The investigator 
must also keep the local IRB/EC informed of any serious and significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996. A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the Sponsor (or designee).
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
review their medical records and data collected during the study. 
For non-commercial use only


Shire
CONFIDENTIAL
Page 77
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
These records and data may, in addition, be reviewed by others including the following: 
independent auditors who validate the data on behalf of the sponsor; third parties with whom the 
sponsor may develop, register, or market SHP633; national or local regulatory authorities; and 
the IRBs/ECs which gave approval for the study to proceed. The sponsor and/or its 
representatives accessing the records and data will take all reasonable precautions in accordance 
with applicable laws, regulations, and guidelines to maintain the confidentiality of subjects’ 
identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject).
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results / Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines 
(eg, Good Publication Practices 2) when forming a publication steering committee, which is 
done for large, multicenter Phase 2-4 and certain other studies as determined by Shire. The 
purpose of the publication steering committee is to act as a non-commercial body that advises or 
decides on dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
For non-commercial use only


Shire
CONFIDENTIAL
Page 78
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
current standards. Participation as an investigator does not confer any rights to authorship of 
publications.
For non-commercial use only


Shire
CONFIDENTIAL
Page 79
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
11
REFERENCES
Drucker, D. J. and Yusta, B. 2014. Physiology and pharmacology of the enteroendocrine 
hormone glucagon-like peptide-2. Annu Rev Physiol, 76, 561-83.
Khan, F. A., Squires, R. H., Litman, H. J., Balint, J., Carter, B. A., Fisher, J. G., Horslen, S. P., 
Jaksic, T., Kocoshis, S., Martinez, J. A., Mercer, D., Rhee, S., Rudolph, J. A., Soden, J., 
Sudan, D., Superina, R. A., Teitelbaum, D. H., Venick, R., Wales, P. W. and Duggan, C. 
2015. Predictors of Enteral Autonomy in Children with Intestinal Failure: A Multicenter 
Cohort Study. J Pediatr, 167, 29-34.e1.
Mouksassi, M. S., Marier, J. F., Cyran, J. and Vinks, A. A. 2009. Clinical trial simulations in 
pediatric patients using realistic covariates: application to teduglutide, a glucagon-like 
peptide-2 analog in neonates and infants with short-bowel syndrome. Clin Pharmacol 
Ther, 86, 667-71.
O'Keefe, S. J., Buchman, A. L., Fishbein, T. M., Jeejeebhoy, K. N., Jeppesen, P. B. and Shaffer, 
J. 2006. Short bowel syndrome and intestinal failure: consensus definitions and overview. 
Clin Gastroenterol Hepatol, 4, 6-10.
Squires, R. H., Duggan, C., Teitelbaum, D. H., Wales, P. W., Balint, J., Venick, R., Rhee, S., 
Sudan, D., Mercer, D., Martinez, J. A., Carter, B. A., Soden, J., Horslen, S., Rudolph, J. 
A., Kocoshis, S., Superina, R., Lawlor, S., Haller, T., Kurs-Lasky, M. and Belle, S. H. 
2012. Natural history of pediatric intestinal failure: initial report from the Pediatric 
Intestinal Failure Consortium. J Pediatr, 161, 723-8.e2.
Tappenden, K. A., Edelman, J. and Joelsson, B. 2013. Teduglutide enhances structural 
adaptation of the small intestinal mucosa in patients with short bowel syndrome. J Clin 
Gastroenterol, 47, 602-7.
Thymann, T., Stoll, B., Mecklenburg, L., Burrin, D. G., Vegge, A., Qvist, N., Eriksen, T., 
Jeppesen, P. B. and Sangild, P. T. 2014. Acute effects of the glucagon-like peptide 2 
analogue, teduglutide, on intestinal adaptation in short bowel syndrome. J Pediatr 
Gastroenterol Nutr, 58, 694-702.
US Department of Health and Human Services, National Institutes of Health and National 
Cancer Institute 2010. Common Terminology Criteria for Adverse Events (CTCAE).
Varni, J. W., Sherman, S. A., Burwinkle, T. M., Dickinson, P. E. and Dixon, P. 2004. The 
PedsQL Family Impact Module: preliminary reliability and validity. Health Qual Life 
Outcomes, 2, 55.
Wales, P. W., de Silva, N., Kim, J., Lecce, L., To, T. and Moore, A. 2004. Neonatal short bowel 
syndrome: population-based estimates of incidence and mortality rates. J Pediatr Surg,
39, 690-5.
For non-commercial use only


Shire
CONFIDENTIAL
Page 80
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
APPENDIX 1
PROTOCOL HISTORY
Document
Date
Global/Country/Site Specific
Original Protocol
08 April 2016
Global
Amendment 1
22 Nov 2016
Global
Amendment 2
23 Mar 2017
Global
Amendment 3
16 May 2018
Global
Amendment 4
01 Oct 2019
Global
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 3
Amendment Date
16 May 2018
Global
Description of Change and Rationale
Section(s) Affected by Change
The primary contact for EU and backup contact for NA was updated to 
.
Emergency Contact Information
To allow the enrollment of subjects who completed SHP633-301 where 
SHP633-301 was registered and approved by the local Health Authorities. 
The study title and eligibility criteria have been modified to accommodate 
younger children completing SHP633-301. 
SHP633-304 will evaluate long-term safety and efficacy in subjects who 
completed SHP633-301 and will provide a mechanism for subjects who 
complete SHP633-301 to receive additional teduglutide treatment if 
clinically indicated. 
Synopsis; Table 1-1; Section 2; 
Section 3.1; Section 4.1; Section 4.5; 
Section 6.2.2; Section 7.1.1; 
Section 7.1.3.1; Section 7.2.1; 
Section 9.5; Section 9.7.1
To minimize risk to subjects, a new escape criterion was added, allowing 
those who had escaped during the follow-up period of a previous teduglutide 
treatment to omit the follow-up period during subsequent teduglutide 
treatment cycles. 
For subjects who previously escaped the follow-up period, CxW24 
assessments can be combined with the next pretreatment visit assessments.
Synopsis; Table 1-3; Figure 3-1; 
Section 3.1; Section 4.6; 
Section 6.2.3; Section 7.1.3.1; 
Section 7.1.3.2; Section 7.1.4; 
Section 7.2.5
Added the recording of parenteral support prescription at screening. 
Table 1-1
Clarified language that all concomitant procedures are to be captured, not 
just gastrointestinal procedures.
Table 1-1; Table 1-2; Table 1-3, 
Section 5.1; Section 7.1.1; 
Section 7.1.2; Section 7.1.3.1; 
Section 7.1.3.2; Section 7.1.5
Updated the information on the clinical studies with teduglutide in pediatric 
subjects to include the results of TED-C14-006 and a description of the 
additional core study, SHP633-301. 
Section 1.3
Added new PK simulation data to further support dosing. 
Section 3.1
Deleted text that was duplicated in other sentences of sections.
Section 5.1
Deleted biological therapy (eg, antitumor necrosis factor) from the table of 
prohibited treatments as it was included in error.
Table 5-1
Clarified that compliance with study drug is calculated from subject diaries
Section 6.5
Added direct bilirubin to the list of laboratory tests.
Table 7-1
For non-commercial use only


Shire
CONFIDENTIAL
Page 81
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 3
Amendment Date
16 May 2018
Global
Description of Change and Rationale
Section(s) Affected by Change
Specified that blood pressure should be collected in the same extremity 
rather than in the same arm as blood pressure is not collected using the arm 
in small children.
Section 7.2.3
Specified that saved serum samples should be omitted for subjects weighing 
less than 10 kg and whenever local blood volume limitations are exceeded.
Section 7.2.8
Clarified that if a child is under 2 years of age or unable to complete a 
quality of life questionnaire (due to developmental delay or other illness) it 
will not constitute a protocol deviation.
Section 7.2.12
Specified that an interim analysis is planned when 6 months of safety data 
have been collected for subjects entering from TED-C14-006. Additional 
interim analyses may be conducted as needed.
Section 9.4
Minor editorial changes and corrections to typographical errors (which do 
not modify content and/or intent of the original document) were made.
Throughout protocol
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 2
Amendment Date
23 Mar 2017
Global
Description of Change and Rationale
Section(s) Affected by Change
Updated emergency contact information
Emergency Contact Information; 
Section 8.1.6; Section 8.2.2; 
Section 8.2.4
To allow for approximately 7 days for subjects to transfer from Study 
TED-C14-006 to Study SHP633-304 (instead of up to 7 days).
Table 1-1; Section 7.1.1
A footnote was added at the pretreatment visit in the Schedule of Events 
for Subjects While Receiving Teduglutide to underscore that, when the 
first pretreatment visit (P1) follows the screening visit, it must occur 
within 12 weeks of screening.
Table 1-3
Revised the language on abstinence as a contraceptive method for 
consistency with the Medicines and Healthcare Products Regulatory 
Agency (MHRA) Clinical Trial Facilitation Group's "Recommendations 
related to contraception and pregnancy testing in clinical trials."
Section 4.7.1
Clarification that ancillary components, in addition to sterile water for 
injection syringes, will also be provided and labeled in accordance with 
the applicable regulatory requirements.
Section 6.3.1
A footnote was added in Table 7-2 to clarify that subjects older than 
18 years of age will continue to use the Child Self Report and Parent 
Proxy-Report for Teens (ages 13-18) when completing the Pediatric 
Quality of Life Generic Core Scale (PEDSQL™).
Section 7.2.12.1 (Table 7-3)
For non-commercial use only


Shire
CONFIDENTIAL
Page 82
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 2
Amendment Date
23 Mar 2017
Global
Description of Change and Rationale
Section(s) Affected by Change
Revised the text on severity categorization to specify that a severe 
treatment-emergent adverse event (TEAE) that might lead to dose 
interruption (Section 8.4.1) or early termination of the study (Section 8.5) 
will also be graded according to the National Cancer Institute’s (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) severity 
grading criteria, in addition to the standard severity categorization. These 
events are no longer limited to only the events described in Table 8-1, 
entitled “CTCAE Criteria for Adverse Events that May Lead to Dose 
Interruption (Prospective Period of Observation Only).” Therefore, Table 
8-1 has been deleted.
Section 8.1.1; Section 8.4; 
Section 8.4.1
Table 8-1 (deleted)
Revised the criteria for early termination of the study: stopping criteria 
were extended to all NCI CTCAE Grade 3 and 4 severity events reported 
as related to the investigational product, and no longer limited to the 
events described in Table 8-1, entitled “CTCAE Criteria for Adverse 
Events that May Lead to Dose Interruption (Prospective Period of 
Observation Only).”
Section 8.5
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 1
Amendment Date
22 Nov 2016
Global
Description of Change and Rationale
Section(s) Affected by Change
Title of the Shire medical monitor has been changed to 
 
for clarity.
Protocol Signature Page
Emergency Contact Information
Clarification has been made that during the no-teduglutide treatment 
period, visits will take place approximately every 12 weeks.
Synopsis
Sections 3.1, 7.1.2
Figure 3-1
The study design flow chart has been edited for clarity.
Synopsis
Figure 3-1
The collection of all actual and prescribed enteral nutrition data has been 
removed to reduce the burden on the subjects and investigators. Enteral 
nutrition data are not required as the efficacy endpoints are limited to 
parenteral support parameters.
Synopsis
Table 1-1, Table 1-2, Table 1-3
Sections 7.1.2, 7.1.3.1, 7.1.3.2, 7.1.5, 
7.2.11.2, 7.2.11.3
Exclusion criterion 11 has been revised to add Smoflipid as other 
experimental drugs that are allowed prior and during the study. Like 
glutamine and Omegaven, Smoflipid is not expected to interfere with the 
assessments of safety and efficacy of teduglutide and many subjects may 
already be receiving the treatments off-label as part of standard medical 
therapy. 
Synopsis
Section 4.5
Exclusion criterion 12 and prohibited treatment have been refined: 
exclusion/prohibition of treatment with growth hormone has been 
extended to 3 months for consistency with other teduglutide studies. 
Synopsis
Section 4.5
Table 5-1
For non-commercial use only


