Clinical trial NCT03571516
Conditions: Short Bowel Syndrome
Keywords: Short bowel syndrome Teduglutide
Sponsor: Shire
Start date: 2018-08-31; Completion date: 2020-09-24
Enrollment: 10 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to evaluate the safety, efficacy/pharmacodynamics (PD) and pharmacokinetics (PK) of teduglutide treatment in infants with short bowel syndrome (SBS) dependent on parenteral (PN) support.

Detailed description:

Arms: arm 1: Participants will receive 0.05 milligram per kilogram (mg/kg) subcutaneous (SC) injection of teduglutide into abdomen or into either the thigh or arm once daily (QD) in addition to standard medical therapy for 24 weeks. arm 2: Participants will receive standard medical therapy for 24 weeks.
Interventions: intervention 1: Teduglutide intervention 2: Standard Medical Therapy intervention 3: Syringe intervention 4: Needle
Intervention descriptions: intervention 1: SC injection of 0.05 mg/kg teduglutide will be administered QD into abdomen or into either the thigh or arm for 24 weeks. intervention 2: Standard medical therapy will be administered for 24 weeks. intervention 3: Teduglutide will be administered using syringe (510k number: K980987). intervention 4: Teduglutide will be administered using needle (510k number: K021475).

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
 
 
NCT Number:   
NCT03571516 
 
Study Title:  
A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic 
Study of Teduglutide in Infants 4 to 12 Months of Age With Short Bowel 
Syndrome Who Are Dependent on Parenteral Support 
 
Study Number:  
SHP633-301 
 
 
Protocol Version and Date:  
 
Original Protocol:  
03 Oct 2017 
Amendment 1:  
18 Jan 2018 
Amendment 2:  
04 Dec 2018 
Amendment 3:  
24 May 2019 
Amendment 4:   
17 Dec 2019 
 


PROTOCOL: SHP633-301
TITLE:
A Randomized, Open-label, 24-Week Safety, Efficacy, and 
Pharmacokinetic Study of Teduglutide in Infants 4 to 12 Months of Age 
with Short Bowel Syndrome Who are Dependent on Parenteral Support
NUMBER
SHP633-301
PHASE
3 
DRUG:
Teduglutide
INDICATION:
Short bowel syndrome
EUDRACT NO.:
2017-003606-40
SPONSOR: 
Shire Human Genetic Therapies, Inc.
300 Shire Way
Lexington, MA 02421 USA
PROTOCOL 
HISTORY:
Original Protocol: 03 Oct 2017
Confidentiality Statement
This document contains confidential and proprietary information of Shire and is disclosed 
pursuant to confidentiality and non-disclosure obligations. This information should be used 
solely for the purposes for which it was provided and should not be copied, shared with, or 
disclosed to any third party without the express written consent of Shire.
For non-commercial use only


PROTOCOL SIGNATURE PAGE 
Sponsor's (Shire) Approval 
Signature: 
, MD P 
, Global C m1cal Development 
Investigator's Acknowledgement 
I have read this protocol for Shire Study SHP633-301. 
Date: 
Title: A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic Study of 
Teduglutide in Infants 4 to 12 Months of Age with Short Bowel Syndrome Who are Dependent 
on Parenteral Support 
I have fully discussed the objective(s) ofthis study and the contents of this protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to tllis protocol and to comply with its requirements, 
subject to etllical and safety considerations and guidelines, and to conduct the study in 
accordance with International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Hun1an Use (ICH) guidelines on Good Clinical Practice (GCP) and with the 
applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Address: 
(please hand print or type) 
Signature: -------------------------------- Date: 
Shire 
CONFIDENTIAL 
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SHP633-301 Protocol 
 
Teduglutide 
 
03 Oct 2017 
 
 
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EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Adverse Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as 
Required by Protocol within 24 hours to the Shire Global Drug Safety Department. Applicable 
fax numbers and e-mail address can be found on the form (sent under separate cover).  A copy of 
this form must also be sent to the Shire Medical Monitor by fax or e-mail:  
Fax:
,  Email: 
For protocol- or safety-related issues, the investigator must contact Quintiles Medical Support:
Primary Contact
Backup Contact 
, MD
, MD
Mobile:  
Mobile: 
US Toll Free Number: 
Phone: 
Phone: 
 
(medical emergencies)
Phone: 
 
(medical emergencies)
Email: 
Email: 
In addition, the investigator may also contact Shire:
, PharmD, MSc
Phone: 
Mobile: 
Email: 
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PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (e.g., inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (e.g., wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
European Union and Rest of World
Telephone numbers (provided for reference, if needed): 
Shire (USA)
 
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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
PRODUCT QUALITY COMPLAINTS..........................................................................................4
TABLE OF CONTENTS.................................................................................................................5
LIST OF TABLES...........................................................................................................................9
LIST OF FIGURES .........................................................................................................................9
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..................................................10
STUDY SYNOPSIS ......................................................................................................................11
STUDY SCHEDULES ..................................................................................................................16
BACKGROUND INFORMATION .......................................................................................20
1.
1.1
Short Bowel Syndrome ............................................................................................20
1.2
Teduglutide...............................................................................................................21
OBJECTIVES.........................................................................................................................22
2.
2.1
Rationale for the Study.............................................................................................22
2.2
Study Objectives ......................................................................................................22
STUDY DESIGN ...................................................................................................................23
3.
3.1
Study Design and Flow Chart ..................................................................................23
3.1.1
Screening Period ....................................................................................................23
3.1.2
Treatment Period....................................................................................................23
3.1.3
Follow-up Period ...................................................................................................24
3.2
Study Duration .........................................................................................................24
3.3
Sites and Regions .....................................................................................................24
STUDY POPULATION.........................................................................................................25
4.
4.1
Inclusion Criteria......................................................................................................25
4.2
Exclusion Criteria.....................................................................................................25
4.3
Reproductive Potential .............................................................................................26
4.4
Discontinuation of Subjects .....................................................................................26
4.4.1
Reasons for Discontinuation..................................................................................27
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit .................................27
PRIOR AND CONCOMITANT TREATMENT ...................................................................28
5.
5.1
Prior Medications and Procedures............................................................................28
5.2
Concomitant Medications and Procedures...............................................................28
5.3
Permitted Treatment.................................................................................................28
5.4
Prohibited Treatment................................................................................................28
INVESTIGATIONAL PRODUCT ........................................................................................29
6.
6.1
Identity of Investigational Product...........................................................................29
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6.2
Administration of Investigational Product ...............................................................29
6.2.1
Interactive Response Technology for Investigational Product Management ........29
6.2.2
Allocation of Subjects to Treatment ......................................................................29
6.2.3
Dosing....................................................................................................................29
6.2.4
Unblinding the Treatment Assignment..................................................................30
6.2.5
Dose Selection Rationale .......................................................................................30
6.3
Labeling, Packaging, and Storage ............................................................................31
6.3.1
Labeling .................................................................................................................31
6.3.2
Storage and Handling.............................................................................................31
6.4
Drug Accountability.................................................................................................32
6.5
Subject Compliance..................................................................................................33
STUDY PROCEDURES........................................................................................................34
7.
7.1
Study Schedule.........................................................................................................34
7.1.1
Screening................................................................................................................34
7.1.2
Treatment Period....................................................................................................34
7.1.3
Follow-up Period ...................................................................................................34
7.2
Study Evaluations and Procedures ...........................................................................34
7.2.1
Demographics and Other Baseline Characteristics................................................34
7.2.2
Efficacy Assessments.............................................................................................35
7.2.3
Safety Assessments................................................................................................36
7.2.4
Pharmacokinetic Assessments ...............................................................................39
7.2.5
Health Economics and Outcomes Research ..........................................................39
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................41
8.
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................41
8.1.1
Severity Categorization..........................................................................................41
8.1.2
Relationship Categorization...................................................................................42
8.1.3
Outcome Categorization ........................................................................................42
8.1.4
Symptoms of the Disease under Study ..................................................................43
8.1.5
Clinical Laboratory and Other Safety Evaluations ................................................43
8.1.6
Pregnancy...............................................................................................................43
8.1.7
Abuse, Misuse, Overdose, and Medication Error ..................................................43
8.2
Serious Adverse Event Procedures ..........................................................................44
8.2.1
Reference Safety Information ................................................................................44
8.2.2
Reporting Procedures.............................................................................................44
8.2.3
Serious Adverse Event Definition .........................................................................45
8.2.4
Serious Adverse Event Collection Time Frame.....................................................45
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................45
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8.2.6
Fatal Outcome........................................................................................................46
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................46
8.3
Adverse Events of Special Interest...........................................................................46
8.4
Dose Interruption Criteria ........................................................................................47
DATA MANAGEMENT AND STATISTICAL METHODS ...............................................48
9.
9.1
Data Collection.........................................................................................................48
9.2
Clinical Data Management.......................................................................................48
9.3
Statistical Analysis Process......................................................................................48
9.4
Planned Interim Analysis, and Data Monitoring Committee ...................................48
9.5
Sample Size Calculation and Power Considerations................................................49
9.6
Study Population ......................................................................................................49
9.7
Efficacy Analyses.....................................................................................................49
9.8
Safety Analyses ........................................................................................................51
9.9
Health Economics and Outcomes Research Analyses .............................................51
9.10
Pharmacokinetics Analyses......................................................................................52
SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES ............................................53
10.
10.1
Sponsor’s Responsibilities .......................................................................................53
10.1.1 Good Clinical Practice Compliance.......................................................................53
10.1.2 Indemnity/Liability and Insurance.........................................................................53
10.1.3 Public Posting of Study Information......................................................................53
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................54
10.1.5 Study Suspension, Termination, and Completion..................................................54
10.2
Investigator’s Responsibilities .................................................................................54
10.2.1 Good Clinical Practice Compliance.......................................................................54
10.2.2 Protocol Adherence and Investigator Agreement ..................................................55
10.2.2.1
Documentation and Retention of Records .............................................55
10.2.2.2
Electronic Case Report Forms................................................................55
10.2.2.3
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................55
10.2.2.4
Audit/Inspection .....................................................................................56
10.2.2.5
Financial Disclosure...............................................................................56
10.3
Ethical Considerations..............................................................................................56
10.3.1 Informed Consent...................................................................................................56
10.3.2 Institutional Review Board or Ethics Committee ..................................................57
10.4
Privacy and Confidentiality......................................................................................57
10.5
Study Results/Publication Policy .............................................................................58
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REFERENCES .......................................................................................................................60
11.
APPENDICES ........................................................................................................................62
12.
Appendix 1
Protocol History .....................................................................................63
Appendix 2
Guidelines for Nutritional Support Management During the Study ......64
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LIST OF TABLES
Table 1:
Study Schedule: Visits -1 to 12 .....................................................................16
Table 2:
Study Schedule: Visits 13-28 ........................................................................18
Table 3:
Prohibited Treatment.....................................................................................28
Table 4:
List of Laboratory Tests ................................................................................37
Table 5:
Approximate Volume of Blood to be Drawn from Each Subject .................38
LIST OF FIGURES
Figure 1:
Study Schematic ............................................................................................23
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation
Definition
AE
adverse event
AUCtau,ss
area under the concentration-time curve at steady-state over the dosing interval
CL/F
apparent clearance
Cmax,ss
maximum plasma concentration at steady state
CRO
contract research organization
eCRF
electronic case report form
DMC
data monitoring committee
EDC
electronic data capture
EMA
European Medicines Agency
EN
enteral nutrition
EOS
end of study
EOT
end of treatment
EQ-5D-5L
5-level EuroQol five dimensions questionnaire
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
gastrointestinal 
GLP
glucagon-like peptide
HIPAA
Health Insurance Portability and Accountability Act
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use
ICMJE
International Committee of Medicinal Journal Editors
I/O
oral fluid intake and urine output
IP
Investigational product
IRB
Institutional Review Board
ITT
intent-to-treat
MedDRA
Medical Dictionary for Regulatory Activities
PK
pharmacokinetics
PN
parenteral nutrition
SAE
serious adverse event
SAP
statistical analysis plan
SBS
short bowel syndrome
SC
subcutaneous
SD
standard deviation
SOC
standard of care
ULN
upper limit of normal 
US
United States
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STUDY SYNOPSIS
Protocol number: SHP633-301
Drug: Teduglutide
Title of the study: A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic Study of 
Teduglutide in Infants 4 to 12 Months of Age with Short Bowel Syndrome Who are Dependent on Parenteral 
Support
Number of subjects (total and for each treatment arm):
At least 10 subjects will be randomized: at least 5 subjects in a teduglutide treatment arm and at least 5 subjects in 
a standard of care (SOC) comparator arm
Investigator(s): Multicenter study
Site(s) and Region(s): 
This study is planned to be conducted in approximately 5 to 10 sites globally.
Study period (planned):
2017-2020
Clinical phase:
3
Objectives:
The objectives of this clinical study are to evaluate the safety, efficacy/pharmacodynamics and pharmacokinetics 
(PK) of teduglutide treatment in infants with short bowel syndrome (SBS) dependent on parenteral support.
Investigational product, dose, and mode of administration:
Teduglutide 0.05 mg/kg by subcutaneous (SC) injection once daily into 1 of the 4 quadrants of the abdomen or 
either thigh or arm.
Methodology:
This is a randomized, multicenter, open-label study, consisting of a minimum 2-week 
screening period, a 24-week treatment period, and a 4-week follow-up period. 
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Study eligibility will be confirmed during the screening period (minimum: 2 weeks; maximum 4 weeks).  At the 
baseline visit (Week 0), subjects will randomized 1:1 to the teduglutide or SOC treatment arm.  Randomization 
will be stratified according to the presence of a small bowel ostomy (end jejunostomy or ileostomy).  During the 
24-week treatment period, subjects in the SOC treatment arm will receive standard medical therapy for SBS; 
while those in the teduglutide arm will receive 0.05 mg/kg SC once daily in addition to standard medical therapy.  
Subjects in both arms will follow the same visit schedule and assessments. Subjects will be monitored weekly 
with phone or clinic visits. Clinic visits will occur at Weeks 1, 2, 4, 6, 9, 12, 16, 20, 24, and 28. At all site visits 
and telephone contacts, safety will be monitored and nutritional support will be reviewed and adjusted as needed. 
To maintain consistency across centers, guidance and training will be provided to help sites follow the nutritional 
support adjustment guidelines (developed with SBS expert input and provided in the protocol) related to decisions 
for parenteral nutrition (PN) reduction and advances in enteral feeds based on weight gain, urine and stool output, 
and clinical stability. Deviations from the guidelines are not considered a protocol deviation.
Sparse PK sampling, in the teduglutide treatment arm only, will occur at baseline (t=0, 1, and 4 hours) and at 
Week 6 or 12 (t= 2 hours) .
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up period until the end 
of study (Week 28/EOS) during which time subjects will receive standard medical therapy, but no investigational 
product will be administered.  At EOS the subject may enroll in an extension study that will capture long-term 
safety data and provide the opportunity for additional teduglutide treatment.  The follow-up period may be 
interrupted and the subject may consent to the extension study immediately if at least one of the following 
“escape” criteria is met:
1.
Increasing PN requirements following discontinuation of teduglutide.
2.
Deteriorating nutritional status (e.g., weight loss or growth failure) despite maximal tolerated enteral 
nutrition (EN) following teduglutide discontinuation.
3.
Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and electrolyte intake 
following teduglutide discontinuation.
4.
Severe diarrhea related to teduglutide discontinuation.
Inclusion and Exclusion Criteria:
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1.
Informed consent by the parent or legal guardian. 
2.
Male or female infant 4 to 12 months corrected gestational age.
3.
Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and baseline.
4.
Short bowel syndrome with dependence on parenteral support to provide at least 50% of fluid or caloric 
needs.
5.
Stable PN requirements for at least 1 month prior to screening, defined as a ≤10% change in the weight-
normalized parenteral total fluid and caloric intake, despite attempts to wean PN, notwithstanding 
transient instability for events such as sepsis or interruption of central venous access.
6.
Lack of terminal ileum and ileocecal valve
7.
Parent or legal guardian understands and is willing and able to fully adhere to study requirements as 
defined in this protocol.
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Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1.
Previous treatment with teduglutide.
2.
Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus inclusion disease, 
etc.
3.
Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility, that is the primary contributing factor to feeding intolerance and 
inability to reduce parenteral support, prior to screening. Dysmotility is defined as severe if it is 
expected to limit the advancement of enteral feeding.
4.
Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral aversion in the 
absence of a feeding tube.
5.
Intestinal obstruction or clinically significant intestinal stenosis.
6.
Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or major intestinal 
resection or anastomosis, within 3 months prior to screening or planned during the study period.
7.
Unstable cardiac disease.
8.
Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
9.
Biliary obstruction, stenosis, or malformation. 
10. Clinically significant pancreatic disease. 
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b.
Platelet count <100×10^3/µl due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d.
Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 2-week period
13. More than 3 serious complications of intestinal failure (e.g., catheter-associated bloodstream infections, 
interruption of nutrition due to feeding intolerance, catheter-associated thrombosis, severe fluid or 
electrolyte disturbances) within 1 month prior to or during screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile polyposis or Beckwith-
Wiedemann syndrome, or first degree relative with early onset of gastrointestinal cancer (including 
hepatobiliary and pancreatic cancers). 
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 (GLP-2); insulin-
like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs of these hormones; or 
glutamine. 
16. Participation in a clinical study using an experimental drug within 3 months or 5.5 half-lives of the 
experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, closely-related 
compounds, or any of the stated ingredients.
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts the subject at any 
undue risk, prevents completion of the study, or interferes with analysis of the study results.
Maximum Duration of Subject Involvement in the Study:
The study consists of a 2-week screening period, a 24- week treatment period, and a 4-week follow-up period.
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Endpoints:
Efficacy
Efficacy endpoints consist of the following:
Primary

