A 24-Week Double-blind, Safety, Efficacy, and Pharmacodynamic Study Investigating Two Doses of Teduglutide in Pediatric Subjects Through 17 Years of Age With Short Bowel Syndrome Who Are Dependent on Parenteral Support
Phase: PHASE3
Conditions: Short Bowel Syndrome
Sponsor: Shire

A 24-Week Double-blind, Safety, Efficacy, and Pharmacodynamic Study
Investigating Two Doses of Teduglutide in Pediatric Subjects Through
17 Years of Age with Short Bowel Syndrome who are Dependent on 
Parenteral Support
Clinical Study Protocol TED-C14-006
Version 2.0
Phase 3
US IND# 058213 
US NDA# 203441
EuDRACT #2015-002252-27
NPS Pharmaceuticals, Inc.
550 Hills Drive, 3rd Floor
Bedminster, NJ 07921
USA
ISSUED:
Amendment 1, version 2.0:
22 June 2015
Original Protocol version 1.0:
12 March 2015

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SYNOPSIS
Protocol TED-C14-006
Title of Study: A 24-Week Double-blind, Safety, Efficacy, and Pharmacodynamic Study 
Investigating Two Doses of Teduglutide in Pediatric Subjects Through 17 Years of Age with 
Short Bowel Syndrome who are Dependent on Parenteral Support
Protocol No: TED-C14-006
Phase of development: 3
Objectives: The objective of this clinical study is to evaluate the safety, tolerability, efficacy, 
and pharmacodynamic effects of teduglutide in pediatric subjects (through 17 years) with short 
bowel syndrome (SBS) who are dependent on parenteral support.
Methodology: This will be a double-blind, 2 arm study in which subjects will be randomized in 
a 1:1 ratio to receive either 0.025 mg/kg/day or 0.05 mg/kg/day of teduglutide for 24 weeks
followed by 4 weeks of no active therapy.  Dosing regimens will be blinded to both investigators 
and subjects.  In addition, an attempt will be made to enroll subjects in a separate standard of
care cohort, which will serve as an observational cohort for the 24-week treatment period and 
4-week follow-up. The subjects in the standard of care cohort will follow the same visit schedule 
as the randomized subjects.
All subjects will be screened for a minimum of 2 weeks prior to start of treatment to verify the 
requirements for nutritional support for each subject and to ensure adherence to eligibility 
parameters. After screening, the 24-week treatment period will consist of site visits at baseline, 
weekly for the first 2 weeks, and then every other week for the next 8 weeks (through Week 12).  
From Weeks 13 to 24, visits at the sites will be conducted at Weeks 15, 18, 21, and 24.  
Telephone contacts will be made on all other weeks during the treatment period.  A final visit 
will be scheduled at Week 28, 4 weeks following the end of treatment (EOT).  Telephone contact 
will be made during the interim weeks from EOT to end of study (EOS).
To maintain consistency across all centers, sites and subjects (treated and standard of care) must 
follow the nutritional support adjustment guidelines (developed with SBS expert input and 
provided in the protocol) for decisions regarding parenteral nutrition/intravenous (PN/IV)
support reduction and advances in enteral feeds based on weight gain, urine, and stool output in 
the setting of clinical stability.

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Number of Subjects:  Approximately 20 teduglutide-naïve subjects (at least 10 subjects per 
treatment arm) will be enrolled into the active treatment groups at approximately 10 to 
20 investigational sites globally.
In addition, attempts will be made to enroll up to 8 teduglutide-naïve subjects in a standard of 
care cohort (who will not be treated with teduglutide) to serve as an observational cohort.
Duration of Study:  There will be, at a minimum, a 2-week screening period followed by 
24 weeks of on-treatment study visits. There will be one final scheduled visit at Week 28, 
4 weeks after the EOT (Week 24).  
The proposed duration of the clinical phase is from July 2015 through December 2016.  The start 
of the clinical phase is defined as first subject screened.  The end of the clinical phase is defined 
as the last visit of the last subject.
Diagnosis and main criteria for inclusion: Male and female children and adolescents, through 
17 years of age, who meet the following inclusion and exclusion criteria will be enrolled in the 
study.
Inclusion Criteria
1. Informed consent by a parent or guardian or emancipated minor prior to any study-related 
procedures
2. When applicable, an informed assent by the subject (as deemed appropriate by the Ethics 
Committee/Institutional Review Board) prior to any study-related procedures
3. Current history of SBS as a result of major intestinal resection, (eg, due to necrotizing 
enterocolitis, midgut volvulus, intestinal atresia, or gastroschisis)
4. Short bowel syndrome that requires PN/IV support that provides at least 30% of caloric 
and/or fluid/electrolyte needs prior to screening
5. Stable PN/IV support for at least 3 months (defined as inability to significantly reduce PN/IV 
support, usually associated with minimal or no advance in enteral feeds [ie, 10% or less 
change in PN or advance in feeds])  prior to screening, as assessed by the investigator
6. Female subjects of child-bearing potential (in the active treatment group only) must use 
medically acceptable methods of birth control during and for 30 days after the treatment 
period.

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Exclusion Criteria
1. Subjects who are not expected to be able to advance oral or tube feeding regimens 
(ie, subjects with oral aversion)
2. Serial transverse enteroplasty or any other bowel lengthening procedure performed within 
3 months of screening
3. Known clinically significant untreated intestinal obstruction contributing to feeding 
intolerance and inability to reduce parenteral support 
4. Unstable absorption due to cystic fibrosis, untreated Hirschsprung’s disease or known DNA 
abnormalities (ie, Familial Adenomatous Polyposis, Fanconi syndrome)
5. Severe, known dysmotility syndrome, such as pseudo-obstruction and persistent, severe, 
active gastroschisis-related motility disorders that are the primary contributing factors to 
feeding intolerance and inability to reduce parenteral support, prior to screening
6. Evidence of clinically significant obstruction on upper gastrointestinal (GI) series done
within 6 months prior to screening
7. Major gastrointestinal surgical intervention including significant intestinal resection within
3 months prior to the screening visit (insertion of feeding tube, anastomotic ulcer repair, 
minor intestinal resections ≤10 cm, or endoscopic procedure is allowed)
8. Unstable cardiac disease, congenital heart disease or cyanotic disease, with the exception of 
subjects who had undergone ventricular or atrial septal defect repair, and patent ductus 
arteriosus (PDA) ligation
9. History of cancer or clinically significant lymphoproliferative disease, not including resected 
cutaneous basal or squamous cell carcinoma, or in situ non-aggressive and surgically 
resected cancer
10. Pregnant or lactating female subjects (in the active treatment group only)
11. Participation in a clinical study using an experimental drug (other than glutamine or 
Omegavan) within 1 month or an experimental antibody treatment within 3 months prior to 
screening, or concurrent participation in any clinical study using an experimental drug that 
would affect the safety of teduglutide
12. Previous use of teduglutide or native/synthetic glucagon-like peptide-2 (GLP-2)

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13. Previous use of glucagon-like peptide-1 analog or human growth hormone within 3 months
prior to screening
14. Previous use of octreotide, or dipeptidyl peptidase-IV (DPP-IV) inhibitors within 3 months
prior to screening
15. Subjects with active Crohn’s disease who had been treated with biological therapy 
(eg, antitumor necrosis factor [anti-TNF] or natalizumab) within the 6 months prior to the 
screening visit
16. Subjects with inflammatory bowel disease (IBD) who required chronic systemic 
immunosuppressant therapy that had been introduced or changed during the 3 months prior 
to screening
17. More than 3 SBS-related or PN-related hospital admissions (eg, documented infection-
related catheter sepsis, clots, bowel obstruction, severe water-electrolyte disturbances) within 
3 months prior to the screening visit
18. Any unscheduled hospital admission which may affect parenteral support requirements 
within 1 month prior to the screening visit (up to 48-hour observations [ie, such as those to 
rule out sepsis/infection] or central line replacement/repair, in an otherwise stable subject, are 
allowed)
19. Body weight < 10 kg at screening and randomization visits
20. Signs of active severe or unstable, clinically significant hepatic impairment shown by any of 
the below laboratory test results during the screening period:
a.
Total bilirubin ≥ 2 x upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥ 7 x ULN
c.
Alanine aminotransferase (ALT) ≥ 7 x ULN
For subjects with Gilbert’s disease: 
d. Indirect (unconjugated) bilirubin ≥ 2 x ULN
21. Signs of known continuous active or unstable, clinically significant renal dysfunction shown 
by any of the below laboratory test results during the screening period:
a.
Serum creatinine ≥ 2 x ULN 
b. Creatinine clearance < 50 mL/min*
*Only applies to subjects with a known history of chronic renal disease who must then 
have a screening creatinine clearance (CrCl) < 50 mL/min or, if CrCl cannot be measured, 
an eGFR level below 40 mL/min/1.73 m2.

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22. Parent(s) and/or subjects who are not capable of understanding or not willing to adhere to the 
study visit schedule and other protocol requirements
23. Unstable, clinically significant active, untreated pancreatic or biliary disease
24. 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.  Examples of potential disease states/illnesses that may be excluded are listed 
in the table below.
Examples of Excluded Diseases and Illnesses
Body system
Known conditions excluded
Related to SBS

Ongoing radiation enteritis 

Untreated celiac disease

Refractory or tropical sprue

Pseudo-obstruction
Gastrointestinal 

Tufting or autoimmune enteropathy or microvillous 
inclusion disease

Untreated pre-malignant or malignant change in upper 
GI, biopsy or polypectomy 

Known, untreated, polyposis conditions (ie, familial 
adenomatous polyposis, Peutz-Jeghers syndrome, 
Turcot syndrome, Juvenile polyposis syndrome, 
Cowden disease, Bannayan-Riley-Ruvalcaba 
syndrome, Gardner’s syndrome, Cronkhite-Canada 
syndrome, Eversmeyerous polypius)
Immune

Compromised immune system (eg, acquired immune 
deficiency syndrome, severe combined 
immunodeficiency).
Psychiatric

Alcohol or drug addiction within the previous year

Major uncontrolled psychiatric illness
General

Significant active, uncontrolled, untreated systemic 
diseases (eg, cardiovascular, respiratory, renal, 
infectious, endocrine, hepatic, or central nervous 
system)
Test Product, Dose, and Mode of Administration:
After randomization, daily doses of either 0.025 mg/kg/day or 0.05 mg/kg/day of teduglutide will 
be administered to the subjects in the active treatment cohorts.  The dose calculation will be 

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based on body weight measured at the Baseline Visit (Visit 2).  No adjustments to dose will be 
made during the study period, unless discussed with the NPS medical monitor.
Teduglutide will be administered by subcutaneous (SC) injection once daily in the morning into 
1 of the 4 quadrants of the abdomen (in subjects without a stoma) or either thigh or arm. For 
subjects with a stoma, the quadrant of the abdomen containing the stoma will not be used.
Reference Therapy, Dose and Mode of Administration:
Not applicable.
Criteria for Evaluation:
Safety and tolerability:
Safety and tolerability will be assessed by evaluation of:

Adverse events, including GI symptoms. A GI Symptom History Worksheet will be 
completed daily during the screening period, prior to baseline.  GI symptoms will be 
recorded as none, mild, moderate, or severe.  The principal investigator will assess the 
aggregate diary entries to determine a baseline of GI symptoms for each subject.

Physical examinations

Vital signs, including oral temperature, heart rate, blood pressure, body weight, head 
circumference (up to 36 months of age), height/length, and length trends on growth charts

Electrocardiograms

Laboratory safety data, including electrolyte balance and glucose

Antibodies to teduglutide (active treatment groups only).  Samples for antibody analysis will 
be drawn at baseline and at the EOT (Week 24) and EOS (Week 28) visits prior to the 
administration of teduglutide and at least 14 hours after the previous dose.  One sample will 
be collected at the final visit 4 weeks after the EOT (EOS, Week 28).  Any subjects testing 
positive for antibodies specific to teduglutide (positive/specific antibodies) at Week 28 will 
have follow-up visits 3 and/or 6 months after the last dose of study drug to assess antibody 
status.

Changes in oral/enteral feeding 

Nutritional intake and urinary/fecal output (where collection is possible)

GI-specific testing including imaging (eg, colonoscopy, sigmoidoscopy) abdominal 
ultrasound, fecal occult blood testing upper GI series with small bowel follow-through

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Pharmacodynamics:
The primary pharmacodynamic (PD) parameter is parenteral support reduction of 20% to 100% 
at 24 weeks (or EOT) compared to baseline.
Analysis of additional PD endpoints will include:

100% reduction in PN/IV volume support (any subjects who are able to completely wean off
PN/IV support) compared to baseline at EOS

A decrease in parenteral support (calories and volume)

An increase in enteral nutritional tolerance (calories and volume)

Change from baseline in PN/IV support, citrulline, and enteral support at Week 24 (or EOT)

Change from baseline in PN/IV support, citrulline, and enteral support at Week 28 (or EOS)

Change from baseline in PN/IV support, citrulline, and enteral support at Week 24 (or EOT) 
compared to Week 28 (or EOS)

Change in urine output (collected or calculated volume)

Change in weight, height (length), and head circumference (where appropriate)

Change in PN/IV support 3 and 6 months (as applicable) after EOT compared to baseline for 
those subjects who developed antibodies specific to teduglutide

Change in hours per day or days per week of PN/IV support.

Intensity of response (PN/IV reduction and advance in enteral support) at each visit.

Proportion of responders (ie, subjects who achieve at least a 20% reduction in parenteral 
support) at Weeks 4, 8, 12, 16, 20, and 24 weeks.
To maintain consistency across all centers, sites and subjects (treated and standard of care) must 
follow the nutritional support adjustment guidelines (developed with SBS expert input) for 
decisions regarding PN/IV support reduction and advances in enteral feeds based on weight gain, 
urine, and stool output in the setting of clinical stability.
Safety and tolerability will be evaluated by a data safety monitoring board (DSMB) every 
3 months during the active study period.  The DSMB review will include all cumulative safety 
data (ie, adverse events, laboratory assessments, physical examinations, etc.) from study 
assessments through each cutoff period including any reasons for dose adjustment and 
discontinuations.

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Statistical methods:
Due to the limited size of the study population 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 categorical variables, statistical summaries will include number of subjects 
and percentages.
Demographics and baseline:
Summary statistics will be presented for demographic and baseline variables.  Analysis of 
variance computations will be applied as appropriate.
Efficacy/Pharmacodynamics:
Efficacy/pharmacodynamics data including reduction in parenteral support, increase in enteral  
nutritional tolerance, change in PN/IV support, citrulline, enteral support, urine output, weight,
height, hours per day or days per week of PN/IV support, and time to PN/IV reduction and 
advance in enteral support will be summarized by visit and time point.
Safety:
Safety data including clinical laboratory tests, physical examinations, concomitant medications, 
electrocardiogram monitoring, and vital signs assessments will be summarized by visit and time 
point.  Adverse events will also be collected and summarized, including Grade 3 and 4 adverse 
events of special interest, based on Common Terminology Criteria for Adverse Events (CTCAE) 
criteria.  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.