Shire
CONFIDENTIAL
Page 83
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 1
Amendment Date
22 Nov 2016
Global
Description of Change and Rationale
Section(s) Affected by Change
The language on escape criteria has been corrected for consistency within 
the protocol. 
Synopsis
Section 4.6
Language in efficacy and safety endpoints has been clarified.
Synopsis
Sections 9.7.1, 9.8.1
Completion and review of intake and output diaries have been clarified. 
Table 1-2, Table 1-3
Sections 7.1.3.2, 7.1.5
When the screening and pretreatment visits are combined, the serum 
pregnancy test required at the pretreatment visit should be performed at the 
local laboratory instead of the central laboratory. This will ensure timely 
results prior to starting treatment with teduglutide.
Table 1-3
Sections 7.1.3.1, 7.2.6
The requirement for urine specimen collection has been revised so that a 
lack of urinalysis will not constitute a protocol deviation for any pediatric 
subjects (not only for subjects wearing diapers).
Table 1-1, Table 1-2, Table 1-3
Section 7.2.4
Clarification has been made that the first no-teduglutide treatment visit 
after the screening visit will occur within 2 to 12 weeks of the screening 
(formerly within 12 weeks of screening).
Synopsis
Table 1-2
Section 7.1.1
Windows have been clarified for visits during the no-teduglutide and 
teduglutide treatment periods.
Table 1-2, Table 1-3
Section 7.1.2
‘Specific’ has been deleted from ‘positive/specific anti-teduglutide 
antibodies’ to eliminate the redundancy. By definition, positive samples 
must be specific (as assessed in the confirmatory assay), or otherwise 
considered negative.
Table 1-2
Sections 7.2.7, 9.8.1
Parental height and gestational age at birth have been removed from 
medical history.
Table 1-1 (footnote b)
Section 7.2.1
For consistency within the protocol, sigmoidoscopy has been added as the 
alternate to colonoscopy throughout the protocol. 
Table 1-1, Table 1-2, Table 1-3
Sections 3.1, 7.1.2, 7.2.9.2
Removal of former footnote i on fecal occult blood test for clarity.
Table 1-3
Clarification has been made on circumstances when the CxW28 visit may 
be combined with the next pretreatment or EOS/ET visit. 
Table 1-3
Section 7.1.4
The text on PS support requirements over time in pediatric subjects with 
SBS has been clarified, and text on intestinal adaptation has been refined.
Section 1.1
Status of current teduglutide approvals for use has been updated.
Section 1.2, 3.1
The term ‘re-challenge’ has been replaced with ‘additional teduglutide 
treatment’ for clarity and consistency with other studies.
Section 3.1
Number of subjects enrolled has been corrected for consistency with 
protocol synopsis.
Section 3.1
Definition of a subject’s completion of the study has been corrected for 
consistency within the protocol.
Section 3.2
Evaluations to be performed when a subject discontinues teduglutide or 
when withdraws from the study have been clarified.
Sections 4.8.1, 4.8.2
For non-commercial use only


Shire
CONFIDENTIAL
Page 84
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number 1
Amendment Date
22 Nov 2016
Global
Description of Change and Rationale
Section(s) Affected by Change
Withdrawal by parent/guardian has been added as reason for 
discontinuation.
Section 4.8.3
COUMADIN has been changed to warfarin for clarity.
Sections 5.1, 5.1.2
Clarification has been made on handling of study drug, which is for single 
use only and should be used within 3 hours following reconstitution. 
Section 6.3.3
The investigator or designee may now dispense the unused study drug 
vials to the same subject if deemed appropriate to ensure sufficient 
supplies between visits. Also, documentation of all dispensed study 
medication has been clarified.
Section 6.4
Clarification has been made that local laboratory results are not required to 
be entered in the eCRFs.
Section 7.2.4
Collection of urine sodium and urine osmolality has been removed.
Section 7.2.4
Clarification has been made that the serum sample will not be collected at 
the pretreatment visit if the subject met a follow-up period escape 
criterion.
Section 7.2.5
Intake and output diaries (formerly in Sections 7.2.11 and 7.2.12, 
respectively) have been moved under a new Section 7.2.11 ‘Diaries’ for 
clarity, and are now Sections 7.2.11.2 and 7.2.11.3, respectively. 
Information on study drug administration diary has been added in Section 
7.2.11.1. Clarification has been made that only available diary data will be 
reviewed at each clinic and telephone visit.
Sections 7.2.11, 7.2.11.1, 7.2.11.2, 
7.2.11.3 
Performance of dipstick specific gravity tests by the subject at home on the 
first urine produced after the daily infusions of PS has been removed. It is 
now at the discretion of the investigator for all subjects, not just those in 
diapers. This change is to align with standard medical practice.
Section 7.2.11.3
Clarifications have been made to the language on dose interruption.
Sections 8.4, 8.4.1
Unscheduled safety follow up assessments (including visits conducted 
after EOS) are not to be recorded. However, clarification has been made 
that they are to be collected where requested.
Section 9.1
The protocol now refers to the data monitoring committee (DMC) Charter 
for the schedule of DMC reviews.
Section 9.4
Changes have been made to the Health economics and outcomes research 
endpoints to include the beginning of each treatment cycle (CxD1) as 
additional baseline. These changes are for clarity and consistency with 
other teduglutide studies. 
Synopsis
Section 9.9.1
Minor corrections have been made to the guidelines for nutritional support 
management during the study.
Appendix 2
For non-commercial use only


Shire
CONFIDENTIAL
Page 85
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
APPENDIX 2
GUIDELINES FOR NUTRITIONAL SUPPORT MANAGEMENT 
DURING THE STUDY
Nutritional support adjustment in volume and calories should be considered at all planned visits. 
Please consider the following clinical parameters identified as markers for adequate management 
of pediatric SBS. These parameters should also be considered for managing nutritional support 
(PS and/or oral/enteral feeding) in terms of volume and calories during the treatment period. 

Growth trajectory, including weight, height (or length), and head circumference (for pediatric 
subjects up to 36 months of age)

Other clinical evaluations

Serum electrolytes

Blood urea nitrogen /creatinine levels

Changes in stool frequency or volume, including mixed output

Stool consistency (ie, Bristol Stool Scale)

Urine specific gravity

General consideration to possible clinical deterioration in SBS

Inability to maintain weight and growth velocity

Diarrhea (≥10 bowel movements per day, ≥80 mL/kg/day from an ostomy, or 
≥75 mL/kg/day mixed output)

Colic/vomiting frequency increased

Electrolyte changes or imbalance

Skin breakdown 

Adjustments should be based on the actual nutritional support in volume and calories the 
subject infuses. Subjects should remain compliant with the nutritional support prescription in 
volume and calories during the study.

Nutritional support constituents may be adjusted at the discretion of the investigator.

During the 48-hour output measurement period prior to the subject’s scheduled visit, no 
further changes to the prescribed nutritional support should be made.

If there is a change in EN or other food or fluid intake, the investigator should consider this 
when adjusting the PS/EN support in volume and calories.
For non-commercial use only


Shire
CONFIDENTIAL
Page 86
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
Figure A-1
Weaning Algorithm for Subjects Who are NOT Toilet Trained and in 
Diapers
For non-commercial use only


Shire
CONFIDENTIAL
Page 87
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
Figure A-2
Weaning Algorithm for Subjects Who are Toilet Trained and NOT in 
Diapers
For non-commercial use only


Shire
CONFIDENTIAL
Page 88
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
Figure A-3
Clinical Dehydration Assessment and PS/EN Adjustment
For non-commercial use only


Shire
CONFIDENTIAL
Page 89
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
APPENDIX 3
CAREGIVER INTERVIEW GUIDE
Exit Interviews With Caregivers
Following Participation in a
Short Bowel Syndrome Clinical Trial
1. Introduction
(5 Minutes)
Introduce interviewers
Confirm caregiver’s first name and study ID
Review consent form and obtain consent
Remind participants of the purpose and format of the interview
We are interested in learning more about your child’s symptoms and impacts due to short 
bowel syndrome and parenteral support. We would also like to understand your experiences 
caring for your child as well as you and your child’s experiences with regard to treatment 
during the clinical trial.
The information you share with us will help the study sponsors learn more about potential 
treatment benefits of the clinical trial drug.
As we go along, please feel comfortable to speak openly and share your opinions freely. 
There are no wrong answers. You are the expert.
Unless you report a side effect potentially related to a medication that our study sponsors 
produce during today’s call, your name will never be associated with anything you share 
with us.

If you do report a side effect during today’s call, I have to let the study sponsors know. I 
may ask you some follow-up questions to fully understand the nature of the experience 
so I can fully communicate information to the study sponsor.
**REMEMBER TO TURN ON THE AUDIO RECORDER ONCE CONSENT IS PROVIDED. 
INTERVIEWER WILL VERBALLY NOTE STUDY ID AND INTERVIEW DATE**
2. History and Symptoms 
(10 minutes)
Just briefly, please tell us about your child’s history with SBS.

How old is your child?

How long has your child had SBS?

How long has your child received parenteral support?
For non-commercial use only


Shire
CONFIDENTIAL
Page 90
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019

What symptoms of SBS does your child experience? What symptoms due to parenteral 
support does your child experience? Are there other symptoms your child experienced in the 
past but doesn’t experience currently? What are those? [Probe for complete list and write 
down each symptom provided by the participant; for each symptom, probe to understand 
whether due to SBS, parenteral support, or both]

Symptom 1: ________________________________

Symptom 2: ________________________________

Symptom 3: ________________________________

Symptom 4: ________________________________

Symptom 5: ________________________________
[If not provided spontaneously by the participant, specific symptoms will be probed.]
Now we would like to discuss other symptoms that some patients or caregivers have described 
to see whether or not they are things your child has experienced as well.

As I read each symptom, please let me know if your child has experienced this symptom in 
relation to his or her SBS or parenteral support. [Only read those symptoms not already 
provided by the participant; probe to understand whether due to SBS, parenteral support, or 
both]

Pain/discomfort

Fatigue

Frequent need to empty bowels/bag

Diarrhea

Of the symptoms you have described which would you say is the most bothersome for your 
child? Why?
3. Impacts
(10 minutes)

How does your child’s SBS and parenteral support affect his or her life? [Probe for complete 
list and write down each impact provided by the caregiver; probe to understand whether 
impact of SBS, parenteral support, or both]

Impact 1: ________________________________

Impact 2: ________________________________

Impact 3: ________________________________

Impact 4: ________________________________

Impact 5: ________________________________
[If not provided spontaneously by the participant, specific impacts will be probed.]
For non-commercial use only


Shire
CONFIDENTIAL
Page 91
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
Now we would like to now discuss other impacts that some patients and caregivers have 
described to see whether or not they are things your child has experienced as well.

As I read each impact, please let me know if you have experienced this in relation to your 
child’s SBS and parenteral support. [Only read those impacts not already provided by the 
participant. For endorsed impacts, ask the participant to describe their experiences with the 
impact and whether they feel it is due to SBS or parenteral therapy or both]

Daily activities, including school if applicable
-
Need to know/plan for bathroom facilities when leaving home

Physical functioning

Social functioning

Emotional functioning

Sleep

Of the impacts you have described, which would you say is the most bothersome to your 
child? Why?
4. Clinical Trial Experiences 
(10 minutes)
Now we would like to talk about your experience during the clinical trial.

What were your expectations of treatment prior to entering the clinical trial?

Thinking back to before you started the clinical trial, what were some of the reasons you 
decided to enroll your child in the trial?

Were there specific symptoms/issues which you most wanted treatment to help? Which 
ones? Why?

How frequently was your child receiving parenteral therapy at the beginning of the trial? 
[Probe on how many times a week, for how many hours, and when administered].

What improvements, if any, have you noticed in your child since starting the study? [Have 
caregivers describe each improvement reported]

Improvement 1: ________________________________

Improvement 2: ________________________________

Improvement 3: ________________________________

Improvement 4: ________________________________

Improvement 5: ________________________________
For non-commercial use only


Shire
CONFIDENTIAL
Page 92
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019

What were the biggest improvements you noticed? How important, if at all, were these 
improvements to you?

Were there smaller or other improvements that you noticed that were also meaningful to 
you? If so, please describe these improvements. [Add these improvements to the list above]

I would like to review each of the improvements that you noticed. Thinking about [a 
symptom from the list], how would you describe them before the study? [Probe mild, 
moderate, or severe, as applicable]

How would you describe them after the study? [Probe none, mild, moderate, or severe, as 
applicable]

[If not reported] Were there any improvements in your child’s parenteral therapy during the 
study? How important, if at all, was this change to you? [Probe to capture current parenteral 
frequency]

Of all of the improvements we have talked about, which do you think was the most important 
to your child? Why? Which was the most important to you? Why?

How would you describe the change in your child’s SBS overall after participating in the 
study? [Probe: very much better, much better, a little better, no change, a little worse, much 
worse, or very much worse]
5. Caregiver Experiences 
(10 minutes)
Now we would like to talk about your experience as a caregiver of a child with SBS.

How has having a child with SBS impacted your life? [Probe for complete list and write down 
each impact provided by the caregiver; probe to understand whether impact of SBS, 
parenteral support, or both]

Impact 1: ________________________________

Impact 2: ________________________________

Impact 3: ________________________________

Impact 4: ________________________________

Impact 5: ________________________________
[If not provided spontaneously by the participant, specific impacts will be probed.]
For non-commercial use only


Shire
CONFIDENTIAL
Page 93
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
Now we would like to now discuss other impacts that some caregivers have described to see 
whether or not they are things you have experienced as well.

As I read each impact, please let me know if you have experienced this in relation to caring 
for your child with SBS [Only read those impacts not already provided by the participant. For 
endorsed impacts, ask participants to describe their experiences with the impact and 
whether they feel it is due to their child’s SBS, parenteral therapy for the SBS, or both.]