Reduction in weight-normalized parenteral nutrition (PN) fluid volume by at least 20% from baseline at 
Week 24/EOT
Secondary

Reduction in weight-normalized parenteral calories by at least 20% from baseline to Week 24/EOT

Achievement of enteral autonomy by week 24

Change in weight-normalized parenteral fluid volume from baseline to each visit

Change in weight-normalized parenteral calories from baseline to each visit

Change in weight-normalized enteral fluid volume from baseline to each visit

Change in weight-normalized enteral caloric intake from baseline to each visit

Increase in weight-normalized enteral fluid intake by at least 20% from baseline to Week 24/EOT

Increase in weight-normalized enteral caloric intake by at least 20% from baseline to Week 24/EOT
Pharmacokinetics
Pharmacokinetic endpoints include but are not limited to the following:

Area under the plasma concentration–time curve at steady state over the dosing internal (AUCtau, ss)

Maximum plasma concentration at steady state (Cmax,ss)

Apparent clearance (CL/F)
Safety
Safety endpoints consist of the following:

Adverse events (AEs)

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output

Stool (including mixed) output  

Antibodies to teduglutide 
Health Economics and Outcomes Research
Health economics and outcomes research (HEOR) endpoints include the following:

The 5-level EuroQol five dimensions questionnaire (EQ5D-5L) quality of life questionnaire to be 
completed by the subjects’ caregivers at baseline and Week 24

Cumulative number of hospitalization days during the study
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Statistical Methods:
Efficacy
Analyses of weekly PN support will be based on 2 data sources: the subject diary data (also referred to as actual 
data) and the investigator prescribed data.  
The number and percentage of subjects who achieve at least a 20% reduction from baseline in weight-normalized 
average daily PN volume at Week 24/EOT and the number and percentage of subjects who achieve at least a 20% 
reduction from baseline in weight-normalized parenteral calories at Week 24/EOT will be summarized by 
treatment arm.
During the treatment period, a subject will be considered to have achieved enteral autonomy (completely weaned 
off PN) at a given visit if the investigator prescribes no PN at that visit and for the remainder of the treatment 
period, and there is no use of PN recorded in the subject diary during the week prior to that visit and for the 
remainder of the treatment period.  During the follow-up period, a subject will be considered to have achieved 
enteral autonomy at a given visit if the investigator prescribes no PN at that visit and there is no use of PN 
recorded in the subject diary during the week prior to that visit. The number and percentage of subjects who 
achieve enteral autonomy at each scheduled visit, as well as at EOT, will be summarized by treatment arm. 
The absolute and percent change in weight-normalized weekly PN volume, parenteral calories, enteral fluid 
volume, and enteral caloric intake, from baseline to each scheduled visit, as well as at EOT, will be summarized 
by treatment arm using descriptive statistics.
The number and percentage of subjects who demonstrate an increase in weight-normalized enteral fluid intake by 
at least 20% from baseline to Week 24/EOT and the number and percentage of subjects who demonstrate an 
increase in weight-normalized enteral caloric intake by at least 20% from baseline to week 24/EOT will be 
summarized by treatment arm.
Pharmacokinetics
Plasma concentrations will be summarized using descriptive statistics (number, mean, and standard deviation) at 
nominal time points. Pharmacokinetic parameters will be derived using a population PK modeling approach and 
summarized using descriptive statistics (number, mean, standard deviation, geometric mean, coefficient of 
variation, minimum, median, and maximum). 
Safety
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Treatment-emergent AEs will be summarized by system organ class and preferred term using descriptive statistics 
(e.g., number and percentage of subjects). Adverse events will be summarized by severity and relationship to 
treatment. In addition, serious adverse events  will also be tabulated by overall and treatment-related events. AEs 
leading to treatment discontinuation and death will also be summarized.
For laboratory tests; vital signs; urine and stool output; weight, length, and head circumference Z-scores; and 
descriptive statistics (e.g., n, mean, standard deviation, median, minimum and maximum values, and the number 
and percentage of subjects in specified categories) will be used to summarize the absolute values and change from 
baseline at each visit.
The number and percentage of subjects classified as having antibodies to teduglutide will be used to summarize 
the presence of antibodies.  
Health Economics and Outcomes Research
The HEOR endpoints will be summarized descriptively.  
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STUDY SCHEDULES
Table 1:
Study Schedule: Visits -1 to 12
Procedures
Screening
Baseline 
(Week 0)
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
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit type
Site
Site
Site
Site
Tel
Site
Tel
Site
Tel
Tel
Site
Tel
Tel
Site
Study day
-14
0
7
14
21
28
35
42
49
56
63
70
77
84
±window (days)
-2 weeks
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Informed consent
X
Eligibility
X
X
Randomization
X
Demographics 
X
SBS history
X
Medical and surgical history
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications and 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
EQ-5D-5L
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, vital signs, 
weight
X
X
X
X
X
X
X
X
Length and head circumference
X
X
X
X
UGI/SBFT
X
Safety labs and urinalysisb, c
X
Xb
X
X
(X)
X
(X)
X
(X)
(X)
X
(X)
(X)
X
PK samplinga
X
[X]d
[X]d
Antibodies to teduglutidea,e
X
Xe
Native GLP-2f
X
Provide intake and output 
diariesg
X
X
X
X
X
X
X
X
Review diaries and nutritional 
support
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional support as 
neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
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Table 1:
Study Schedule: Visits -1 to 12
Procedures
Screening
Baseline 
(Week 0)
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
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit type
Site
Site
Site
Site
Tel
Site
Tel
Site
Tel
Tel
Site
Tel
Tel
Site
Study day
-14
0
7
14
21
28
35
42
49
56
63
70
77
84
±window (days)
-2 weeks
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Dispense IPa, i
X
X
X
X
X
X
X
EN=enteral nutrition;EQ-5D-5L=five-level EuroQol five dimensions questionnaire; GLP-2=glucagon-like peptide 2; INR=international normalized ratio; IP=investigational product; 
PK=pharmacokinetics; PN=parenteral nutrition; PT=prothrombin time; UGI/SBFT=upper GI series with short bowel follow-through 
a Applicable to the teduglutide treatment arm only. 
b At baseline, safety labs (Table 4) and PK can be separated by 1 day if blood volumes are limiting. Safety labs at telephone visits will be collected at the discretion of the investigator. For all subjects in 
the teduglutide treatment arm, PT and INR will be tested at baseline, and repeated if clinically indicated.
c Urinalysis will consist of urine sodium and specific gravity. Urine collection should be attempted, but inability to obtain urinalysis is not a protocol deviation.
d Subjects will have blood samples taken for teduglutide PK analysis predose and 1 and 4 hours post dose at baseline (Visit 0).  Subjects also will have blood samples taken for teduglutide PK analysis 
2 hours post dose at Week 6 (Visit 6) or Week 12 (Visit 12) of the treatment period.
e Samples for antibody analysis will be drawn at the baseline and Week 12 visits.  Blood samples while subjects are receiving teduglutide should be drawn at least 14 hours after the previous dose.
f Blood samples for native GLP-2 should be collected postprandial.  Native GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at investigator 
discretion based on weekly/monthly total volume.  
g Intake diaries will collect actual PN volume and hours per day and EN volume and calories. Intake diaries should be completed daily throughout the study. Urine and stool output should be recorded in 
the output diary over a 48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PN prescription. 
h Parenteral support adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment provided in Appendix 2.
i The initial dose will be calculated based on body weight measured at baseline (Visit 0), and adjusted as needed, based on body weight measured at each in-clinic study visit.
Note: (X) denotes optional assessments; [X] denotes possible PK sampling time point (Refer to footnote “e”.)
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Table 2:
Study Schedule: Visits 13-28
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 
(EOT/ET)
Week 
25
Week 
26
Week 
27
Week 
28 
(EOS)a
Visit number
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit type
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Study day
91
98
105
112
119
126
133
140
147
154
161
168
175
182
189
196
±window (days)
±3
±3
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications 
and procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
EQ-5D-5L
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, vital 
signs, weight
X
X
X
X
Length and head 
circumference
X
X
X
X
Safety labs and 
urinalysisb,c
(X)
(X)
(X)
X
(X)
(X)
(X)
X
(X)
(X) 
(X)
X
(X)
(X)
(X)
X
Antibodies to 
teduglutided,e
X
Native GLP-2f
X
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Table 2:
Study Schedule: Visits 13-28
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 
(EOT/ET)
Week 
25
Week 
26
Week 
27
Week 
28 
(EOS)a
Visit number
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit type
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Study day
91
98
105
112
119
126
133
140
147
154
161
168
175
182
189
196
±window (days)
±3
±3
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
Provide intake and output 
diaries
X
X
X
Review diaries and 
nutritional supportg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional support 
as neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess follow-up period 
escape criteria
X
X
X
X
Dispense IPd, i
X
X
EN=enteral nutrition; EOS=end of study; EOT=end of treatment; EQ-5D-5L=five-level EuroQol five dimensions questionnaire; ET=early termination; GLP-2=glucagon-like peptide 2; 
INR=international normalized ratio; IP=investigational product; PN=parenteral nutrition; PT=prothrombin time; UGI/SBFT=upper GI series with short bowel follow-through
a At EOS subjects may enroll in an extension study, if subjects require treatment before the end of the 4-week follow-up they may enter the extension study immediately.
bSafety labs at telephone visits will be collected at the discretion of the investigator. For all subjects in the teduglutide treatment arm, PT and INR are tested if clinically indicated.
c Urinalysis will consist of urine sodium and specific gravity.  
d Applicable to the teduglutide treatment arm only. 
e Samples for antibody analysis will be drawn at the EOS (Week 28) visit.
f Blood samples for native GLP-2 should be collected postprandial.  Native GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at investigator 
discretion based on weekly/monthly total volume.
g Intake diaries will collect actual PN volume and hours per day and EN volume and calories. Intake diaries should be completed daily throughout the study. Urine and stool output should be recorded in 
the output diary over a 48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PN prescription. 
h Parenteral support adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment provided in Appendix 2.
Note: (X) denotes optional assessments.
i The dose will be adjusted as needed, based on body weight measured at each in-clinic study visit.
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BACKGROUND INFORMATION
1.
1.1
Short Bowel Syndrome
Short bowel syndrome (SBS) is a rare disorder resulting from congenital abnormalities or severe 
intestinal diseases that result in major surgical resections of the small intestine (O'Keefe et al., 
2006).  Unlike the adult population, the majority of cases of SBS in pediatric subjects are due to 
congenital anomalies or catastrophic events that occur during infancy such as necrotizing 
enterocolitis, gastroschisis, intestinal atresia, midgut volvulus, or long-segment Hirschsprung 
disease (Beattie et al., 2010; Goulet and Ruemmele, 2006).  A Canadian population-based study 
in neonates estimates an overall incidence of SBS to be 24.5 cases per 100,000 live births (Wales 
et al., 2004).  
The small intestine is capable of remarkable adaptation, but excessive loss of absorptive surface 
area or specialized functions can lead to dependence on parenteral nutrition (PN) fluids (O'Keefe 
et al., 2006).  Although PN is life-sustaining in intestinal failure, it is associated with serious 
complications, including liver disease, life-threatening catheter-related blood stream infections, 
and central venous thrombosis (Beattie et al., 2010; Goulet and Ruemmele, 2006).  Dependence 
on PN is also associated with reduced quality of life in both patients and caregivers and has an 
extremely high cost of care (Huisman-de Waal et al., 2007).  About 30% of infants with SBS 
become independent of PN requirements within 12 months of the initial insult, and an additional 
10% wean off PN within 24 months. After this time, linear intestinal growth slows.  It is 
estimated that 42% to 86% of pediatric patients with SBS are able to become independent of PN 
within 1 to 3 years (Gonzalez-Hernandez et al., 2017; Khan et al., 2015; Squires et al., 2012).  
Nevertheless, despite optimal medical management, some children remain dependent on PN for 
many years (Squires et al., 2012).  Infants who have less than 10% of expected small intestinal 
length for their gestational age have a low likelihood of ever achieving enteral autonomy (i.e., 
independence from parenteral support).  Providing the maximum tolerated amount of enteral 
nutrition (EN) has been the primary strategy to promote enteral adaptation (Spencer et al., 2005).  
Accelerating the adaptive process and achieving enteral autonomy is an urgent goal for all 
patients with SBS who are dependent on PN (Khan et al., 2015; Squires et al., 2012).  The 
adaptive process is in part controlled by glucagon-like peptide 2 (GLP-2), a 33 amino acid 
peptide hormone secreted from L-type enteroendocrine cells in the terminal ileum and colon in 
response to luminal nutrients and bile acids (Martin et al., 2006).  The post-prandial plasma 
concentration of GLP-2 in infants with SBS correlates with length of the remaining small 
intestine (Sigalet et al., 2004).  Infants who lack terminal ileum may have impaired adaptation 
due to inadequate production of GLP-2.
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1.2
Teduglutide
Teduglutide is a novel, recombinant analog of naturally occurring human GLP-2 that regulates 
the functional and structural integrity of the cells lining the gastrointestinal (GI) tract. 
Teduglutide is a 33-amino acid peptide that differs from native GLP-2 in the substitution of 
glycine for alanine at the second position at the N-terminus.  As a result, teduglutide 
demonstrates resistance to degradation by dipeptidyl peptidase 4 (DPP-4) and therefore 
maintains a longer elimination half-life (t1/2), approximately 2 hours in healthy adult subjects, 
1.3 hours in adult SBS subjects, and 0.22 hours in pediatric SBS subjects, compared to the native 
peptide, which has a t1/2 of approximately 7 minutes.  Teduglutide has been shown in animal 
studies and previous human clinical trials to increase villus height and crypt depth in the 
intestinal epithelium, thereby increasing the absorptive surface area of the intestines (Tappenden 
et al., 2013; Thymann et al., 2014). 
A Phase 3 study, TED-C13-003, has been completed in pediatric SBS subjects.  In this study, 
teduglutide was administered to 3 cohorts of pediatric subjects from ages 1-17 years.  
Thirty-seven pediatric subjects received teduglutide at doses of 0.0125, 0.025, or 0.05 mg/kg/day 
for 12 weeks.  Five additional pediatric subjects were enrolled in an observational standard of 
care (SOC) cohort.  There were clear dose-dependent effects of teduglutide seen at the 0.025 and 
0.05 mg/kg/day doses compared to SOC and the 0.0125 mg/kg/day dose.  In the 
0.025 mg/kg/day cohort there was a reduction in PN volume at Week 12 of 37%, including 
complete independence from PN support in 1 subject, and a reduction of 3.94 hours per day 
infusion time.  In the 0.05 mg/kg/day cohort there was a reduction in PN volume at Week 12 of 
39%, including complete independence from PN support in 3 subjects, and a reduction of 
4.18 hours per day infusion time.  Teduglutide was generally safe and well tolerated by pediatric 
subjects in all dosing cohorts.  There were no deaths during the study and no treatment-emergent 
serious adverse events (SAEs) related to teduglutide were reported.  No discontinuations from 
study were due to adverse events (AEs).  Additional studies in pediatric patients with SBS are 
ongoing.
Teduglutide (0.05 mg/kg/day) is currently approved for the treatment of adult patients with SBS 
in >30 countries.  On 29 Jun 2016, the European Commission granted an extension of the Market 
Authorization for teduglutide for the treatment of patients aged 1 year and above with SBS.  
Always refer to the latest version of the investigator’s brochure for the overall risk/benefit 
assessment and the most accurate and current information regarding the drug metabolism, 
pharmacokinetics, efficacy and safety of teduglutide (SHP633).
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OBJECTIVES
2.
2.1
Rationale for the Study 
There is no approved pharmacological therapy to improve intestinal adaptation in infants with 
SBS who are dependent on parenteral support.  This study will evaluate whether teduglutide is 
safe and effective in this patient population.  
2.2
Study Objectives
The objectives of this study are to evaluate the safety, efficacy/pharmacodynamics and 
pharmacokinetics (PK) of teduglutide treatment in infants with SBS dependent on parenteral 
support.
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STUDY DESIGN
3.
3.1
Study Design and Flow Chart
This is a randomized, multicenter, open-label study, consisting of a minimum 2-week screening 
period, a 24-week treatment period and a 4-week follow-up period. A schematic representation 
of the study design is presented in Figure 1.
Figure 1:
Study Schematic
3.1.1
Screening Period 
Study eligibility will be confirmed during the screening period (minimum: 2 weeks; maximum:
4 weeks).  The schedule of evaluations to be conducted during the Screening Period can be found 
in Table 1.
3.1.2
Treatment Period
At the baseline visit (Week 0), subjects will randomized 1:1 to the teduglutide or SOC treatment 
arm. Randomization will be stratified according to the presence of a small bowel ostomy (end 
jejunostomy or ileostomy).  During the 24-week treatment period, subjects in the SOC treatment 
arm will receive standard medical therapy for SBS, while those in the teduglutide arm will 
receive 0.05 mg/kg by subcutaneous (SC) injection once daily in addition to standard medical 
therapy. 
Subjects in both arms will follow the same visit schedule and assessments. Subjects will be 
monitored weekly with phone or clinic visits. Clinic visits will occur at Weeks 1, 2, 4, 6, 9, 12, 
16, 20, 24, and 28. At all site visits and telephone contacts, safety will be monitored and 
nutritional support will be reviewed and adjusted as needed.  To maintain consistency across 
centers, guidance and training will be provided to help sites follow the nutritional support 
adjustment guidelines (developed with SBS expert input and provided in the protocol) related to
decisions for PN reduction and advances in enteral feeds based on weight gain, urine and stool 
output, and clinical stability (Appendix 2). Deviations from the guidelines are not considered a 
protocol deviation.
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Sparse PK sampling, in the teduglutide treatment arm, will occur at baseline (t=0, 1, and 4 hours) 
and at Week 6 or 12 (t=2 hours).
The schedule of evaluations for the Treatment Period can be found in Table 1 (Visits -1 to 12) 
and Table 2 (Visits 13 to 28).  
3.1.3
Follow-up Period
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up 
period until the end of study (Week 28/EOS) during which time subjects will receive standard 
medical therapy, but no investigational product (IP) will be administered. At EOS the subject 
may enroll in an extension study that will capture long-term safety data and provide the 
opportunity for additional teduglutide treatment. The follow-up period may be interrupted and 
the subject may consent to the extension study immediately if at least one of the following 
"escape" criteria is met:
1. Increasing PN requirements following discontinuation of teduglutide.
2. Deteriorating nutritional status (e.g., weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation.  
4. Severe diarrhea related to teduglutide discontinuation.
The schedule of evaluations for the Follow-up Period can be found in Table 2 (Visits 13 to 28).
3.2
Study Duration
The study consists of a minimum 2-week screening period, a 24-week treatment period and a 
4-week follow-up period.
3.3
Sites and Regions
This study is planned to be conducted at approximately 5 to 10 sites globally.
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STUDY POPULATION
4.
At least 10 subjects will be randomized: at least 5 subjects in a teduglutide treatment arm and at 
least 5 subjects in an SOC comparator arm.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1. Informed consent by the parent or legal guardian. 
2. Male or female infant 4 to 12 months corrected gestational age.
3. Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and 
baseline.
4. Short bowel syndrome with dependence on parenteral support to provide at least 50% of 
fluid or caloric needs.
5. Stable PN requirements for at least 1 month prior to screening, defined as a ≤10% change 
in the weight-normalized parenteral total fluid and caloric intake, despite attempts to 
wean PN, notwithstanding transient instability for events such as sepsis or interruption of 
central venous access.
6. Lack of terminal ileum and ileocecal valve.
7. Parent or legal guardian understands and is willing and able to fully adhere to study 
requirements as defined in this protocol.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1. Previous treatment with teduglutide.
2. Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus 
inclusion disease, etc.
3. Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, 
active gastroschisis-related dysmotility, that is the primary contributing factor to feeding 
intolerance and inability to reduce parenteral support, prior to screening. Dysmotility is 
defined as severe if it is expected to limit the advancement of enteral feeding.
4. Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral 
aversion in the absence of a feeding tube.
5. Intestinal obstruction or clinically significant intestinal stenosis.
6. Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or 
major intestinal resection or anastomosis, within 3 months prior to screening or planned 
during the study period.
7. Unstable cardiac disease.
8. Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
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9. Biliary obstruction, stenosis, or malformation. 
10. Clinically significant pancreatic disease. 
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following 
parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b. Platelet count <100×10^3/µL due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d. Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 
2 week period.
13. More than 3 serious complications of intestinal failure (e.g., catheter-associated 
bloodstream infections, interruption of nutrition due to feeding intolerance, 
catheter-associated thrombosis, severe fluid or electrolyte disturbances) within 1 month
prior to or during screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile 
polyposis or Beckwith-Wiedemann syndrome, or first degree relative with early onset of 
gastrointestinal cancer (including hepatobiliary and pancreatic cancers). 
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 
(GLP-2); insulin-like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs 
of these hormones; or glutamine. 
16. Participation in a clinical study using an experimental drug within 3 months or 
5.5 half-lives of the experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, 
closely-related compounds, or any of the stated ingredients.  
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts 
the subject at any undue risk, prevents completion of the study, or interferes with analysis 
of the study results.
4.3
Reproductive Potential 
Not applicable; this study will enroll infants.
4.4
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution.  The investigator or sponsor may 
withdraw the subject at any time (e.g., in the interest of subject safety).  The investigator should 
discuss withdrawal of a subject from investigational product with the medical monitor as soon as 
possible.
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 24/EOT/early termination are to be performed as completely as possible. Whenever 
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possible, all discontinued subjects should also undergo the protocol-specified 4-week Follow-up 
Period. Comments (spontaneous or elicited) or complaints pertaining to IP discontinuation made 
by the subject must be recorded in the source documents. The reason for discontinuation, the 
date and the total amount of investigational product administered must be recorded in the 
electronic case report form (eCRF) and source documents.
Subjects who discontinue will not be replaced. 
4.4.1
Reasons for Discontinuation
The reason(s) for permanent discontinuation of treatment and/or withdrawal from the study must 
be determined by the investigator, and recorded in the subject’s medical record and in the eCRF.  
If a subject is withdrawn for more than 1 reason, each reason should be documented in the source 
document, and the most clinically relevant reason should be entered in the eCRF.
Reasons for discontinuation include, but are not limited to:

Adverse event

Death

Lost to follow-up

Physician decision

Protocol deviation

Study terminated by sponsor

Withdrawal by parent/guardian

Lack of efficacy

Other
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact the parent(s)/guardian(s) of any 
subject lost to follow-up at any time point prior to the last scheduled contact (office visit or 
telephone contact). At least 1 of these documented attempts must include a written 
communication sent to the subject’s last known address via courier or mail (with an 
acknowledgement of receipt request) asking that they return to the site for final safety 
evaluations and return any unused investigational product.
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PRIOR AND CONCOMITANT TREATMENT
5.
5.1
Prior Medications and Procedures
Prior treatment includes all treatment and procedures (including but not limited to prescription 
treatments, herbal treatments, vitamins, non-pharmacological treatment, as appropriate) received 
within 14 days prior to the screening visit (Visit -1) (or pharmacokinetic equivalent of 5 half 
lives, whichever is longer, must be recorded on the appropriate eCRF page.
5.2
Concomitant Medications and Procedures
The administration of all medications including concomitant medications (including prescription 
and nonprescription medications, dietary and nutritional supplements, and vitamins) and PN 
must be recorded from the first dose of investigational product and for the duration of the study 
in the appropriate sections of the eCRF.  Any diagnostic, surgical or other therapeutic treatments 
received by a subject during the course of the study will also be recorded on the eCRF.
The mechanism of action of teduglutide may increase enteral absorption of oral drugs (e.g., 
drugs used for management of SBS such as motility medication, opioids, psychotropics, 
metronidazole), so consideration should be given to modifying concomitant enteral medication 
regimens. Titration of concomitant enteral medications should be considered when drugs, 
especially those with a narrow therapeutic index (e.g., warfarin, digoxin, psychotropics) are 
given.
5.3
Permitted Treatment
Standard medical therapy for SBS should be continued.
5.4
Prohibited Treatment
The following medications are prohibited during teduglutide treatment and within the provided 
timeframe prior to the pretreatment visit (Table 3):
Table 3:
Prohibited Treatment
Prior Therapy
Time Restriction Prior to 
the Pretreatment Visit
Teduglutide
Any
GLP-2, human growth hormone, or analogs of these hormones
6 months
Octreotide, GLP-1 analogs, and enteral glutamine
30 days
GLP=glucagon-like peptide
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INVESTIGATIONAL PRODUCT
6.
6.1
Identity of Investigational Product
The SOC treatment arm will receive standard medical therapy for SBS; while those in the 
teduglutide arm will receive 0.05 mg/kg SC once daily in addition to standard medical therapy.
Teduglutide will be provided in sterile, single-use 3 mL vials containing 5 mg or 1.25 mg 
teduglutide as a white lyophilized powder to be reconstituted before use with 0.5 mL sterile 
water for injection. In addition to the active ingredient (teduglutide), each vial of teduglutide 
contains L-histidine, mannitol, monobasic sodium phosphate monohydrate, and dibasic sodium 
phosphate as excipients. Additional information is provided in the current investigator’s 
brochure.
6.2
Administration of Investigational Product
6.2.1
Interactive Response Technology for Investigational Product Management
All investigative study sites will be initially provided with sufficient investigational product to 
randomly assign a subject into the study (for either of the proposed treatment groups).  
Randomization will occur through an interactive response system. Random assignment of a 
subject will trigger replacement supplies for that investigative study site.
6.2.2
Allocation of Subjects to Treatment
Subjects will be randomized 1:1 to the teduglutide or SOC treatment arm.  The actual treatment 
given to individual subjects is determined by a randomization schedule.
Subject numbers are assigned to all subjects as they consent to take part in the study.  Within 
each site (numbered uniquely within a protocol), the subject number is assigned to subjects 
according to the sequence of presentation for study participation.  
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined.
6.2.3
Dosing
The initial dose will be calculated based on body weight measured at baseline (Visit 0), and 
adjusted as needed, based on body weight measured at each in-clinic study visit.  No other 
adjustments to dose will be made during the teduglutide treatment period, unless discussed with 
the sponsor’s medical monitor.  
Following reconstitution, teduglutide will be administered by SC injection once daily (QD) into 
1 of the 4 quadrants of the abdomen (in subjects without a stoma) or into either the thigh or arm.
For subjects with a stoma, the quadrant of the abdomen containing the stoma should not be used. 
Teduglutide should be used as soon as possible after reconstitution, but no more than 3 hours 
later.
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The subject should be dosed at approximately the same time each day. Consecutive doses should 
be separated by at least 12 hours.  Each day, the injection site should be alternated.  
Any subject who achieves complete independence from PN support at any time during the 
treatment period will continue to receive teduglutide treatment.
The first SC injection in teduglutide-naïve subjects should be administered under the supervision 
of the investigator or designee and the subject observed for hypersensitivity reactions for at least 
4 hours during their initial dosing visit.  The site of administration (arm, thigh, and abdomen) of 
the first teduglutide dose must be specified and recorded in the eCRF. 
Detailed instructions for reconstitution and injection of the investigational product can be found 
in the Instructions for Use. 
Following the 24-week Treatment Period, subjects will enter a 4-week follow-up period. During 
the follow-up, the investigator will assess the subject via weekly telephone visits. The follow-up 
period may be interrupted and the subject may consent to the extension study immediately if at 
least one of the following criteria is met:
1. Increasing PN requirements following teduglutide discontinuation.
2. Deteriorating nutritional status (e.g., weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation.  
4. Severe diarrhea related to teduglutide discontinuation.
6.2.4
Unblinding the Treatment Assignment
Not applicable for this open-label study.
6.2.5
Dose Selection Rationale
Teduglutide is approved for adult and pediatric use in the EU at a dose of 0.05 mg/kg SC once 
daily.  A completed 12-week dose finding study (TED-C13-003) demonstrated that teduglutide 
dosing at 0.025 and 0.05 mg/kg/day was associated with a favorable benefit-risk profile most 
meaningful at the 0.05 mg/kg/day dose (Carter et al., 2017). 
Population pharmacokinetic modeling and simulations were conducted to determine the optimal 
dose to be used in pediatric subjects using data from 8 adult clinical studies including adult Phase 
1 studies and Phases 2/3 studies as well as TED-C13-003 and suggested the same adult dose 
(0.05mg/kg) in pediatric subjects (aged between 1.67-14.7 years) (Marier et al., 2017).
To support dosing in the current age group, further PK simulation was conducted based on the 
population PK model previously established and a virtual population of 1000 pediatric patients 
created based on Centers for Disease Control (CDC) growth charts in the target age group (4 to 
12 months) and taking into consideration body weights of pediatric patients with SBS enrolled in 
study TED-C13-003 (approximately 15% lower than healthy subjects in the same age group).  
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Monte Carlo simulations for all age groups were performed according to the SC dosing regimens 
of 0.0125, 0.025 and 0.05 mg/kg every 24 hours.  Rich concentration-time profiles were 
simulated with the customized population PK model to derive the exposure metrics area under 
the concentration curve at steady state (AUCss) and maximum concentration at steady state 
(Cmax,ss).  Following 0.05 mg/kg daily SC administration, the median Cmax,ss of teduglutide in 
neonate patients (24.9 ng/mL) was within 20% of that observed in the 2 to 4 and 4 to 6 years age 
groups (26.9 and 29.4 ng/mL, respectively); and approximately ~28% lower than that in adult 
patients with SBS.  The clinical package in conjunction with Cmax was considered to support 
teduglutide dose selection since AUCss was previously shown not to correlate with efficacy.  
Thus, the 0.05 mg/kg dose is proposed for testing in this age group.
6.3
Labeling, Packaging, and Storage
6.3.1
Labeling
The investigational product will be packaged, labeled, and shipped to the study site by the 
sponsor or designee.  Kits containing 7 vials of investigational product will be provided for this 
study.  The vials will be labeled in accordance with applicable regulatory requirements. 
Ancillary kits, containing supplies needed for the reconstitution and administration of the 
investigational product will also be provided and labeled in accordance with the applicable 
regulatory requirements. 
All investigational product used in this study will be manufactured, tested, labeled, and released 
according to current legal requirements and Good Manufacturing Practice.
6.3.2
Storage and Handling
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.
Investigational product must be kept in a locked area with access restricted to specific study 
personnel. Investigational product will be stored refrigerated at a temperature between 2-8°C 
(35.6-46.4°F) until dispensed to a subject. Once dispensed to a subject, the IP can be stored 
refrigerated or up to a controlled room temperature (acceptable range of 2-25°C, or 35.6-77°F). 
Parent/legal guardian will be instructed to keep the subject’s IP and sterile water diluent at 
controlled room temperature. If there are concerns that the controlled room temperature cannot 
be maintained, the IP may be refrigerated. The IP is for single use only, and should be used 
within 3 hours following reconstitution.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
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means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (i.e., certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), e.g., fumigation of a 
storage room.
Investigational products are distributed by the pharmacy or nominated member of the study 
team. The pharmacist/nominated team member will enter the unique subject identifier on the 
investigational product bottle/carton labels, as they are distributed.
6.4
Drug Accountability
Investigational product will not be dispatched to the study site until the sponsor or 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 investigational product 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.  Kits will be shipped to the site once the 
subject is screened.
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects.  The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition.  Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for dispensing investigational product.  Where 
permissible, tasks may be delegated to a qualified designee (e.g., a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator.  
This delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee will dispense the investigational product only to subjects 
included in this study following the procedures set out in the study protocol.  Investigational 
product kits will be dispensed at each of the applicable study visits at which the subject is 
required to be at the clinic.  Each investigational product kit is sufficient for a treatment period of 
1 week and enough kits will be supplied to cover the period until the next planned study visit.  
Additional study kits will be provided as necessary.
Each subject will be given the investigational product according to the protocol.  The 
investigator is to keep a current record of the inventory and dispensing of all clinical supplies.  
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All dispensed medication will be documented on the eCRFs and/or other investigational product 
record. The investigator is responsible for assuring the retrieval of all study supplies from 
subjects.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor.  If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.
At the end of the study, or as instructed by the sponsor, all unused stock, subject returned 
investigational product, and empty/used investigational product packaging are to be sent to the 
sponsor or designee.  The investigator is responsible for assuring the retrieval of all study 
supplies from subjects.
Returned investigational product must be counted and verified by clinical site personnel and the 
sponsor (or study monitor). Shipment return forms, when used, must be signed prior to shipment 
from the site.  Contact the sponsor for authorization to return any investigational product prior to 
shipment.  Shipment of all returned investigational product must comply with local, state, and 
national laws. 
Please see the Pharmacy Manual for additional information.
6.5
Subject Compliance
The parent(s)/guardian(s) of subjects must be instructed to bring unused investigational product 
and empty/used investigational product packaging to every visit. Drug accountability must be 
assessed and recorded at the container/packaging level for unused investigational product that is 
contained within the original tamper-evident sealed container (e.g., bottles, trays, vials) or at the 
individual count level for opened containers/packaging. 
Subjects who have received 80% of the planned doses administered will be assessed as being 
compliant with the study protocol.
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STUDY PROCEDURES
7.
7.1
Study Schedule
Detailed study procedures and assessments to be performed for subjects throughout the study are 
outlined in the study schedules (Table 1and Table 2) and must be referred to in conjunction with 
the instructions provided in this section. 
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 24/EOT are to be performed as completely as possible.  Whenever possible, all 
discontinued subjects should also undergo the protocol-specified 4-week Follow-up Period.  
7.1.1
Screening
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent/assent from the 
parent(s)/guardian(s) of the subject. The screening visit assessments and procedures, beginning 
with informed consent/assent, will be performed as outlined in Table 1.
7.1.2
Treatment Period
The randomized Treatment Period will comprise Weeks 1 to 24, during which all assessments 
will be performed as outlined in Table 1 and Table 2.
7.1.3
Follow-up Period
The Follow-up Period will comprise Weeks 25 to 28, during which all assessments will be 
performed as outlined in Table 2.
7.2
Study Evaluations and Procedures
7.2.1
Demographics and Other Baseline Characteristics
Demographics and Medical History
Demographic and/or other baseline variables obtained at the screening and/or baseline visits are 
listed below. Abnormal findings of clinical significance (if any) will be recorded as past medical 
history.