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PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT PAGE
Protocol TED-C14-006
I agree:
To assume responsibility for the proper conduct of this clinical study at this site and to conduct 
the study in compliance with this protocol, any future amendments, and with any other study 
conduct procedures provided by the sponsor,
That I am aware of, and will comply with, the internationally recognized code of Good Clinical 
Practice (GCP) and all other applicable regulatory requirements to obtain written and dated 
approval from the Institutional or Central Review Board (IRB) or Independent Ethics 
Committee (IEC) for the study protocol and any amendments thereof, written informed consent 
or updates thereof, subject recruitment procedures (eg, advertisements), and any other written 
information to be provided to the subjects, before initiating this clinical study,
Not to implement any changes to, or deviations from the protocol without prior agreement 
from the sponsor and review and documented approval from the IRB/IEC, except to eliminate 
an immediate hazard to the study subjects, or when change(s) involves only logistical or 
administrative aspects of the clinical study,
To permit direct monitoring and auditing by the sponsor or sponsor’s representatives and 
inspection by the appropriate regulatory authority(ies),
That I am thoroughly familiar with the appropriate use of the investigational product(s), as 
described in this protocol, and any other information provided by the sponsor or designee, 
including, but not limited to, the current Investigator’s Brochure or equivalent document and 
approved product label (if applicable),
To provide sufficient time and an adequate number of qualified staff and facilities for the 
foreseen duration of the clinical study in order to conduct the study properly, ethically, and 
safely,
To ensure that all persons assisting in this study are adequately informed about the protocol, 
investigational product(s), and their clinical study-related duties and functions,
To maintain drug records, electronic copies of case report forms, laboratory records, data 
sheets, correspondence records, and signed subject consent/assent documents for at least 
5 years or until instructed in writing by the sponsor that records may be destroyed or forwarded 
to the sponsor.  
Principal Investigator (Print Name)
Principal Investigator (Signature)
Date (DD MMM YYYY)

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TABLE OF CONTENTS
SYNOPSIS......................................................................................................................................2
SIGNATURE PAGE....................................................................................................................10
PRINCIPAL INVESTIGATOR PROTOCOL AGREEMENT PAGE..................................11
TABLE OF CONTENTS ............................................................................................................12
LIST OF IN-TEXT TABLES AND FIGURES.........................................................................14
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.............................................15
1
INTRODUCTION..................................................................................................................16
1.1
Background .....................................................................................................................16
1.2
Rationale for the Clinical Study......................................................................................18
1.3
Rationale for Study Design .............................................................................................19
2
OBJECTIVES ........................................................................................................................21
2.1
Primary Objective ...........................................................................................................21
3
STUDY DESIGN....................................................................................................................21
3.1
Overall Design and Control Methods..............................................................................21
3.2
Study Duration ................................................................................................................25
4
SUBJECT SELECTION AND PARTICIPATION ............................................................25
4.1
Number of Subjects.........................................................................................................25
4.2
Inclusion Criteria.............................................................................................................25
4.3
Exclusion Criteria............................................................................................................26
4.4
Subject Withdrawal Criteria............................................................................................29
4.5
Data Safety Monitoring Board ........................................................................................30
5
TREATMENTS AND TREATMENT PLAN .....................................................................30
5.1
Treatment Administered..................................................................................................30
Identification of Investigational Product .................................................................30
5.1.1
Packaging and Labeling...........................................................................................31
5.1.2
Storage, Accountability, and Stability .....................................................................31
5.1.3
5.2
Methods of Assigning Subjects to Treatment Groups ....................................................32
5.3
Dose Regimens................................................................................................................32
Selection of Doses in Study .....................................................................................33
5.3.1
Selection and Timing of Dose for Each Subject......................................................33
5.3.2
Compliance with Dosing Regimens.........................................................................33
5.3.3

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Prior and Concomitant Medications ........................................................................34
5.3.4
6
STUDY EVALUATIONS AND PROCEDURES ...............................................................34
6.1
Evaluations for Safety and Tolerability ..........................................................................34
Adverse Events ........................................................................................................35
6.1.1
Serious Adverse Events ...........................................................................................37
6.1.2
Unblinding ...............................................................................................................40
6.1.3
Dose Interruption of Individual Subjects.................................................................40
6.1.4
Early Termination of the Clinical Study..................................................................42
6.1.5
Laboratory Evaluations............................................................................................42
6.1.6
Physical Examinations.............................................................................................44
6.1.7
Vital Signs and Body Weight ..................................................................................44
6.1.8
Electrocardiograms ..................................................................................................45
6.1.9
Gastrointestinal-specific Testing .............................................................................45
6.1.10
Concomitant Medication Assessment......................................................................46
6.1.11
Nutritional Support Usage .......................................................................................46
6.1.12
Diaries......................................................................................................................47
6.1.13
Female Subjects of Child-bearing Potential ............................................................48
6.1.14
7
DATA MANAGEMENT.......................................................................................................58
7.1
Data Collection................................................................................................................58
7.2
Record Retention.............................................................................................................59
8
STATISTICAL METHODOLOGY AND SAMPLE SIZE ...............................................59
8.1
Demographic and Baseline Variables .............................................................................59
8.2
Safety and Tolerability Variables....................................................................................61
8.3
Pharmacodynamic Variables...........................................................................................61
8.4
Other Variables ...............................................................................................................62
8.5
Analysis Populations, Data Sets, and Time Points..........................................................63
Analysis Populations................................................................................................63
8.5.1
8.6
Statistical/Analytical Issues.............................................................................................63
Adjustments for Covariates......................................................................................63
8.6.1
Handling of Dropouts or Missing Data....................................................................63
8.6.2
Interim Analyses and Data Monitoring....................................................................63
8.6.3
Multiple Comparisons/Multiplicity .........................................................................63
8.6.4
Use of an Efficacy Subset of Subjects .....................................................................63
8.6.5
Examination of Subgroups.......................................................................................63
8.6.6

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8.7
Determination of Sample Size.........................................................................................63
8.8
Changes to Planned Statistical Analyses.........................................................................64
9
ADMINISTRATIVE AND ETHICAL REQUIREMENTS ..............................................64
9.1
Declaration of Helsinki and Ethical Review...................................................................64
9.2
Subject Information, Informed Consent and Assent.......................................................64
9.3
Subject Data Protection...................................................................................................65
9.4
Financial Disclosure........................................................................................................65
9.5
Changes to the Protocol...................................................................................................66
9.6
Investigator Obligations..................................................................................................66
9.7
Confidentiality/Publication of the Study.........................................................................67
9.8
Selection of a Primary Principal Investigator .................................................................67
9.9
Study Termination...........................................................................................................67
10 REFERENCES.......................................................................................................................68
APPENDIX 1:    CONSIDERATIONS FOR MANAGEMENT OF NUTRITIONAL 
SUPPORT DURING THE STUDY......................................................................................69
LIST OF IN-TEXT TABLES AND FIGURES
Table 4-1 
Excluded Diseases and Illnesses............................................................................28
Table 6-1
Schedule of Evaluations and Procedures – Screening to Week 12 – Active 
Treatment Groups ..................................................................................................49
Table 6-2
Schedule of Evaluations and Procedures –Weeks 13 to 28 – Active Treatment 
Groups....................................................................................................................52
Table 6-3
Schedule of Evaluations and Procedures – Screening to Week 12 – Standard 
of Care Cohort........................................................................................................54
Table 6-4
Schedule of Evaluations and Procedures – Weeks 13 to 28 – Standard of Care 
Cohort ....................................................................................................................56
Figure 3-1 
Study Diagram .......................................................................................................23
Figure A-1
Weaning Algorithm for Subjects Who Are Not Toilet Trained and in Diapers ....69
Figure A-2
Weaning Algorithm for Subjects Who Are Toilet Trained and not in Diapers.....70
Figure A-3
Clinical Dehydration Assessment and PN/EN Adjustment...................................71

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
AE
Adverse event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
CrCl
Creatinine Clearance
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
DSMB
Data Safety Monitoring Board
ECG
Electrocardiogram
eCRF
Electronic case report form
EN
Enteral nutrition
EOS
End of study
EOT
End of treatment
FDA
Food and Drug Administration
FOCBP
Females of child-bearing potential
GFR
Glomerular filtration rate
GI
Gastrointestinal
GLP-2
Glucagon-like peptide 2
IB
Investigator’s Brochure
IBD
Inflammatory bowel disease
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ITT
Intent-to-treat
IV
Intravenous
IVRS
Interactive Voice Response System
MedDRA
Medical Dictionary for Regulatory Activities
NDA
New Drug Application
NOAEL
No Observed Adverse Effect Level
NPS
NPS Pharmaceuticals, Inc.
PD
Pharmacodynamic
PK
Pharmacokinetic
PN
Parenteral nutrition
QD
Once daily
SAE
Serious adverse event
SAP
Statistical Analysis Plan
SBS
Short bowel syndrome
SC
Subcutaneous
SMT
Safety Management Team 
SUSAR
Suspected, unexpected, serious, adverse reaction
ULN
Upper limit of normal
WMA
World Medical Association

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1
INTRODUCTION
1.1
Background
Compound
Teduglutide is a novel, recombinant analog of naturally occurring human glucagon-like 
peptide-2 (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 and 
therefore maintains a longer elimination half-life (t1/2) 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.  The 
European Commission granted a centralised marketing authorization valid throughout the 
European Union for teduglutide (Revestive™) on 30 August 2012 and a New Drug Application 
(NDA) for teduglutide (Gattex®) was approved by the US Food and Drug Administration 
(FDA) on 21 December 2012 for the treatment of adult patients with Short Bowel Syndrome 
(SBS) who are dependent on parenteral support.
Subsequent supplemental submissions in the US and EU in 2013 and 2014 provided long-term 
data from the completed long-term safety and efficacy study in support of subsequent changes 
to the label which provide for long-term use of Gattex.
Preclinical Studies
A comprehensive preclinical evaluation of the toxicological profile of teduglutide has been 
conducted (acute and repeat dose toxicology, safety pharmacology, genetic and reproductive 
toxicology, juvenile animal studies, carcinogenicity, and special studies). Subcutaneous 
injections of teduglutide have been shown to be well tolerated at acute doses as high as 
200 mg/kg/day (mouse) or repeated doses of up to 50 mg/kg/day for 6 months in mice and 
25 mg/kg/day for 12 months in Cynomolgus monkeys. At dose levels of teduglutide up to 
50 mg/kg/day, there were no adverse effects on in utero fetal development in rats and rabbits or 
on reproductive parameters (viability, growth, mating) or fertility in the offspring of treated 
rats. Toxicity studies in juvenile animals have been completed using mini-pigs. A No Observed 
Adverse Effect Level (NOAEL) of teduglutide in juvenile mini-pigs treated subcutaneously 
twice daily for 14 days was found to be 25 mg/kg/day. In a 90-day toxicology study in juvenile 
mini-pigs, the changes observed in the gastrointestinal tract were consistent with those 
observed in studies conducted using adult animals (rodents and primates). No treatment-related 
malignant tumors were noted in a 2-year carcinogenicity study in rats; treatment-related 
changes included benign tumors of the bile duct epithelium and adenomas of the jejunal 
mucosa in males treated at 35 mg/kg/day. The results from a second 2-year carcinogenicity 

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study in Crl:CD1(ICR) mice were provided to the agency in a NDA Supplement which 
received agency approval on 26 June 2014. Subcutaneous doses of 1, 3.5 and 12.5 mg/kg/day 
(about 20, 70, and 250 times the recommended daily human dose of 0.05 mg/kg, respectively) 
were studied and adenocarcinoma in the jejunum was present in males given a dose of 
12.5 mg/kg/day.
Clinical Studies
Two completed studies (CL0600-004 and CL0600-005) evaluated safety and tolerability of 
daily teduglutide dosing for up to 12 months in SBS subjects who were dependent on 
parenteral nutrition/intravenous fluids (PN/IV).  Study CL0600-004, a double-blind, placebo-
controlled study in which 83 subjects were enrolled and 67 dosed with teduglutide, assessed 
the effects of teduglutide (0.05 and 0.10 mg/kg/day) on reductions in PN/IV.  There was a 
statistically significant difference favoring the 0.05 mg/kg/day group over placebo (p=0.007) 
by using a graded response at the end of the study.  The reduction of PN/IV volume was 
similar in the 2 active groups (2.5 L each). The extension study, CL0600-005, assessed the 
long-term safety of teduglutide and the proportion of responders in the CL0600-004 study that 
maintained their response at the end of a further 28 weeks of treatment.  The extension study 
also assessed the effects of teduglutide at 28 weeks on those subjects previously receiving 
placebo in Study CL0600-004.
Results from the extension study supported the clinical benefits of the 0.05 mg/kg/day dose, 
teduglutide treatment in the initial phase 3 study, which included significant reductions in 
PN/IV.  There was 75% of the subjects who previously responded to teduglutide treatment in 
Study CL0600-004 who maintained this response or experienced further improved benefit 
from teduglutide treatment.  More than 60% of the subjects previously receiving placebo in 
Study CL0600-004 achieved a clinical response after switching to teduglutide treatment for 
6 months. The majority of adverse events (AEs) reflected the underlying disease and were not 
treatment-related.
Study CL0600-020 was a randomized, double-blind, placebo-controlled study in which 
subjects were randomized to either teduglutide 0.05 mg/kg/day or placebo on a 1:1 ratio.  The 
first stage of the study included a screening and optimization period and a stabilization period 
that demonstrated stable administration of PN/IV volume for a minimum of 4 weeks up to a 
maximum of 8 weeks.  The second stage was a dosing period of 24 weeks.  Subjects on 
0.05 mg/kg/day teduglutide achieved a higher responder rate (defined as a 20% to 100% 
reduction from baseline in PN/IV volume at Weeks 20 and 24) than the placebo-treated 
subjects (27/43 subjects, 62.8% and 13/43 subjects, 30.2%, respectively).  This difference was 
clinically and statistically significant in both the Intent-to-Treat (ITT) (p = 0.002) and Per 
Protocol (p < 0.001) populations.  Generally, the incidence of treatment-emergent AEs 
(TEAEs) was distributed similarly across all treatment groups.  The TEAEs with a higher 
incidence in the teduglutide group were mainly of GI origin.  A long-term, open-label 