Caregiver’s daily activities
-
Need to know/plan for bathroom facilities when leaving home with child

Caregiver’s physical functioning

Caregiver’s emotional functioning

Caregiver’s social functioning

Caregiver’s sleep

Financial impact

Of the impacts you have described which would you say is the most bothersome for you? 
Why?

Which, if any, of the above do you feel was improved during your child’s participation in the 
clinical trial? How important, if at all, was this improvement?
6. Closing
Is there anything else you would like to add about your child’s SBS?
Thank you for taking the time to meet with us today. Your input has been very helpful and will 
also be helpful for the patients that will participate in further research on SBS. Thank you again.
For non-commercial use only


Shire
CONFIDENTIAL
Page 94
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
APPENDIX 4
PEDIATRIC SUBJECT INTERVIEW GUIDE
Exit Interviews With Pediatric Subjects
Following Participation in a
Short Bowel Syndrome Clinical Trial
7. Introduction
(5 Minutes)
Introduce interviewers
Confirm subject’s first name and study ID with caregiver
Review parental consent form and confirm consent
Confirm pediatric subject assent 
Remind participants of the purpose and format of the interview
We are interested in learning more about your symptoms and impacts due to short bowel 
syndrome and parenteral support (the nutrition and fluids you get because of your short 
bowel). We would also like to understand your experiences during the study you were in. 
The information you share with us will help the study sponsors learn more about potential 
treatment benefits of the clinical trial drug.
As we go along, please feel free to speak openly and share your opinions freely. There are 
no wrong answers. You are the expert.
Unless you report a side effect that might be related to a medication that our study sponsors 
produce during today’s call, your name will never be associated with anything you share 
with us.

If you do report a side effect during today’s call, I have to let the study sponsors know. I 
may ask you some follow-up questions to fully understand what happened so I can fully 
share this with the study sponsor.
**REMEMBER TO TURN ON THE AUDIO RECORDER ONCE CONSENT IS PROVIDED. 
INTERVIEWER WILL VERBALLY NOTE STUDY ID AND INTERVIEW DATE**
8. History and Symptoms 
(15 minutes)
Just briefly, please tell us about history with SBS.

How old are you? 

How long have you had SBS?

How long have you been getting parenteral support? [Confirm participant understanding 
of term and use term if understood/used or use the participant preferred term throughout 
the interview]
For non-commercial use only


Shire
CONFIDENTIAL
Page 95
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019

What symptoms of SBS do you experience? What symptoms due to parenteral support do 
you experience? Are there other symptoms you have had in the past but do not experience 
today? What are those? [Probe for complete list and write down each symptom provided by 
the participant; for each symptom, probe to understand whether due to SBS, parenteral 
support, or both]

Symptom 1: ________________________________

Symptom 2: ________________________________

Symptom 3: ________________________________

Symptom 4: ________________________________

Symptom 5: ________________________________
[If not provided spontaneously by the participant, specific symptoms will be probed.]
Now we would like to discuss other symptoms that some patients have described to see 
whether or not they are things you have experienced as well.

As I read each symptom, please let me know if you have experienced this symptom in 
relation to your SBS or parenteral support. [Only read those symptoms not already provided 
by the participant; probe to understand whether due to SBS, parenteral support, or both]

Pain/discomfort

Fatigue

Frequent need to empty bowels/bag

Diarrhea

Of the symptoms you have described which would you say is the most bothersome for you? 
Why?
9. Impacts
(15 minutes)

How does your SBS and parenteral support affect your life? [Probe for complete list and 
write down each impact provided by the participant; probe to understand whether impact of 
SBS, parenteral support, or both]

Impact 1: ________________________________

Impact 2: ________________________________

Impact 3: ________________________________

Impact 4: ________________________________

Impact 5: ________________________________
[If not provided spontaneously by the participant, specific impacts will be probed.]
For non-commercial use only


Shire
CONFIDENTIAL
Page 96
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019
Now we would like to now discuss other impacts that some patients have described to see 
whether or not they are things you have experienced as well.

As I read each impact, please let me know if you have experienced this in relation to your 
SBS and parenteral support. [Only read those impacts not already provided by the 
participant. For endorsed impacts, ask the participant to describe their experiences with the 
impact and whether they feel it is due to SBS or parenteral therapy or both]

Daily activities, including school if applicable
-
Need to know/plan for bathroom facilities when leaving home

Physical functioning

Social functioning

Emotional functioning

Sleep

Of the impacts you have described, which would you say is the most bothersome to? Why?
10.
Clinical Trial Experiences 
(10 
minutes)
Now we would like to talk about your experience during the clinical trial.

What did you think the study would be like before you started it? 

Thinking back to before you started the study, what were some of the reasons you decided 
to be a part of the study? 

Were there specific symptoms/issues which you most wanted treatment to help? Which 
ones? Why?

How frequently were you child receiving parenteral therapy at the beginning of the trial? 
[Probe on how many times a week, for how many hours, and when administered].

What improvements, if any, have you noticed since you started the study? [Have 
participants describe each improvement reported]

Improvement 1: ________________________________

Improvement 2: ________________________________

Improvement 3: ________________________________

Improvement 4: ________________________________

Improvement 5: ________________________________
For non-commercial use only


Shire
CONFIDENTIAL
Page 97
SHP633-304 Protocol Amendment 4
Teduglutide
01 Oct 2019

What were the biggest improvements you noticed? How important, if at all, were these 
improvements to you?

Were there smaller or other improvements that you noticed that were also meaningful to 
you? If so, please describe these improvements. [Add these improvements to the list above]

I would like to review each of the improvements that you noticed. Thinking about [a 
symptom from the list], how would you describe them before the study? [Probe mild, 
moderate, or severe, as applicable]

How would you describe them after the study? [Probe none, mild, moderate, or severe, as 
applicable]

[If not reported] Were there any improvements in your parenteral therapy during the study? 
How important, if at all, was this change to you? [Probe to capture current parenteral 
frequency]

Of all of the improvements we have talked about, which do you think was the most important 
to you? Why? 

How would you describe the change in your SBS overall after being in the study? [Probe: 
very much better, much better, a little better, no change, a little worse, much worse, or very 
much worse]
11.
Closing
Is there anything else you would like to add about your SBS?
Thank you for taking the time to meet with us today. Your input has been very helpful and will 
also be helpful for the patients that will participate in further research on SBS. Thank you again.
For non-commercial use only

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
 
 
NCT Number:   
NCT02954458 
 
Study Title:  
A Prospective, Open-label, Long-term Safety and Efficacy Study of Teduglutide in 
Pediatric Patients with Short Bowel Syndrome Who Completed TED-C14-006 
 
Study Number:  
SHP633-304 
 
 
SAP Version and Date:   
Version 3.0: 
  