Demography (including age, gestational age, sex, and race)

Medical history (including surgical history)

SBS history, including remnant anatomy
Upper Gastrointestinal Series with Short Bowel Follow-through
An upper GI contrast series with small bowel follow-through will be performed on all subjects 
during the screening period if one has not been done since the subject's last GI surgery.
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7.2.2
Efficacy Assessments
Subject Diaries
All available diary data will be reviewed by the investigator or their designee at each clinic and 
telephone visit to assess clinical status and opportunity for PN reduction and advance in feeds.  
Parenteral support adjustments should be made after review of the intake and output diaries and 
the safety lab data according to the guidance for nutrition support adjustment provided in 
Appendix 2.
Intake Diary
Intake diaries will be used to collect and evaluate each subject’s nutritional support.  The 
parent/legally authorized representative/study site staff will complete the appropriate fields of the 
PN and EN sections of the intake diary daily throughout the study.
The following data will be captured in the intake diaries:

Parenteral support volume and infusion duration

Enteral nutrition (formula) including volume and calories
Site personnel will determine the actual PN and EN daily calories based on diary entries.
Output Diary
Urine and stool output should be recorded in the output diary over a 48-hour period of nutritional 
stability before every clinic visit; in addition, output should be recorded for subjects within 
1 week of implementing a change in the PN prescription.
Urine data:

Measure and record the weight of all urine-only diapers. Urine volume will be calculated 
using the following formula: 1 g (scale weight) = 1 mL or 1 cc

At the discretion of the investigator, the parent or legal guardian/study site staff may be 
asked to collect the first void after the daily PN infusion to measure specific gravity
Stool data (includes diapers with mixed urine and stool):

Record the weight of diapers containing stool (including diapers with mixed urine and 
stool) as stool output and score the stool consistency (see Output diary). Stool volume 
will be calculated using the formula: 1 g (scale weight)=1 mL or 1 cc
All ostomy output volume should be recorded.  
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Native GLP-2
Blood samples for native GLP-2 should be collected postprandial. Native GLP-2 may not be 
collected in some subjects if blood volumes are limiting based on subject weight or at 
investigator discretion based on weekly/monthly total volume.  
7.2.3
Safety Assessments
Laboratory Evaluations
Safety laboratory tests to be performed at site visits consist of clinical chemistry, hematology, 
and urinalysis and will be performed as outlined in the study plan (Table 1 and Table 2). 
Scheduled laboratory testing will be processed by a central lab. All laboratory assays will be 
performed according to the central laboratory’s normal procedures. Reference ranges are to be 
supplied by the laboratory. The investigator should assess out-of-range clinical laboratory values 
for clinical significance, indicating if the value(s) is/are not clinically significant or clinically 
significant. Abnormal clinical laboratory values, which are unexpected or not explained by the 
subject’s clinical condition, may, at the discretion of the investigator or sponsor, be repeated as 
soon as possible until confirmed, explained, or resolved.
During the Treatment Period, subjects will also have safety labs within approximately 5 to7 days 
after a PN adjustment.  Safety labs performed after PN adjustment and between site visits will 
consist of clinical chemistry and urinalysis and may be processed by the central laboratory or a 
local laboratory.  Local lab results are not required to be entered in the eCRFs; however, if the 
local lab results indicate any new clinically significant changes, they must be reported as an 
adverse event (see Section 8). Urine specimen collection should be attempted as part of the 
safety labs, but lack of urinalysis will not constitute a protocol deviation.
At baseline, blood samples for safety labs and PK can be separated by 1 day if blood volumes are 
limiting.  
Safety labs at telephone visits will be collected at the discretion of the investigator.  
For all subjects in the teduglutide treatment arm, prothrombin time (PT) and international 
normalized ratio (INR), tested at baseline, will be repeated if clinically indicated.
New clinically significant labs should be reported as AEs.
Close monitoring criteria related to liver test abnormalities:  The investigator should contact the 
medical monitor within 24 hours of their awareness if the subject develops any of the following 
changes in laboratory parameters:

ALT or AST >5x ULN and >2x baseline value

Total or direct bilirubin that is >2x baseline value or an absolute increase of ≥3 mg/dL 
(51.3 µmol/L)
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If such changes are observed, the labs should be repeated along with an INR, and an inquiry 
should be made as to the presence of clinical symptoms consistent with new liver injury. The 
subject should be followed closely to determine the trajectory of the laboratory abnormalities and 
appropriate evaluations should be made, such as abdominal ultrasound with Doppler imaging to 
exclude vascular causes and biliary obstruction, consideration of sepsis, liver hypoperfusion, 
acute viral hepatitis (such as hepatitis A, EBV, or HSV), exposure to hepatotoxic medications, 
mitochondrial hepatopathy, or metabolic liver disease (such as hereditary fructose intolerance or 
arginosuccinate synthetase deficiency).  Further evaluations can be performed at the discretion of 
the investigator in consultation with the Shire medical monitor.
The following clinical laboratory assessments will be performed according to the study 
schedules:
Table 4:
List of Laboratory Tests
Biochemistry:

Albumin 

Alkaline phosphatase 

Alanine aminotransferase 

Amylase

Aspartate aminotransferase 

Bicarbonate

Bilirubin (total and indirect)

Blood urea nitrogen 

Calcium (total)

Chloride

Cholesterol

C-reactive protein 

Creatinine

Estimated Glomerular Filtration Rate 
(Schwartz formula)

Gamma-glutamyl transferase 

Glucose

Lipase

Magnesium

Phosphorus

Potassium 

Sodium 
Triglycerides
Hematologya:

Hematocrit 

Hemoglobin 

Platelet count

Red blood cell count 

Red blood cell morphology, if needed

White blood cell count with differential
Coagulationb:

Prothrombin time

International normalized ratio
Urinalysis: 

Specific gravity  

Urine Sodium
a Hematology is not collected at Week 1 or at telephone visits.
b For all subjects in the teduglutide treatment arm, PT and INR will be tested at baseline and repeated only if clinically indicated.
Antibodies to Teduglutide 
Blood samples will be drawn to test for antibodies to teduglutide.  Samples will be taken before 
teduglutide administration at the screening visit (Visit -1) and at least 14 hours after the previous 
dose at Week 12 (Visit 12); samples may be drawn from a central line or peripheral access. One 
additional sample will be collected at the EOS 4 weeks after the EOT (i.e., Week 28 or EOS).  
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Volume of Blood
Efforts will be made to minimize the amount of blood drawn from all pediatric subjects 
participating in this study. The volumes of blood to be drawn from each subject will vary 
depending on clinical status. Approximate volumes of blood to be drawn from each subject are 
shown in Table 5.
Table 5:
Approximate Volume of Blood to be Drawn from Each Subject 
Assessment
Sample 
Volume (mL)
No. 
Samples 
Total 
Volume (mL)
Notes
Subjects Receiving Teduglutide Treatment
Biochemistry 
0.6
12
7.2
Hematology
0.6
11
6.6
Coagulation Parameters
0.6
1
0.6
PT and INR tested at baseline 
only, repeat while on study 
only if clinically indicated.
Antibodies
1.5
5
7.5
Pharmacokinetics
1.5
4
6
Baseline: 3 timepoints
Week 6: 1 timepoint OR
Week 12: 1 timepoint
Native GLP-2
0.1
3
0.3
Total mL:
4.9
36
28.2
Subjects Receiving Standard of Care
Biochemistry 
0.6
12
7.2
Hematology
0.6
11
6.6
Native GLP-2
0.1
3
0.3
Total mL:
1.3
26
14.1
GLP=glucagon-like peptide; INR=international normalized ratio; PT=prothrombin time
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment. When more than 1 blood assessment is to be done at the time 
point/period, if they require the same type of tube, the assessments should be combined. Blood 
volume estimates do not include safety labs performed after PN adjustment, and anti-teduglutide 
antibody testing during no-teduglutide treatment.
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Physical Examinations, Vital Signs, Weight, Length, and Head Circumference
Physical examinations will be performed according to the study schedules (Table 1, and Table 
2). Any new clinically significant findings noted during physical examinations should be 
recorded on the appropriate AE page of the eCRF.
Vital signs will be measured according to the study schedules. Measurements will include 
systolic and diastolic blood pressure (mmHg), pulse (beats per minute), and body temperature 
(°C/°F). Blood pressure should be determined by the appropriate size cuff (using the same 
method, the same leg, and in the supine position throughout the study, when possible).  Blood 
pressure measurements should be attempted as part of the vital signs, but lack of blood pressure 
results will not constitute a protocol deviation.  New clinically significant vital sign 
abnormalities should be recorded on the appropriate AE page of the eCRF.
Body weight will also be recorded in the eCRF; subjects should be weighed on the same scale 
at each study visit. Length and head circumference will be measured at selected visits. A height 
z-score, weight Z-score, and weight/length ratio will be calculated by the sponsor using the 
site-provided height and weight data collected at each site visit.
7.2.4
Pharmacokinetic Assessments
Subjects will have blood samples taken for teduglutide PK analysis predose and 1 and 4 hours 
post dose at baseline (Visit 0).  Subjects also will have blood samples taken for teduglutide PK 
analysis 2 hours post dose at Week 6 (Visit 6) or Week 12 (Visit 12) of the treatment period.  
Blood for PK sampling should be collected via peripheral IV or venipuncture, not from a central 
line.  The site of teduglutide administration prior to PK blood draws (arm, thigh, abdomen) must 
be specified.  
7.2.5
Health Economics and Outcomes Research
Five-level EuroQol Five-dimensions Questionnaire
To assess caregiver burden, parents/legally authorized representatives will be asked to complete 
the 5-level EuroQol five dimensions questionnaire (EQ-5D-5L) at the visits specified in Table 1, 
and Table 2. The EQ-5D-5L is a generic, multi-attribute, health related QOL questionnaire 
composed of a descriptive system and a visual analog scale (VAS) (Herdman et al., 2011).
The EQ-5D-5L descriptive system has the following 5 dimensions: mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression.  Each dimension has 5 levels: no problems, 
slight problems, moderate problems, severe problems, or extreme problems.  In addition to 
showing which levels the subject selected for the 5 dimensions, the information from the 
5 dimensions can also be combined to provide a value from 0, representing death, to 1, 
representing perfect health.  The VAS provides results from 0, labeled “worst imaginable health 
state” to 100, labeled “best imaginable health state.”  
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Hospitalizations
Each hospitalization that occurs during the study will be recorded, including date of admission, 
date of discharge, reasons for hospitalization, discharge diagnosis, and discharge status. 
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ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.3. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, 
then each symptom should be listed individually. All AEs should be captured on the appropriate 
AE pages in the eCRF and in source documents. In addition to untoward AEs, unexpected 
benefits outside the investigational product indication should also be captured on the AE eCRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
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8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of 
the investigational product is compelling and/or follows a known or 
suspected response pattern to that product, and the event cannot be 
explained by the subject’s medical condition, other therapies, or 
accident.
Not Related
The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident and no 
plausible temporal or biologic relationship exists between the 
investigational product and the event.
AEs that are related to IP that are not resolved at EOS will be followed until the event resolves or 
stabilizes, as judged by the investigator.
Laboratory values, vital signs, and clinical findings at the scheduled physical examinations must 
be reported as AEs if the investigator considers the finding to be a clinically significant change 
from the baseline.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the eCRF. Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved with Sequelae 

Recovering/Resolving

Unknown
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8.1.4
Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE. It is assumed that some of the infants participating in this study may be 
hospitalized for planned surgery(ies) that will occur during their participation in the study. Such 
pre-planned, elective surgeries, do not need to be reported as SAEs for this protocol. 
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory or vital sign can represent an AE if the change is 
clinically relevant or if, during the study, a shift of a parameter is observed from a normal value 
to an abnormal value, or a further worsening of an already abnormal value. When evaluating 
such changes, the extent of deviation from the reference range, the duration until return to the 
reference range, either while continuing treatment or after the end of treatment with the 
investigational product, and the range of variation of the respective parameter within its 
reference range, must be taken into consideration.
If, during the study, there are abnormal clinical laboratory values or vital signs which were not 
present at the beginning of the study, further investigations should be performed until the values 
return to within the reference range or until a plausible explanation (e.g., concomitant disease) is 
found for the abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory or vital sign is clinically significant and 
therefore represents an AE.
8.1.6
Pregnancy
Not applicable.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for 
a non-medical purpose (e.g., to alter one’s state of consciousness or get high) in a manner 
that may be detrimental to the individual and/or society.
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
Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol).

Overdose – Administration of a dose greater than the allocated dose of the study 
medication or at a frequency greater than the dosing interval specified by the protocol.

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product. For studies, medication errors are reportable to the sponsor 
only as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error. 
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally-authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator brochure which the sponsor 
has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Drug Safety Department and the Shire Medical Monitor within 24 hours of the first awareness of 
the event. Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, 
misuse, overdose, or medication errors (see Section 8.1.7) unless they result in an SAE.
All Adverse Events of Special Interest, as defined in Section 8.3, must be reported by the 
investigator to the Shire Global Drug Safety Department and the Shire Medical Monitor within 
24 hours of the first awareness of the event even if the event does not fulfill seriousness criterion.
The investigator must complete, sign, and date the Shire Clinical Study Adverse Event Form for 
SAEs and Non-serious AEs as Required by Protocol, and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested). Fax or e-mail the completed form to the Shire Global Drug Safety 
Department. A copy of the completed Shire Clinical Study Adverse Event Form for Serious 
Adverse Events (SAEs) and Non-serious AEs as Required by Protocol (and any applicable 
follow-up reports) must also be sent to the Shire medical monitor or designee using the details 
specified in the emergency contact information section of the protocol.
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8.2.3
Serious Adverse Event Definition
A SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose: 

Results in death

Is life-threatening. Note: The term 'life-threatening' in the definition of "serious" refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for pre 
existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse. 
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.3, and must be reported 
to the Shire Global Drug Safety Department and the Shire Medical Monitor within 24 hours of 
the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Drug Safety Department within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
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In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (i.e., the SAE was noted as the primary cause of 
death) must have fatal checked as an outcome with the date of death recorded as the resolution 
date. For all other events ongoing at the time of death that did not contribute to the subject’s 
death, the outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (e.g., drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death.  
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting 
The Sponsor and/or Clinical Contract Research Organization (CRO) is responsible for notifying 
the relevant regulatory authorities, and US central Institutional Review Boards (IRBs)/EU central 
ethics committees (ECs), of related, unexpected SAEs.
In addition, the Clinical CRO is responsible for notifying active sites of all related, unexpected 
SAEs occurring during all interventional studies across the SHP633 program.
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
8.3
Adverse Events of Special Interest
An AE of special interest is an AE (serious or nonserious) of scientific and medical concern 
specific to the sponsor’s product or program and for which ongoing monitoring and immediate 
notification by the investigator to the sponsor is required.
The AEs of special interest that require expedited regulatory reporting include the following:

Growth of pre-existing polyps of the colon

Benign neoplasia of the GI tract including the hepatobiliary system

Tumor-promoting ability (e.g., benign and/or malignant neoplasia of any kind, not 
limited to those of the GI or hepatobiliary system)
For AEs of special interest, the sponsor must be informed within 24 hours of first awareness as 
per the SAE notification instructions described in Section 8.2.2 even if the event does not fulfill 
the seriousness criteria.
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8.4
Dose Interruption Criteria
The investigator is responsible for contacting the sponsor/designee when the subject’s 
teduglutide dosing regimen is interrupted. The length of dose interruption, and whether 
teduglutide administration resumes or is permanently discontinued, depends on the clinical 
situation.
Investigational product must be interrupted if any of the following events occur:

An adverse event of special interest (see Section 8.3) 

Intestinal obstruction

Biliary obstruction

Pancreatic duct obstruction
Investigational product must be permanently discontinued if any of the following events occur: 

Severe hypersensitivity, such as anaphylaxis, determined by the 
investigator to be related to IP. 