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extension study (CL0600-021) assessed safety and efficacy for up to 24 additional months 
(ie, up to 30 months of exposure for subjects who received teduglutide in Study CL0600-020).
Overall, 30 of 43 subjects who received teduglutide in Study CL0600-020 and entered 
Study CL0600-021 completed a total of 30 months of treatment with teduglutide.  Of these,
28 subjects (93%) achieved a 20% or greater reduction of parenteral support resulting in a 
PN/IV volume reduction of 7.55 L/week, corresponding to a mean reduction of 65.6% relative 
to baseline prior to exposure to teduglutide at the beginning of Study CL0600-021.  PN/IV 
frequency was reduced by at least 1 day per week in 21 of 30 subjects (70%) who completed 
30 months of treatment.  Of the 39 subjects who entered Study CL0600-021 after receiving 
placebo in Study CL0600-020, 29 completed 24 months of treatment with teduglutide.  The 
mean reduction in PN/IV volume was 3.11 L/week from baseline at the start of 
Study CL0600-021 (an additional 28% reduction).  Sixteen (55.2%) of the 29 completers 
achieved a 20% or greater reduction of parenteral support.  Of the 12 subjects entering 
Study CL0600-021 directly, 6 completed 24 months of treatment with teduglutide.  The mean 
reduction in PN/IV volume was 4.0 L/week (a 39.4% reduction from baseline at the start of 
Study CL0600-021) and 4 of the 6 completers (66.7%) achieved a 20% or greater reduction of 
parenteral support
1.2
Rationale for the Clinical Study
Short bowel syndrome is a rare disorder.  At the time of the initial development program with 
teduglutide, the Oley Foundation in 1992 reported an estimated prevalence of about 10,000 to 
15,000 parenteral nutrition (PN)-dependent adult SBS patients in the U.S. Most recently, 
market research performed in 2012 indicates that the true addressable adult patient population 
is between 3000 to 5000 patients which qualifies SBS as an ultra-orphan condition.  In addition 
to adult SBS patients, it is estimated that, at most, there are a few hundred children 1 year and 
older with SBS.  As a result of congenital abnormalities or severe intestinal disease in children 
and adolescents, major surgical resections of the intestine can become necessary, resulting in 
SBS.  Common causes of SBS in children include necrotizing enterocolitis (NEC) in infants, 
midgut volvulus (volvulus), intestinal atresia, and gastroschisis (Duro et al, 2008).  SBS in 
older children may stem from the same etiologies as in adults (ie, Crohn’s disease, trauma, 
cancer). As the characteristics are similar to the adult disease, pediatric SBS is defined as a 
disease where there is diminished absorptive capacity for fluids and/or nutrients, sometimes 
requiring a dependence on PN/IV support to maintain energy and clinical status.
There is heterogeneity within SBS.  Where some patients with intestinal insufficiency are able 
to adapt metabolically and compensate for their malabsorption of fluids, electrolytes, trace 
elements, vitamins or nutrients by increasing oral/enteral intake (Messing et al, 1999; Jeppesen
et al, 2000), other patients with intestinal failure depend on PN/IV for nutritional support 
(Fleming et al, 1980; O’Keefe et al, 2006; Buchman et al, 2003).  Although PN/IV can provide 
this nutritional support for patients with compromised fluid and nutritional status, it is also 

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associated with serious complications, such as infections and liver damage.  The risk for these 
effects increases over time with longer duration of PN/IV support.
The same treatment options are currently available for children and the same associated risks 
prevail.  Treatment of both pediatric and adult patients is focused on achieving adequate 
intestinal absorption to allow for minimization or discontinuation of PN/IV support.  This is 
achieved far more successfully in infants who develop SBS during the neonatal period and 
frequently come off their PN/IV requirements within 6 to 12 months of their initial surgical 
insult such that they achieve enteral autonomy by age 1 year.  Recent data suggest that up to 
85% of patients achieve spontaneous adaptation by age 1 year.
In the US, data from the Organ Procurement and Transplant Network reflect improvement in 
the medical and non-transplant surgical management of intestinal failure after 2010.  The peak
number of pediatric intestinal transplants in North America occurred between 2004 to 2009 (up 
to 111 in 2007) with falling levels from about 2010 onward (52 to 62 transplants annually). In 
2012, 56 transplants took place and in 2013, 36 transplants took place.
This study proposes to investigate the safe and appropriate use of teduglutide in the pediatric 
population for up to 24 weeks for the purpose of providing longer-term data in regard to safety 
and potential to explore further efficacy including PN reduction and ability to completely wean 
off parenteral support.  This protocol was developed with input from expert advisors from 
intestinal rehabilitation centers who offered advice on the most appropriate use of teduglutide
in pediatric patients.  The aim of teduglutide treatment is to increase absorptive capacity in 
order to yield decreases in parenteral support.  The experts anticipated that there would be 
several direct benefits from decreased parenteral support, including less exposure to PN/IV 
constituents, less central line manipulation with lower risk of infection, and more time to focus 
on oral rehabilitation strategies.
1.3
Rationale for Study Design 
Dose
The efficacy and safety of teduglutide has been investigated at doses ranging from 0.03 to 
0.15 mg/kg once daily (QD) in adult SBS subjects requiring PN.  The recommended clinical 
dosage for the adult SBS patient population is 0.05 mg/kg QD.  Population pharmacokinetic 
(PK) modeling and simulations were conducted to determine the dose to be used in pediatric 
subjects.  Subcutaneous dosing of teduglutide in pediatric patients with SBS was based on data 
collected in 5 adult Phase 1 studies and 3 adult Phases 2/3 studies, as well as an adult 
population PK meta-analysis. The PK results from the adult SBS clinical program also were 
used to model and simulate PK parameters in pediatric SBS patients to provide guidance on 
pediatric dosing for teduglutide.  An ongoing 12 week pediatric study (TED-C13-003) includes 
doses of 0.0125, 0.025, and 0.05 mg/kg/day.  Interim data evaluated by the DSMB has 
concluded that all three doses are safe and tolerable with trends of PN/IV volume reduction 

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and advance in feeds observed. Modeling and simulation data from previously completed
studies suggested that pediatric patients are likely to require the same dose as used in adults 
and that the 0.05 mg/kg/day adult dose will be sufficient to provide similar blood levels in all 
subjects over 1 year of age.  To further explore additional safety and efficacy, a 24 week study 
is currently proposed.
Treatment Duration/Design
Safety, tolerability and pharmacodynamic measures over a 24-week period will be the main 
outcomes of the current study.  The main PD effect of teduglutide to be measured in children 
will include a decrease in the volume of PN/IV requirement.  Measurement of a decrease in 
PN/IV volume requirements was the primary endpoint in the adult SBS clinical studies and can 
be used in children with SBS who are dependent on PN/IV support.
A 20% reduction or greater (including complete weaning) from baseline in volume of PN/IV at 
the end of 24 weeks of treatment was used as the primary endpoint in the adult clinical 
development program during pivotal Phase 3 studies and will be the same endpoint used in the 
current pediatric study.
The current study will employ a double-blind, 2 arm design with treatment of either 
0.025 mg/kg/day or 0.05 mg/kg/day of teduglutide for up to 24 weeks.  The 24-week treatment 
period will provide further information on longer term safety and additional efficacy including 
complete weaning of treatment beyond the 12-week period previously evaluated in the first 
pediatric study.
Thus, this study is designed to provide further information on the safety and PD profile of 
teduglutide in pediatric subjects treated for up to 24 weeks.
Subject Population
The current significant unmet medical need is for patients over age 1 year who remain 
dependent on parenteral support.  These patients reach a plateau in their ability to advance 
oral/enteral feeds or decrease PN/IV support and are not expected to achieve spontaneous 
adaptation.  The subjects in the study will be children whose intestines have not reached full 
enteral adaptation after 12 months of PN/IV treatment and whose PN/IV requirement had been 
stable without any clinically meaningful or substantial reduction in parenteral support for the 
3 months prior to study enrollment.
Therefore, this study will be performed in PN/IV-dependent children with SBS through 
17 years of age who have demonstrated that they have reached a plateau with regard to their 
ability to fully continue intestinal adaptation in terms of their ability to advance feeds and 
subsequently reduce their needs for parenteral support.  Stability for these subjects will be
defined as at least 3 months in which patients still are requiring at least 30% of their volume 
and/or calories from PN/IV with no clinically meaningful change in advances in their enteral 
feeds (specialized nutrition such as formula via mouth or tube).

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This study will conducted in accordance with FDA Guidance E11, Clinical Investigation of 
Medicinal Products in the Pediatric Population (December 2000).
Gastrointestinal Screening Measures
Pediatric SBS patients who are dependent on PN/IV have significant comorbidities such as 
biliary disease in addition to risk for obstruction due to history of surgery. Teduglutide has 
been found to have a targeted intenstinotrophic effect on the GI tract and areas of special 
interest in regards to safety have been identified throughout the development program. Taken 
into account the patient population and the pharmacologic effect of teduglutide, GI-specific 
screening tests which are usually part of the routine care of these subjects will be performed on 
subjects in the active treatment groups to ensure safety. These include: abdominal ultrasound, 
upper GI series with contrast, fecal occult blood testing, and, if deemed clinically relevant, 
colonoscopy/sigmoidoscopy.
General Guidance for Nutritional Support Adjustment
Consideration for advancement of oral/enteral feed and reductions to PN/IV volume will be 
based on clinical status, which will include measures for weight, growth, and hydration status.  
The pharmacodynamic endpoint for this study is a ≥20% reduction in PN/IV support guided 
by clinical status. A suggested guidance for nutrition support adjustment is provided in 
Appendix 1 and should be followed by all sites to ensure uniform care across study sites and 
participants.
2
OBJECTIVES
2.1
Primary Objective
The objective of this clinical study is to evaluate the safety, tolerability, efficacy, and 
pharmacodynamic effects of teduglutide in pediatric subjects (through 17 years) with SBS who 
are dependent on parenteral support.
See Section 8.2 and Section 8.3 for further details of the variables being measured.
3
STUDY DESIGN
3.1
Overall Design and Control Methods
This will be a double-blind, 2 arm study in which subjects will be randomized in a 1:1 ratio to 
receive either 0.025 mg/kg/day or 0.05 mg/kg/day of teduglutide for 24 weeks followed by 
4 weeks of no active therapy.  Dosing regimens will be blinded to both investigators and 
subjects.  In addition, an attempt will be made to enroll subjects in a separate standard of care 
cohort, which will serve as an observational cohort for the 24-week treatment period and 
4-week follow-up.  The subjects in the standard of care cohort will follow the same visit 
schedule as the randomized subjects.

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All subjects will be screened for a minimum of 2 weeks prior to start of treatment to verify the 
requirements for nutritional support for each subject and to ensure adherence to eligibility 
parameters.  After screening, the 24-week treatment period will consist of visits at baseline, 
weekly for the first 2 weeks, and then every other week through Week 12.  From Weeks 13 to 
24, visits at the sites will be conducted at Weeks 15, 18, 21, and 24.  Telephone contacts will 
be made on all other weeks during the treatment period in order to monitor safety.  A final visit
will be scheduled at Week 28, 4 weeks following the end of treatment (EOT).  Telephone 
contact will be made during the interim weeks from EOT to end of study (EOS).  If necessary, 
unscheduled visits can be arranged in place of the telephone contacts.  Schedules of study 
parameters are displayed in Table 6-1 and Table 6-2.
To maintain consistency across all centers, sites and subjects (treated and standard of care) 
must follow the nutritional support adjustment guidelines (developed with SBS expert input 
and provided in Appendix 1) for decisions regarding PN/IV support reduction and advances in 
enteral feeds based on weight gain, urine, and stool output in the setting of clinical stability.
At the conclusion of the follow-up period (Week 28), if subjects are determined to have 
positive/specific antibodies, they will be asked to return for a follow-up visit 3 months post
EOT for another antibody sample. If the subjects continued to have positive/specific antibodies
at 3 months post EOT, they will be asked to return for follow-up visit(s) up to 6 months 
post-treatment in order to determine their antibody status. At all follow-up visits, an assessment 
of the subject’s current PN/IV support and an adverse event determination will be conducted.
Safety and tolerability results will be evaluated by a DSMB every 3 months during the active 
study period (date of the first subject’s first dose to date of the last subject’s last dose).  The 
DSMB review will include all cumulative safety data (ie, adverse events, laboratory 
assessments, physical examinations, etc.) from study assessments through each cutoff period 
including any reasons for dose adjustment and discontinuations.
A schematic representation of the study design is displayed in Figure 3-1.

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Figure 3-1
Study Diagram
Note:  The Standard of Care cohort follows the same visit schedule as the active treatment groups.

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3.2
Study Duration
There will be, at a minimum, a 2-week screening period followed by 24 weeks of treatment.  
There will be one final scheduled visit 4 weeks after the end of treatment. Those subjects who 
test positive for teduglutide-specific antibodies at the 4-week follow up visit (Week 28) will be 
asked to return for additional follow-up visit(s) as described in Section 6.1 in order to 
determine their antibody status.
The proposed duration of the clinical phase is from July 2015 through December 2016.  The 
start of the clinical phase is defined as first subject screened.  The end of the clinical phase is 
defined as the last visit of the last subject.
4
SUBJECT SELECTION AND PARTICIPATION
4.1
Number of Subjects
Approximately 20-30 teduglutide-naïve subjects (minimum 10 subjects per treatment arm) will 
be enrolled into the active treatment groups.  
In addition, attempts will be made to enroll up to 8 teduglutide-naïve subjects in the standard of 
care cohort.  
Subjects will be enrolled at approximately 10 to 20 investigational sites globally.
4.2
Inclusion Criteria
Male and female children and adolescents, through 17 years of age, who meet the following 
inclusion criteria will be enrolled in the study.
1. Informed consent by a parent or guardian or emancipated minor prior to any study-related 
procedures
2. When applicable, an informed assent by the subject prior to any study-related procedures 
(as deemed appropriate by the Ethics Committee/Institutional Review Board)
3. Current history of SBS as a result of major intestinal resection, (eg, due to necrotizing 
enterocolitis, midgut volvulus, intestinal atresia, or gastroschisis) 
4. Short bowel syndrome that requires PN/IV support that provides at least 30% of caloric 
and/or fluid/electrolyte needs prior to screening
5. Stable PN/IV support for at least 3 months (defined as inability to significantly reduce 
PN/IV support, usually associated with minimal or no advance in enteral feeds [ie, 10% or 
less change in PN or advance in feeds])  prior to screening, as assessed by the investigator

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6. Sexually active female subjects of child-bearing potential (in the active treatment group 
only) must use medically acceptable methods of birth control during and for 30 days after 
the treatment period
4.3
Exclusion Criteria
Subjects who meet any of the following exclusion criteria at baseline are not eligible for 
enrollment into the study:
1. Subjects who are not expected to be able to advance oral or tube feeding regimens 
(ie, subjects with oral aversion)
2. Serial transverse enteroplasty or any other bowel lengthening procedure performed within 
3 months of screening
3. Known clinically significant untreated intestinal obstruction
4. Unstable absorption due to cystic fibrosis, untreated Hirschsprung’s disease or known 
DNA abnormalities (ie, Familial Adenomatous Polyposis, Fanconi syndrome)
5. Severe, known dysmotility syndrome, such as pseudo-obstruction and persistent, severe, 
active gastroschisis-related motility disorders that are the primary contributing factors to 
feeding intolerance and inability to reduce parenteral support prior to screening
6. Evidence of clinically significant obstruction on upper GI series done within 6 months prior 
to screening
7. Major gastrointestinal surgical intervention including significant intestinal resection within
3 months prior to the screening visit (insertion of feeding tube, anastomotic ulcer repair, 
minor intestinal resections ≤10 cm, or endoscopic procedure is allowed)
8. Unstable cardiac disease, congenital heart disease or cyanotic disease, with the exception of 
subjects who had undergone ventricular or atrial septal defect repair, and patent ductus 
arteriosus (PDA) ligation
9. History of cancer or clinically significant lymphoproliferative disease, not including 
resected cutaneous basal or squamous cell carcinoma, or in situ non-aggressive and 
surgically resected cancer
10. Pregnant or lactating female subjects (in the active treatment group only)
11. Participation in a clinical study using an experimental drug (other than glutamine or 
Omegavan) within 1 month or an experimental antibody treatment within 3 months prior to 