17 Dec 2020 


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 1 of 48
STATISTICAL ANALYSIS PLAN
(PROSPECTIVE DATA)
SHP633-304
A Prospective, Open-label, Long-term Safety and Efficacy Study of
Teduglutide in Pediatric Patients with Short Bowel Syndrome Who
Completed TED-C14-006 or SHP633-301
AUTHOR:
VERSION NUMBER AND DATE: V3, 17 DEC 2020
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 2 of 48
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE
Statistical Analysis Plan Draft V3 (Dated 17Dec2020) for Protocol SHP633-304
Upon review of this document, the undersigned approves this version of the Statistical 
Analysis Plan, authorizing that the content is acceptable for the reporting of this study.
Name
Signature
Date
Approved By:
Position:
, GI Statistics
Company:
Shire Pharmaceuticals, Inc. a Takeda Company
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 3 of 48
MODIFICATION HISTORY
Unique 
Identifier 
for 
this 
Version
Date of the 
Document 
Version
Author
Significant Changes from 
Previous Authorized Version
Draft 1.0
11AUG2017
Not Applicable – First Version
Version 
1.1
2FEB2018
To include subgroup analysis for 25%, 
50%, 75% reduction in PS Volume
Version 
2.0
11JUN2018
To incorporate Changes to Planned 
Statistical 
Analysis 
Plan 
dated 
03May2018, which clarifies
*extent of exposure
*hours per day
*change from baseline labs for certain 
continuous variables due to different 
central lab between 006 study and 304 
study.
Also removed, number of days on 
teduglutide for each cycle.
Version 
3.0
17Dec2020
Update SAP per Protocol Amendment #4 
incorporate roll over subjects from 301 
study
Remove mentioning of Quintiles or Shire 
Modification of CRO
Add extension of exposure for categories 
for longer exposure, add overall exposure 
with core since exposure calculation to 
account for longer duration
Add hours per non-zero days as 
sensitivity analysis 
Change from baseline to will not be 
calculated for lab parameters that have 
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 4 of 48
different normal ranges between core 
and extension. 
Clarified analysis for Quality of life stratify 
parents and self-reported data, handling 
between Ted and NT periods.
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 5 of 48
TABLE OF CONTENTS
1.
LIST OF ABBREVIATIONS..............................................................................................................9
2.
INTRODUCTION.............................................................................................................................10
3.
STUDY OBJECTIVES......................................................................................................................10
3.1.
Primary Objective......................................................................................................................................10
3.2.
Secondary Objective..................................................................................................................................10
4.
STUDY DESIGN...............................................................................................................................10
4.1.
General Description...................................................................................................................................10
4.2.
Schedule of Events.....................................................................................................................................12
4.3.
Changes to Analysis from Protocol ............................................................................................................12
5.
PLANNED ANALYSES....................................................................................................................12
5.1.
Interim Analysis of Prospective Data .........................................................................................................13
5.2.
Final Analysis.............................................................................................................................................13
6.
ANALYSIS SETS ..............................................................................................................................13
6.1.
All Subjects Screened [SRN] Set.................................................................................................................14
6.2.
Safety Population ......................................................................................................................................14
7.
GENERAL CONSIDERATIONS.....................................................................................................14
7.1.
Reference Start Date and Study Day..........................................................................................................14
7.2.
Baseline.....................................................................................................................................................14
7.3.
Retests, Unscheduled Visits and Early Termination Data...........................................................................15
7.4.
Study visit Conventions .............................................................................................................................15
7.5.
Windowing Conventions............................................................................................................................16
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 6 of 48
7.6.
Statistical Tests..........................................................................................................................................16
7.7.
Common Calculations................................................................................................................................16
7.8.
Software Version.......................................................................................................................................16
8.
STATISTICAL CONSIDERATIONS .............................................................................................17
8.1.
Adjustments for Covariates and Factors to be Included in Analyses ..........................................................17
8.2.
Multicenter Studies ...................................................................................................................................17
8.3.
Missing data ..............................................................................................................................................17
8.4.
Multiple Comparisons/ Multiplicity...........................................................................................................17
8.5.
Examination of Subgroups.........................................................................................................................17
9.
OUTPUT PRESENTATIONS.........................................................................................................17
10. DISPOSITION AND WITHDRAWALS .......................................................................................17
11. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS..........................................19
11.1.
Derivations................................................................................................................................................20
12. MEDICAL HISTORY.......................................................................................................................20
12.1.
Medical and Surgical History .....................................................................................................................20
12.2.
Short Bowel Syndrome History..................................................................................................................21
13. CONCOMITANT TREATMENTS .................................................................................................21
13.1.
Concomitant Medications..........................................................................................................................21
13.2.
Diagnostic, Surgical, or Therapeutic Procedures ........................................................................................22
14. STUDY DRUG EXPOSURE............................................................................................................22
14.1.
Derivations................................................................................................................................................22
15. STUDY DRUG COMPLIANCE.......................................................................................................23
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 7 of 48
15.1.
Derivations................................................................................................................................................23
16. EFFICACY OUTCOMES..................................................................................................................23
16.1.
Efficacy Endpoints .....................................................................................................................................24
Efficacy Variables & Derivations...............................................................................................................24
16.1.1.1.
≥ 20%, 50%, and 75% Reduction in PS volume.................................................................................25
16.1.1.2.
Change and percent change from baseline in PS volume and intake calories .................................25
16.1.1.3.
Complete weaning off PS..................................................................................................................25
16.1.1.4.
Change and percent change from baseline in hours per day and days per week of PS ...................25
Analyses of Efficacy Variables...................................................................................................................26
17. HEALTH-RELATED QUALITY OF LIFE ANALYSIS................................................................26
17.1.
Pediatric Quality of Life Generic Core Scale (PedsQL™), Acute version ......................................................27
Variables & Derivations ............................................................................................................................27
17.2.
Pediatric Quality of Life Family Impact Module (PedsQL™), Acute version ................................................28
Variables & Derivations ............................................................................................................................28
17.3.
PedsQL Gastrointestinal Symptoms Module (PedsQL™), Acute version.....................................................29
Variables & Derivations ............................................................................................................................29
17.4.
Missing Data Methods...............................................................................................................................29
17.5.
Analysis of HRQOL Variables......................................................................................................................29
18. SAFETY OUTCOMES......................................................................................................................30
18.1.
Adverse Events ..........................................................................................................................................30
All TEAEs ...................................................................................................................................................31
18.1.1.1.
Severity .............................................................................................................................................31
18.1.1.2.
Relationship to Teduglutide..............................................................................................................31
Serious Adverse Events.............................................................................................................................31
AEs Leading to Discontinuation of Study Drug .........................................................................................31
AEs Leading to Discontinuation of Study..................................................................................................32
Adverse Events Leading to Death.............................................................................................................32
Adverse Events of Special Interest ...........................................................................................................32
18.2.
Laboratory Evaluations..............................................................................................................................32
Laboratory Reference Ranges and Markedly Abnormal Criteria..............................................................34
18.3.
Pregnancy Testing......................................................................................................................................35
18.4.
Antibodies to Teduglutide .........................................................................................................................35
18.5.
Gastrointestinal-Specific Testing ...............................................................................................................35
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 8 of 48
18.6.
Physical Examination.................................................................................................................................36
18.7.
Vital Signs..................................................................................................................................................36
Vital Signs Specific Derivations .................................................................................................................37
18.8.
Fecal and Urine Output..............................................................................................................................37
19. DATA NOT SUMMARIZED OR PRESENTED...........................................................................38
APPENDIX 1.PROGRAMMING CONVENTIONS FOR OUTPUTS...............................................38
APPENDIX 2.
PARTIAL DATE CONVENTIONS...................................................................40
Imputation of Partial AE Dates..............................................................................................................................40
Imputation of Partial Medication Data..................................................................................................................43
APPENDIX 3.
MARKEDLY ABNORMAL LABORATORY CRITERIA .........................47
APPENDIX 4.TABLE, FIGURE AND DATA LISTING SHELLS ....................................................48
Table and Figure Shells..........................................................................................................................................48
Data Listing Shells .................................................................................................................................................48
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 9 of 48
1. LIST OF ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Events of Special Interest
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
BMI
Body Mass Index 
CDC
Centers for Disease Control and Prevention 
CTMS
Clinical Trial Management System
CxDy
Cycle x Day y
eCRF
Electronic Case Report Form
EOS
End of Study 
ET
Early Termination
FOBT
Fecal Occult Blood Testing
FOCBP
Females of Childbearing Potential
GFR
Glomerular Filtration Rate
GGT
Gamma Glutamyl Transferase
HRQoL
Health-Related Quality of Life
ICF
Informed Consent Form
INR
Prothrombin International Normalized Ratio
IVRS
Interactive Voice Response System
LLQ
Lower Limit of Quantification
MedDRA
Medical Dictionary for Regulatory Activities 
NTT
No-Teduglutide Treatment
NTx
No-Teduglutide Period x
PedsQL
Pediatric Quality of Life
PS
Parenteral Support 
PT
Preferred Term 
Px
Pre-Treatment Visit x
QD
Once Daily
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan 
SBS
Short Bowel Syndrome 
SC
Subcutaneous
SOC
System Organ Class
SRN
All Subjects Screened
TEAE
Treatment-Emergent Adverse Event
TED
Teduglutide
TESAE
Treatment-Emergent Serious Adverse Event
TFLs
Tables, Figures and Listings
ULQ
Upper Limit of Quantification
WHODD
Who Drug Dictionary
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 10 of 48
2. INTRODUCTION
This document describes the rules and conventions to be used in the presentation and 
analysis of prospective data for Protocol SHP633-304. It describes the data to be summarized 
and analyzed, including specifics of the statistical analyses to be performed.
This statistical analysis plan (SAP) version 1.1 was based on protocol amendment 2, dated 23 
March 2017. The updated version 2.0 was based on protocol amendment 4, dated 01 Oct 
2019.
3. STUDY OBJECTIVES
3.1.
PRIMARY OBJECTIVE
The primary objective of the study is to evaluate the long-term safety and tolerability of 
teduglutide treatment in pediatric subjects with Short Bowel Syndrome (SBS) who completed 
TED-C14-006 or SHP633-301.
3.2.
SECONDARY OBJECTIVE
The secondary objective of the study is to evaluate the long-term efficacy of teduglutide 
treatment in pediatric subjects with SBS who completed TED-C14-006 or SHP633-301.
4. STUDY DESIGN
4.1.
GENERAL DESCRIPTION
This is a Phase 3, prospective, open-label, long-term extension study to evaluate the safety 
and efficacy of teduglutide in pediatric subjects who completed the TED-C14-006 or SHP633-
301 studies (the “core studies”). 
At the time of entry into the TED-C14-006 study, subjects were less than 18 years of age, were 
dependent on parenteral nutrition to provide at least 30% of their caloric or fluid needs, and 
had not been able to significantly reduce parenteral support (PS) for at least 3 months prior to 
enrollment. During TED-C14-006, some subjects elected to receive standard of care instead of 
teduglutide treatment. Subjects who elected to receive teduglutide were randomized to 0.025 
mg/kg or 0.05 mg/kg once daily (QD) dosing in a double-blinded manner. 
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 11 of 48
At the time of entry into SHP633-301, subjects were 4 to 12 months corrected gestational age, 
were dependent on parenteral nutrition to provide at least 35% of their caloric or fluid needs, 
and had not been able to significantly reduce PS for at least 1 month prior to enrollment. During 
SHP633-301, subjects were randomized to receive standard of care or teduglutide 0.05 mg/kg 
SC QD. 
The TED-C14-006 and SHP633-301 studies will also be referred to as the core studies
interchangeably throughout this analysis plan.
Approximately 65 subjects who complete the core studies are expected to enroll in this 
extension study. All subjects who completed either core study, including those who received 
standard of care, may be eligible to enter SHP633-304. To be eligible to receive teduglutide 
treatment within SHP633-304, subjects must meet ≥1 of the teduglutide treatment inclusion 
criteria and none of the teduglutide treatment exclusion criteria. 
Subjects not receiving teduglutide treatment (i.e., in a no-teduglutide treatment [NTT] 
period), will be seen approximately every 12 weeks for safety, PS requirements, and quality of 
life. The first NTx visit following the screening visit should occur within 2 to 12 weeks of 
screening. At any point after screening or during a NTT period, subjects who meet at least one 
teduglutide treatment inclusion criteria, may proceed immediately to the pre-treatment visit 
if the investigator, subject, and parent agree to proceed with teduglutide therapy. 
After the pre-treatment visit, subjects who meet at least one of the teduglutide treatment 
inclusion criteria, and meet none of the teduglutide treatment exclusion criteria, will start a 
28-week cycle, consisting of 24 weeks of teduglutide treatment at 0.05 mg/kg SC QD, followed 
by a 4-week follow-up period (during which no teduglutide is administered). During the 28-
week cycle, clinic visits will occur at weeks 1, 2, 4, 6, 9, 12, 16, 20, 24, and 28. Phone visits are 
required approximately 1 week after adjustments in PS during the teduglutide treatment 
period (between weeks 1 and 24), and weekly during the teduglutide follow-up period 
(between weeks 24 and 28). Safety and PS requirements will be evaluated at every visit, and 
quality of life assessments will be made approximately every 12 weeks. If a subject has clinical 
deterioration and meets follow-up period escape criteria after stopping teduglutide, the 
subject may "escape" the follow-up period early and proceed immediately to another pre-
treatment visit. Following completion of the 28-week treatment cycle, the subject will 
proceed to an NTT visit within approximately 12 weeks.
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 12 of 48
Table A:
Study Design Flow Chart
4.2.
SCHEDULE OF EVENTS
Schedule of events for prospective data collection can be found in Table 1-1, Table 1-2, Table 
1-3 and Section 7.1 of the protocol. 
4.3.
CHANGES TO ANALYSIS FROM PROTOCOL
There is no change of analysis from the protocol. 
5. PLANNED ANALYSES
The following analyses will be performed for this study:

Interim Analysis of Prospective Data

Final Analysis
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 13 of 48
5.1.
INTERIM ANALYSIS OF PROSPECTIVE DATA
An interim analysis is planned to complete the requirements for sNDA submission and the 
determination of extension of orphan drug exclusivity according to the pediatric written 
request.
Derivations and definitions for the interim analysis will be based on those required for the 
final analysis contained in this analysis plan, unless deviations are stated within the text. The 
list of outputs provided with the full set of output templates (planned for the final analysis) 
will highlight which of these outputs will also be provided for the interim analysis. 
5.2.
FINAL ANALYSIS
All final, planned analyses identified in this SAP will be performed with sponsor authorization 
of this statistical analysis plan and analysis sets. The final analyses will be performed following 
the sponsor-authorized SAP and analysis sets for the clinical study report.
6. ANALYSIS SETS
Analysis of efficacy and safety endpoints will be performed based on the analysis sets defined 
in this section and as specified for each endpoint throughout this SAP. 
Subjects will be classified in treatment groups based on whether they received teduglutide in 
the core studies TED-C14-006 (as either 0.025 mg/kg or 0.05 mg/kg) or SHP633-301 (as 0.05 
mg/kg) and/or during the prospective observation period in this study at the time of analysis:

NTT/NTT – subjects who participated in standard of care arm in the core study and did 
not receive any teduglutide treatment in the extension study;

NTT/TED – subjects who participated in the standard of care arm in the core study but 
who subsequently received teduglutide in the extension study;

TED/NTT – subjects who took teduglutide in the core study but did not receive any 
teduglutide treatment in the extension study;

TED/TED – subjects who received teduglutide in the core study and in the extension 
study;

ANY TED – subjects who received teduglutide in either the core study or in the 
extension study. 
For Teduglutide Treatment Period tables, only NTT/TED and TED/TED will be presented, and 
ANY TED will be presented for safety data.   
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 14 of 48
If a treatment group defined above doesn’t have any enrolled subjects at the time of analysis, 
that treatment group will be removed from the tables.
6.1.
ALL SUBJECTS SCREENED [SRN] SET 
The all subjects screened (SRN) set will contain all subjects who provide signed informed 
consent for the study.
Data for subjects who fail to meet study inclusion eligibility criteria will be included in the 
listings but will not be included in any analyses.
6.2.
SAFETY POPULATION
The safety population will contain all subjects in the SRN set who meet all of the inclusion 
criteria. Unless specified, the safety population will be used for both safety and efficacy 
analyses.
7. GENERAL CONSIDERATIONS
7.1.
REFERENCE START DATE AND STUDY DAY
Study Day will be calculated from the reference start date, and will be used to show start/stop 
day of assessments and events. 
Reference start date is defined as the baseline visit date of TED-C14-006 or SHP633-301 (Day 
1). Study days before the reference start date will be negative. 
If the date of the event is on or after the reference start date then: 
                Study Day = (date of event – reference start date) + 1.
If the date of the event is prior to the reference start date then: 
                Study Day = (date of event – reference start date).
In the situation where the event date is partial or missing, the date will appear partial or 
missing in the listings, and Study Day will be missing.
7.2.
BASELINE
The baseline is defined as the last non-missing measurement on or prior to the treatment in 
the core studies TED-C14-006 or SHP633-301 or in the 304 study. 
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 15 of 48
NTT/NTT
NTT/TED
TED/NTT
TED/TED
Any TED
Efficacy
006 or 301 BL
Prior to 
treatment in 304
006 or 301 BL
006 or 301 BL NA 
Demographics
006 or 301 BL
006 or 301 BL
006 or 301 BL
006 or 301 BL 006 or 301 BL
Growth and Labs 006 or 301 BL
Prior to 
treatment in 304 
006 or 301 BL
006 or 301 BL Prior to treatment
in 304 or 006/301
Quality of Life 
(collected only in 
extension study)
First reported C1D1 
First reported
C1D1 
7.3.
RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION DATA
In general, for by-visit summaries, data recorded at the nominal visit will be presented. 
Unscheduled measurements will not be included in by-visit summaries, but can contribute to 
the best/worst case value where applicable. Unscheduled PS prescription adjustments carry 
forward until the next adjustment, and as such, may be assigned to subsequent visits.
Listings will include scheduled, unscheduled, retest and early discontinuation data.
7.4.
STUDY VISIT CONVENTIONS
Visits will be summarized and displayed by pretreatment visit (if applicable), or, by cycle and 
weeks for teduglutide treatment periods, or, by no-teduglutide treatment visit NTx for NTT 
periods. For each teduglutide treatment period, Cycle x Day 1, Cycle x Week 1, …, Cycle x 
Week 24, Cycle x Week 25 Follow-up, Cycle x Week 26 Follow-up, Cycle x Week 27 Follow-up 
and Cycle x Week 28 data will be collected according to the schedule of events. For each NTT 
period, NTx data will be collected. Teduglutide treatment periods and NTT period data will be 
presented in separately.
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 16 of 48
7.5.
WINDOWING CONVENTIONS 
For teduglutide treatment period, nominal visits will occur within two days of the scheduled 
week 1, 2, 4 and 6 visits, within four days of the scheduled week 9, 12, 16, 20, to week 24 
visits and within two days of the follow-up visits week 25 to week 28. For NTT period, nominal 
visits will occur within seven days of the scheduled 12-week intervals. There will be no 
windowing of scheduled visits based on study day, and unscheduled visits will not be included 
in by-visit summaries. Early termination data and end of treatment visits in a teduglutide 
treatment cycle will be mapped to a scheduled visit if it falls into the appropriate visit window 
as defined in the protocol and if that scheduled visit did not occur. 
7.6.
STATISTICAL TESTS
Due to the limited sample size, descriptive statistics will be used with a goal of summarizing 
the sample. As such, no claims of significance will be made for any of the data. 
Continuous variables, including those assessed on a discrete scale, will be summarized using 
descriptive statistics including number of subjects, mean, median, standard deviation, 
maximum, and minimum. For efficacy continuous variables, the following will also be 
described standard error, quartile 1 and 3.  For categorical variables, statistical summaries will 
include number of subjects and percentages. 
7.7.
COMMON CALCULATIONS
For quantitative measurements, change from baseline will be calculated as:
Test Value at Visit X – Baseline Value
Percent change from baseline will be calculated as:
(Test Value at Visit X – Baseline Value) / Baseline Value *100
Change (or percent change) from baseline tables will be calculated based on the number of 
subjects in the treatment group with a non-missing value at baseline and at the time point 
being analyzed. 
7.8.
SOFTWARE VERSION
All analyses will be conducted using SAS version 9.4 or higher. 
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 17 of 48
8. STATISTICAL CONSIDERATIONS
8.1.
ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE INCLUDED IN ANALYSES
No adjustments for covariates are planned for the statistical analyses. 
8.2.
MULTICENTER STUDIES
This study will be conducted by multiple investigators at multiple centers internationally. 
8.3.
MISSING DATA
Missing data will in general not be imputed. However, partial dates will contribute to the 
analysis as described in Appendix 2. All available data will be included in the safety analysis.
Details for the imputation algorithm for the missing endpoint values for PS parameters 
(volume, calories and etc.) will be described in Section 16.1.1 of this analysis plan. 
8.4.
MULTIPLE COMPARISONS/ MULTIPLICITY
Given the small sample size, no hypothesis testing will be conducted. Therefore, there will be 
no adjustment for alpha level. 
8.5.
EXAMINATION OF SUBGROUPS
No subgroup analysis will be performed.
9. OUTPUT PRESENTATIONS
APPENDIX 1 shows conventions for presentation of data in outputs. The output templates 
provided together with this SAP describe the presentations for the analyses of this study. The 
format and content of the summary tables, figures and listings (TFLs) will be produced.
10.
DISPOSITION AND WITHDRAWALS
All subjects who provide informed consent in the extension study will be accounted for in the 
analyses. After signed consent (and informed assent, if applicable), a subject will be 
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 18 of 48
considered enrolled in the study if the subject meets all of the inclusion criteria at the 
screening. Teduglutide treatment eligibility does not impact study eligibility. 
If the investigational product is discontinued prematurely during a teduglutide treatment 
cycle and the subject wishes to remain in the study, the evaluations listed for the EOT visit are 
to be performed. A 4-week follow-up period will ensue, consisting of weekly telephone visits 
(CxW25-27) and the week 28 clinic visit (CxW28). The subject would then enter a NTT period 
and could be evaluated for subsequent teduglutide treatment eligibility according to the study 
schedules. The reason for permanent treatment discontinuation will be captured.
The reason(s) for permanent discontinuation of treatment and/or withdrawal from the study 
must be determined by the investigator, and recorded in the subject’s medical record and in 
the electronic case report form (eCRF). If a subject is withdrawn for more than one reason, 
each reason should be documented in the source document, and the most clinically relevant 
reason should be entered in the eCRF. Overall reasons for discontinuation of treatment and 
withdrawal from study will be summarized separately based on the following categories:

Adverse event

Protocol deviation

Lack of efficacy

Physician decision

Withdrawal by subject

Withdrawal by parent/guardian

Lost to follow-up

Pregnancy

Death

Other
The ongoing subjects will be counted in the table for interim analysis. 
Protocol deviations as obtained from a clinical trial management system (CTMS) will be 
assessed throughout the study. All identified deviations will be reported in the CTMS. Protocol 
deviations from the CTMS will be coded to categories and provided as part of the CTMS 
transfer to Biostatistics. Shire will review the protocol deviation tracker.
A protocol deviation is defined as a deviation from protocol-related procedures that could affect 
integrity of the data or adversely affect subjects. Protocol deviation categories from CTMS 
include:
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 19 of 48
1. Informed Consent Criteria
2. Eligibility and Entry Criteria
3. Concomitant Medication Criteria
4. Laboratory Assessment Criteria
5. Study Procedures Criteria
6. Serious Adverse Event Criteria
7. Randomization Criteria (Not applicable to this study)
8. Visit Schedule Criteria
9. Investigational Product Compliance
10. Efficacy Criteria
11. Administrative Criteria
12. Source Document Criteria
13. Regulatory or Ethics Approvals Criteria
14. Other Criteria
The presentation of planned listings will include the following:

Subject disposition (SRN set)

Study Inclusion criteria violations (SRN set)

Treatment Eligibility Criteria 

Follow-up Period Escape Criteria

Protocol deviations
The following summary tables are planned for presentation:

Subject disposition (SRN set) 

protocol deviations 
11.
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Demographic data and other baseline characteristics will be presented.
The following demographic and other baseline characteristics will be summarized:

Age (years) at baseline of TED-C14-006 or SHP633-301
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 20 of 48

Age Group – Age is categorized in pre-defined groups: <1, 1 to <12, 12 to <17, 17 to 18.

Sex (if female, the reproductive status will be reported)

Race 

Ethnicity

Weight Z-score at baseline of TED-C14-006 or SHP633-301

Height Z-score at baseline of TED-C14-006 or SHP633-301

Body Mass Index (BMI) Z-score at baseline of TED-C14-006 or SHP633-301

Head Circumference Z-score at Baseline (only for subjects who are <= 36 months of 
age) of TED-C14-006 or SHP633-301
The demographic data collected in the eCRF will be listed by subject.
11.1.
DERIVATIONS

BMI (kg/ m2) = 10000*weight (kg)/ height (cm)2

Z-score of weight, height, BMI and head circumference will be calculated based on the 
method described in Section 18.7.1.
12.
MEDICAL HISTORY
Medical history will be presented for the safety population.
12.1.
MEDICAL AND SURGICAL HISTORY
Medical and Surgical History will supplement the medical history information collected at the 
start of the TED-C14-006 or SHP633-301 core studies and will consist of the following:

Adverse events that were ongoing at the time of completion of TED-C14-006 or 
SHP633-301

Events that occurred during the period between completion of TED-C14-006 or 
SHP633-301 and informed consent to SHP-633-304

Updates to previously reported medical history
Medical and Surgical History will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA). Data captured on the Medical and Surgical History page of the CRF will be 
presented by System Organ Class (SOC) and Preferred Term (PT). SOC will be sorted 
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 21 of 48
alphabetically and PT within SOC will be sorted by descending incidence in the any teduglutide 
(ANY TED) treatment group. 
12.2.
SHORT BOWEL SYNDROME HISTORY
If the subject has any changes to the SBS history collected at the baseline visit of the TED-C14-
006 or SHP633-301 study, that information (updated SBS history) will be collected. The data at 
the baseline visit of the TED-C14-006 or SHP633-301 will be used if there is no update for the 
enrolled subjects in the extension study.
The following SBS History will be summarized:

Primary reason for the diagnosis of SBS 

Presence of stoma; if Y, stoma type 

Presence any remaining colon; if Y, estimated percent colon remaining and whether 
the colon is in continuity 