Any malignancy 
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DATA MANAGEMENT AND STATISTICAL METHODS
9.
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the eCRF.  A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy.  Discrepancies 
between source data and data entered on the eCRF will be addressed by qualified site personnel.  
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel.  Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting.  Once a subject is randomized, it is expected that site 
personnel will complete the eCRF entry within approximately 3 business days of the subject’s 
visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the data management plan. Quality 
control and data validation procedures are applied to ensure the validity and accuracy of the 
clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Statistical Analysis Process
The study will be analyzed by the sponsor or designee. All statistical analyses will be performed 
using SAS® (SAS Institute, Cary, NC, US) version 9.3 or higher.
The statistical analysis plan (SAP) will provide the definitions and statistical methods  for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed.
9.4
Planned Interim Analysis, and Data Monitoring Committee 
No interim analyses is planned for this the study. 
A data monitoring committee (DMC) will be involved in the management of this study. The 
DMC members will review the data approximately every 3 months according to the DMC 
Charter. The DMC review will include all cumulative safety data (i.e., AEs, laboratory 
assessments, physical examinations, etc.) from study assessments through each cutoff period. 
Further details regarding the DMC can be found in the DMC charter, which will be available 
prior to the administration of investigational product. 
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The DMC for this study will be conducted in accordance with the FDA Guidance for Clinical 
Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees 
(March 2006).
The DMC will be an external, independent board comprised of physicians with relevant training. 
The DMC will be restricted to individuals free of significant conflicts of interest, including, but 
not limited to, financial, scientific, or regulatory in nature. The DMC will be governed by a 
Charter agreed to by members of the Board and the sponsor. Members of the Board may not be 
study investigators or be employed at the same institution as a study investigator, individuals 
employed by the sponsor, independent contractors hired by the sponsor, or members of 
regulatory agencies. The DMC may make recommendations to the sponsor regarding study 
aspects including stopping, modifying or continuing the study; however, the sponsor will have 
the final responsibility to determine whether the study should be modified or temporarily or 
permanently stopped. 
9.5
Sample Size Calculation and Power Considerations
The sample size is determined based on enrollment feasibility for this rare condition and the age 
of the study population. 
9.6
Study Population
Intent to treat (ITT) population: All subjects randomized in the study.
Safety analysis population: All subjects who have at least one safety assessment after the 
baseline visit.
Per-protocol population: All subjects in the ITT population without a major protocol deviation 
that affects interpretation of efficacy results.
Pharmacokinetic analysis population: All subjects randomized in the teduglutide treatment arm 
for which the primary PK data are sufficient and interpretable.
9.7
Efficacy Analyses
Efficacy endpoints consist of the following:
Primary Efficacy Endpoint 

Reduction in weight-normalized PN fluid volume by at least 20% from baseline at 
Week 24/EOT
Secondary Efficacy Endpoints

Reduction in weight-normalized parenteral calories by at least 20% from baseline to 
Week 24/EOT

Achievement of enteral autonomy by Week 24

Change in weight-normalized parenteral fluid volume from baseline to each visit
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
Change in weight-normalized parenteral calories from baseline to each visit

Change in weight-normalized enteral fluid volume from baseline to each visit

Change in weight-normalized enteral caloric intake from baseline to each visit

Increase in weight-normalized enteral fluid intake by at least 20% from baseline to week 
24/EOT

Increase in weight-normalized enteral caloric intake by at least 20% from baseline to 
week 24/EOT
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 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.
Analyses of weekly PN support will be based on 2 data sources: the subject diary data (also 
referred to as actual data) and the investigator prescribed data.  
The number and percentage of subjects who achieve at least a 20% reduction from baseline in 
weight-normalized average daily PN volume at Week 24/EOT and the number and percentage of 
subjects who achieve at least a 20% reduction from baseline in weight-normalized parenteral 
calories at Week 24/EOT will be summarized by treatment arm.
During the treatment period, a subject will be considered to have achieved enteral autonomy 
(completely weaned off PN) at a given visit if the investigator prescribes no PN at that visit and 
for the remainder of the treatment period, and there is no use of PN recorded in the subject diary 
during the week prior to that visit and for the remainder of the treatment period.  During the 
follow-up period, a subject will be considered to have achieved enteral autonomy at a given visit 
if the investigator prescribes no PN at that visit and there is no use of PN recorded in the subject 
diary during the week prior to that visit. The number and percentage of subjects who achieve 
enteral autonomy at each scheduled visit, as well as at EOT, will be summarized by treatment 
arm.  
The absolute and percent change in weight-normalized weekly PN volume, parenteral calories, 
enteral fluid volume, and enteral caloric intake, from baseline to each scheduled visit, as well as 
at EOT, will be summarized by treatment arm using descriptive statistics.
The number and percentage of subjects who demonstrate an increase in weight-normalized 
enteral fluid intake by at least 20% from baseline to Week 24/EOT and the number and 
percentage of subjects who demonstrate an increase in weight-normalized enteral caloric intake 
by at least 20% from baseline to week 24/EOT will be summarized by treatment arm.
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9.8
Safety Analyses
Safety endpoints consist of the following:

Adverse events

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for 
gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output

Stool (including mixed) output

Antibodies to teduglutide
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Treatment-emergent AEs will be summarized by system organ class and preferred 
term using descriptive statistics (e.g., number and percentage of subjects).  Adverse events will 
be summarized by severity and relationship to treatment.  In addition, SAEs will also be 
tabulated by overall and treatment-related events.  AEs leading to treatment discontinuation and 
death will also be summarized.
For laboratory tests; vital signs; urine and stool output; weight, length, and head circumference 
Z-scores, and descriptive statistics (e.g., n, mean, standard deviation, median, minimum and 
maximum values, and the number and percentage of subjects in specified categories) will be 
used to summarize the absolute values and change from baseline at each visit.
The number and percentage of subjects classified as having antibodies to teduglutide will be used 
to summarize the presence of antibodies.  
9.9
Health Economics and Outcomes Research Analyses
Health economics and outcomes research endpoints consist of the following:

EQ5D-5L

Cumulative number of hospitalization days during the study
Health economics and outcomes research endpoints will be summarized using descriptive 
statistics (number, mean and standard deviation) at nominal time points.  
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9.10
Pharmacokinetics Analyses
Pharmacokinetic endpoints include but are not limited to the following:

Area under the plasma concentration-time curve at steady-state 
over the dosing interval (AUCtau,ss)

Maximum plasma concentration at steady-state (Cmax,ss)

Apparent clearance (CL/F)
Plasma concentrations will be summarized using descriptive statistics (number, mean, and 
standard deviation) at nominal time points.  Pharmacokinetic parameters will be estimated using 
a population PK modeling approach as appropriate and summarized using descriptive statistics 
(number, mean, standard deviation, geometric mean, coefficient of variation, minimum, median, 
and maximum). 
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SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES
10.
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements. 
The name and address of each third-party vendor (e.g., CRO) used in this study will be 
maintained in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996), EU 
Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines.  If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study.  An insurance certificate is supplied as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
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10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of the end of 
the study completion date for pediatric studies and within 1 year for non-pediatric studies as per 
guidance.  The sponsor will provide the ECs with a copy of the same summary.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.  The sponsor will make an end-of-study declaration to the relevant competent 
authority as required by Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator will be appointed to review the final clinical study report 
for multicenter studies.  Agreement with the final clinical study report is documented by the 
signed and dated signature of the principal investigator (single-site study) or coordinating 
principal investigator (multicenter study), in compliance with Directive 2001/83/EC as amended 
by Directive 2003/63/EC and ICH Guidance E3 (1995).
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10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.2.1
Documentation and Retention of Records
10.2.2.2
Electronic Case Report Forms
Electronic case report forms are supplied by the sponsor or designee and should be handled in 
accordance with instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Electronic case report forms 
must be completed by the investigator or designee as stated in the site delegation log.  All data 
will have separate source documentation; no data will be recorded directly onto the eCRF.
All data sent to the sponsor must be endorsed by the investigator.  
The study monitor will verify the contents against the source data per the monitoring plan. If the 
data are unclear or contradictory, queries are sent for corrections or verification of data.
10.2.2.3
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject diaries, and original clinical laboratory reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
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The study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF entries 
against the source documents. The consent form includes a statement by which the 
parent/guardian agrees to the monitor/auditor from the sponsor or its representatives, national or 
local regulatory authorities, or the IRB/EC, having access to source data (e.g., subject’s medical 
file, appointment books, original laboratory reports, X-rays etc). Non-study site personnel will 
not disclose any personal information or personal medical information.
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (e.g., the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.2.4
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the European Medicines Agency (EMA), the 
Medicines and Healthcare products Regulatory Agency, other regulatory authorities, the sponsor 
or its representatives, and the IRB/EC for each site.
10.2.2.5
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent and assent, where 
applicable, from the parent(s)/guardian(s) of all study subjects prior to any study-related 
procedures including screening assessments. All consent and assent documentation must be in 
accordance with applicable regulations and GCP. Each subject’s legally authorized 
representative is requested to sign and date the subject informed consent form or a certified 
translation if applicable, after the subject has received and read (or been read) the written subject 
information and received an explanation of what the study involves, including but not limited to: 
the objectives, potential benefits and risk, inconveniences, and the subject’s rights and 
responsibilities. A copy of the informed consent and assent documentation (i.e., a complete set of 
subject information sheets and fully executed signature pages) must be given to the subject’s 
legally authorized representative, as applicable. 
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This document may require translation into the local language. Signed consent forms must 
remain in each subject’s study file and must be available for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form (and assent form
where applicable) that was reviewed by the IRB/EC and received their favorable 
opinion/approval. A copy of the IRB/EC’s written favorable opinion/approval of these 
documents must be provided to the sponsor prior to the start of the study unless it is agreed to 
and documented (abiding by regulatory guidelines and national provisions) prior to study start 
that another party (i.e., sponsor or coordinating principal investigator) is responsible for this 
action. Additionally, if the IRB/EC requires modification of the sample subject information and 
consent document provided by the sponsor, the documentation supporting this requirement must 
be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the sponsor/designee has received 
written IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB/EC informed of any serious and 
significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996.  A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the sponsor/designee.
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The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market teduglutide; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (e.g., to confirm 
that laboratory results have been assigned to the correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines 
(e.g., Good Publication Practices 2) when forming a publication steering committee, which is 
done for large, multicenter Phase 2 to 4 and certain other studies as determined by Shire. The 
purpose of the publication steering committee is to act as a non-commercial body that advises or 
decides on dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, royalty 
free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
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Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days prior to
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.
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REFERENCES
11.
Beattie, L. M., Barclay, A. R. & Wilson, D. C. 2010. Short bowel syndrome and intestinal failure 
in infants and children. Paediatrics and Child Health, 20, 485-491.
Carter, Cohran, Cole, Corkins, Dimmitt, Duggan, Hill, Horslen, Lim, Mercer, Merritt, Nichol, 
Sigurdsson, Teitelbaum, Thompson, Vanderpool, Vaughan, Li, Youssef, Venick & 
Kocoshis 2017. Outcomes from a 12-Week, Open-Label, Multicenter Clinical Trial of 
Teduglutide in Pediatric Short Bowel Syndrome. Journal of Pediatrics, The, 181, 102-
111.e5.
Gonzalez-Hernandez, Prajapati, Ogola, Channabasappa, Drews & Piper 2017. Predicting time to 
full enteral nutrition in children after significant bowel resection. Journal of Pediatric 
Surgery, 52, 764-767.
Goulet, O. & Ruemmele, F. 2006. Causes and Management of Intestinal Failure in Children. 
Gastroenterology, 130, S16-S28.
Herdman, M., Gudex, C., Lloyd, A., Janssen, M., Kind, P., Parkin, D., Bonsel, G. & Badia, X. 
2011. Development and preliminary testing of the new five-level version of EQ-5D (EQ-
5D-5L). Quality of Life Research, 20, 1727-1736.
Huisman-de Waal, G., Schoonhoven, L., Jansen, J., Wanten, G. & van Achterberg, T. 2007. The 
impact of home parenteral nutrition on daily life-A review. Clinical Nutrition, 26, 275-
288.
Khan, F. A., Squires, R. H., Litman, H. J., Balint, J., Carter, B. A., Fisher, J. G., Horslen, S. P., 
Jaksic, T., Kocoshis, S., Martinez, J. A., Mercer, D., Rhee, S., Rudolph, J. A., Soden, J., 
Sudan, D., Superina, R. A., Teitelbaum, D. H., Venick, R., Wales, P. W. & Duggan, C. 
2015. Predictors of Enteral Autonomy in Children with Intestinal Failure: A Multicenter 
Cohort Study. J Pediatr, 167, 29-34.e1.
Marier, J., Kassir, N., Martin, P. & Wang, Y. 2017. Population pharmacokinetic modeling of 
teduglutide to support dosing in pediatric patients with short bowel syndrome. Clinical 
Pharmacology & Therapeutics, 101, S91.
Martin, G.-R., Beck, P.-L. & Sigalet, D.-L. 2006. Gut hormones, and short bowel syndrome: the 
enigmatic role of glucagon-like peptide-2 in the regulation of intestinal adaptation. World 
Journal of Gastroenterology, 12, 4117-29.
O'Keefe, S. J., Buchman, A. L., Fishbein, T. M., Jeejeebhoy, K. N., Jeppesen, P. B. & Shaffer, J.
2006. Short bowel syndrome and intestinal failure: consensus definitions and overview. 
Clin Gastroenterol Hepatol, 4, 6-10.
Sigalet, D. L., Martin, G., Meddings, J., Hartman, B. & Holst, J. J. 2004. GLP-2 levels in infants 
with intestinal dysfunction. Pediatr Res, 56, 371-6.
Spencer, A. U., Neaga, A., West, B., Safran, J., Brown, P., Btaiche, I., Kuzma-O'Reilly, B. & 
Teitelbaum, D. H. 2005. Pediatric Short Bowel Syndrome: Redefining Predictors of 
Success. Annals of Surgery, 242, 403-412.
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Squires, R. H., Duggan, C., Teitelbaum, D. H., Wales, P. W., Balint, J., Venick, R., Rhee, S., 
Sudan, D., Mercer, D., Martinez, J. A., Carter, B. A., Soden, J., Horslen, S., Rudolph, J. 
A., Kocoshis, S., Superina, R., Lawlor, S., Haller, T., Kurs-Lasky, M. & Belle, S. H. 
2012. Natural history of pediatric intestinal failure: initial report from the Pediatric 
Intestinal Failure Consortium. J Pediatr, 161, 723-8.e2.
Tappenden, K. A., Edelman, J. & Joelsson, B. 2013. Teduglutide enhances structural adaptation 
of the small intestinal mucosa in patients with short bowel syndrome. J Clin 
Gastroenterol, 47, 602-7.
Thymann, T., Stoll, B., Mecklenburg, L., Burrin, D. G., Vegge, A., Qvist, N., Eriksen, T., 
Jeppesen, P. B. & Sangild, P. T. 2014. Acute effects of the glucagon-like peptide 2 
analogue, teduglutide, on intestinal adaptation in short bowel syndrome. J Pediatr 
Gastroenterol Nutr, 58, 694-702.
Wales, P. W., de Silva, N., Kim, J., Lecce, L., To, T. & Moore, A. 2004. Neonatal short bowel 
syndrome: population-based estimates of incidence and mortality rates. J Pediatr Surg,
39, 690-5.
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APPENDICES
12.
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Appendix 1
Protocol History
Document
Date
Global/Country/Site Specific
Original Protocol
03 Oct 2017
Global
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Appendix 2
Guidelines for Nutritional Support Management During the Study
The nutritional support adjustment guidelines are designed to standardize management of 
parenteral and enteral nutritional support in this study. Adjustments to nutritional support should 
be considered at every scheduled clinic visit. Adjustments at phone visits may also be performed, 
but nutritional assessments at phone visits serve primarily to confirm that nutritional adjustments 
at prior clinic visits were tolerated.
All attempts should be made to follow the guidelines, but departure from the guidelines will not 
constitute a protocol deviation.
Clinical judgment is required within the algorithm. Each decision point requires integrating 
multiple sources of information into a yes/no decision. When individual data points are 
conflicting, the investigator must use their best judgment in the assessment.
If intestinal adaptation is occurring, reductions in parenteral support volume and calories are 
expected to be in decrements of 5 to 10% relative to baseline values. Parenteral support 
components are at the discretion of the investigator, but care should be taken to balance 
carbohydrate, fat, and protein. Likewise, if intestinal adaptation is occurring, enteral nutrition 
volume and calories should be increased in increments of approximately 10% relative to baseline 
values.
Assessment of the severity of malabsorption may require estimation of stool output for children 
who have mixed stool and urine output.
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.
During the 48-hour output measurement period prior to the subject’s scheduled visit, no further 
changes to the prescribed nutritional support should be made.
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Figure A-1:
Parenteral Nutrition/Intravenous Adjustment Algorithm for All Subjects 
BUN=blood urea nitrogen; Cr=creatinine; PN=parenteral nutrition; UNa=urine sodium; UOP=urine output; USpGr=Urine specific 
gravity; VS=vital signs; vol=volume
Adequately hydrated?
•
Normal exam and VS
•
Weight stable
•
UOP > 1 ml/kg/h
•
USpGr < 1.020
•
UNa > 20 meq/L
•
Stable, normal BUN/Cr
yes
no
Adequate weight gain 
and linear growth?
↑ PN kcal or no change
↓PN vol and kcal
↑ PN vol +/- kcal
yes
no
Assess severity of malabsorption
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1111 
I 
Protocol Administrative Clarification 
MEMORANDUM 
To: 
SHP633-301 Trial Master File (TMF), SHP633-301 Study Sites 
From: 
, MS -
 and 
, MBA -
 