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screening, or concurrent participation in any clinical study using an experimental drug that 
would affect the safety of teduglutide
12. Previous use of teduglutide or native/synthetic glucagon-like peptide-2 (GLP-2)
13. Previous use of glucagon-like peptide-1 analog or human growth hormone within 3 months
prior to screening
14. Previous use of octreotide, or dipeptidyl peptidase-IV (DPP-IV) inhibitors within 3 months 
prior to screening
15. Subjects with active Crohn’s disease who had been treated with biological therapy
(eg, antitumor necrosis factor [anti-TNF] or natalizumab) within the 6 months prior to the 
screening visit
16. Subjects with inflammatory bowel disease (IBD) who required chronic systemic 
immunosuppressant therapy that had been introduced or changed during the 3 months prior 
to screening
17. More than 3 SBS-related or PN-related hospital admissions (eg, documented infection-
related catheter sepsis, clots, bowel obstruction, severe water-electrolyte disturbances) 
within 3 months prior to the screening visit
18. Any unscheduled hospital admission which may affect parenteral support requirements
within 1 month prior to the screening visit(up to 48-hour observations [ie, such as those to 
rule out sepsis/infection] or central line replacement/repair, in an otherwise stable subject, 
are allowed)
19. Body weight < 10 kg at the screening and randomization visits
20. Signs of active severe or unstable, clinically significant hepatic impairment shown by any 
of the below laboratory test results during the screening period:
a.
Total bilirubin ≥ 2 x upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥ 7 x ULN
c.
Alanine aminotransferase (ALT) ≥ 7 x ULN
For subjects with Gilbert’s disease: 
d. Indirect (unconjugated) bilirubin ≥ 2 x ULN
21. Signs of known continuous active or unstable, clinically significant renal dysfunction
shown by any of the below laboratory test results during the screening period:

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a.
Serum creatinine ≥ 2 x ULN
b. Creatinine clearance < 50 mL/min*
*Only applies to subjects with a known history of chronic renal disease who must then 
have a screening creatinine clearance (CrCl) < 50 mL/min or, if CrCl cannot be measured, 
an eGFR level below 40 mL/min/1.73 m2.  
22. Parent(s) and/or subjects who are not capable of understanding or not willing to adhere to 
the study visit schedule and other protocol requirements
23. Unstable, clinically significant active, untreated pancreatic or biliary disease
24. 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.  Examples of potential disease states/illnesses that may be excluded are 
listed in the table below.
Table 4-1
Excluded Diseases and Illnesses
Body system
Known conditions excluded
Related to SBS
Ongoing radiation enteritis 
Untreated celiac disease
Refractory or tropical sprue
Pseudo-obstruction
Gastrointestinal 
Active IBD which required chronic systemic 
immunosuppressant therapy that had been introduced or 
changed during the last 3 months
IBD that required chronic systemic immunosuppressant 
therapy for symptom control 
Tufting or autoimmune enteropathy or microvillous 
inclusion disease
Untreated pre-malignant or malignant change in upper GI, 
biopsy or polypectomy
Known, untreated, polyposis conditions (ie, familial 
adenomatous polyposis, Peutz-Jeghers syndrome, Turcot 
syndrome, Juvenile polyposis syndrome, Cowden disease, 
Bannayan-Riley-Ruvalcaba syndrome, Gardner’s 
syndrome, Cronkhite-Canada syndrome, Eversmeyerous 
polypius)
Intestinal or other major surgery scheduled within the time 
frame of the study
Chronic active pancreatitis 
Cholecystitis

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Table 4-1
Excluded Diseases and Illnesses
Body system
Known conditions excluded
Immune
Compromised immune system (eg, acquired immune 
deficiency syndrome, severe combined immunodeficiency)
Psychiatric
Alcohol or drug addiction within the previous year
Major uncontrolled psychiatric illness
General
Significant active, uncontrolled, untreated systemic 
diseases (eg, cardiovascular, respiratory, renal, infectious, 
endocrine, hepatic, or central nervous system)
4.4
Subject Withdrawal Criteria
All subjects are free to withdraw from participation in this study at any time, for any reason, 
specified or unspecified.  However, a discussion should be held by the investigator and the 
NPS Medical Monitor prior to the patient discontinuing/withdrawing.  A subject may (but not 
automatically) be withdrawn from the study under any of the following circumstances:

Withdrawal of informed consent and/or assent when applicable

If, in the opinion of the investigator, Institutional Review Board (IRB) or NPS, it is no 
longer in the subject’s best interest to continue in the study

Subject no longer meets all inclusion criteria or meets any criterion for exclusion

Lack of compliance with study procedures or study drug administration, as determined by 
the investigator

Occurrence of a serious adverse event (SAE) determined by the investigator to be possibly 
related to study drug and not alleviated with treatment of symptoms

Adverse event (including Grade 3 or 4 events of special interest [Section 6.1.4])

Hypersensitivity determined by the investigator to be possibly related to study drug

Administrative reasons
In all cases, the reason for withdrawal must be recorded in the electronic case report form 
(eCRF) and in the subject’s medical records.  If the reason is not known, the subject must be 
followed-up to establish whether the reason was an AE and, if so, the AE must be reported in 
accordance with the procedures described in Section 6.1.1.  Reasons for discontinuation other 
than AEs must be reported within 4 weeks of the EOS date in order to be included in the 
database.  Any reason for discontinuation obtained after this time will be included in the 
subject’s medical record only unless the EOS visit date is amended and the database remains 
open.

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As far as possible, all examinations scheduled for the EOT evaluations must be performed on 
all subjects who participate even if they do not complete the study according to the protocol.
4.5
Data Safety Monitoring Board
The DSMB 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 DSMB will be an external, independent board comprised of physicians with relevant 
training and an independent statistician (not associated with NPS, study sites, or investigators). 
The DSMB will be restricted to individuals free of significant conflicts of interest, including, 
but not limited to, financial, scientific, or regulatory in nature. The DSMB 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, individuals employed by NPS, independent contractors hired by NPS, or 
members of regulatory agencies. The DSMB may serve as an advisory board to NPS; however, 
NPS will have the final responsibility to determine whether the study should be modified or 
temporarily or permanently stopped. 
The DSMB members will review the data approximately every 3 months after the beginning of 
dosing of the first subject and then approximately every 3 months thereafter.  The DSMB will 
be provided the following:  1) all cumulative safety data from the study for safety assessments; 
2) data related to pharmacodynamics and the nutritional progress (ie, any changes in the use of 
PN/IV and/or enteral nutrition) of each subject; and 3) any other data supporting the decision to 
discontinue teduglutide throughout the study.
5
TREATMENTS AND TREATMENT PLAN
5.1
Treatment Administered
Daily doses of either 0.025 mg/kg/day or 0.05 mg/kg/day of teduglutide will be administered 
once daily in the morning to the subjects in the active treatment cohorts.  The dose calculation 
will be based on body weight measured at the Baseline Visit (Visit 2).  No adjustments to dose 
will be made during the study period. Teduglutide will be administered by SC injection into 
1 of the 4 quadrants of the abdomen (in subjects without a stoma) or either thigh or arm. For 
subjects with a stoma, the quadrant of the abdomen containing the stoma will not be used.
Identification of Investigational Product
5.1.1
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.  The 5-mg vial is 10 mg/mL solution upon reconstitution.  The 2.5-mg vial is 
5 mg/mL. A maximum of 0.38 mL of reconstituted solution can be withdrawn from the vial.

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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.
All vial strengths have the same formulation except for a reduced concentration of the active 
ingredient in the lower strength.
Packaging and Labeling
5.1.2
The study drug will be packaged, labeled, and shipped to the study site by the sponsor or 
designee.  Study drug vial will be supplied in kits containing 7 vials and labeled with the 
protocol number, the investigational drug warning, general dosage instructions, storage 
conditions, expiry date, kit number, lot number, and company name.  Space will be provided 
for recording study site and subject numbers at the study site. Ancillary supply kits containing 
syringes with needles for injection and reconstitution, sterile water, and alcohol swabs will also 
be provided.
All study drug used in this study will be manufactured, tested, labeled, and released according 
to current legal requirements and Good Manufacturing Practice (GMP).
Storage, Accountability, and Stability
5.1.3
Study drug will not be dispatched to the study site until the sponsor/designee has received all 
required documents from the study site in accordance with applicable regulatory requirements 
and relevant standard operating procedures.  Upon receipt, the study site’s pharmacist or 
delegate is responsible for ensuring that all study drug received at the site is inventoried and 
accounted for throughout the study.  A copy of the shipping documents must be maintained for 
the investigator’s records.
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 oC (35.6 to 46.4 oF) until 
dispensed to a subject.  Once dispensed to a subject, the study drug can be stored refrigerated 
up to a controlled room temperature (acceptable range of 2 to 25 oC, or 35.6 to 77 oF).  
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.
Study drug kits will be dispensed at each of the study visits at which the subject is required to 
be at the clinic. Each study drug kit is sufficient for a treatment period of 1 week and enough 
kits will be supplied to cover the period to the next planned study visit. Additional study kits
will be provided as necessary.
The investigator is to keep a current record of the inventory and dispensing 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 

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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.
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
usedf and unused vials must be returned to the distribution center according to the sponsor’s 
instruction.  No vial/kit may be destroyed on site.
5.2
Methods of Assigning Subjects to Treatment Groups
At screening, subjects will be assigned an 8-digit subject number.  The first 4 digits consist of 
the study site number.  The last 4 digits will be assigned sequentially starting with 0001.  These
numbers will be used to identify the subjects throughout the study period, including any 
subjects in the standard of care cohort.  
At any time during the 2-week minimum screening period, the subject or subject’s 
parent/guardian/caretaker will decide whether to participate in the dosing cohort or the 
standard of care cohort.  At the end of the screening period, the investigator will review and 
confirm that the subject continues to meet all Inclusion/Exclusion criteria.  If the subject or 
subject’s parent/guardian/caretaker decides to participate in the dosing cohort, the investigator 
or designee will request the subject be randomized at the Baseline Visit using an interactive 
voice response system (IVRS) at a 1:1 ratio, centrally administered as described in the IVRS 
Manual of Procedures.
Study drug kits will be assigned through IVRS to each subject at each on-site visit through
completion of the dosing period. The IVRS will automatically assign the correct number of kits 
for each visit based on the date of randomization. If additional kits are needed (eg., subject is 
going on holiday), the IVRS and NPS will need to be notified so that the additional kits can be 
assigned.  Subjects will be randomized across centers rather than within center.
Those subjects opting for the standard of care cohort will continue in the study but without the 
study drug.
5.3
Dose Regimens
Teduglutide will be supplied in 2 strengths:

5.0 mg/vial for subjects receiving 0.05 mg/kg/day of teduglutide

2.5 mg/vial for subjects requiring 0.025 mg/kg/day
Subjects in the active treatment groups are to have the study drug administered daily in the 
morning by SC injection into 1 of the 4 quadrants of the abdomen or into either thigh or arm, 
for 24 weeks. For subjects with a stoma, the quadrant of the abdomen containing the stoma 

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will not be used. The initial dose will be calculated based on body weight measured at the 
Baseline Visit (Visit 2).
Selection of Doses in Study
5.3.1
A recently completed 12-week pediatric study (TED-C13-003) included doses of 0.0125, 
0.025, and 0.05 mg/kg/day.  Data evaluated by the DSMB concluded that all 3 doses were safe 
and tolerable with trends of PN/IV volume reduction and advance in feeds observed.  Modeling 
and simulation data from previously completed studies suggested that pediatric patients are 
likely to require the same dose as used in adults and that the 0.05 mg/kg/day adult dose will be 
sufficient to provide similar blood levels in all subjects over 1 year of age.  
Selection and Timing of Dose for Each Subject
5.3.2
The study drug will be administered immediately after reconstitution by SC injection into 1 of 
the 4 quadrants of the abdomen or into either thigh or arm. The first SC injection 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, abdomen) of the first teduglutide dose must be specified and 
recorded in the eCRF.  Detailed instructions for reconstitution and injection of the study drug 
can be found in the Injection Instructions. Each day, the injection site should be changed. For 
subjects with a stoma, the abdominal quadrant in which the stoma is situated should be 
avoided.
The subject should be dosed at approximately the same time each day, preferably in the 
morning. If a morning dose is forgotten, that day’s dose should be administered as soon as
possible, even if this is later in the day or evening. Consecutive doses should be separated by 
approximately 12 hours.  The time of the dose should be captured in the appropriate area in the 
subject diary (ie, Daily [yes/no], Morning [yes/no], and option for other).
The investigator is responsible for contacting the sponsor/designee prior to interrupting the 
subject’s daily study drug dosing regimen. Reasons for dosage interruptions may include but 
are not limited to hospitalization, adverse events, forgotten doses, lapse in study drug delivery, 
etc.  A single discontinuation period of study drug should not exceed 10 consecutive days. 
Dosage interruptions of study drug for a maximum of 21 days total during the entire 24 weeks 
are permissible.
Compliance with Dosing Regimens
5.3.3
Subject compliance with study drug dosing will be monitored by the sponsor /designee by 
counting and examining used and unused vials. In addition, compliance will be checked by 
site personnel at every visit by asking the subject or the subject’s parent or guardian if they 
have administered the study drug according to instructions.  If any doses have been missed, the 

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reason for missed dose should be documented in the subject’s source documentation including, 
as applicable, the eCRF.
Compliance is considered to be achieved if the subject has 80% of the planned doses 
administered.
Prior and Concomitant Medications
5.3.4
The administration of all medications including concomitant medications must be recorded in 
the appropriate sections of the eCRF.
In general, no new medications should be started during the screening period or throughout the 
24-week treatment period, unless medically necessary and prescribed by the investigator or by 
another qualified physician involved in the subject’s clinical care and who is aware of the 
subject’s study participation.
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, digoxin), so consideration should be given to modifying 
concomitant medication regimens. Down-titration of concomitant medications should be 
considered when drugs, including those with a narrow therapeutic range, are given at dosages 
that are higher than usual.
6
STUDY EVALUATIONS AND PROCEDURES
6.1
Evaluations for Safety and Tolerability
Safety variables will be assessed by the following evaluations, according to Schedules of 
Evaluations and Procedures as outlined in Table 6-1 and Table 6-2, with opportunities for more 
frequent tests as clinically necessary.  Safety variables for the standard of care cohort are 
displayed in Table 6-3 and Table 6-4.

Adverse events, including GI symptoms.  A GI Symptom History Worksheet will be
completed daily during the screening period, prior to baseline.  GI symptoms will be 
recorded as none, mild, moderate, or severe.  The principal investigator will assess the 
aggregate diary entries to determine a baseline of GI symptoms for each subject.

Physical examinations

Vital signs, including oral temperature, heart rate, blood pressure, body weight, head 
circumference (up to 36 months of age), height/length, and length trends on growth charts

Electrocardiograms

Laboratory safety data, including electrolyte balance and glucose

Antibodies to teduglutide (active treatment groups only).  Samples for antibody analysis 
will be drawn at baseline and at the EOT (Week 24) and EOS (Week 28) visits prior to the 

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administration of teduglutide and at least 14 hours after the previous dose.  One sample will 
be collected at the final visit 4 weeks after the EOT (EOS, Week 28).  Any subjects testing 
positive for antibodies specific to teduglutide (positive/specific antibodies) at Week 28 will 
have follow-up visits 3 and/or 6 months after the last dose of study drug to assess antibody 
status.