Total estimated remaining small intestinal length

Presence of distal/terminal ileum and ileocecal valve 
Date of first major surgical resection, date of last major surgical resection, the secondary 
reason for the diagnosis for SBS, date of diagnosis of SBS and method of determination for 
length of remaining anatomy will be presented in the listing only.
13.
CONCOMITANT TREATMENTS
Medications and procedures will be presented for the safety population.
Concomitant treatments are defined as all treatments taken between the dates of informed 
consent for the SHP633-304 extension study and end of study (EOS), inclusive. Concomitant 
treatments include all non-study treatments (medications, herbal treatments, vitamins, 
invasive and diagnostic procedures). Concomitant treatment information will be recorded on 
the Prior and Concomitant Medications and Diagnostic/Surgical/Therapeutic Procedures eCRF 
pages.
13.1.
CONCOMITANT MEDICATIONS
Medications will be coded to preferred name using WHO Drug Dictionary (WHODD). 
Concomitant medication use will be summarized by preferred name using the number and 
percentage of subjects by treatment group. Medications will be sorted alphabetically by 
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 22 of 48
preferred name. Subjects with multiple occurrences of a medication in preferred name will 
only be counted once within each preferred name. Medication summaries will be presented 
by treatment group for the safety population.
Listings of all medications will be presented. 
13.2.
DIAGNOSTIC, SURGICAL, OR THERAPEUTIC PROCEDURES 
The diagnostic, surgical, or therapeutic procedures during the study are recorded in the eCRF 
and will only be presented in a listing.
14.
STUDY DRUG EXPOSURE
The total extent of exposure is defined as the number of days on teduglutide during the core 
study and prospective observation period combined. Exposure summary will be presented by 
treatment group (TED/TED, NTT/TED and ANY TED only) as a numeric variable. It will also be 
categorized and presented in pre-defined groups by 6 weeks intervals: 0 – < 6, 6 - <12, etc.. .
The overall number of cycles on teduglutide will also be summarized as a numeric variable. 
Finally, the number of days on teduglutide for each cycle will be summarized.
14.1.
DERIVATIONS
The extent of exposure in days will be calculated as:
Extent of exposure in Extension study (weeks) 
= [the sum of the durations of all the teduglutide treatment periods where the 
individual duration is calculated by (the last dose date of the treatment cycle X – Cycle 
X Day 1 + 1)] / 7.
Total exposure (Core+Extension) (weeks) 
= [the sum of the durations of all the teduglutide treatment periods in weeks] and 
Core extent of exposure in weeks.
The extent of observation will be calculated as:
Extent of observation = (end of study visit – informed consent date of 304)/7.
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 23 of 48
15.
STUDY DRUG COMPLIANCE 
Study drug administration diary data will be used to measure study drug compliance. Only 
diary entries with “Yes” in response to the question “Was the study drug administered per 
instructions today?” will be deemed compliant days.
Subjects will be considered compliant overall for study drug administration if the calculated 
overall compliance is >= 80%. Overall and by-cycle treatment compliance will be presented for 
percent compliance calculations using descriptive statistics and the number and percentage of 
subjects entering the timeframe who are >= 80% compliant by treatment group for the safety 
population. 
15.1.
DERIVATIONS
For each treatment cycle, compliance will be calculated as the number of doses administered 
divided by the planned number of doses expressed as a percentage. This can be summarized 
as:
Percent compliance = (Total number of diary days marked “Yes” for study drug 
administration / Number of days on treatment) * 100 
where number of days on treatment within each cycle will be calculated as (the last dose date 
in the treatment cycle X -  the visit date of Cycle X Day 1 +1) and dose interruption days will 
not be excluded.
16.
EFFICACY OUTCOMES
Efficacy endpoints for PS will be analyzed at the end of each teduglutide treatment period 
(Week 24 or EOT), and at each study visit, relative to the baseline of the core study (TED-C14-
006 or SHP633-301) and/or first exposure to teduglutide. The last period of the last cycle for 
each patient will also be summarized.
The efficacy analyses will be performed on PS diary data and PS prescribed data for safety 
population. The descriptive statistics of efficacy outcomes will be summarized by treatment 
group as defined in Section 6. The listings for efficacy measures which are collected on the 
CRF forms will be provided.
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 24 of 48
16.1.
EFFICACY ENDPOINTS
EFFICACY VARIABLES & DERIVATIONS
The efficacy endpoints will be analyzed in two ways: 1) based on the subject diary data (also 
referred to as “actual”), and 2) based on the investigator-prescribed data (referred to as 
“prescribed”). PS will be reported in both subject diary data and the investigator-prescribed 
data in the eCRF. Investigator-prescribed data are the most recent PS prescription 
(prescription adjustments) prior to or on the date of visit, captured in the PS adjustments 
eCRFs. Data collected include prescribed weekly total kilocalories, volume, number of days per 
week, and average hours per day. PS diary data are collected 2 weeks prior to all scheduled 
site visits (except at pre-treatment visit) in the Intake Diary eCRFs over 24-hour periods that 
start on the assigned date. Depending on the time of day at which the 24 hour period begins, 
which can vary by subject, overnight PS volumes after midnight may be associated with the 
prior date. Data collected include actual PS total infusion duration, total volume and total 
kilocalories on the assigned date.
For subject who received teduglutide treatment in core studies, the baseline from core values 
will be used, otherwise efficacy baseline will be derived from 304 data.
Data will also be presented separately for teduglutide treatment cycles and no treatment 
periods. 
The calculation of average daily prescribed PS volume/caloric intake normalized to weight will 
follow the formula below:
Average daily value = (prescribed weekly PS parameter / 7) / last available weight prior 
to or on the date of visit.
The calculation of average daily actual PS will be based on the daily support recorded in 
subjects’ diaries within 7 days prior to the date of each scheduled visit. If more than 2 days’ 
values in a week are missing, the average daily value will not be calculated and will be 
assigned as missing. The same strategy will be used to calculate all other average diary 
parameters. The calculation of actual PS volume normalized to weight will follow the formula 
below:
Average daily value = [(sum of non-missing daily values in the diary / number of days 
with non-missing values)] / last available body weight prior to the visit
Baseline actual PS will be calculated using all the diary data collected within 14 days prior to 
the first dose or baseline visit of the core study. If more than 5 days’ values in two weeks 
before the baseline visit the core study are missing, the baseline value will not be calculated.
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 25 of 48
16.1.1.1. ≥ 20%, 50%, and 75% Reduction in PS volume 
PS volume reduction at the end of each teduglutide treatment period (Week 24 or EOT) and at 
all other study scheduled visits compared to the baseline [See Section 7.2 for baseline 
description]will be calculated using average daily values. The number and percentage of 
subjects who achieve at least a 20%, 50%, and 75% reduction in PS volume (mg/kg/day) at the 
end of each teduglutide treatment period and each NT visit will be summarized. This 
parameter will be summarized for both actual and prescribed data.
16.1.1.2. Change and percent change from baseline in PS volume and intake calories
Changes and percent change in prescribed and actual PS volume and calories from baseline to 
all the study visits will be calculated following common calculations in Section 7.7 [See Section 
7.2 for baseline description]. These parameters will be summarized for both actual and 
prescribed data.
16.1.1.3. Complete weaning off PS
A subject will be considered to have achieved independence from PS (completely weaned off 
PS) at a given visit if the investigator prescribes no PS at that visit and there is no use of PS 
recorded in the subject diary during the week prior to that visit. 
The analysis will summarize how many subjects achieve complete weaning off PS at the end of 
each teduglutide treatment period (Week 24 or EOT). 
16.1.1.4. Change and percent change from baseline in hours per day and days per week of 
PS 
Change and percent change in hours per day and days per week of PS from baseline to each 
study visit will be summarized.
Hours per day of actual PS for all visits except the baseline visit will be calculated as follows: 
Hours per day of actual PS 
= (sum of hours per day for each day that PS intake data is recorded within the 7 days 
prior to the visit / number of days that PS hours per day data is recorded as non-zero
within the 7 days prior to the visit)
Hours per non-zero day of actual PS for all visits will be calculated as sensitivity analysis: 
Hours per Non-zero day of actual PS 
= (sum of hours per day for each day that PS intake data is recorded as non-zero within 
the 7 days prior to the visit / number of days that PS hours per day data is recorded as 
non-zero within the 7 days prior to the visit)
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 26 of 48
Days per week of actual PS for all visits except the baseline visit will be calculated as follows: 
Days per week of actual PS = (number of days with non-zero values for PS volume 
within the 7 days prior to the visit / number of days for which any PS intake data is 
recorded within the 7 days prior to the visit) * 7 
Prescribed PS hours per day and days per week for each visit (including baseline) will be taken 
from the most recent prescription data prior to or at that visit.
The change and percent change in hours per day and days per week of PS will be summarized by ≥ 
20%, ≥ 50%, and ≥ 75% reduction in PS volume.
ANALYSES OF EFFICACY VARIABLES
For the variables of pre-specified percent reduction in PS volume, the number and percentage 
of subjects will be presented by treatment group for treatment cycles and NTT periods. 
Baseline values, post-baseline values, change from baseline and percent change from the 
baseline in PS will be summarized by study visit and treatment group using descriptive 
statistics including number of subjects, mean, standard deviation, median, minimum and 
maximum. 
17.
HEALTH-RELATED QUALITY OF LIFE ANALYSIS
Throughout the study, health-related quality of life (HRQoL) assessments will be performed 
using the Pediatric Quality of Life (PedsQL) Generic Core Scales at the time points CxD1, CxD12 
and CxD24 for treatment period, at 12-week intervals for NTx and at EOS. 
The scales include self-reports for pediatric subjects and adolescents aged 5 to 18 years and 
proxy-reports from parents of pediatric subjects aged 2 to 18 years. 
Subscale scores and summary scores will be computed separately based on subject self-report 
and parent report.
The baseline is defined as the assessment collected during the subject’s first study period, 
either at the visit of Cycle 1 Day 1 for the treatment period or the assessment at the visit of 
first 12-week interval for the no-treatment period, as appropriate.
The HRQoL will not be included in the interim analysis.
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 27 of 48
17.1.
PEDIATRIC QUALITY OF LIFE GENERIC CORE SCALE (PEDSQL™), ACUTE VERSION
The PedsQL Generic Core Scale is designed to measures health-related quality of life (HRQoL) 
in pediatric subjects and adolescents (2-18 years of age). The developmentally appropriate 
PedsQL Generic Core Scale will be completed by either the parent or legal guardian and 
subject at the time points.
The Parent Report for Toddlers (ages 2-4) of the PedsQL Generic Core Scale is composed of 21 
items comprising 4 dimensions as follows: 1) Physical Functioning (8 items), 2) Emotional 
Functioning (5 items), 3) Social Functioning (5 items), 4) School Functioning (3 items).
The Child and Parent Reports of the PedsQL Generic Core Scale for Young Pediatric subjects 
(ages 5-7), Pediatric subjects (ages 8-12), and Teens (ages 13-18) are composed of 23 items 
comprising 4 dimensions as follows: 1) Physical Functioning (8 items), 2) Emotional 
Functioning (5 items), 3) Social Functioning (5 items), 4) School Functioning (5 items).
VARIABLES & DERIVATIONS
Items are collected as either a 5-point Likert scale [from 0 (Never) to 4 (Almost always)] or 3-
point scale [0 (Not at all), 2 (Sometimes) and 4 (A lot)] are transformed on a scale from 0 to 
100. Items are reversed scored and linearly transformed to a 0-100 scale as follows: 0=100, 
1=75, 2=50, 3=25, and 4=0. If more than 50% of the items in the defined subscale are missing, 
the corresponding subscale score should not be computed. If 50% or more items are 
completed, impute the mean of the completed items in a defined subscale, where mean is 
calculated as the sum of the items over the number of items answered. If any subscale score is 
missing in the summary score calculation, the summary score will be missing.

Subscale Scores
Physical Functioning 
Emotional Functioning 
Social Functioning 
School Functioning 

Summary Scores 
Psychosocial Health Summary Score - Sum of the items over the number of items 
answered in the Emotional, Social, and School Functioning Subscales
Physical Health Summary Score - Physical Functioning Subscale Score
Total Scores - Sum of all the items over the number of items answered on all the 
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 28 of 48
subscales
17.2.
PEDIATRIC QUALITY OF LIFE FAMILY IMPACT MODULE (PEDSQL™), ACUTE 
VERSION
The PedsQL Family Impact Module is a parent-report multidimensional instrument that will be 
completed by the parent or legal guardian. The PedsQL Family Impact Module is a specific 
module of the PedsQL that is used to measure the impact of pediatric chronic health 
conditions on parents and the family. The 36-item PedsQL Family Impact Module consists of 6 
scales measuring parent self-reported functioning as follows: 1) Physical Functioning (6 items),
2) Emotional Functioning (5 items), 3) Social Functioning (4 items), 4) Cognitive Functioning (5 
items; worries about treatment and disease), 5) Communication (3 items), 6) Worry (5 items). 
Two additional scales measure parent reported family functioning as follows: 1) Daily 
Activities (3 items), and 2) Family Relationships (5 items). 
VARIABLES & DERIVATIONS
Items are collected as a 5-point Likert scale from 0 (Never) to 4 (Almost always) which are 
transformed on a scale from 0 to 100. Items are reversed scored and linearly transformed to a 
0-100 scale as follows: 0=100, 1=75, 2=50, 3=25, and 4=0. If more than 50% of the items in the 
defined subscale are missing, the corresponding subscale score should not be computed. If 
50% or more items are completed, impute the mean of the completed items in a defined 
subscale, where mean is calculated as the sum of the items over the number of items 
answered. If any subscale score is missing in the summary score calculation, the summary 
score will be missing.

Subscale Scores
Physical Functioning
Emotional Functioning
Social Functioning 
Cognitive Functioning
Communication
Worry
Daily Activities
Family Relationships

Summary Scores 
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 29 of 48
Parent HRQL Summary Score - Sum of the items divided by the number of items 
answered in the Physical, Emotional, Social, and Cognitive Functioning subscales
Family Functioning Summary Score - Sum of the items divided by the number of
items answered in the Daily Activities and Family Relationships subscales
Total Scores - Sum of all the items over the number of items answered on all the 
subscales
17.3.
PEDSQL GASTROINTESTINAL SYMPTOMS MODULE (PEDSQL™), ACUTE VERSION
The PedsQL Gastrointestinal Symptom Module is a disease-specific 58-item module, 
comprised of 10 different symptom scales that assess gastrointestinal symptom-related 
quality of life. Only the scales of Food and Drink Limits (6 items) and Diarrhea (7 items) will be 
collected in this study. The scales will be completed by either the parent or legal guardian and 
subject. 
VARIABLES & DERIVATIONS
Items are collected as a 5-point Likert scale from 0 (Never) to 4 (Almost always) that are 
transformed to a 0 to 100 scale. Items are reversed scored and linearly transformed to a 0-100 
scale as follows: 0=100, 1=75, 2=50, 3=25, and 4=0. If more than 50% of the items in the scale 
are missing, the corresponding scale score should not be computed. If 50% or more items are 
completed, impute the mean of the completed items in a scale, where mean is calculated as 
the sum of the items over the number of items answered. 

Symptoms Total Scales Score
Food and Drink Limits Scale Score 
Diarrhea Scale Score 
17.4.
MISSING DATA METHODS 
Missing item scales will not be imputed. The subscale scores and the total scores will be set to 
missing if more than 50% of the items in the scale are missing in the scale.
17.5.
ANALYSIS OF HRQOL VARIABLES
Total scores, subscale scores and summary scores will be summarized by study visit and 
treatment group using descriptive statistics including number of subjects, mean, standard 
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 30 of 48
deviation, median, minimum and maximum. Change from baseline by visit will be 
summarized, with subjects excluded from change from baseline summaries at the visit 
associated with the subject’s baseline measurement.
18.
SAFETY OUTCOMES
There will be no statistical comparisons between the treatment groups for safety data. 
18.1.
ADVERSE EVENTS
Adverse Events collected during the prospective observation period will be coded using 
Medical Dictionary for Regulatory Activities (MedDRA) central coding dictionary.  
Investigator verbatim as well as preferred terms and system organ classes will be included in 
the listings. 
Treatment-emergent adverse events (TEAEs) are defined as adverse events that started or 
worsened on or after the date of first dose of teduglutide in either the core study or the 
extension study for treatment groups TED/TED, TED/NTT, NTT/TED and ANY TED and adverse 
events that started or worsened on or after the baseline visit of the core study for NTT/NTT.  
Adverse Events will be summarized in 3 categories: Overall, Prior Teduglutide, and After 
Teduglutide. 
For events that start or worsen on the date of first dose, any available start time will be 
compared to the time of first dose for the treated subjects.
See APPENDIX 2 for handling of partial dates for AEs. In the case where it is not possible to 
define an AE as treatment-emergent or not, the AE will be classified by the worst case; i.e. 
treatment-emergent. 
An overall summary of number of subjects within each of the categories described below will 
be provided as specified in the templates. Adverse events will be summarized using 
descriptive statistics (e.g., number and percentage of subjects). The number of events will also 
be presented except for summaries by highest category. The summary will include any TEAE, 
severity of TEAEs (highest category), investigator assessment of relationship of TEAEs to study 
drug, treatment-emergent serious AEs (TESAEs), investigator assessment of relationship of 
TESAEs to study drug, TEAEs leading to study drug discontinuations, TEAEs leading to study 
discontinuations and TEAEs leading to death. Adverse events will be tabled separately for 
teduglutide treatment cycles and no treatment periods according to AE start date. In addition, 
no treatment periods will be further subset as prior to any teduglutide exposure and following 
teduglutide exposure.
Listings will include both TEAEs and Non-TEAEs.  And, Listings will be provided for serious 
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 31 of 48
adverse events, adverse events leading to death, adverse events leading to discontinuation of 
study drug, adverse events leading to discontinuation of study and adverse events of special 
interest. Listings will indicate whether an AE is treatment emergent or not. Information for 
severe adverse events that are graded according to CTCAE criteria will only be presented in 
the listings. 
ALL TEAES 
Incidence of TEAEs will be presented by System Organ Class (SOC) and Preferred Term (PT) for 
all TEAEs, related TEAEs, TESAEs, and related TESAEs. Incidence will also be presented by SOC
and PT for severity and maximum severity. Summaries by SOC and PT will present SOC in 
alphabetical order and PT within the SOC in descending order of incidence in the any 
teduglutide (ANY TED) treatment group.
18.1.1.1. Severity
Severity is categorized as mild, moderate, or severe. Adverse events with a missing severity 
will be classified as severe. If a subject reports a TEAE more than once within that SOC/PT, 
summaries by severity will only provide the highest severity classification of the subject for 
the corresponding incidence summaries by SOC/PT.
18.1.1.2. Relationship to Teduglutide
Relationship, as indicated by the Investigator, is classed as “not related” or “related”. TEAEs 
with a missing relationship to teduglutide will be regarded as “related” to teduglutide. TEAE
summaries by relationship will exclude the NTT/NTT treatment group.
SERIOUS ADVERSE EVENTS
Serious adverse events (SAEs) are those events recorded as “Serious” on the Adverse Events 
Form of the eCRF. Any SAE that occurs from the time of the signing of the informed consent
form (ICF) for the SHP633-304 extension study through last study visit (EOS) will be captured. 
A summary of TESAEs by SOC and PT will be prepared, as well as summaries by event and 
causal relationship to study drugs. A listing of SAEs will be presented as well.
AES LEADING TO DISCONTINUATION OF STUDY DRUG
AEs leading to temporary or permanent discontinuation of study drug will be identified by the 
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 32 of 48
“Drug Withdrawn” response for action taken with study treatment in the Adverse Events 
Form of the eCRF. 
A listing will be provided for AEs leading to discontinuation of study drug. 
AES LEADING TO DISCONTINUATION OF STUDY 
AEs leading to permanent discontinuation of study will be identified by the “Yes” response for 
the question “Did this adverse event cause the subject to be discontinued from the study?” in 
the Adverse Events Form of the eCRF. 
A listing will be provided for AEs leading to permanent discontinuation of study. 
ADVERSE EVENTS LEADING TO DEATH
AEs leading to Death are those events which are recorded as “Fatal” on the Adverse Events 
Form of the eCRF. A listing of AEs leading to death will be presented.
ADVERSE EVENTS OF SPECIAL INTEREST
An AE of special interest is an AE (serious or nonserious) of scientific and medical concern 
specific to the sponsor’s product or program and for which ongoing monitoring and 
immediate notification by the investigator to the sponsor is required.
The AEs of special interest that require expedited regulatory reporting include the following:

Growth of pre-existing polyps of the colon

Benign neoplasia of the GI tract including the hepatobiliary system

Tumor-promoting ability (e.g., benign and/or malignant neoplasia of any kind, not 
limited to those of the GI or hepatobiliary system)
A review of preferred terms will be performed by a medical reviewer prior to interim and final 
analysis, with the identified events of special interest being documented prior to the analysis 
data transfer. The AEs of special interest will be presented in a listing.
18.2.
LABORATORY EVALUATIONS
Laboratory evaluations that are done at study site visits will be collected and processed via a 
central laboratory, including panels for Hematology, Clinical Chemistry, Coagulation and 
Urinalysis. During the teduglutide treatment period, subjects will also have safety labs within 
approximately 5-7 days after a PS adjustment. Laboratory evaluations that are required at 
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 33 of 48
intervals that do not coincide with study site visits may be obtained by a local laboratory. The 
local laboratory data will be collected on the local laboratory tests form of eCRF. Laboratory 
evaluations to be included in the tables or listings are presented in the lab test table (Table B) 
below.
Table B:
Laboratory Tests
Hematology
Chemistry
Coagulation
Urinalysis
Hemoglobin
Albumin
Prothrombin Time 
Ur Blood*
Hematocrit
Alkaline Phosphatase
Prothrombin 
International 
Normalized Ratio (INR)
Ur Glucose*
Platelets
Alanine 
Aminotransferase (ALT)
Ur Microscopic*
Erythrocytes
Aspartate 
Aminotransferase (AST)
Ur pH
RBC Morphology*
Amylase
Leukocytes
Lipase
Ur Protein
Neutrophils
Bicarbonate
Lymphocytes
Bilirubin
Ur Specific Gravity
Monocytes
Direct Bilirubin
Ur Leukocytes
Eosinophils
Indirect Bilirubin
Basophils
Blood Urea Nitrogen
Neutrophils/Leukocytes
Calcium
Lymphocytes/Leukocytes
Chloride
Monocytes/Leukocytes
Cholesterol
Eosinophils/Leukocytes
Creatinine
Basophils/Leukocytes
C Reactive Protein
Glomerular Filtration 
Rate (GFR) Schwartz 
formula
Glucose
Gamma Glutamyl 
Transferase (GGT)
Lipase
Magnesium
Phosphorus
Potassium
Sodium
Triglycerides
Uric Acid
Note: * lab tests with categorical results.
Lab data will be presented in SI units. The summaries will be based on central lab results only.
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 34 of 48
Quantitative laboratory measurements reported as “< X”, i.e. below the lower limit of 
quantification (LLQ), or “> X”, i.e. above the upper limit of quantification (ULQ), will be 
converted to X for the purpose of quantitative summaries, but will be presented as recorded, 
i.e. as “< X” or “> X” in the listings.
The following summaries will be provided for hematology, clinical chemistry and selected 
urinalysis laboratory data with quantitative results:

Actual and change from baseline at Cycle x Day 1, Cycle x Week 12, Cycle x Week 24, 
each NTx visit and End of Study 

Shift from baseline according to normal range criteria at Cycle x Day 1, Cycle x Week 
12, Cycle x Week 24, each NTx visit, and End of Study

Incidence of markedly abnormal values according to criteria defined in section 
APPENDIX 3

Listing of subjects meeting markedly abnormal criteria

Change from baseline will not be calculated for lab values with drastically different 
normal ranges between core and extension.
LABORATORY REFERENCE RANGES AND MARKEDLY ABNORMAL CRITERIA
Quantitative laboratory measurements will be compared with the relevant laboratory 
reference ranges in SI units and categorized as:

Low: Below the lower limit of the laboratory reference range. 

Normal: Within the laboratory reference range (upper and lower limit inclusive).

High: Above the upper limit of the laboratory reference range.
In addition to the high and low quantitative laboratory assignments (as identified by means of 
the laboratory reference ranges), markedly abnormal quantitative safety (and other) 
laboratory assessments will also be identified in accordance with the predefined markedly 
abnormal criteria as presented in APPENDIX 3. 
The number and percentage of subjects whose post-baseline results qualify as markedly 
abnormal will be summarized by treatment group and the parameter. A listing will present all 
values for a subject and laboratory parameter if at least one post-baseline value for that 
subject and parameter is markedly abnormal.
Laboratory results will also be included in appendix data listings for each lab panel (chemistry, 
hematology, coagulation and urinalysis) by treatment, subject, visit and parameter. Values 
outside the normal range will be flagged. Local lab test results will only be presented in 
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 35 of 48
appendix data listings. Categorical test results, coagulation and pregnancy results (B-hCG, 
Qualitative and B-hCG, Quantitative) also will only be included in data listings. 
18.3.
PREGNANCY TESTING
A serum pregnancy test is performed on all females of childbearing potential (FOCBP) at the 
teduglutide pre-treatment visit (when the pre-treatment and screening visits are combined, 
the serum pregnancy test should be performed at the local laboratory). Urine pregnancy tests 
will be administrated at all other visits according to the study schedules. The pregnancy test 
result (Positive, Negative) will be presented in a listing.
18.4.
ANTIBODIES TO TEDUGLUTIDE
Blood samples for antibodies will be drawn for all the teduglutide-exposed subjects. The 
sample drawn on CxD1 must be drawn prior to administration of the first dose of teduglutide. 
Once the subject has started teduglutide treatment (CxW12 and CxW24), samples must be 
drawn at least 14 hours after dosing. 
At each visit, all subjects will be assessed for a screening anti-drug antibodies test. For those 
subjects who test positive for screening anti-drug antibodies, a confirming anti-drug 
antibodies test will be given. Either screening or confirmed anti-drug antibodies test shows
negative result, antibodies to teduglutide is considered negative. If both tests show positive
result, antibodies to teduglutide is consider positive. Subjects who test positive for antibodies 
to teduglutide will also be tested for titer of anti-drug antibodies and neutralizing anti-drug 
antibodies. Subjects who have been previously treated with teduglutide, and who test positive 
for antibodies to teduglutide, will have follow-up blood draws for antibodies to teduglutide 
every 12 weeks while on study until a negative result is obtained.
The number and percent of subjects with an antibody finding (Antibodies to Teduglutide 
Negative/Positive, Neutralizing Antibodies Present/ No Neutralizing Antibodies Present) will 
be summarized at CxD1, CxW12, CxW24, CxW28, each NTx, and EOS. Non-specific antibodies 
will be categorized as Negative.
The follow-up antibody assessments after study completion will not be transferred from the 
lab vendor for any statistical analysis. 
18.5.
GASTROINTESTINAL-SPECIFIC TESTING
Fecal occult blood testing (FOBT) must be performed on all subjects at the pre-treatment visit 
(Px), CxW12, and CxW24 of the teduglutide cycle. During NTT periods, FOBT must be 
performed on teduglutide-exposed subjects (subjects who have received teduglutide any time 
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 36 of 48
in the past and are therefore not teduglutide-naïve) on a roughly annual basis (approximately 
every 48-60 weeks). The colonoscopy or sigmoidoscopy will be performed in response to 
positive FOBTs.
GI-specific testing will be summarized for the teduglutide treatment cycles only. The clinically 
significant abnormal results will be presented in a data listing. Fecal occult blood testing will 
be summarized as ‘Negative’, ‘Positive, not clinically significant’, ‘Positive, clinically 
significant’. The results of colonoscopy or sigmoidoscopy will be reported as ‘Normal’, 
‘Abnormal, not clinically significant’, or ‘Abnormal, clinically significant’. All FOBT, along with 
subsequent colonoscopy or sigmoidoscopy testing, will be presented in an appendix listing.
18.6.
PHYSICAL EXAMINATION 
Physical examination dates and reason that an examination was not done will be presented in 
data listings.  Any clinically significant findings for physical examination are recorded as 
adverse events. 
18.7.
VITAL SIGNS
The following vital signs measurements will be reported for this study:

Systolic Blood Pressure (mmHg)

Diastolic Blood Pressure (mmHg)

Pulse Rate (bpm)

Temperature (°C)

Weight (kg)

Height or length (cm) 

Head circumference (cm) for subjects ≤36 months of age
The following vital signs parameters will be derived for this study:

BMI (kg/m2)

Height Z-score

Weight Z-score

BMI Z-score

Head Circumference Z-score 
Descriptive statistics will be used to summarize vital signs measurements and derived BMI in 
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 37 of 48
actual value and change from baseline for each treatment group by age group (age 
stratification used for randomization in the core studies TED-C14-006 or SHP633-301: <1 year, 
1-<12 years, 12-<17 years and 17-<18 years and overall) at study site visits where associated 
parameters are collected. Z-scores of vital signs by site visits will also be summarized and 
presented in Mean ± SE Plot. A listing will also be provided.
VITAL SIGNS SPECIFIC DERIVATIONS 

BMI
BMI = 10000* Body weight (kg)/body height (cm)2, where both body weight and body 
height data are available at the same scheduled visit 

Height, Weight and BMI Z-scores
Official and validated SAS programs created by Centers for Disease Control and Prevention 
(CDC) will be used to calculate the Z-scores (standard deviations) for a child’s sex and age 
(up to 20 years of age) for BMI, weight, and height based on the CDC growth charts for 
children age 2 years and older and the WHO growth charts for infants and children < 2 
years 
of 
age. 
For 
more 
information 
on 
the 
CDC 
SAS 
programs, 
see 
http://www.cdc.gov/growthcharts/computer_programs.htm.
Z-scores are calculated as the formula below:
Z-score= [((observed value / M) ^ L) – 1] / (S * L)
In which ‘observed value’ is the child’s height, weight, head circumference or derived BMI. 
The L, M, and S values vary according to the child’s sex and age. For more information on 
the LMS method, see http://www.ncbi.nlm.nih.gov/pmc/articles/PMC27365/.
18.8.
FECAL AND URINE OUTPUT
Urine and stool output data is recorded over a 48 hour period of PS stability before every 
scheduled site visit and within 1 week of implementing any PS adjustment. 
The average daily urine output (mL/kg/day) at the scheduled site visit will be calculated as 
follows:
(Total urine output over 48 hours / 2) / body weight (kg) at the scheduled visit
where total urine output is calculated as the sum of the urine output in mL and the urine-only 
diaper weights in g (1g = 1mL) for the subject collected on the output diary form of eCRF. 
Values will not be calculated if the urine output is not available at the visit. If the body weight 
at the scheduled visit is missing, the last available weight assessment will be used. 
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 38 of 48
The average daily fecal output will be summarized separately by the average number of stools 
per day, the average typical stool form score using Bristol Stool Form Scale, the average total 
daily stool/mixed stool diaper weight (g/kg/day) and the average ostomy output per day 
(mL/kg/day) for each visit. The average number of stools per day and the average typical stool 
form score will be calculated as (sum of the daily data in a 48-hour period / 2). The body 
weight will be used to calculate the daily stool/mixed stool diaper weight (g/kg/day) and the 
total ostomy output per day (mL/kg/day) using the same formula as for the average daily 
urine output.
The change in average daily output for fecal and urine output from baseline to each scheduled 
visit of treatment periods, as well as at 12-week intervals of NTx, will be presented by 
treatment group using descriptive statistics. A listing will also be provided.
19.
DATA NOT SUMMARIZED OR PRESENTED
Any information not described will not appear in the interim analysis but may contribute to 
datasets that support listings for the final study report.
Other data collected in eCRF, Interactive Voice Response System (IVRS) or any other clinical 
trial data collection system which is not described above will be presented in the appendix 
listings.
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS

Statistics Presentation
For the by-time-point tables, the number of subjects at each timepoint (n) represents the 
number that had a valid result for a given parameter at that timepoint.
The default summary statistics presented in the table shells for continuous variables include n, 
mean, standard deviation, median, minimum, and maximum. For efficacy continuous 
variables, SE, Q1, Q3 will be added. For categorical variables, the count (n) and percent (%) 
are the default statistics; unless otherwise stated or the associated number of subjects for the 
corresponding time point is provided, the denominator for percentages is N (the number of 
subjects in the treatment group/analysis set).  Note that for any summary by subgroups (e.g., 
by sex), the denominator is the number of subjects in that subgroup/treatment group/analysis 
set.  For most safety tables the study teams should use the default statistics; the study team 
should carefully consider and give sufficient justification prior to requesting the use of other 
summary statistics.  Percentages will be reported to 1 decimal place, except when the 
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 39 of 48
percentage equals exactly 100 where it will be displayed as an integer (100).  For zero, only 
count and no percentage will be displayed.