Date: 
08 Nov 2017 
Subject: Protocol Administrative Clarification Memorandum 
EUDRACT NO: 2017-003606-40 
Protocol Title: 
A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic Study of Teduglutide in Infants 
4 to 12 Months of Age with Short Bowel Syndrome Who are Dependent on Parenteral Support 
Protocol Version: 
Original Protocol 03 Oct 2017 
The following Administrative Letter is for Protocol SHP633-301, Original Version dated 03 Oct 2017. These changes are considered 
administrative in nature and the clarifications do not compromise the scope, design, or integrity of the study. These changes do not 
compromise subject safety in any way. 
The administrative changes include: 
1. 
To clarify the duration of the screening period and total time on study: The study consists of a screening period of 2-4 
weeks, a 24-week treatment period, and a 4-week follow-up period for a total of up to 30-32 weeks total time on study. 
2. 
To clarify the study schematic: The study schematic will be replaced with the following diagram: 
Screening 
Teduglutide 0.05 mg/kg SC once daily for 24 weeks 
4 
6 
4 
6 
Baseline: treatment 
randomization 
. . . 
9 
12 
16 
20 
-- Site Visit ····Telephone Visit 
Standard of care for 24 weeks 
. . 
. . . 
. 
. . . . . . . 
9 
12 
16 
20 
cc: SHP633-301 TMF Main Study File 
. . 
. . 
. . 
. 
. . 
24 
Extension 
study 
28 
For non-commercial use only


3. 
To provide a clear definition of the end of the trial: The end of trial is defined as the last subject, last visit. This is the visit 
date at which the last subject on the study has his or her last follow-up visit on study (whether during the 24-week treatment 
period or the 4-week follow-up period). 
4. 
To clarify the timing of the required pharmacokinetic (PK) draws after investigational product administration: There 
are no PK draw windows after the first dose of investigational product identified in the protocol. The sponsor wishes to clarify 
that all PK draw windows are permitted to be +/- 10 minutes from scheduled time of draw. 
5. 
To clarify the procedures for assessing subject compliance in Section 6.5: In addition to counting returned vials, subject 
compliance will be checked by site personnel at every visit by reviewing the subject diaries and asking the subject or the 
subject's parent or legally-authorized representative if they have administered the investigational product according to 
instructions. If any doses have been missed, the reason for missed dose should be documented in the subject's source 
documentation including, as applicable, the eCRF. 
The sponsor also wishes to clarify that the investigator is responsible for contacting the sponsor or designee when the 
subject's daily investigational product dosing regimen is interrupted. Attempts should be made to contact the sponsor or 
designee prior to dose interruption. Reasons for dosage interruption may include but are not limited to hospitalization and AEs, 
a lapse in investigational product delivery, etc. 
The protocol will be updated with these changes during any subsequent amendment. 
Copies of this letter shall be distributed to the Principal Investigators of the study and should be forwarded to the site Ethics Committees 
as necessary. 
If you have further questions, please do not hesitate to contact your CRA or Shire directly. 
I have reviewed the above Memorandum and am in agreement with the specified administrative clarifications. 
, Pharm.D., MSc. 
-Teduglutide 
SHP633-301 Medical Monitor 
cc: SHP633-301 TMF Main Study File 
Date 
For non-commercial use only


PROTOCOL: SHP633-301
TITLE:
A Randomized, Open-label, 24-Week Safety, Efficacy, and 
Pharmacokinetic Study of Teduglutide in Infants 4 to 12 Months of Age 
with Short Bowel Syndrome Who are Dependent on Parenteral Support
NUMBER
SHP633-301
PHASE
3 
DRUG:
Teduglutide
INDICATION:
Short bowel syndrome
EUDRACT NO.:
2017-003606-40
SPONSOR: 
Shire Human Genetic Therapies, Inc.
300 Shire Way
Lexington, MA 02421 USA
PROTOCOL 
HISTORY:
Original Protocol: 03 Oct 2017
Amendment 1: 18 Jan 2018
Confidentiality Statement
This document contains confidential and proprietary information of Shire and is disclosed 
pursuant to confidentiality and non-disclosure obligations. This information should be used 
solely for the purposes for which it was provided and should not be copied, shared with, or 
disclosed to any third party without the express written consent of Shire.
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Page2 
SHP633-301 Protocol 
Teduglutide 
18 Jan 2018 
PROTOCOL SIGNATURE PAGE 
Sponsor's (Shire) Approval 
Signature: 
, MD PhD 
, Global Clinical Development 
Investigator's Acknowledgement 
I have read this protocol for Shire Study SHP633-301. 
Date: 
Title: A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic Study of 
Teduglutide in Infants 4 to 12 Months of Age with Short Bowel Syndrome Who are Dependent 
on Parenteral Support 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) guidelines on Good Clinical Practice (GCP) and with the 
applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Address: 
(please hand print or type) 
Signature: 
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SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Adverse Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as 
Required by Protocol within 24 hours to the Shire Global Drug Safety Department. Applicable 
fax numbers and e-mail address can be found on the form (sent under separate cover).  A copy of 
this form must also be sent to the Shire Medical Monitor by fax or e-mail:  
Fax:
,  Email: 
For protocol- or safety-related issues, the investigator must contact IQVIA Medical Support:
Primary Contact
Backup Contact 
, MD
, MD
Mobile:  
Mobile: 
US Toll Free Number: 
Phone: 
Phone: 
 
(medical emergencies)
Phone: 
 
(medical emergencies)
Email:  
Email: 
In addition, the investigator may also contact Shire:
, PharmD, MSc
Phone: 
Mobile: 
Email: 
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Teduglutide
18 Jan 2018
PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (e.g., inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (e.g., wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
European Union and Rest of World
Telephone numbers (provided for reference, if needed): 
Shire (USA)
 
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SUMMARY OF CHANGES FROM PREVIOUS VERSION
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change
Section(s) Affected by 
Change
Updated emergency contact information to reflect the change 
of the Contract Research Organization’s name.
Emergency Contact 
Information
Clarified the duration of the screening period and total time 
on study.  
Provided a clear definition of study completion.
Synopsis, Section 3.1, 
Section 3.2
Updated the study schematic to reflect the study design 
changes.
Revised the telephone and clinic visit schedule to assure 
laboratory measurement could be collected without exceeding 
weekly/monthly total blood volume restrictions.  
Synopsis, Table 1, 
Section 3.1.2
Moved the PK sampling from Week 6 to Week 7 so that the 
samples could be collected without exceeding 
weekly/monthly total blood volume restrictions.
Synopsis, Table 1, 
Section 3.1.2, Section 7.2.4, 
Table 5
Clarified that blood for pharmacokinetic samples of postdose 
may be taken within ± 10 minutes of the time pre-specified.
Clarified that end jejunostomy or ileostomy are examples  of 
small bowel ostomy rather than the stratification factors.
Synopsis, Section 3.1.2,
Section 6.2.2
Clarified that all subjects regardless of treatment arm are 
eligible for the extension study.
Synopsis, Section 3.1.3
Clarified that if a subject treated with teduglutide meets the 
escape criteria, the assessments scheduled for the EOS visit 
should be conducted.
Synopsis, Table 2, 
Section 3.1.3, Section 6.2.3
Clarified that subjects must be 4 to 12 months corrected 
Synopsis, Section 4.1
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SHP633-301 Protocol Amendment 1
Teduglutide
18 Jan 2018
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change
Section(s) Affected by 
Change
gestational age at screening.
Changed dose adjustments to Week 12 rather than at every 
clinic visit to reduce site burden.
Synopsis, Table 1, 
Section 6.2.3
Clarified the definition of enteral autonomy.
Synopsis, Section 9.7.2
Updated the pharmacokinetic endpoint and analysis to reflect 
that only descriptive statistics will be calculated on plasma 
teduglutide concentration values. Pharmacokinetic parameters 
will be estimated using a population PK modeling approach 
as appropriate and reported separately.
Synopsis, Section 9.10
Removed assessment of the 5-level EuroQol five dimensions 
questionnaire to reduce caregiver burden.
Synopsis, Table 1, 
Section 7.2.5, Section 9.9
Clarified that native GLP-2 samples drawn while subjects are 
receiving teduglutide should be drawn at least 14 hours after 
the previous dose.
Table 2, Section 7.2.2
Inserted a footnote to clarify that parenteral support and 
parenteral nutrition are used interchangeably.
Section 1.1
Removed the 5 mg vial of teduglutide as this size vial will not 
be supplied for this study.
Section 6.1
Clarified the procedures for assessing subject compliance. 
Section 6.5
Specified that it is acceptable to only enroll subjects who 
have already had an upper GI series with small bowel follow 
through performed since the subject’s most recent surgery.  
Section 7.2.1
Corrected the volume of blood to be collected for native 
GLP-2.
Table 5
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change
Section(s) Affected by 
Change
Removed references to subject assent as assent is not possible 
in a study of infants. 
Section 7.1.1, Section 10.3.1
Clarified the definitions of the analysis sets.
Section 9.6
Clarified that an adjustment to enteral nutrition as appropriate
is part of the PN/IV adjustment algorithm.
Figure A-1
Minor editorial changes and corrections to typographical 
errors (which do not modify content and/or intent of the 
original document) were made.
Throughout protocol.
See Appendix 1 for protocol history, including all amendments.  
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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
PRODUCT QUALITY COMPLAINTS..........................................................................................4
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................5
TABLE OF CONTENTS.................................................................................................................8
LIST OF TABLES.........................................................................................................................12
LIST OF FIGURES .......................................................................................................................12
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..................................................13
STUDY SYNOPSIS ......................................................................................................................14
STUDY SCHEDULES ..................................................................................................................19
BACKGROUND INFORMATION .......................................................................................23
1.
1.1
Short Bowel Syndrome ............................................................................................23
1.2
Teduglutide...............................................................................................................24
OBJECTIVES.........................................................................................................................25
2.
2.1
Rationale for the Study.............................................................................................25
2.2
Study Objectives ......................................................................................................25
STUDY DESIGN ...................................................................................................................26
3.
3.1
Study Design and Flow Chart ..................................................................................26
3.1.1
Screening Period ....................................................................................................26
3.1.2
Treatment Period....................................................................................................26
3.1.3
Follow-up Period ...................................................................................................27
3.2
Study Duration .........................................................................................................27
3.3
Sites and Regions .....................................................................................................28
STUDY POPULATION.........................................................................................................29
4.
4.1
Inclusion Criteria......................................................................................................29
4.2
Exclusion Criteria.....................................................................................................29
4.3
Reproductive Potential .............................................................................................30
4.4
Discontinuation of Subjects .....................................................................................30
4.4.1
Reasons for Discontinuation..................................................................................31
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit .................................31
PRIOR AND CONCOMITANT TREATMENT ...................................................................32
5.
5.1
Prior Medications and Procedures............................................................................32
5.2
Concomitant Medications and Procedures...............................................................32
5.3
Permitted Treatment.................................................................................................32
5.4
Prohibited Treatment................................................................................................32
INVESTIGATIONAL PRODUCT ........................................................................................33
6.
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6.1
Identity of Investigational Product...........................................................................33
6.2
Administration of Investigational Product ...............................................................33
6.2.1
Interactive Response Technology for Investigational Product Management ........33
6.2.2
Allocation of Subjects to Treatment ......................................................................33
6.2.3
Dosing....................................................................................................................33
6.2.4
Unblinding the Treatment Assignment..................................................................34
6.2.5
Dose Selection Rationale .......................................................................................34
6.3
Labeling, Packaging, and Storage ............................................................................35
6.3.1
Labeling .................................................................................................................35
6.3.2
Storage and Handling.............................................................................................35
6.4
Drug Accountability.................................................................................................36
6.5
Subject Compliance..................................................................................................37
STUDY PROCEDURES........................................................................................................39
7.
7.1
Study Schedule.........................................................................................................39
7.1.1
Screening................................................................................................................39
7.1.2
Treatment Period....................................................................................................39
7.1.3
Follow-up Period ...................................................................................................39
7.2
Study Evaluations and Procedures ...........................................................................39
7.2.1
Demographics and Other Baseline Characteristics................................................39
7.2.2
Efficacy Assessments.............................................................................................40
7.2.3
Safety Assessments................................................................................................41
7.2.4
Pharmacokinetic Assessments ...............................................................................44
7.2.5
Health Economics and Outcomes Research ..........................................................44
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................45
8.
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................45
8.1.1
Severity Categorization..........................................................................................45
8.1.2
Relationship Categorization...................................................................................46
8.1.3
Outcome Categorization ........................................................................................46
8.1.4
Symptoms of the Disease under Study ..................................................................47
8.1.5
Clinical Laboratory and Other Safety Evaluations ................................................47
8.1.6
Pregnancy...............................................................................................................47
8.1.7
Abuse, Misuse, Overdose, and Medication Error ..................................................47
8.2
Serious Adverse Event Procedures ..........................................................................48
8.2.1
Reference Safety Information ................................................................................48
8.2.2
Reporting Procedures.............................................................................................48
8.2.3
Serious Adverse Event Definition .........................................................................49
8.2.4
Serious Adverse Event Collection Time Frame.....................................................49
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8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................49
8.2.6
Fatal Outcome........................................................................................................50
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................50
8.3
Adverse Events of Special Interest...........................................................................50
8.4
Dose Interruption Criteria ........................................................................................51
DATA MANAGEMENT AND STATISTICAL METHODS...............................................52
9.
9.1
Data Collection.........................................................................................................52
9.2
Clinical Data Management.......................................................................................52
9.3
Statistical Analysis Process......................................................................................52
9.4
Planned Interim Analysis, and Data Monitoring Committee...................................52
9.5
Sample Size Calculation and Power Considerations................................................53
9.6
Study Population ......................................................................................................53
9.7
Efficacy Analyses.....................................................................................................54
9.7.1
Efficacy Endpoints.................................................................................................54
9.7.1.1
Primary Efficacy Endpoint.....................................................................54
9.7.1.2
Secondary Efficacy Endpoints ...............................................................54
9.7.2
Method of Analysis-Efficacy Endpoints................................................................54
9.8
Safety Analyses ........................................................................................................55
9.8.1
Safety Endpoints ....................................................................................................55
9.8.2
Method of Analysis-Safety Endpoints...................................................................55
9.9
Health Economics and Outcomes Research Analyses .............................................56
9.10
Pharmacokinetics Analyses......................................................................................56
SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES ............................................57
10.
10.1
Sponsor’s Responsibilities .......................................................................................57
10.1.1 Good Clinical Practice Compliance.......................................................................57
10.1.2 Indemnity/Liability and Insurance.........................................................................57
10.1.3 Public Posting of Study Information......................................................................57
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................58
10.1.5 Study Suspension, Termination, and Completion..................................................58
10.2
Investigator’s Responsibilities .................................................................................58
10.2.1 Good Clinical Practice Compliance.......................................................................58
10.2.2 Protocol Adherence and Investigator Agreement ..................................................59
10.2.2.1
Documentation and Retention of Records .............................................59
10.2.2.2
Electronic Case Report Forms................................................................59
10.2.2.3
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................59
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10.2.2.4
Audit/Inspection .....................................................................................60
10.2.2.5
Financial Disclosure...............................................................................60
10.3
Ethical Considerations..............................................................................................60
10.3.1 Informed Consent...................................................................................................60
10.3.2 Institutional Review Board or Ethics Committee ..................................................61
10.4
Privacy and Confidentiality......................................................................................61
10.5
Study Results/Publication Policy .............................................................................62
REFERENCES .......................................................................................................................64
11.
APPENDICES ........................................................................................................................66
12.
Appendix 1
Protocol History .....................................................................................67
Appendix 2
Guidelines for Nutritional Support Management During the Study ......68
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LIST OF TABLES
Table 1:
Study Schedule: Visits -1 to 12 .....................................................................19
Table 2:
Study Schedule: Visits 13-28 ........................................................................21
Table 3:
Prohibited Treatment.....................................................................................32
Table 4:
List of Laboratory Tests ................................................................................42
Table 5:
Approximate Volume of Blood to be Drawn from Each Subject .................43
LIST OF FIGURES
Figure 1:
Study Schematic ............................................................................................26
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation
Definition
AE
adverse event
AUCss
area under the concentration-time curve at steady-state 
Cmax,ss
maximum plasma concentration at steady state
CRO
contract research organization
eCRF
electronic case report form
DMC
data monitoring committee
EDC
electronic data capture
EMA
European Medicines Agency
EN
enteral nutrition
EOS
end of study
EOT
end of treatment
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
gastrointestinal 
GLP
glucagon-like peptide
HIPAA
Health Insurance Portability and Accountability Act
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use
ICMJE
International Committee of Medicinal Journal Editors
I/O
oral fluid intake and urine output
IP
Investigational product
IRB
Institutional Review Board
ITT
intent-to-treat
MedDRA
Medical Dictionary for Regulatory Activities
PK
pharmacokinetics
PN
parenteral nutrition
SAE
serious adverse event
SAP
statistical analysis plan
SBS
short bowel syndrome
SC
subcutaneous
SD
standard deviation
SOC
standard of care
ULN
upper limit of normal 
US
United States
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STUDY SYNOPSIS
Protocol number: SHP633-301
Drug: Teduglutide
Title of the study: A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic Study of 
Teduglutide in Infants 4 to 12 Months of Age with Short Bowel Syndrome Who are Dependent on Parenteral 
Support
Number of subjects (total and for each treatment arm):
At least 10 subjects will be randomized: at least 5 subjects in a teduglutide treatment arm and at least 5 subjects in 
a standard of care (SOC) comparator arm
Investigator(s): Multicenter study
Site(s) and Region(s): 
This study is planned to be conducted in approximately 5 to 10 sites globally.
Study period (planned):
2017-2020
Clinical phase:
3
Objectives:
The objectives of this clinical study are to evaluate the safety, efficacy/pharmacodynamics and pharmacokinetics 
(PK) of teduglutide treatment in infants with short bowel syndrome (SBS) dependent on parenteral support.
Investigational product, dose, and mode of administration:
Teduglutide 0.05 mg/kg by subcutaneous (SC) injection once daily into 1 of the 4 quadrants of the abdomen or 
either thigh or arm.
Methodology:
This is a randomized, multicenter, open-label study, consisting of a 2 to 4 week screening period, a 24-week 
treatment period, and a 4-week follow-up period. 
* At EOS all subjects regardless of treatment arm may enroll in an extension study that will 
capture long-term safety data and provide the opportunity for additional teduglutide treatment.  
The follow-up period for subjects in the teduglutide treatment arm may be interrupted and the 
Extension 
study* 
1
24
1
3
5
7
9
12
16
20
28
2 to 4
Weeks
Screening
Teduglutide 0.05 mg/kg SC once daily for 24 weeks
Site Visit 
Telephone Visit
Standard of care for 24 weeks
Baseline: treatment 
randomization
0
24
3
5
7
9
12
16
20
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subjects may proceed immediately to the EOS if at least one “escape” criteria is met.
Study eligibility will be confirmed during the screening period (minimum: 2 weeks; maximum 4 weeks). At the 
baseline visit (Week 0), subjects will be randomized 1:1 to the teduglutide or SOC treatment arm. Randomization 
will be stratified according to the presence of a small bowel ostomy (e.g., end jejunostomy or ileostomy). During 
the 24-week treatment period, subjects in the SOC treatment arm will receive standard medical therapy for SBS; 
while those in the teduglutide arm will receive 0.05 mg/kg SC once daily in addition to standard medical therapy. 
Subjects in both arms will follow the same visit schedule and assessments. Subjects will be monitored weekly 
with phone or clinic visits. Clinic visits will occur at Weeks 1, 3, 5, 7, 9, 12, 16, 20, 24, and 28. At all site visits 
and telephone contacts, safety will be monitored and nutritional support will be reviewed and adjusted as needed. 
To maintain consistency across centers, guidance and training will be provided to help sites follow the nutritional 
support adjustment guidelines (developed with SBS expert input and provided in the protocol) related to decisions 
for parenteral nutrition (PN) reduction and advances in enteral feeds based on weight gain, urine and stool output, 
and clinical stability. Deviations from the guidelines are not considered a protocol deviation.
Sparse PK sampling, in the teduglutide treatment arm only, will occur at baseline (predose and 1 hour 
±10 minutes and 4 hours ±10 minutes postdose) and at Week 7 or 12 (2 hours±10 minutes postdose).
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up period until the end 
of study (Week 28/EOS) during which time subjects will receive standard medical therapy, but no investigational 
product will be administered.  At EOS all subjects regardless of treatment arm may enroll in an extension study 
that will capture long-term safety data and provide the opportunity for additional teduglutide treatment.  The 
follow-up period for subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed 
immediately to the EOS if at least one of the following “escape” criteria is met:
1.
Increasing PN requirements following discontinuation of teduglutide.
2.
Deteriorating nutritional status (e.g., weight loss or growth failure) despite maximal tolerated enteral 
nutrition (EN) following teduglutide discontinuation.
3.
Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and electrolyte intake 
following teduglutide discontinuation.
4.
Severe diarrhea related to teduglutide discontinuation.
Inclusion and Exclusion Criteria:
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1.
Informed consent by the parent or legal guardian. 
2.
Male or female infant 4 to 12 months corrected gestational age at screening.
3.
Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and baseline.
4.
Short bowel syndrome with dependence on parenteral support to provide at least 50% of fluid or caloric 
needs.
5.
Stable PN requirements for at least 1 month prior to screening, defined as a ≤10% change in the weight-
normalized parenteral total fluid and caloric intake, despite attempts to wean PN, notwithstanding 
transient instability for events such as sepsis or interruption of central venous access.
6.
Lack of terminal ileum and ileocecal valve
7.
Parent or legal guardian understands and is willing and able to fully adhere to study requirements as 
defined in this protocol.
Exclusion Criteria
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Subjects are excluded from the study if any of the following exclusion criteria are met:
1.
Previous treatment with teduglutide.
2.
Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus inclusion disease, 
etc.
3.
Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility, that is the primary contributing factor to feeding intolerance and 
inability to reduce parenteral support, prior to screening.  Dysmotility is defined as severe if it is 
expected to limit the advancement of enteral feeding.
4.
Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral aversion in the 
absence of a feeding tube.
5.
Intestinal obstruction or clinically significant intestinal stenosis.
6.
Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or major intestinal 
resection or anastomosis, within 3 months prior to screening or planned during the study period.
7.
Unstable cardiac disease.
8.
Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
9.
Biliary obstruction, stenosis, or malformation. 
10. Clinically significant pancreatic disease. 
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b.
Platelet count <100×10^3/µl due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d.
Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 2-week period
13. More than 3 serious complications of intestinal failure (e.g., catheter-associated bloodstream infections, 
interruption of nutrition due to feeding intolerance, catheter-associated thrombosis, severe fluid or 
electrolyte disturbances) within 1 month prior to or during screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile polyposis or Beckwith-
Wiedemann syndrome, or first degree relative with early onset of gastrointestinal cancer (including 
hepatobiliary and pancreatic cancers). 
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 (GLP-2); insulin-
like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs of these hormones; or 
glutamine. 
16. Participation in a clinical study using an experimental drug within 3 months or 5.5 half-lives of the 
experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, closely-related 
compounds, or any of the stated ingredients.
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts the subject at any 
undue risk, prevents completion of the study, or interferes with analysis of the study results.
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Maximum Duration of Subject Involvement in the Study:
The study consists of a 2 to 4 week screening period, a 24-week treatment period, and a 4-week follow-up period. 
The maximum duration of participation for each subject is 32 weeks.
Study completion is defined as the last subject, last visit. This is the visit date at which the last subject on the 
study has his or her last follow-up visit on the study (whether during the 24-week treatment period or the 4-week 
follow-up period).
Endpoints:
Efficacy
Efficacy endpoints consist of the following:
Primary