Changes in oral/enteral feeding 

Nutritional intake and urinary/fecal output (when available)

GI-specific testing including imaging (eg, colonoscopy, sigmoidoscopy), abdominal 
ultrasound, fecal occult blood testing, upper GI series with small bowel follow-through
Adverse Events
6.1.1
The investigator is responsible for the detection and documentation of any AE or SAE, as 
defined in this protocol, during the study.
6.1.1.1
Adverse Event Definition
An AE is defined as any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical/medicinal product.  An AE does not necessarily have to 
have a causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (including a clinically significant 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of a medicinal product (investigational or marketed), whether or not considered related to 
treatment with the medicinal product.
An AE includes:

An exacerbation of a pre-existing illness, sign, symptom, or clinically significant (as 
determined by the investigator) laboratory test abnormality and clinically significant ECG 
abnormality

An illness, sign, symptom, or clinically significant laboratory abnormality that is detected 
or diagnosed after study drug administration

Pre-treatment or post-treatment events that occur as a result of protocol-mandated 
procedures
An AE does not include:

The disease or disorder being studied or signs and symptoms associated with the disease or 
disorder, unless there is worsening of the condition of the disease or disorder

A pre-existing disease or condition, present at the start of the study, that does not worsen

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Overdose
Defined as an accidental or intentional administration of an excessive dose of a product, an 
overdose should be reported to the sponsor using the SAE form. This information will be 
shared with the NPS Safety Management Team (SMT) and the sponsor’s medical monitor.
6.1.1.2
Procedures for Reporting Adverse Events
Adverse events may be spontaneously reported by the subject or subject’s parent/guardian, 
obtained through nonleading questioning, or noted during examination of a subject.  All AEs 
and SAEs will be recorded from the signing of the informed consent form (ICF) and, if 
applicable, the informed assent form, through the last study visit or the last study required 
procedure (including study visit).  SAEs will be monitored with a telephone call by the 
investigator, as necessary, for approximately 4 weeks after the last dose of study drug or until 
resolution or until the SAE is judged by the investigator to have stabilized.   
As they occur, new AEs will be recorded sequentially on the AE page of the eCRF.  The AE 
term should note the diagnosis whenever possible, not the individual signs or symptoms 
(eg, myocardial infarction should be recorded rather than chest pain, elevated cardiac enzymes, 
and abnormal ECG).  Also recorded are: 

Start and stop date and time

Whether the event is continuing

Frequency (intermittent, continuous)

Intensity (mild, moderate, severe)
o
Mild:  usually transient, requiring no special treatment and generally not interfering 
with usual daily activities
o
Moderate:  usually ameliorated by simple therapeutic maneuvers and impairs usual 
activities
o
Severe:  requires vigorous therapeutic intervention and interrupts usual activities;
hospitalization may or may not be required.

Relationship to study drug (not related, related): identify relationship as “related” if a 
causal relationship between the investigational product and an AE is at least a reasonable 
possibility (ie, the relationship cannot be ruled out)

Whether the AE is serious (ie, an SAE).  If identified as an SAE, the AE should be reported 
on the SAE form according to Section 6.1.2 below

Actions taken (none; study drug dose changed, interrupted, or discontinued; other 
medication change; nondrug therapy) 

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
Outcome (resolved, resolved with sequelae, ongoing, fatal).  An individual AE receives 
only one outcome.
Adverse events that are related to study drug and not resolved at the end of treatment will be 
followed by the site until resolution or until the AE is judged by the investigator to have 
stabilized.
Laboratory values, blood pressure, ECG evaluations, and clinical findings at the scheduled 
physical examinations must be reported as AEs if they:

Are considered clinically significant by the investigator

Fulfill SAE criteria, and/or

Cause subject discontinuation from the study
Serious Adverse Events
6.1.2
A serious event must be reported as described in Section 6.1.2.2 and recorded on the sponsor’s 
SAE Form.  An SAE requires expeditious handling to comply with regulatory requirements.  
Any SAEs occurring from the signing of the ICF through 30 days after the last dose of study 
drug will be captured and must be reported within 24 hours after the investigator is made aware 
of the event.
6.1.2.1
Serious Adverse Event Definition
An SAE is an AE that results in any of the following outcomes:

Death 

Is life-threatening.  A life-threatening AE is any AE that places the subject - in the 
investigator’s opinion - at immediate risk of death from the reaction as it occurred.  It does 
not include a reaction that, had it occurred in a more serious form, might have caused 
death.

Persistent or significant incapacity or substantial disruption of ability to conduct normal life 
functions

Hospitalization or prolongation of existing hospitalization

Congenital anomaly/birth defect

Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the subject or may require medical or surgical intervention 
to prevent one of the other 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 hospitalization, or the 
development of drug dependency or drug abuse.

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Scheduled and/or elective hospitalizations occurring under the following circumstances will 
not be defined as SAEs for this clinical study:

planned before entry into the clinical study

are for elective treatment of a condition unrelated to the studied indication or its treatment

occur on an emergency, outpatient basis and do not result in admission (unless fulfilling the 
previous criteria)

are part of the normal treatment or monitoring of the studied indication and not associated 
with any deterioration in condition
Any laboratory test result that meets the criteria for an SAE must also be recorded in an SAE 
report so that the sponsor/designee can collect additional information about that abnormality, 
including information regarding relationship to investigational product or other causes, any 
action taken, and outcome.
6.1.2.2
Procedures for Reporting Serious Adverse Events
Within 24 hours of becoming aware of ANY SAE (regardless of its relationship to 
investigational product) that occurs during the course of the clinical study from the time the 
ICF/assent is signed through 30 days after the study drug is completed, the investigator must 
notify the sponsor.  The SAE information, including the time and date that the investigator 
became aware of the event, must be entered into the SAE reporting system and supplemental 
data (eg, medical records or lab values, if applicable) faxed to the sponsor. This ensures timely 
reporting of applicable reports to Health Authorities.  
Note:  Minimum criteria for reporting an SAE are the SAE term, an identifiable subject, a 
suspect investigational medical product (study drug), and a reporter.  Hospitalization is not an 
AE, but a serious event criterion.  The SAE term is the medical event that led to the 
hospitalization.  Surgery is not an adverse event, but the event that required the subject to have 
surgery is the SAE term.  Death is not an SAE, but an outcome.
The sponsor/designee will provide a FAX cover sheet for the investigators in the Study 
Reference Manual.
Autopsy reports, if applicable, will be forwarded as they become available.  All pertinent 
laboratory results should be entered on the sponsor’s SAE form.
All SAEs must be reported, whether or not they are considered causally related to the study 
drug.  Appropriate clinical, diagnostic, and laboratory measures should be performed to 
delineate the cause of the SAE in question and the results reported.  Follow-up for the SAE 
should occur at appropriate intervals until the event/laboratory abnormality:

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
Returns to baseline or

Becomes stable to a clinically acceptable level that is safe for the subject.
The investigator is required to assess the causal relationship of each reported SAE, to the study 
drug (see below).  A causality assessment should always be included on the sponsor’s SAE 
form.  The investigator should make the causality assessment based on the information 
available at the time of the event.  The causality can be updated at a future date if additional 
information is received.
The causality categories are:
Not related

May or may not follow a reasonable temporal sequence from administration of the study 
product

Is biologically implausible and does not follow a known response pattern to the suspect 
study product (if response pattern is previously known)

Can be explained by the known characteristics of the subject’s clinical state or other modes 
of therapy administered to the subject
Related (Possibly Related/Probably Related/Related)

A single occurrence of an event that is uncommon and known to be strongly associated 
with drug exposure (eg, angioedema, hepatic injury, Stevens-Johnson Syndrome)

Follows a reasonable temporal sequence from administration of the study product

May follow a known response pattern to the study product (if response pattern is previously 
known)

Could not be reasonably explained by the known characteristics of the subject’s clinical 
state or other modes of therapy administered to the subject, if applicable

Recurs upon rechallenge after withholding and then reintroducing study product
Contact information for SAE reporting and emergency contact details can be found at the 
beginning of the protocol and in the Study Reference Manual.
As required by International Conference of Harmonisation (ICH) guidelines and global health 
authorities, the sponsor/designee will notify investigators of all adverse drug reactions that are 
serious, unexpected, and deemed by the reporting investigator or sponsor to be related to study 
drug (suspected, unexpected, serious, adverse reaction [SUSAR]).  Causality, while assessed, 
does not negate reporting requirements to the sponsor.  An AE, whether serious or not serious, 
is designated unexpected (unlabeled) if it is not reported in the clinical safety section of the 
Investigator Brochure (IB) or if the event is of greater frequency, specificity, or severity than is 
mentioned in the IB.  The investigator will receive a copy of the current valid version of the IB 
prior to the start of the study; however, the investigator will not be required to assess 

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expectedness, nor should expectedness impact the investigator reporting SAEs within the 
timeframe herein defined.
Upon receiving such notices, the investigator must review and retain the notice.  As per 
regulatory guidance, if it is determined that there is an unanticipated signal, the NPS SMT will 
analyze the data and prepare a summary supporting the determination and interpretation of the 
findings.  The sponsor/designee will send this summary to the investigators with instructions to 
provide it to their IEC/IRB.
The investigator should also comply with the IEC/IRB procedures for reporting any other 
safety information (ie, autopsy reports).
NPS Pharmaceuticals (sponsor) will be responsible for submitting SUSAR reports to the 
appropriate health authorities.  These reports will be submitted within the expedited timeframe.  
All fatal and life-threatening SUSAR reports will be submitted by the sponsor or designee 
within 7 days of receipt (Day 0) of the initial report.  All other SUSAR reports will be 
submitted by Day 15 following the event.
Unblinding
6.1.3
If a subject becomes pregnant or seriously ill during the study, the blind should be broken only 
if knowledge of the study medication administered will affect treatment options available to the 
subject.  Before breaking the blind, the investigator should contact the NPS Medical Monitor 
for discussion on whether unblinding of the subject is warranted.  If warranted, the principal 
investigator or the sponsor or designee will place an unblinding call to the IVRS to receive 
treatment assignment information.  In the case of an extreme emergency and if the Medical 
Monitor is immediately unreachable, the investigator should break the blind through the IVRS. 
Please see Manual of Procedures for further details.
In the event prior authorization from the NPS Medical Monitor is not possible, the NPS 
Medical Monitor must be notified by telephone immediately, but no later than 24 hours 
following the unblinding of any subject for any reason.  A record should be kept of when the 
blind was broken, who broke it, and why.
Dose Interruption of Individual Subjects
6.1.4
Teduglutide administration for an individual subject may need to be stopped if the subject has 
an adverse event of special interest (see risks in table below) that is Grade 3 or higher as 
defined by the National Cancer Institute’s Common Terminology Criteria for Adverse Events 
(CTCAE).  This may occur if an event is attributable to study drug or a subject experiences an 
unexplained CTCAE Grade 3 or higher that is not reasonably related to the underlying disease 
process. The determination of length of the discontinuation, temporary or permanent, depends 
on the clinical situation. A treatment-emergent SAE of special interest that leads to study drug 

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interruption/discontinuation will be assigned a Grade 3 or 4, if applicable, by the investigator 
during the SAE reporting and follow-up process.
Investigators and the DSMB should be guided by the descriptions of Grade 3 and 4 events 
below, as they relate to identified risks associated with the administration of teduglutide.
Identified Risk
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
Alkaline Phosphatase 
increased
> 5.0 to 20.0 x Upper limit of normal
> 20.0 x Upper limit of normal
Blood bilirubin 
increased
> 3.0 to 10.0 x Upper limit of normal
> 10.0 x Upper limit of normal
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

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Identified Risk
Grade 3 Description
Grade 4 Description
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 5.0 x Upper limit of normal
> 5.0 x Upper limit of normal
Lipase increaseda
> 2.0 to 5.0 x Upper limit of normal
> 5.0 x Upper limit of normal
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)
aIn the setting of clinically acute and symptomatic pancreatitis 
Source: Common Terminology Criteria for Adverse Events, version 4.03, 14 June 2010
Early Termination of the Clinical Study
6.1.5
The DSMB may recommend to stop the study if:

≥ 2 subjects being administered study drug develop the same CTCAE Grade 3 or

1 subject develops a CTCAE Grade 4 adverse event which is attributable to study drug 
or is not reasonably related to the underlying disease process
Laboratory Evaluations
6.1.6
The following laboratory parameters will be examined according to the Schedules of 
Evaluations and Procedures as outlined in Table 6-1 and Table 6-2 (Table 6-3 and Table 6-4
for the standard of care cohort). While not all abnormal laboratory results would be considered 
clinically significant as determined by the investigator (ie, those that are associated with the 
disease state and were present at baseline), those that are determined to be a clinically 
significant change (ie, worsening) from baseline or known medical history will be considered 
adverse events.  All such abnormal laboratory values that are considered AEs must be recorded 
on the appropriate eCRF.  A result outside of the normal range may be repeated for 
confirmation.  Any laboratory test result that meets the criteria for an SAE (Section 6.1.2) must 
also be recorded in an SAE report so that the sponsor/designee can collect additional 
information about that abnormality, including information regarding relationship to 
investigational product or other causes, any action taken, and outcome.

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6.1.6.1
Safety Laboratory Tests and Procedures
Hematology
Serum Chemistry
Albumin
Alkaline phosphatase
ALT
Amylase
AST 
Bicarbonate
Bilirubin (total and indirect)
Blood urea nitrogen 
Calcium (total)
Chloride
Cholesterol
Citrulline (plasma)
Creatinine
Creatinine clearance
C-reactive protein 
Creatinine clearance (or Glomerular Filtration 
Rate [GFR])
Glucose
Gamma glutamyl transferase 
Lipase
Magnesium
Phosphate
Potassium
Sodium
Triglycerides
Uric acid
Urinalysis
Blood
Glucose
Leucocytes
Microscopic analysis
Specific gravity
pH and osmolality
Protein
Sodium
Pregnancy tests (females of child-bearing 
potential) – for active treatment group only
Procedures
Upper GI with contrast
Abdominal ultrasound
Colonoscopy/sigmoidoscopy (subjects 12 years and older or if fecal occult blood testing 
result is positive regardless of age without a documented or known etiology to explain the 
fecal positive results, ie, fissures, etc.).
Fecal occult blood testing
Hemoglobin
Hematocrit
Platelets
Red blood cell (RBC) count
White blood cell (WBC) count with differential

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6.1.6.2
Plasma Citrulline
Plasma citrulline will be measured as an assessment of enterocyte mass, according to the 
Schedules of Evaluations and Procedures (Table 6-1 and Table 6-2).  If peripheral venous 
access is not possible, blood samples for citrulline may be drawn from a central line.  The 
samples will be processed according to instructions in the Laboratory Manual and will be 
collected from subjects from both active treatment and standard of care groups who participate 
in this study.
6.1.6.3
Antibodies to Teduglutide
Blood samples will be drawn only from the active treatment groups for the analysis of 
positive/specific antibodies to teduglutide according to the Schedules of Evaluations and 
Procedures (Table 6-1 and Table 6-2).
Physical Examinations
6.1.7
Complete and comprehensive physical examinations will be performed by a medically 
qualified person during the study to assess the subject’s physical status, according to the 
Schedules of Evaluations and Procedures (Table 6-1 and Table 6-2) (Table 6-3 and Table 6-4
for the standard of care cohort).
Any significant finding at baseline should be included in the subject’s medical history eCRF, 
including known lab abnormalities such as decreased hemoglobin as part of anemia, history of 
elevated liver enzymes, etc. Any clinically significant changes from baseline (in the opinion of 
the investigator) noted during the physical examinations, whether or not these procedures are 
required by the protocol, should be recorded on the appropriate AE page of the eCRF. This 
will assist the sponsor/designee in collecting additional information about that abnormality, 
including information regarding relationship to investigational product or other causes, any 
action taken, and outcome.
Vital Signs and Body Weight 
6.1.8
Vital signs will be measured according to the Schedules of Evaluations and Procedures (Table 
6-1 and Table 6-2) (Table 6-3 and Table 6-4 for the standard of care cohort). Measurements 
will include systolic and diastolic blood pressure (mmHg), pulse (beats per minute), and body 
temperature (oC/oF).  Body weight (kg), height (length [cm]), and head circumference (in cm
for subjects ≤ 36 months of age) will also be recorded on the eCRF.   Subjects should be 
weighed on the same scale at each study visit.
A weight Z-score will be calculated using the site-provided height and weight data collected at
each site visit.
Any clinically significant changes (ie, worsening) in the opinion of the investigator noted in 
vital signs assessments (ie, those that are associated with the disease state and were present at 
baseline), should be recorded on the appropriate AE page of the eCRF. This will assist the 