Alignment
Output should be aligned so that in the body of the table, where applicable, text is left-
justified within a cell, stats output is aligned centrally within a cell and lined up by decimal 
point.
Handling of missing values:  In listings, missing values for numerical data will be reported as a 
period “.” and missing values for character data as a blank “ ”.  In the summary tables for 
categorical data, “Missing” will always be displayed as a category to represent missing data, 
where applicable. The default denominator will be all subjects in the analysis set unless 
otherwise specified in the SAP.  For both tables and listings where there are no observations 
(and hence there would be no output), the table/listing should be produced with all titles and 
footnotes as per its shell, but with the text showing no observations in the body of the output.

Decimal Places and Rounding Rules
o
For measures of median and mean, use 1 decimal place beyond those used for the 
measurement.
o
For measures of standard deviation and standard error, use 2 decimal places beyond 
those used for the measurement.
o
For measures of minimum and maximum values, use the same number of decimal 
places as those used for the measurement.
o
>=5 is rounded up away from zero, whereas <5 is rounded down toward zero to 
account for rounding of negative numbers.
o
BMI should be rounded to 1 decimal place for reporting.
o
Derived questionnaire scores, and other similar efficacy parameters recorded as 
integers, should be rounded to 1 decimal place for reporting.

Presentation of Treatment Groups
Tables will present NTT/NTT group first, followed by NTT/TED, TED/NTT and TED/TED. When 
required, a column for all subjects who exposed to teduglutide in core study in the extension 
study will be included and it will be labeled “ANY TED”. The subjects will be grouped based on 
the treatment they received in the core studies TED-C14-006 or SHP633-301 (teduglutide 
exposed and non-exposed) and prospective period (teduglutide exposed and non-exposed). 
For teduglutide treatment period tables, only NTT/TED and TED/TED will be presented. If the 
number of treatment groups dictates that not all can fit on 1 page, then, unless specified in 
the corresponding “General considerations”, it will be left to the discretion of the shell author, 
following discussions with study team, as to how these will be presented. For example, some 
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 40 of 48
of the treatment groups may be presented in a separate table. If the study is to be 
summarized by dose group rather than treatment group, then the nomenclature “Actual 
Dose” will be used in place of “Treatment Group” throughout. If presenting subgroups, 
TFL4Shire recommends that sub-headers are added so that a tabulation is repeated by 
subgroup (rather than adding extra columns in the table to show the subgroups). These 
should be ordered per the CRF decode e.g. 1=Male, 2=Female. 
APPENDIX 2.
PARTIAL DATE CONVENTIONS
Imputed dates will NOT be presented in the listings. The reference start date for adverse 
events (excluding those event entered as part of the medical history) will be the first 
tedugludtide dose date, if the subject entered a teduglutide treatment period during the 
study, otherwise the start date of the first non-teduglutide period. The reference start date 
for medications will be the informed consent date.  The reference end date will be the EOS 
date.
IMPUTATION OF PARTIAL AE DATES
START DATE
STOP DATE
ACTION
Known
Partial
If AE start year and month are known, impute stop date as 
latest possible date (that is the last day of the month if day 
is unknown or 31st December if day and month are 
unknown).
Missing
If AE stop date is unknown leave as missing.
Partial
Known
If AE start year and month are known and it is the month 
and year of the reference start date: Impute start date as 
the reference start date if AE stop date > the reference 
start date;
Else if AE start year and month are known and it is the 
month and year of the informed consent: Impute start 
date as the informed consent date if AE start year and 
month < the year and month of the reference start date;
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 41 of 48
START DATE
STOP DATE
ACTION
Else if AE start year and month are known and are not the 
month and year of the reference start date or informed 
consent: Impute start date as the first day of the month;
Else if only AE start year is known and is the year of the 
reference start date: Impute start date as the reference 
start date if AE stop date > the reference start date;
Else if only AE start year is known and is after year of the 
reference start date: Impute start date as the first day of 
the year (1st January).
Partial
If AE start year and month are known and it is the month 
and year of the reference start date: Impute start date as 
the reference start date if AE stop year and month are 
known and >= the year and month of the reference start 
date Or If only AE stop year is known and >= year of the 
reference start date;
Else if AE start year and month are known and it is the 
month and year of the informed consent: Impute start 
date as the informed consent date if AE start year and 
month < the year and month of the reference start date;
Else if AE start year and month are known and are not the 
month and year of the reference start date or informed 
consent: Impute start date as the first day of the month;
Else if only AE start year is known and is the year of the
reference start date: Impute start date as the reference 
start date if AE stop year and month are known and >= the 
year and month of the reference start date Or If only AE 
stop year is known and >= year of the reference start date;
Else if only AE start year is known and is after year of the 
reference start date: Impute start date as the first day of 
the year (1st January).
Impute stop date as latest possible date (that is the last 
day of the month if day is unknown or 31st December if 
day and month are unknown).
Missing
If AE start year and month are known and it is the month 
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 42 of 48
START DATE
STOP DATE
ACTION
and year of the reference start date: Impute start date as 
the reference start date;
Else if AE start year and month are known and it is the 
month and year of the informed consent: Impute start 
date as the informed consent date if AE start year and 
month < the year and month of the reference start date;
Else if AE start year and month are known and are not the 
month and year of the reference start date or informed 
consent: Impute start date as the first day of the month;
Else if only AE start year is known and is the year of the 
reference start date: Impute start date as the reference 
start date;
Else if only AE start year is known and is after year of the 
reference start date: Impute start date as the first day of 
the year (1st January).
If AE stop date is unknown leave as missing.
Missing
Known
If AE start date is unknown leave as missing; event will be 
considered treatment-emergent if stop date >= the 
reference start date.
Partial
If AE start date is unknown leave as missing; event will be 
considered treatment-emergent if stop date partial stop 
date >= same partial portions of the reference start date
Missing
If AE start or stop date is unknown leave as missing; event 
will be considered treatment-emergent.
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 43 of 48
IMPUTATION OF PARTIAL MEDICATION DATA
START DATE
STOP DATE
ACTION
Known
Partial
If medication stop year and month are known and the 
reference end date during that month and year: Impute 
stop date as the reference end date if medication start 
date <= the reference end date;
Else if medication stop year and month are known and 
are not the month and year of the reference start date: 
Impute stop date as the last day of the month;
Else if only medication stop year is known and is the year 
of the reference end date: Impute stop date as the 
reference end date if medication start date <= the 
reference end date;
Else if only medication stop year is known and is prior to 
the year of the reference end date: Impute stop date as 
the last day of the year (31st December).
Missing
If medication stop date is unknown leave as missing.
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 44 of 48
START DATE
STOP DATE
ACTION
Partial
Known
If medication start year and month are known and it is 
the month and year of the reference start date: Impute 
start date as the reference start date if medication stop 
date > the reference start date;
Else if medication start year and month are known and it 
is the month and year of the informed consent: Impute 
start date as the informed consent date if medication 
start year and month < the year and month of the 
reference start date;
Else if medication start year and month are known and 
are not the month and year of the reference start date or 
informed consent: Impute start date as the first day of 
the month;
Else if only medication start year is known and is the year 
of the reference start date: Impute start date as the 
reference start date if medication stop date > the 
reference start date;
Else if only medication start year is known and is the year 
of the informed consent date: Impute start date as the 
informed consent date if medication start year < the year 
of the reference start date;
Else if only medication start year is known and is after 
year of the reference start date: Impute start date as the 
first day of the year (1st January).
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 45 of 48
START DATE
STOP DATE
ACTION
Partial
If medication start year and month are known and it is 
the month and year of the reference start date: Impute 
start date as the reference start date if medication stop 
year and month are known and >= the year and month of 
the reference start date Or If only AE stop year is known 
and >= year of the reference start date;
Else if medication start year and month are known and it 
is the month and year of the informed consent: Impute 
start date as the informed consent date if medication 
start year and month < the year and month of the 
reference start date;
Else if medication start year and month are known and 
are not the month and year of the reference start date or 
informed consent: Impute start date as the first day of 
the month;
Else if only medication start year is known and is the year 
of the reference start date: Impute start date as the 
reference start date if medication stop year and month 
are known and >= the year and month of reference start 
date Or If only AE stop year is known and >= year of 
reference start date;
Else if only medication start year is known and is after 
year of the reference start date: Impute start date as the 
first day of the year (1st January).
If medication stop year and month are known and study 
drug stopped during that month and year: Impute stop 
date as the stop date of study drug if medication start 
date <= the stop date of study drug;
Else if medication stop year and month are known and 
are not the month and year of the reference start date: 
Impute stop date as the last day of the month;
Else if only medication stop year is known and is the year 
of the reference end date: Impute stop date as the 
reference end date if medication start date <= the 
reference end date;
Else if only medication stop year is known and is prior to 
the year of the reference end date: Impute stop date as 
the last day of the year (31st December).
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 46 of 48
START DATE
STOP DATE
ACTION
Missing
If medication start year and month are known and it is 
the month and year of the reference start date: Impute 
start date as the reference start date;
Else if medication start year and month are known and it 
is the month and year of the informed consent: Impute 
start date as the informed consent date if medication 
start year and month < the year and month of the 
reference start date;
Else if medication start year and month are known and 
are not the month and year of the reference start date or 
informed consent: Impute start date as the first day of 
the month;
Else if only medication start year is known and is the year 
of the reference start date: Impute start date as the 
reference start date;
Else if only medication start year is known and is after 
year of the reference start date: Impute start date as the 
first day of the year (1st January).
If medication stop date is unknown leave as missing.
Missing
Known
If medication stop date is unknown leave as missing.
Partial
If medication stop date is unknown leave as missing.
Missing
If medication stop date is unknown leave as missing.
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 47 of 48
APPENDIX 3.
MARKEDLY ABNORMAL LABORATORY CRITERIA  
Lab Parameter
Unit
Lower Limit Criteria
Upper Limit Criteria
Chemistry
Albumin 
g/L
<20
>68
Alkaline Phosphatase 
U/L
>5 x ULN
Alanine Aminotransferase 
(ALT)
U/L
>8 x ULN
Aspartate 
Aminotransferase (AST)
U/L
>8 x ULN
Amylase
U/L
>3 x ULN
Lipase
U/L
>3 x ULN
Bilirubin Total
umol/L
>3 x ULN
Direct Bilirubin
umol/L
>34.208
Blood Urea Nitrogen 
mmol/L
>12.495
Calcium 
mmol/L
<1.5
>3
Creatinine
umol/L
>132.6 if age < 10 y;
>150.28 if age 10-<13 y;
>176.8 if age 13-<16 y;
>221 if age 16+
C Reactive Protein 
mg/L
>=100
Glucose
mmol/L
<2.22
>13.875
Magnesium 
mmol/L
<0.4114
>1.2342
Phosphorus 
mmol/L
<0.644
>2.254
Potassium 
mmol/L
<2.5
>6.5
Sodium 
mmol/L
<120
>160
For non-commercial use only


SHIRE Pharmaceuticals, a Takeda Company
STATISTICAL ANALYSIS PLAN: PROTOCOL SHP633-304
Page 48 of 48
Triglycerides 
mmol/L
>5.65
Hematology
Hemoglobin 
g/L
<70
>200
Hematocrit 
fraction 
of 1
<0.21
>0.60
Platelets 
10^9/L
<75
>700
Leukocytes 
10^9/L
<2
>30
Neutrophils, absolute
10^9/L
<0.5
APPENDIX 4. TABLE, FIGURE AND DATA LISTING SHELLS
TABLE AND FIGURE SHELLS
See separate file.
DATA LISTING SHELLS
See separate file.
For non-commercial use only