Reduction in weight-normalized PN fluid volume by at least 20% from baseline at Week 24/EOT
Secondary

Reduction in weight-normalized parenteral calories by at least 20% from baseline to Week 24/EOT

Achievement of enteral autonomy by week 24

Change in weight-normalized parenteral fluid volume from baseline to each visit

Change in weight-normalized parenteral calories from baseline to each visit

Change in weight-normalized enteral fluid volume from baseline to each visit

Change in weight-normalized enteral caloric intake from baseline to each visit

Increase in weight-normalized enteral fluid intake by at least 20% from baseline to Week 24/EOT

Increase in weight-normalized enteral caloric intake by at least 20% from baseline to Week 24/EOT
Pharmacokinetics
The pharmacokinetic endpoint is plasma teduglutide concentration at nominal time point.
Safety
Safety endpoints consist of the following:

Adverse events (AEs)

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output

Stool (including mixed) output  

Antibodies to teduglutide 
Health Economics and Outcomes Research
Health economics and outcomes research (HEOR) endpoints include the following:

Cumulative number of hospitalization days during the study
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Statistical Methods:
Efficacy
Analyses of weekly PN support will be based on 2 data sources: the subject diary data (also referred to as actual 
data) and the investigator prescribed data.  
The number and percentage of subjects who achieve at least a 20% reduction from baseline in weight-normalized 
average daily PN volume at Week 24/EOT and the number and percentage of subjects who achieve at least a 20% 
reduction from baseline in weight-normalized parenteral calories at Week 24/EOT will be summarized by 
treatment arm.
During the treatment period, a subject will be considered to have achieved enteral autonomy (completely weaned 
off PN) at a given visit if the investigator prescribes no PN at that visit and for the remainder of the treatment 
period, and there is no use of PN recorded in the subject diary during the week prior to that visit and for the 
remainder of the treatment period. During the follow-up period, a subject will be considered to have achieved 
enteral autonomy at a given visit if the investigator prescribes no PN at that visit and for the remainder of the 
follow-up period and there is no use of PN recorded in the subject diary during the week prior to that visit and for 
the remainder of the follow-up period. The number and percentage of subjects who achieve enteral autonomy at 
each scheduled visit, as well as at EOT, will be summarized by treatment arm. 
The absolute and percent change in weight-normalized weekly PN volume, parenteral calories, enteral fluid 
volume, and enteral caloric intake, from baseline to each scheduled visit, as well as at EOT, will be summarized 
by treatment arm using descriptive statistics.
The number and percentage of subjects who demonstrate an increase in weight-normalized enteral fluid intake by 
at least 20% from baseline to Week 24/EOT and the number and percentage of subjects who demonstrate an 
increase in weight-normalized enteral caloric intake by at least 20% from baseline to week 24/EOT will be 
summarized by treatment arm.
Pharmacokinetics
Plasma concentrations will be summarized using descriptive statistics (number, mean, standard deviation, 
geometric mean, coefficient of variation, minimum, median, and maximum) at nominal time points. 
Pharmacokinetic parameters will be estimated using a population PK modeling approach as appropriate and 
reported separately.
Safety
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Treatment-emergent AEs will be summarized by system organ class and preferred term using descriptive statistics 
(e.g., number and percentage of subjects). Adverse events will be summarized by severity and relationship to 
treatment. In addition, serious adverse events  will also be tabulated by overall and treatment-related events. AEs 
leading to treatment discontinuation and death will also be summarized.
For laboratory tests; vital signs; urine and stool output; weight, length, and head circumference Z-scores; and 
descriptive statistics (e.g., n, mean, standard deviation, median, minimum and maximum values, and the number 
and percentage of subjects in specified categories) will be used to summarize the absolute values and change from 
baseline at each visit.
The number and percentage of subjects classified as having antibodies to teduglutide will be used to summarize 
the presence of antibodies.  
Health Economics and Outcomes Research
The HEOR endpoints will be summarized descriptively.  
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STUDY SCHEDULES
Table 1:
Study Schedule: Visits -1 to 12
Procedures
Screening
Baseline 
(Week 0)
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
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit type
Site
Site
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Tel
Site
Study day
-14
0
7
14
21
28
35
42
49
56
63
70
77
84
±window (days)
-2 weeks
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Informed consent
X
Eligibility
X
X
Randomization
X
Demographics 
X
SBS history
X
Medical and surgical history
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications and 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, vital signs, 
weight
X
X
X
X
X
X
X
X
Length and head circumference
X
X
X
X
UGI/SBFT
X
Safety labs and urinalysisb, c
X
Xb
X
(X)
X
(X)
X
(X)
X
(X)
X
(X)
(X)
X
PK samplinga
X
 
[X]d
[X]d
Antibodies to teduglutidea,e
X
Xe
Native GLP-2f
X
Provide intake and output 
diariesg
X
X
X
X
X
X
X
X
Review diaries and nutritional 
support
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional support as 
neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense IPa, i
X
X
X
X
X
X
X
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Table 1:
Study Schedule: Visits -1 to 12
Procedures
Screening
Baseline 
(Week 0)
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
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit type
Site
Site
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Tel
Site
Study day
-14
0
7
14
21
28
35
42
49
56
63
70
77
84
±window (days)
-2 weeks
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Adjust IP dosej
X
EN=enteral nutrition; GLP-2=glucagon-like peptide 2; INR=international normalized ratio; IP=investigational product; PK=pharmacokinetics; PN=parenteral nutrition; PT=prothrombin time; 
UGI/SBFT=upper GI series with small bowel follow-through 
a Applicable to the teduglutide treatment arm only. 
b At baseline, safety labs (Table 4) and PK can be separated by 1 day if blood volumes are limiting. Safety labs at telephone visits will be collected at the discretion of the investigator. For all subjects in 
the teduglutide treatment arm, PT and INR will be tested at baseline, and repeated if clinically indicated.
c Urinalysis will consist of urine sodium and specific gravity. Urine collection should be attempted, but inability to obtain urinalysis is not a protocol deviation.
d Subjects will have blood samples taken for teduglutide PK analysis predose and 1 hour ±10 minutes and 4 hours ±10 minutes postdose at baseline (Visit 0). Subjects also will have blood samples taken 
for teduglutide PK analysis 2 hours ±10 minutes postdose at Week 7 (Visit 7) or Week 12 (Visit 12) of the treatment period.
e Samples for antibody analysis will be drawn at the baseline and Week 12 visits.  Blood samples while subjects are receiving teduglutide should be drawn at least 14 hours after the previous dose.
f Blood samples for native GLP-2 should be collected postprandial.  Native GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at investigator 
discretion based on weekly/monthly total volume.  
g Intake diaries will collect actual PN volume and hours per day and EN volume and calories. Intake diaries should be completed daily throughout the study. Urine and stool output should be recorded in 
the output diary over a 48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PN prescription. 
h Parenteral support adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment provided in Appendix 2.
i The initial dose will be calculated based on body weight measured at baseline (Visit 0).
j  The dose will be adjusted as needed, based on body weight measured at Week 12 visit.
Note: (X) denotes optional assessments; [X] denotes possible PK sampling time point (Refer to footnote “e”.)
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Table 2:
Study Schedule: Visits 13-28
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 
(EOT/ET)
Week 
25
Week 
26
Week 
27
Week 
28 
(EOS)a
Visit number
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit type
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Study day
91
98
105
112
119
126
133
140
147
154
161
168
175
182
189
196
±window (days)
±3
±3
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications 
and procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, vital 
signs, weight
X
X
X
X
Length and head 
circumference
X
X
X
X
Safety labs and 
urinalysisb,c
(X)
(X)
(X)
X
(X)
(X)
(X)
X
(X)
(X)
(X)
X
(X)
(X)
(X)
X
Antibodies to 
teduglutided,e
X
Native GLP-2f
X
Provide intake and output 
diaries
X
X
X
Review diaries and 
nutritional supportg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional support 
as neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess follow-up period 
escape criteriad
Xi
Xi
Xi
X
Dispense IPd
X
X
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Table 2:
Study Schedule: Visits 13-28
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 
(EOT/ET)
Week 
25
Week 
26
Week 
27
Week 
28 
(EOS)a
Visit number
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit type
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Study day
91
98
105
112
119
126
133
140
147
154
161
168
175
182
189
196
±window (days)
±3
±3
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
EN=enteral nutrition; EOS=end of study; EOT=end of treatment; ET=early termination; GLP-2=glucagon-like peptide 2; INR=international normalized ratio; IP=investigational product; PN=parenteral 
nutrition; PT=prothrombin time; UGI/SBFT=upper GI series with small bowel follow-through
a At EOS subjects may enroll in an extension study, if subjects require treatment before the end of the 4-week follow-up they may enter the extension study immediately.  
bSafety labs at telephone visits will be collected at the discretion of the investigator. For all subjects in the teduglutide treatment arm, PT and INR are tested if clinically indicated.
c Urinalysis will consist of urine sodium and specific gravity.  
d Applicable to the teduglutide treatment arm only. 
e Samples for antibody analysis will be drawn at the EOS (Week 28) visit.
f Blood samples for native GLP-2 should be collected postprandial.  Blood samples drawn while subjects are receiving teduglutide should be drawn at least 14 hours after the previous dose. Native GLP-
2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at investigator discretion based on weekly/monthly total volume.  
g Intake diaries will collect actual PN volume and hours per day and EN volume and calories. Intake diaries should be completed daily throughout the study. Urine and stool output should be recorded in 
the output diary over a 48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PN prescription. 
h Parenteral support adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment provided in Appendix 2.
Note: (X) denotes optional assessments.
i If a subject treated with teduglutide meets the escape criteria, the assessments scheduled for the EOS visit should be conducted.
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BACKGROUND INFORMATION
1.
1.1
Short Bowel Syndrome
Short bowel syndrome (SBS) is a rare disorder resulting from congenital abnormalities or severe 
intestinal diseases that result in major surgical resections of the small intestine (O'Keefe et al., 
2006).  Unlike the adult population, the majority of cases of SBS in pediatric subjects are due to 
congenital anomalies or catastrophic events that occur during infancy such as necrotizing 
enterocolitis, gastroschisis, intestinal atresia, midgut volvulus, or long-segment Hirschsprung 
disease (Beattie et al., 2010; Goulet and Ruemmele, 2006).  A Canadian population-based study 
in neonates estimates an overall incidence of SBS to be 24.5 cases per 100,000 live births (Wales 
et al., 2004).  
The small intestine is capable of remarkable adaptation, but excessive loss of absorptive surface 
area or specialized functions can lead to dependence on parenteral nutrition (PN)1 fluids 
(O'Keefe et al., 2006).  Although PN is life-sustaining in intestinal failure, it is associated with 
serious complications, including liver disease, life-threatening catheter-related blood stream 
infections, and central venous thrombosis (Beattie et al., 2010; Goulet and Ruemmele, 2006).  
Dependence on PN is also associated with reduced quality of life in both patients and caregivers 
and has an extremely high cost of care (Huisman-de Waal et al., 2007).  About 30% of infants 
with SBS become independent of PN requirements within 12 months of the initial insult, and an 
additional 10% wean off PN within 24 months. After this time, linear intestinal growth slows.  It 
is estimated that 42% to 86% of pediatric patients with SBS are able to become independent of 
PN within 1 to 3 years (Gonzalez-Hernandez et al., 2017; Khan et al., 2015; Squires et al., 2012).  
Nevertheless, despite optimal medical management, some children remain dependent on PN for 
many years (Squires et al., 2012).  Infants who have less than 10% of expected small intestinal 
length for their gestational age have a low likelihood of ever achieving enteral autonomy (i.e., 
independence from parenteral support).  Providing the maximum tolerated amount of enteral 
nutrition (EN) has been the primary strategy to promote enteral adaptation (Spencer et al., 2005).  
Accelerating the adaptive process and achieving enteral autonomy is an urgent goal for all 
patients with SBS who are dependent on PN (Khan et al., 2015; Squires et al., 2012).  The 
adaptive process is in part controlled by glucagon-like peptide 2 (GLP-2), a 33 amino acid 
peptide hormone secreted from L-type enteroendocrine cells in the terminal ileum and colon in 
response to luminal nutrients and bile acids (Martin et al., 2006).  The post-prandial plasma 
concentration of GLP-2 in infants with SBS correlates with length of the remaining small 
intestine (Sigalet et al., 2004).  Infants who lack terminal ileum may have impaired adaptation 
due to inadequate production of GLP-2.
                                                