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sponsor/designee in collecting additional information about that abnormality, including 
information regarding relationship to investigational product or other causes, any action taken, 
and outcome.,
Electrocardiograms
6.1.9
Twelve-lead electrocardiograms will be performed according to the Schedules of Evaluations 
and Procedures (Table 6-1 and Table 6-2; Table 6-3 and Table 6-4 for the standard of care 
cohort). The ECG tracing will be read by a local experienced physician. Results (normal, 
abnormal not clinically significant, and abnormal clinically significant with description of the 
finding) will be recorded on the eCRFs.
Any clinically significant changes (in the opinion of the investigator) noted during the ECG 
evaluations should be recorded on the appropriate AE page of the eCRF. This will assist the 
sponsor/designee in collecting additional information about that abnormality, including 
information regarding relationship to study drug or other causes, any action taken, and 
outcome.
Gastrointestinal-specific Testing
6.1.10
Gastrointestinal testing will be done for all subjects in the active treatment group during the 
screening period, as needed.  Follow-up testing will be performed as necessary according to the 
guidelines noted below. See Table 6-1 and Table 6-2 for details and scheduling.
6.1.10.1
Upper Gastrointestinal Series with Contrast
An upper GI with small bowel follow through (UGI/SBFT) will be performed following the 
ingestion of barium contrast material.  Results from procedures performed within 6 months 
prior to Visit 1 will also be acceptable.
6.1.10.2
Abdominal Ultrasound
An abdominal ultrasound will be performed. Results from procedures performed within 
6 months prior to Visit 1 will also be acceptable.
6.1.10.3
Fecal Occult Blood Testing
Fecal occult blood testing will be performed at screening and at the end of treatment. Subjects
with positive results for fecal occult blood will undergo a confirmatory 
colonoscopy/sigmoidoscopy.  If no known underlying documented etiology can be attributed to 
this finding, the results should be discussed with the NPS Medical Monitor.

Subjects with negative scope results may enroll in the study

Subjects with positive scope results who receive treatment may enroll in the study

Subjects with positive scope results who do not receive treatment will be excluded from the 
study

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
In those subjects with positive results for fecal occult blood at the end of the study, the 
investigator will have to determine the cause for the finding and may perform an additional 
colonoscopy/sigmoidoscopy, if clinically warranted.
6.1.10.4
Colonoscopy/Sigmoidoscopy
Subjects age 12 years and older will undergo a colonoscopy/sigmoidoscopy at screening.  
Children under the age of 12 years will also undergo the procedure if they had a positive result 
on the fecal occult blood testing (see above). Results from procedures performed within 1 year
prior to Visit 1 will also be acceptable.
Concomitant Medication Assessment
6.1.11
The subject’s usage of concomitant medication will be assessed at each clinic visit and the 
details of any medications and changes in medication or dosage of medications will be 
recorded on the eCRF.
Nutritional Support Usage
6.1.12
Consideration for advancement of oral/enteral feed and reductions to PN/IV volume will be 
based on clinical status which will include measures for weight, growth, and hydration status.  
The pharmacodynamic endpoints for this study include decreases in PN/IV volume reduction 
including a ≥ 20% or greater reduction up to 100% reduction (or complete weaning) in PN/IV 
support guided by clinical status.  A 20% decrease in PN/IV volume over 24 weeks is 
considered clinically meaningful to these PN/IV-dependent children who have plateaued in 
their ability to wean PN/IV and advance their oral/enteral feeds.  A decrease of this magnitude 
may translate to several hours a day for more age-appropriate activities or an opportunity to 
introduce an extra oral/enteral feed to encourage oral rehabilitation. A guidance for nutrition 
support adjustment to be followed for this protocol is provided in Appendix 1.
Evaluation of each subject’s nutritional support will be made during screening and at all visits 
at the study site.  The following information will be collected and can be used to evaluate each 
subject’s nutritional support:

Daily PN/IV support volume and calories

Daily enteral nutrition (EN) volume and calories (oral or tube feeds, including formula 
and specialized electrolyte solution)

Other nutritional intake (regular diet and drink)

72-hour urine output prior to each phone and site visit

72-hour stool output collected by volume, stool count, or stool consistency (when 
available)

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Diaries
6.1.13
Subjects or subjects’ parent or guardian will be required to complete the following:

Intake Diaries, completed daily, which will include:
o
PN/IV volume and calories (days per week, hours per day)
o
EN (formula and specialized electrolyte solutions) volume and calories (days 
per week, hours per day)
o
Other Nutrition (regular diet and drink) intake

Urine/Stool Output Diary, completed for 3 days (72 hours) just prior to the upcoming 
scheduled visit or telephone contact, consisting of :  
o
Collection of urine data:

For those who are toilet trained and NOT in diapers: urine volume 

For those who are NOT toilet trained and in diapers:  measure of urine 
volume/weight from urine-only diapers.  Volume will be calculated 
based on the formula:  1g (scale weight) = 1 ml or 1 cc.  

The subject/parent of subject will also be required to perform dipstick 
specific gravity tests on the first urine produced after the completion of 
the previous day’s/or overnight PN/IV support at the end of each day 
during the 72-hour collection periods.  
o
Collection of stool output data (including stool only and mixed urine/stool 
diapers):

For those who are toilet trained and NOT in diapers:  a stool count will 
be attempted.  

For those who are NOT toilet trained and in diapers: stool volume 
(including diapers that are stool only or mixed stool/urine).  Stool 
volume will be calculated based on the formula: 1 g (scale weight 
= 1 ml or 1 cc

Ostomy output will only be used if no stool is passed via the rectum 
(applicable to those subjects without a colon).  Ostomy output will be 
measured in cc or ml.   

In addition all subjects (toilet trained or not) will report on the average 
consistency (form) of the stool passed each day during the 72-hour 
period.  The subjects/parent of subject will use the Bristol Stool Form 
Scale (Lewis and Heaton, 1997) to make the assessment.  

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Teduglutide (rDNA origin) for injection
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During the screening period, these diaries focusing on Intake and Output will be completed 
every day.
All diaries will be reviewed by the investigator or their designee at each visit or telephone 
contact to assess clinical status and opportunity for PN/IV changes and advance in feeds.  At 
each visit, the diaries will be reviewed for completeness and accuracy of the data.
Female Subjects of Child-bearing Potential
6.1.14
Any female subject in an active treatment group who has reached menarche must have a 
negative urine pregnancy test to enroll or continue in the study. Pregnancy tests will be 
performed at screening and at all study visits. Female subjects in the standard of care group
subjects will not be required to undergo pregnancy testing.  Sexually active females of child-
bearing potential (FOCBP) must use medically acceptable methods of birth control during and 
for 30 days after the treatment period (eg, true abstinence1, oral contraceptive pills, barrier 
methods with spermicide) in a manner such that the risk of failure is minimized.  The 
investigator will discuss these methods as well as their side effects with the subject.
At the time of signing the ICF/assent, FOCBP must be advised of the importance of avoiding 
pregnancy during trial participation, and the potential risk factors for pregnancy. Male subjects 
must be advised that their partners must use medically acceptable methods of birth control 
during and for 30 days after the treatment.
In the event a subject becomes pregnant during the study, study drug will be discontinued and a 
Pregnancy Form will be completed to capture potential drug exposure during pregnancy.  The 
pregnancy will be reported within 24 hours of becoming aware of the condition.  The subject 
will be followed until an outcome is known (ie, normal delivery, abnormal delivery, 
spontaneous abortion (miscarriage), voluntary abortion, or therapeutic abortion).  If a pregnant 
subject also experiences an SAE, the SAE form will be completed and submitted within 
24 hours as discussed above.
In the event a female partner of a subject becomes pregnant within 30 days after the subject 
completes the trial and she or the fetus experiences an SAE, the SAE is deemed “suspected” to 
study drug by the principal investigator and a supplemental SAE form will be completed to 
capture the event.
                                                
1 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).

Pediatric Study TED-C14-006 – Amendment 1
Teduglutide (rDNA origin) for injection
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Final v2.0
22 June 2015
Table 6-1
Schedule of Evaluations and Procedures – Screening to Week 12 – Active Treatment Groups
Procedures
Screen-
ing
Baseline
Week
1
Week
2
Week
3
Week
4
Week
5
Week
6
Week 
7
Week
8
Week
9
Week 
10
Week 
11
Week 
12
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit Type
Site
Site
Site
Site
Phone
Site
Phone
Site
Phone
Site
Phone
Site
Phone 
Site
Study Day
≥-14
0
7
14
21
28
35
42
49
56
63
70
77
84
Visit Window (days)
2
2
2
2
2
2
2
2
2
2
2
2
Informed Consenta
X
Eligibility
X
X
Demographics 
X
Medical history
X
SBS history
X
Review nutritional 
support usageb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Nutritional support 
adjustment (as 
needed)c
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
X
X
X
X
Upper GI with small 
bowel follow 
throughd
X
Abdominal 
ultrasoundd
X
Fecal occult blood 
testingd,e
X
X
Colonoscopy/ 
Sigmoidoscopyd,e
X
Vital signs including 
body weight and head 
circumferencef
X
X
X
X
X
X
X
X
X
Electrocardiogram
X
X
Safety laboratory 
tests
X
X
(X)g
(X)g
(X)g
X
(X)g
(X)g
(X)g
X
(X)g
(X)g
(X)g
X

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Teduglutide (rDNA origin) for injection
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Final v2.0
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Table 6-1
Schedule of Evaluations and Procedures – Screening to Week 12 – Active Treatment Groups
Procedures
Screen-
ing
Baseline
Week
1
Week
2
Week
3
Week
4
Week
5
Week
6
Week 
7
Week
8
Week
9
Week 
10
Week 
11
Week 
12
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit Type
Site
Site
Site
Site
Phone
Site
Phone
Site
Phone
Site
Phone
Site
Phone 
Site
Study Day
≥-14
0
7
14
21
28
35
42
49
56
63
70
77
84
Visit Window (days)
2
2
2
2
2
2
2
2
2
2
2
2
Pregnancy testingh
X
X
X
X
X
X
X
X
X
Citrullinei
X
X
Antibodies to 
teduglutidej
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense GI 
Symptoms History 
Worksheet
X
Dispense Intake
Diaries
X
X
X
X
X
X
X
X
X
Dispense Urine/Stool 
Output Diary
X
X
X
X
X
X
X
X
X
Review GI 
Symptoms History 
Worksheet
X
Review Intake
Diariesk
X
X
X
X
X
X
X
X
X
X
X
X
X
Review Urine/Stool
Output Diaryl
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomizationm
X
Drug dispensingn
X
X
X
X
X
X
X
X

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Teduglutide (rDNA origin) for injection
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Final v2.0
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Table 6-1
Schedule of Evaluations and Procedures – Screening to Week 12 – Active Treatment Groups
Procedures
Screen-
ing
Baseline
Week
1
Week
2
Week
3
Week
4
Week
5
Week
6
Week 
7
Week
8
Week
9
Week 
10
Week 
11
Week 
12
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit Type
Site
Site
Site
Site
Phone
Site
Phone
Site
Phone
Site
Phone
Site
Phone 
Site
Study Day
≥-14
0
7
14
21
28
35
42
49
56
63
70
77
84
Visit Window (days)
2
2
2
2
2
2
2
2
2
2
2
2
eCRF = electronic case report form; EN = enteral feeds; GI = gastrointestinal; PN/IV = parenteral nutrition/intravenous fluid; SBS = Short Bowel Syndrome; SC = subcutaneous 
a Informed Consent and, if applicable, informed assent must be obtained prior to performing any study-related procedure.
b Nutritional support includes PN/IV, EN feeds (formula and other specialized electrolyte solutions), and regular diet/drink.
c Nutritional support adjustments can be made after review of the subject’s intake and output data recorded on the diaries and the subject’s safety lab data following the guidance 
for nutrition support adjustment provided in Appendix 1.
d If it is necessary to perform the upper GI with small bowel follow-through, abdominal ultrasound, fecal occult blood testing, and/or colonoscopy/sigmoidoscopy, these tests can 
be performed at any time after signing of consent but must be completed and results available prior to the baseline visit. The results must be available and reviewed prior to the 
baseline visit.
e Colonoscopy/sigmoidoscopy will be conducted on subjects 12 years of age and older or subjects who have a positive fecal occult blood result without etiology to explain.  Results 
of colonoscopies done within the prior year may also be used.
f Head circumference is to be collected as appropriate (ie, up to 36 months of age).
g Safety lab assessments to be done approximately 7 days following any PN/IV adjustment.
h Female subjects of child-bearing potential only 
iCitrulline should be collected 2 to 4 hours post prandially, whenever possible.
j Antibody collection to be done prior to first study drug administration at study site.
k Intake Diaries will collect data on  PN/IV support volume, EN feeds (formula and specialized electrolyte solutions), and regular diet/drink taken DAILY.  
l Urine/Stool Output Diary will collect data on urine and stool output for the 72 hours prior to the next scheduled visit or telephone contact.
mRandomization and therapy assignment is to be completed prior to drug dispensing.
n The first SC injection 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.

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Teduglutide (rDNA origin) for injection
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Final v2.0
22June 2015
Table 6-2
Schedule of Evaluations and Procedures –Weeks 13 to 28 – Active Treatment Groups
Procedures
Week
13
Week
14
Week
15
Week
16
Week
17
Week
18
Week 
19
Week
20
Week
21
Week 
22
Week 
23
Week 24
(or EOT)j
Week 
28j
Visit Number:
15
16
17
18
19
20
21
22
23
24
25
26
27
Visit Type
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone 
Site
Site
Study Day
91
98
105
112
119
126
133
140
147
154
161
168
196
Visit Window (days)
2
2
2
2
2
2
2
2
2
2
2
2
4
Review nutritional 
support usagea
X
X
X
X
X
X
X
X
X
X
X
X
X
Nutritional support 
adjustment (as 
needed)b
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
Fecal occult blood 
testing
Xk
Colonoscopy/ 
Sigmoidoscopy
(X)k
Vital signs including 
body weight and head 
circumferencec
X
X
X
X
X
Electrocardiogram
X
X
Safety laboratory 
tests
(X)d
(X)d
X
(X)d
(X)d
X
(X)d
(X)d
X
(X)d
(X)d
X
X
Pregnancy testinge
X
X
X
X
X
Citrullinef
X
X
Antibodies to 
teduglutide
Xg
Xg
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant
medication
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense Intake
Diaries
X
X
X
X

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Final v2.0
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Table 6-2
Schedule of Evaluations and Procedures –Weeks 13 to 28 – Active Treatment Groups
Procedures
Week
13
Week
14
Week
15
Week
16
Week
17
Week
18
Week 
19
Week
20
Week
21
Week 
22
Week 
23
Week 24
(or EOT)j
Week 
28j
Visit Number:
15
16
17
18
19
20
21
22
23
24
25
26
27
Visit Type
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone 
Site
Site
Study Day
91
98
105
112
119
126
133
140
147
154
161
168
196
Visit Window (days)
2
2
2
2
2
2
2
2
2
2
2
2
4
Dispense Urine/Stool
Output Diary
X
X
X
X
Review Intake 
Diariesh
X
X
X
X
X
X
X
X
X
X
X
X
X
Review Urine/Stool 
Output Diaryi
X
X
X
X
X
X
X
X
X
X
X
X
X
Drug dispensing
X
X
X
EOT = end of treatment; EN = enteral feeds; PN/IV = parenteral nutrition/intravenous fluid; SBS = Short Bowel Syndrome 
a Nutritional support includes PN/IV and , EN feeds (formula and other specialized electrolyte solutions), and regular diet/drink.
b Nutritional support adjustments can be made after review of the subject’s intake and output data recorded on the diaries and the subject’s safety lab data following the guidance 
for nutrition support adjustment provided in Appendix 1.
c Head circumference is to be collected as appropriate (ie, up to 36 months of age).
d Safety lab assessments to be done approximately 7 days following any PN/IV adjustment.
e Female subjects of child-bearing potential only
f Citrulline should be collected 2 to 4 hours post prandially, whenever possible.
g EOT antibody blood draw is to be taken prior to the last dose of study drug, at least 14 hours following the previous dose of study drug. Subjects who test positive/specific for 
antibodies to teduglutide at the Week 28 visit will have follow-up blood draws for positive/specific antibodies to teduglutide at approximately 3 months following the last dose of 
study drug. If antibodies are still positive/specific they will be collected again approximately 6 months after the last dose of study drug.  Adverse events and PN/IV support will 
also be assessed at these visits.
hIntake Diaries will collect data on PN/IV support volume, EN (formula and specialized electrolyte solutions), and regular diet/drink taken DAILY.    
iUrine/Stool Output Diary will collect data on urine and stool output for the 72 hours prior to the next scheduled visit or telephone contact.
j During the period between Visits 26 and 27 (Weeks 25, 26, and 27), the study staff will complete follow-up telephone contact(s) with the subject and parent/guardian/caretaker in 
order to monitor safety.  If a visit to the site by the subject is necessary, this can be completed as an Unscheduled Visit.
k If fecal/occult blood is positive without explanation, then a colonoscopy/sigmoidoscopy may be warranted.

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Teduglutide (rDNA origin) for injection
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Table 6-3
Schedule of Evaluations and Procedures – Screening to Week 12 – Standard of Care Cohort
Procedures
Screen-
ing
Baseline
Week
1
Week
2
Week
3
Week
4
Week
5
Week
6
Week 
7
Week
8
Week
9
Week 
10
Week 
11
Week 
12
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit Type
Site
Site
Site
Site
Phone
Site
Phone
Site
Phone
Site
Phone
Site
Phone 
Site
Study Day
≥-14
0
7
14
21
28
35
42
49
56
63
70
77
84
Visit Window (days)
2
2
2
2
2
2
2
2
2
2
2
2
Informed Consenta
X
Eligibility
X
X
Demographics 
X
Medical history
X
SBS history
X
Review Nutritional 
support usageb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Nutritional support
adjustment (as 
needed)c
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
X
X
X
X
Vital signs including 
body weight and head 
circumferenced
X
X
X
X
X
X
X
X
X
Safety laboratory 
tests
X
X
(X)e
(X)e
(X)e
X
(X)e
X
(X)e
X
Citrullinef
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense GI 
Symptoms History 
Worksheet
X
Dispense Intake 
Diaries
X
X
X
X
X
X
X
X
X

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Teduglutide (rDNA origin) for injection
Page 54 of 71
Final v2.0
22June 2015
Table 6-3
Schedule of Evaluations and Procedures – Screening to Week 12 – Standard of Care Cohort
Procedures
Screen-
ing
Baseline
Week
1
Week
2
Week
3
Week
4
Week
5
Week
6
Week 
7
Week
8
Week
9
Week 
10
Week 
11
Week 
12
Visit Number:
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Visit Type
Site
Site
Site
Site
Phone
Site
Phone
Site
Phone
Site
Phone
Site
Phone 
Site
Study Day
≥-14
0
7
14
21
28
35
42
49
56
63
70
77
84
Visit Window (days)
2
2
2
2
2
2
2
2
2
2
2
2
Dispense Urine/Stool 
Output Diary
X
X
X
X
X
X
X
X
X
Review GI 
Symptoms History 
Worksheet
X
Review Intake 
Diariesg
X
X
X
X
X
X
X
X
X
X
X
X
X
Review Urine/Stool 
Output Diaryh
X
X
X
X
X
X
X
X
EN = enteral feeds; GI = gastrointestinal; PN/IV = parenteral nutrition/intravenous fluid; SBS = Short Bowel Syndrome; SC = subcutaneous 
a Informed Consent and, if applicable, informed assent must be obtained prior to performing any study-related procedure.
b Nutritional support includes PN/IV and EN feeds (formula and other specialized electrolyte solutions), and regular diet/drink
c Nutritional support adjustments can be made after review of the subject’s intake and output data recorded on the diaries and the subject’s safety lab data following the guidance 
for nutrition support adjustment  provided in Appendix 1.
d Head circumference is to be collected as appropriate (ie, up to 36 months of age).
e Safety lab assessments to be done approximately 7 days following any PN/IV adjustment.
f Citrulline should be collected 2 to 4 hours post prandially, whenever possible.
g Intake Diaries will collect data on  PN/IV support volume, EN (formula and specialized electrolyte solutions), and regular diet/drink taken DAILY.  
h Urine/Stool Output Diary will collect data on urine and stool output for the 72 hours prior to the next scheduled visit or telephone contact.

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Teduglutide (rDNA origin) for injection
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22June 2015
Table 6-4
Schedule of Evaluations and Procedures – Weeks 13 to 28 – Standard of Care Cohort
Procedures
Week
13
Week
14
Week
15
Week
16
Week
17
Week
18
Week 
19
Week
20
Week
21
Week 
22
Week 
23
Week 24
(or EOT)h
Week 
28h
Visit Number:
15
16
17
18
19
20
21
22
23
24
25
26
27
Visit Type
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone 
Site
Site
Study Day
91
98
105
112
119
126
133
140
147
154
161
168
196
Visit Window (days)
2
2
2
2
2
2
2
2
2
2
2
2
4
Nutritional support
usagea
X
X
X
X
X
X
X
X
X
X
X
X
X
Nutritional support
adjustment (as 
needed)b
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
Vital signs including 
body weight and head 
circumferencec
X
X
X
X
X
Safety laboratory 
tests
(X)d
(X)d
X
(X)d
(X)d
X
(X)d
(X)d
X
(X)d
(X)d
X
X
Citrullinee
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant
medication
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense Intake 
Diaries
X
X
X
X
Dispense Urine/Stool 
Output Diary
X
X
X
X
Review Intake
Diariesf
X
X
X
X
X
X
X
X
X
X
X
X
X
Review Urine/Stool 
Output Diaryh
X
X
X
X
X

Pediatric Study TED-C14-006 – Amendment 1
Teduglutide (rDNA origin) for injection
Page 56 of 71
Final v2.0
22June 2015
Table 6-4
Schedule of Evaluations and Procedures – Weeks 13 to 28 – Standard of Care Cohort
Procedures
Week
13
Week
14
Week
15
Week
16
Week
17
Week
18
Week 
19
Week
20
Week
21
Week 
22
Week 
23
Week 24
(or EOT)h
Week 
28h
Visit Number:
15
16
17
18
19
20
21
22
23
24
25
26
27
Visit Type
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone
Site
Phone
Phone 
Site
Site
Study Day
91
98
105
112
119
126
133
140
147
154
161
168
196
Visit Window (days)
2
2
2
2
2
2
2
2
2
2
2
2
4
EOT = end of treatment; EN = enteral feeds; PN/IV = parenteral nutrition/intravenous fluid; SBS = Short Bowel Syndrome 
a Nutritional support includes PN/IV and, EN feeds (formula and other specialized electrolyte solutions), and regular diet/drink.
b Nutritional support adjustments can be made after review of the subject’s intake and output data recorded on the diaries and the subject’s safety lab data following the guidance 
for nutrition support adjustment provided in Appendix 1.
c Head circumference is to be collected as appropriate (ie, up to 36 months of age).
d Safety lab assessments to be done approximately 7 days following any PN/IV adjustment.
e Citrulline should be collected 2 to 4 hours post prandially, whenever possible.
f Intake Diaries will collect data on PN/IV support volume, EN (formula and specialized electrolyte solutions), and regular diet/drink taken DAILY.  
g Urine/Stool Output Diary will collect data on urine and stool output for the 72 hours prior to the next scheduled visit or telephone contact.
h During the period between Visits 26 and 27 (Weeks 25, 26, and 27), the study staff will complete follow-up telephone contact(s) with the subject and parent/guardian/caretaker in 
order to monitor safety.  If a visit to the site by the subject is necessary, this can be completed as an Unscheduled Visit.

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Teduglutide (rDNA origin) for injection
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7
DATA MANAGEMENT
7.1
Data Collection
Upon entry into the study (informed consent/assent signed), all subjects will be assigned an 
eight-digit subject number, including subjects in the standard of care cohort.  The first four 
digits consist of the study site number.  The last four digits will be assigned sequentially 
starting with 0001.  This number is the main identifier for subjects.
Data collected during the study will be recorded in the subject’s eCRF by the investigational 
site staff. The staff will keep records of the subject’s visit in the files considered as source 
documents for that site (eg, hospital chart, research chart, etc.). Source data are all information 
contained in original records of clinical findings, observations, or other trial-related activities 
necessary for evaluation and reproducibility of data (eg, progress notes, hospital records, 
computer print-outs, screening logs, and recorded data from automated instruments). In case 
of computerized source data, the investigator must provide the sponsor access to the subject 
files at each monitoring visit. To ensure that data has been entered correctly on the eCRF, they 
will be 100% source-data verified by a site monitor from the sponsor/designee, who will notify 
the investigator regarding any questions or discrepant data. The investigator or designee will 
be responsible for the timely recording of subject data into the eCRF. 
The investigator and study site must permit study-related monitoring, audits, IEC/IRB review, 
and regulatory inspections by providing direct access to source data/documents.
The investigator or designee will review all eCRFs (including the termination page after the 
subject’s final visit) for completeness and accuracy, and will sign the eCRF via an electronic 
signature. The investigator will be responsible for reviewing the data in a timely manner. Non-
eCRF data (eg, labs) will be sent to the sponsor/designee via a data transfer from the 
appropriate vendor for assimilation into the database. Paper copies of laboratory reports and 
other non-eCRF data (eg, ECGs) will be signed and dated by the investigator and filed. 
Diaries will be used by the subjects’ parent or guardian to record study information, including
PN/IV support, enteral administration, regular diet/drink intake, urine output (as either 
collected or calculated volume), stool form, and urine specific gravity.  The time of the dose 
should be captured in the appropriate area in the subject diary (ie, Daily [yes/no], Morning 
[yes/no], and option for other). The subject diaries will provide the source documentation for 
the diary data that is to be recorded in the eCRF by the study staff.
All data collected in this study will be entered into an appropriate pre-formatted database and 
submitted for statistical evaluation. The sites will be provided with eCRF guidelines outlining 
the specific procedures to use when entering the data into the clinical database. Data validation 
and edit checks will be conducted on the data. Any discrepancies will generate queries that 
must be resolved at the study site in a timely manner. 

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Teduglutide (rDNA origin) for injection
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When all subjects’ data have been entered into the database, verified, and all outstanding issues 
have been resolved with the site, the data will be evaluated for quality purposes. A clean file is 
defined as when the data in the database and the reference values are complete and logical 
according to the clinical study protocol, general guidelines, and data management plan. Once 
the sponsor/designee acknowledges that all data are acceptable, the data will be declared a 
“clean file,” and the data will be frozen/locked.
A quality audit will be performed by the Data Management group.  When all issues from the 
audit are resolved, and all data management processes are completed for finalizing the 
database, the database will be ready for statistical analysis by NPS or designee.
7.2
Record Retention
All source documents, records, and reports will be retained by the study site in accordance with 
ICH guidelines. These documents include all primary data or copies thereof (eg, drug records, 
copies of eCRFs, laboratory records, data sheets, correspondence, signed subject 
consent/assent documents, ECGs, photographs, and computer records) which are a result of the 
original observations and activities of the study and are necessary for the reconstruction and 
evaluation of any study report.
The clinical investigators will maintain copies of these essential documents for approximately 
10 years or as dictated by local regulatory requirements or until instructed in writing by the 
sponsor that records may be destroyed or forwarded to the sponsor.  In accordance with 
regulatory guidelines, these records will be available for inspection and copying if requested by 
a properly authorized employee of the FDA/EU Health Authorities.
8
STATISTICAL METHODOLOGY AND SAMPLE SIZE
Detailed statistical analysis methods will be conducted as described in the Statistical Analysis 
Plan (SAP) for this study.  Deviations from the SAP (if any) will be described and justified in 
the clinical study report (CSR). 
Due to the limited size of the study population descriptive statistics will be used with a goal of
summarizing the sample which discourages the use of inferential statistics.
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.
8.1
Demographic and Baseline Variables
Demographic and/or other Baseline variables obtained at the screening and baseline visit are 
listed below.  Abnormal findings of clinical significance (if any) will be recorded as past 
medical history.

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
Demography (including age, sex, and race)

Medical history

SBS history, including remnant anatomy

Vital signs, including oral temperature, heart rate, blood pressure, body weight, head 
circumference (up to 36 months of age), height/length, and length trends on growth charts

Physical examination

Prior medications (medications used within 14 days prior to screening), including drug 
name, dose, route, reason for use, and therapy dates.  Medications used concomitantly will 
be recorded as concomitant medications.

Electrocardiogram (12-lead) variables will include general findings of
(normal/abnormal/abnormal, clinically significant).  The cause of any clinically significant 
ECG will be specified.

Laboratory test results:  Serum chemistries, hematology, and urinalysis

Citrulline levels

Presence of antibodies to teduglutide and titer level, if present (active treatment groups 
only)

Gastrointestinal imaging (upper GI with contrast, abdominal ultrasound, 
colonoscopy/sigmoidoscopy, fecal occult blood) (active treatment groups only)

Pregnancy testing for children of child-bearing potential (active treatment groups only)

Nutritional support (eg, PN/IV volume and calorie usage)

Data entered in the nutritional diaries
Descriptive statistics (mean, median, standard deviation, minimum and maximum values, and 
the number and percentage of subjects in specified categories by treatment group) will be 
presented, as appropriate, to summarize the demographic and baseline variables. 
Prior and concomitant medications will be coded using the current version of the World Health 
Organization Drug Dictionary with regard to drug class and drug name.  The number and 
percentage of subjects with specific prior medications will be summarized by treatment group. 
Medical history (including surgical history) will be coded using the current version of the
Medical Dictionary for Regulatory Activities (MedDRA).  The number and percentage of 
subjects with specific histories will be summarized by system organ class and preferred term 
for each treatment group.

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Teduglutide (rDNA origin) for injection
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8.2
Safety and Tolerability Variables
The safety and tolerability variables include:

Adverse events, including GI symptoms 

Physical examination

Vital signs, including oral temperature, heart rate, blood pressure, body weight, head 
circumference (up to 36 months of age), height/length, and length trends on growth charts

Electrocardiograms

Laboratory safety data, including electrolyte balance and glucose 

Antibodies to teduglutide

Oral/enteral feeding tolerance

Nutritional intake and urinary/fecal output (intake/output) (when available)

GI-specific testing including imaging (eg, colonoscopy, sigmoidoscopy) abdominal 
ultrasound, fecal occult blood testing and upper GI series with small bowel follow-through
Adverse events will be coded using the current version of MedDRA. Treatment emergent AEs 
will be summarized by system organ class and preferred term for each treatment group. The 
number and percentage of subjects with AEs, SAEs, AEs that lead to discontinuation, study 
drug-related AEs (determined by the investigator), and AEs that lead to death will be 
summarized by treatment group. AEs will also be summarized by treatment group with regard 
to intensity and relationship to study drug.  For AEs of special interest, the CTCAE grading 
system will be used as described in Section 6.1.4.
For laboratory tests, vital signs, body weight, ECG, 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 absolute 
values and change from baseline at each scheduled visit for each treatment group.
The number and percentage of subjects classified as having positive specific antibodies to 
teduglutide will be used to summarize the presence of antibodies for each treatment group.
8.3
Pharmacodynamic Variables
The following pharmacodynamic parameters will be measured:

20% to 100% parenteral support reduction at Week 24 (EOT)

100% reduction in PN/IV volume support  (any subjects who are able to completely wean 
off PN/IV support) compared to baseline at EOS

A  decrease in parenteral support (calories and volume)

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
An increase in enteral nutritional tolerance (calories and volume)

Change from baseline in PN/IV support, citrulline, and enteral support at Week 24 
(or EOT)

Change from baseline in PN/IV support, citrulline, and enteral support at Week 28 
(or EOS)

Change from baseline in PN/IV support, citrulline, and enteral support at Week 24 
(or EOT) compared to Week 28 (or EOS)

Urine output (collected or calculated volume)

Change in weight, height (length), and head circumference (where appropriate)

Change in PN/IV support 3 and 6 months (as applicable) after EOT compared to baseline 
for those subjects who developed antibodies specific to teduglutide

Change in hours per day or days per week of PN/IV support.

Intensity of  response (PN/IV reduction and advance in enteral support) at each visit

Proportion of responders (ie, subjects who achieve at least a 20% reduction in parenteral 
support) at Weeks 4, 8, 12, 16, 20, and 24 weeks
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 each treatment group.
8.4
Other Variables 
Other variables will be analyzed by treatment group including:

Subject disposition

Duration of study drug exposure

Subjects will be considered compliant if study drug was taken according to protocol and 
assigned treatment group for ≥ 80% of doses. Data will be taken from the Study Drug 
Accountability completed by the site staff.  The number and percentage of subjects who 
were compliant will be presented by treatment group.

The number and percentage of subjects who complete the study, are lost to follow up, or
discontinued from the study (including reason for study withdrawal) will be summarized by 
treatment group

The study drug dose by duration will be summarized by treatment group.

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8.5
Analysis Populations, Data Sets, and Time Points
Analysis Populations
8.5.1
The intent-to-treat (ITT) population is defined as any subjects who were randomized into the
study.  The safety population is defined as the subset of ITT with subjects who received at least 
one administration of study drug with any safety follow-up.  The primary population analyzed 
for efficacy will be the ITT population.  An additional per-protocol population analysis will 
also be performed as secondary/sensitivity analysis.  Detailed per-protocol evaluable 
definitions will be documented in the SAP.
8.6
Statistical/Analytical Issues
Adjustments for Covariates
8.6.1
No Baseline stratification parameter is employed in this study.
Handling of Dropouts or Missing Data
8.6.2
All subjects randomized will be included in the analyses. Missing safety parameters will not be
imputed. Details for the imputation algorithm for the missing endpoint values for PN/IV 
volume will be detailed in the SAP.
Interim Analyses and Data Monitoring
8.6.3
No interim analyses are planned.
An independent DSMB will review the data on a routine basis and may have access to data 
from the study for safety assessment. Details of the roles and responsibilities of the DSMB 
members and the structure and scope of the DSMB meetings will be provided in a separate 
DSMB Charter.
Multiple Comparisons/Multiplicity
8.6.4
Given the small sample size, no hypothesis testing will be conducted. Therefore, there will be 
no adjustment for alpha level.
Use of an Efficacy Subset of Subjects
8.6.5
A per-protocol population will be analyzed for this study.
Examination of Subgroups
8.6.6
Because a small number of subjects are expected at each study site, data from all study sites 
will be pooled.
8.7
Determination of Sample Size
The sample size is determined based on the small patient population and the feasibility of the 
study, rather than power calculation.

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8.8
Changes to Planned Statistical Analyses
Changes made to planned statistical analyses (if any) described within this protocol will be 
incorporated into the SAP and any deviations from the SAP will be documented and justified 
in the final CSR.
9
ADMINISTRATIVE AND ETHICAL REQUIREMENTS
9.1
Declaration of Helsinki and Ethical Review
This protocol will be conducted in accordance with the current applicable ICH Guidelines, 
Good Clinical Practice, and the World Medical Association (WMA) Declaration of Helsinki 
and its amendments concerning medical research in humans.
In accordance with guidelines, the protocol, any advertisements and, informed consent/assent
forms will be reviewed and approved by the IEC/IRB. The sponsor will supply relevant 
material for the investigator to submit to the IRB for the protocol’s review and approval.  
Verification of the IEC/IRB approval of the protocol and the written consent/assent form will 
be forwarded to the sponsor/designee.
The investigator will inform the IEC/IRB of subsequent protocol amendments and any 
SUSARs if the NPS SMT has assessed it as an unanticipated problem.  Approval for protocol 
amendments will be transmitted in writing to the investigator.
The investigator will provide the IEC/IRB with progress reports at appropriate intervals (not to 
exceed 1 year) and a study summary report following the completion, termination, or 
discontinuation of the investigator’s participation in the study.
9.2
Subject Information, Informed Consent and Assent
In accordance with applicable guidelines, informed consent/assent shall be documented by the 
use of a written consent/assent approved by the IEC/IRB and signed by the subject and/or 
subject’s parent or guardian before any screening and protocol-specific procedures are 
performed.  A consent/assent form template will be provided by the sponsor/designee and 
adapted by the investigator to meet study site, state, and country ethical guidelines, as 
appropriate.
The investigator (or designee) will explain to the subject and/or the subject’s parent or 
guardian the nature of the study, the action of the test product, and any risks and benefits.  The 
subject and/or subject’s parent or guardian will be informed that participation is voluntary and 
that the subject can be withdrawn from the study at any time without prejudice to their 
subsequent care.
The subject and/or the subject’s parent or guardian will be given a copy of the fully executed 
consent/assent and the original will be maintained with the subject’s records.

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9.3
Subject Data Protection
All data provided to the sponsor/designee will be identified only by subject number and 
initials, thereby ensuring that the subject’s identity remains unknown.  The subject and/or the 
subjects’ parent or guardian should be informed in writing, that the subject’s data will be stored 
and analyzed in a computer, with confidentiality maintained in accordance with national and 
local legislation.  Study site-specific information must be added to the consent/assent as 
appropriate.
The subjects and/or the subjects’ parent or guardian also should be informed in writing that 
authorized representatives of the sponsor/designee and/or regulatory authorities may require 
access to those parts of the hospital/clinic records which are relevant to the study, including 
medical history, for data verification purposes.
The principal investigator is responsible for keeping a subject identification list of all subjects 
screened and enrolled which includes the following information: subject number, full name, 
and a secondary unique identifier (ie, hospital/clinic number).  A list of subjects who failed 
screening must also be maintained and be available for inspection.
9.4
Financial Disclosure
The FDA guidance document entitled “Financial Disclosure by Clinical Investigators” 
(February 2013) provides guidance to industry on its final rule on financial disclosure that 
became effective 02 February 1999 and was published as Title 21 Code of Federal Regulations 
Part 54.  This rule applies to all investigators participating in clinical studies to be submitted to 
the FDA in support of an application for market approval.  The financial disclosure statement 
must be updated if any relevant changes occur during the course of the study, again at the site 
close-out visit, and for 1 year after the completion of the study.
According to the guidance, financial arrangements that must be disclosed are defined as the 
following:

Compensation made to the investigator in which the value of compensation could be 
affected by study outcome 

A proprietary interest in the tested product, including, but not limited to, a patent, 
trademark, copyright, or licensing agreement

Any equity interest in the sponsor of a covered study (ie, any ownership interest, stock 
options, or other financial interest whose value cannot be readily determined through 
reference to public prices) 

An equity interest in a publicly held company that exceeds $50,000 in value 

Significant payments of other sorts, which are payments that have a cumulative monetary 
value of $25,000 or more made by the sponsor of a covered study to the investigator or the 
investigator’s institution to support activities of the investigator exclusive of the costs of 

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conducting the clinical study or other clinical studies, (eg, a grant to fund ongoing research, 
compensation in the form of equipment or retainers for ongoing consultation, or honoraria) 
during the time the clinical investigator is carrying out the study and for 1 year after 
completion of the study
Clinical investigator means only a listed or identified investigator or subinvestigator who is 
directly involved in the treatment or evaluation of research subjects.  The term also includes 
the spouse and each dependent child of the investigator.  Participating investigators must 
provide this information and complete necessary documentation as requested by the sponsor.
The intent of this regulation is to ensure the proper identification and disclosure of financial 
interests of clinical investigators that could affect the reliability of data submitted to the FDA 
in support of a market application.  Companies must meet these financial disclosure 
requirements, and failure to do so may result in the refusal by the FDA to accept an application 
for market approval of the study drug.
9.5
Changes to the Protocol
No change in the study procedures shall be effected without the mutual agreement of the 
sponsor and the investigator.  All changes must be documented as signed protocol 
amendments, or as a revised protocol.  Changes to the protocol may require notification to or 
approval by the IEC/IRB and the regulatory authorities before implementation. Local 
regulatory requirements must be followed.  Instructions for reporting deviations from the 
protocol can be found in the Study Reference Manual.
The sponsor/designee is responsible for the distribution of and training on any protocol 
amendment(s) to the principal investigator(s) and those concerned within the conduct of the 
study.  The principal investigator is responsible for the distribution of all amendments to the 
IEC/IRB and all staff concerned at his/her study site.
9.6
Investigator Obligations
The principal investigator at each study site must provide the following to the sponsor/designee 
prior to the start of the study:

A completed and signed FDA Form 1572.  If during the course of the study any changes 
are made that are not reflected on the original FDA Form 1572, a revised form must be 
completed and returned to the sponsor for submission to the FDA.

A current (within 2 years) signed and dated curriculum vitae for the principal investigator 
and all subinvestigators listed on FDA Form 1572, including a current office address which 
matches the address on the FDA Form 1572

Financial disclosure statement for the principal investigator, and subinvestigators (listed on 
the FDA Form 1572).  An updated financial disclosure statement must be provided at the 

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study close-out visit and/or annually to the sponsor and 1 year after completion of the 
study.

A copy of the original approval for conducting the study from the IEC/IRB. Renewals must 
be submitted at yearly intervals if the study is ongoing or as required by the institution.

A copy of the IEC/IRB-approved ICF/assent

IRB membership list or Department of Health and Human Services General Assurance 
Number, which must be maintained current during the trial

Laboratory certification and normal ranges, unless a central laboratory is being used 
exclusively
The “Principal Investigator Protocol Agreement Page” of this protocol must be signed and 
dated by the principal investigator for the study site.
9.7
Confidentiality/Publication of the Study
Any information shared by the sponsor regarding this study, including this protocol, is 
considered proprietary information and should be kept confidential.
The data generated by this clinical study are the property of the sponsor.  These data may be 
used by the sponsor, now and in the future, for presentation or publication at the sponsor’s 
discretion and/or for submission to regulatory agencies.  In addition, the sponsor reserves the 
right to review data from this study relative to the potential release of proprietary information 
30 days prior to submission to any publication or for any presentation.
9.8
Selection of a Primary Principal Investigator
The sponsor will select one primary principal investigator as a representative of all 
investigators for this study.  Roles, affiliations, and qualifications for the principal investigators 
will be included in the CSR appendices.  Where the signature of the principal investigator is 
required by regulatory authorities, this will also be included in the CSR appendices.
9.9
Study Termination
The sponsor reserves the right to discontinue the study for medical and/or administrative 
reasons at any time.

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10
REFERENCES
Buchman AL, Scolapio J, Fryer J. AGA technical review on short bowel syndrome and 
intestinal transplantation. Gastroenterology. 2003;124:1111-1134.
Common Terminology Criteria for Adverse Events (CTCAE).  US Department of Health and 
Human Services, National Institutes of Health, National Cancer Institute. Version 4.03, 
June 14, 2010.
Duro D, Kamin D, Duggan C.  Overview of Pediatric Short Bowel Syndrome.  J Pediatr Gastro 
and Nutr. 2008;47:S33-S36.
Fleming CR, Witzke D, Beart RW Jr.  Catheter-related Complications in patients Receiving 
Home Parenteral Nutrition. Ann Surg. 1980 Nov;192(5):593-599.
Jeppesen PB, Langholz E, Mortensen PB.  Intestinal failure defined by measurements of 
intestinal energy and wet weight absorption.  Gut. 2000;46:701-706.
Lewis SJ and Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J 
Gastroenterol. 1997 Sep;32(9):920-924.
O’Keefe SJ, Buchman AL, Fishbein TM, Jeejeebhoy KN, Jeppesen PB, Shaffer J. Short bowel 
syndrome and intestinal failure: consensus definitions and overview. Clin Gastroenterol 
Hepatol. 2006;4:6-10.
Messing B, Crenn P, Beau PBoutron-Ruault MC, Rambaud J-C, Matuchansky C.  Long-term 
survival and parenteral nutrition dependence in adult patients with the short bowel syndrome. 
Gastroenterology. 1999;117:1043-1050.

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APPENDIX 1:    CONSIDERATIONS FOR MANAGEMENT OF NUTRITIONAL 
SUPPORT DURING THE STUDY
Please consider the following clinical parameters identified as markers for adequate 
management of pediatric short bowel syndrome.  These parameters should also be considered 
for managing nutritional support (PN/IV and/or oral/enteral feeding) in terms of volume and 
calories during the treatment period.  

Considerations to adjust nutritional support in volume and calories will be made at all 
planned visits.

Maintaining growth (including weight and length and head circumference [for children up 
to 36 months of age]) by the subjects trending along their growth chart and adjusting 
calories/volumes to maintain the trend.

Other clinical evaluations
o
Normal serum electrolytes
o
Stable BUN/creatinine levels
o
Increase in the Volume Intake/Output ratio, including mixed output that can be 
collected

General consideration to possible clinical deterioration in SBS
o
Ability to maintain weight and growth velocity
o
Diarrhea (> 50 mL/kg/day with ostomy or >80mg/kg/day without ostomy)
o
Colic/vomiting frequency increased
o
Electrolyte changes or imbalance
o
Skin breakdown (“butt rot”)

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 72-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 oral fluid intake, the investigator should consider this 
when adjusting the PN/EN support in volume and calories.

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Figure A-1
Weaning Algorithm for Subjects Who are NOT Toilet Trained and in 
Diapers

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Figure A-2
Weaning Algorithm for Subjects Who are Toilet Trained and NOT in 
Diapers

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Figure A-3
Clinical Dehydration Assessment and PN/EN Adjustment