1 For the purpose of the study the terms parenteral support (PS) and parenteral nutrition (PN) are used 
interchangeably.
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1.2
Teduglutide
Teduglutide is a novel, recombinant analog of naturally occurring human GLP-2 that regulates 
the functional and structural integrity of the cells lining the gastrointestinal (GI) tract. 
Teduglutide is a 33-amino acid peptide that differs from native GLP-2 in the substitution of 
glycine for alanine at the second position at the N-terminus.  As a result, teduglutide 
demonstrates resistance to degradation by dipeptidyl peptidase 4 (DPP-4) and therefore 
maintains a longer elimination half-life (t1/2), approximately 2 hours in healthy adult subjects, 
1.3 hours in adult SBS subjects, and 0.22 hours in pediatric SBS subjects, compared to the native 
peptide, which has a t1/2 of approximately 7 minutes.  Teduglutide has been shown in animal 
studies and previous human clinical trials to increase villus height and crypt depth in the 
intestinal epithelium, thereby increasing the absorptive surface area of the intestines (Tappenden 
et al., 2013; Thymann et al., 2014). 
A Phase 3 study, TED-C13-003, has been completed in pediatric SBS subjects.  In this study, 
teduglutide was administered to 3 cohorts of pediatric subjects from ages 1-17 years.  
Thirty-seven pediatric subjects received teduglutide at doses of 0.0125, 0.025, or 0.05 mg/kg/day 
for 12 weeks.  Five additional pediatric subjects were enrolled in an observational standard of 
care (SOC) cohort.  There were clear dose-dependent effects of teduglutide seen at the 0.025 and 
0.05 mg/kg/day doses compared to SOC and the 0.0125 mg/kg/day dose.  In the 
0.025 mg/kg/day cohort there was a reduction in PN volume at Week 12 of 37%, including 
complete independence from PN support in 1 subject, and a reduction of 3.94 hours per day 
infusion time.  In the 0.05 mg/kg/day cohort there was a reduction in PN volume at Week 12 of 
39%, including complete independence from PN support in 3 subjects, and a reduction of 
4.18 hours per day infusion time.  Teduglutide was generally safe and well tolerated by pediatric 
subjects in all dosing cohorts.  There were no deaths during the study and no treatment-emergent 
serious adverse events (SAEs) related to teduglutide were reported.  No discontinuations from 
study were due to adverse events (AEs).  Additional studies in pediatric patients with SBS are 
ongoing.
Teduglutide (0.05 mg/kg/day) is currently approved for the treatment of adult patients with SBS 
in >30 countries.  On 29 Jun 2016, the European Commission granted an extension of the Market 
Authorization for teduglutide for the treatment of patients aged 1 year and above with SBS.  
Always refer to the latest version of the investigator’s brochure for the overall risk/benefit 
assessment and the most accurate and current information regarding the drug metabolism, 
pharmacokinetics, efficacy and safety of teduglutide (SHP633).
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OBJECTIVES
2.
2.1
Rationale for the Study 
There is no approved pharmacological therapy to improve intestinal adaptation in infants with 
SBS who are dependent on parenteral support.  This study will evaluate whether teduglutide is 
safe and effective in this patient population.  
2.2
Study Objectives
The objectives of this study are to evaluate the safety, efficacy/pharmacodynamics and 
pharmacokinetics (PK) of teduglutide treatment in infants with SBS dependent on parenteral 
support.
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STUDY DESIGN
3.
3.1
Study Design and Flow Chart
This is a randomized, multicenter, open-label study, consisting of a 2 to 4-week screening period, 
a 24-week treatment period and a 4-week follow-up period.  A schematic representation of the 
study design is presented in Figure 1.
Figure 1:
Study Schematic
*At EOS all subjects regardless of treatment arm may enroll in an extension study that will capture long-term safety data and 
provide the opportunity for additional teduglutide treatment.  The follow-up period for subjects in the teduglutide treatment arm 
may be interrupted and the subjects may proceed immediately to the EOS if at least one “escape” criteria is met.
3.1.1
Screening Period 
Study eligibility will be confirmed during the screening period (minimum: 2 weeks; maximum: 
4 weeks).  The schedule of evaluations to be conducted during the Screening Period can be found 
in Table 1.
3.1.2
Treatment Period
At the baseline visit (Week 0), subjects will randomized 1:1 to the teduglutide or SOC treatment 
arm. Randomization will be stratified according to the presence of a small bowel ostomy (e.g., 
end jejunostomy or ileostomy). During the 24-week treatment period, subjects in the SOC 
treatment arm will receive standard medical therapy for SBS, while those in the teduglutide arm 
will receive 0.05 mg/kg by subcutaneous (SC) injection once daily in addition to standard 
medical therapy. 
Extension 
study* 
1
24
1
3
5
7
9
12
16
20
28
2 to 4
Weeks
Screening
Teduglutide 0.05 mg/kg SC once daily for 24 weeks
Site Visit 
Telephone Visit
Standard of care for 24 weeks
Baseline: treatment 
randomization
0
24
3
5
7
9
12
16
20
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Subjects in both arms will follow the same visit schedule and assessments. Subjects will be 
monitored weekly with phone or clinic visits. Clinic visits will occur at Weeks 1, 3, 5, 7, 9, 12, 
16, 20, 24, and 28. At all site visits and telephone contacts, safety will be monitored and 
nutritional support will be reviewed and adjusted as needed. To maintain consistency across 
centers, guidance and training will be provided to help sites follow the nutritional support 
adjustment guidelines (developed with SBS expert input and provided in the protocol) related to 
decisions for PN reduction and advances in enteral feeds based on weight gain, urine and stool 
output, and clinical stability (Appendix 2). Deviations from the guidelines are not considered a 
protocol deviation.
Sparse PK sampling, in the teduglutide treatment arm only, will occur at baseline (predose and 
1 hour ±10 minutes and 4 hours ±10 minutes postdose) and at Week 7 or 12 (2 hours±10 minutes 
postdose).
The schedule of evaluations for the Treatment Period can be found in Table 1 (Visits -1 to 12) 
and Table 2 (Visits 13 to 28).  
3.1.3
Follow-up Period
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up 
period until the end of study (Week 28/EOS) during which time subjects will receive standard 
medical therapy, but no investigational product (IP) will be administered. At EOS, all subjects
regardless of treatment arm may enroll in an extension study that will capture long-term safety 
data and provide the opportunity for additional teduglutide treatment. The follow-up period for 
subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed 
immediately to the EOS visit if at least one of the following “escape” criteria is met:
1. Increasing PN requirements following discontinuation of teduglutide.
2. Deteriorating nutritional status (e.g., weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation.  
4. Severe diarrhea related to teduglutide discontinuation.
The schedule of evaluations for the Follow-up Period can be found in Table 2 (Visits 13 to 28).
3.2
Study Duration
The study consists of a 2 to 4-week screening period, a 24-week treatment period and a 4-week 
follow-up period.  The maximum duration of participation for each subject is 32 weeks.
Study completion is defined as the last subject, last visit. This is the visit date at which the last 
subject on the study has his or her last follow-up visit on the study (whether during the 24-week 
treatment period or the 4-week follow-up period).
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3.3
Sites and Regions
This study is planned to be conducted at approximately 5 to 10 sites globally.
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STUDY POPULATION
4.
At least 10 subjects will be randomized: at least 5 subjects in a teduglutide treatment arm and at 
least 5 subjects in an SOC comparator arm.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1. Informed consent by the parent or legal guardian. 
2. Male or female infant 4 to 12 months corrected gestational age at screening.
3. Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and 
baseline.
4. Short bowel syndrome with dependence on parenteral support to provide at least 50% of 
fluid or caloric needs.
5. Stable PN requirements for at least 1 month prior to screening, defined as a ≤10% change 
in the weight-normalized parenteral total fluid and caloric intake, despite attempts to 
wean PN, notwithstanding transient instability for events such as sepsis or interruption of 
central venous access.
6. Lack of terminal ileum and ileocecal valve.
7. Parent or legal guardian understands and is willing and able to fully adhere to study 
requirements as defined in this protocol.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1. Previous treatment with teduglutide.
2. Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus 
inclusion disease, etc.
3. Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, 
active gastroschisis-related dysmotility, that is the primary contributing factor to feeding 
intolerance and inability to reduce parenteral support, prior to screening.  Dysmotility is 
defined as severe if it is expected to limit the advancement of enteral feeding.
4. Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral 
aversion in the absence of a feeding tube.
5. Intestinal obstruction or clinically significant intestinal stenosis.
6. Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or 
major intestinal resection or anastomosis, within 3 months prior to screening or planned 
during the study period.
7. Unstable cardiac disease.
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8. Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
9. Biliary obstruction, stenosis, or malformation. 
10. Clinically significant pancreatic disease. 
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following 
parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b. Platelet count <100×10^3/µL due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d. Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 
2 week period.
13. More than 3 serious complications of intestinal failure (e.g., catheter-associated 
bloodstream infections, interruption of nutrition due to feeding intolerance, 
catheter-associated thrombosis, severe fluid or electrolyte disturbances) within 1 month 
prior to or during screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile 
polyposis or Beckwith-Wiedemann syndrome, or first degree relative with early onset of 
gastrointestinal cancer (including hepatobiliary and pancreatic cancers). 
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 
(GLP-2); insulin-like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs 
of these hormones; or glutamine. 
16. Participation in a clinical study using an experimental drug within 3 months or 
5.5 half-lives of the experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, 
closely-related compounds, or any of the stated ingredients.  
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts 
the subject at any undue risk, prevents completion of the study, or interferes with analysis 
of the study results.
4.3
Reproductive Potential 
Not applicable; this study will enroll infants.
4.4
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution.  The investigator or sponsor may 
withdraw the subject at any time (e.g., in the interest of subject safety).  The investigator should 
discuss withdrawal of a subject from investigational product with the medical monitor as soon as 
possible.
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If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 24/EOT/early termination are to be performed as completely as possible. Whenever 
possible, all discontinued subjects should also undergo the protocol-specified 4-week Follow-up 
Period. Comments (spontaneous or elicited) or complaints pertaining to IP discontinuation made 
by the subject must be recorded in the source documents. The reason for discontinuation, the 
date and the total amount of investigational product administered must be recorded in the 
electronic case report form (eCRF) and source documents.
Subjects who discontinue will not be replaced. 
4.4.1
Reasons for Discontinuation
The reason(s) for permanent discontinuation of treatment and/or withdrawal from the study must 
be determined by the investigator, and recorded in the subject’s medical record and in the eCRF.  
If a subject is withdrawn for more than 1 reason, each reason should be documented in the source 
document, and the most clinically relevant reason should be entered in the eCRF.
Reasons for discontinuation include, but are not limited to:

Adverse event

Death

Lost to follow-up

Physician decision

Protocol deviation

Study terminated by sponsor

Withdrawal by parent/guardian

Lack of efficacy

Other
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact the parent(s)/guardian(s) of any 
subject lost to follow-up at any time point prior to the last scheduled contact (office visit or 
telephone contact). At least 1 of these documented attempts must include a written 
communication sent to the subject’s last known address via courier or mail (with an 
acknowledgement of receipt request) asking that they return to the site for final safety 
evaluations and return any unused investigational product.
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PRIOR AND CONCOMITANT TREATMENT
5.
5.1
Prior Medications and Procedures
Prior treatment includes all treatment and procedures (including but not limited to prescription 
treatments, herbal treatments, vitamins, non-pharmacological treatment, as appropriate) received 
within 14 days prior to the screening visit (Visit -1) (or pharmacokinetic equivalent of 5 half 
lives, whichever is longer, must be recorded on the appropriate eCRF page.
5.2
Concomitant Medications and Procedures
The administration of all medications including concomitant medications (including prescription 
and nonprescription medications, dietary and nutritional supplements, and vitamins) and PN 
must be recorded from the first dose of investigational product and for the duration of the study 
in the appropriate sections of the eCRF.  Any diagnostic, surgical or other therapeutic treatments 
received by a subject during the course of the study will also be recorded on the eCRF.
The mechanism of action of teduglutide may increase enteral absorption of oral drugs (e.g., 
drugs used for management of SBS such as motility medication, opioids, psychotropics, 
metronidazole), so consideration should be given to modifying concomitant enteral medication 
regimens. Titration of concomitant enteral medications should be considered when drugs, 
especially those with a narrow therapeutic index (e.g., warfarin, digoxin, psychotropics) are 
given.
5.3
Permitted Treatment
Standard medical therapy for SBS should be continued.
5.4
Prohibited Treatment
The following medications are prohibited during teduglutide treatment and within the provided 
timeframe prior to the pretreatment visit (Table 3):
Table 3:
Prohibited Treatment
Prior Therapy
Time Restriction Prior to 
the Pretreatment Visit
Teduglutide
Any
GLP-2, human growth hormone, or analogs of these hormones
6 months
Octreotide, GLP-1 analogs, and enteral glutamine
30 days
GLP=glucagon-like peptide
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INVESTIGATIONAL PRODUCT
6.
6.1
Identity of Investigational Product
The SOC treatment arm will receive standard medical therapy for SBS; while those in the 
teduglutide arm will receive 0.05 mg/kg SC once daily in addition to standard medical therapy.
Teduglutide will be provided in sterile, single-use 3 mL vials containing 1.25 mg teduglutide as a 
white lyophilized powder to be reconstituted before use with 0.5 mL sterile water for injection. 
In addition to the active ingredient (teduglutide), each vial of teduglutide contains L-histidine, 
mannitol, monobasic sodium phosphate monohydrate, and dibasic sodium phosphate as 
excipients. Additional information is provided in the current investigator’s brochure.
6.2
Administration of Investigational Product
6.2.1
Interactive Response Technology for Investigational Product Management
All investigative study sites will be initially provided with sufficient investigational product to 
randomly assign a subject into the study (for either of the proposed treatment groups).  
Randomization will occur through an interactive response system. Random assignment of a 
subject will trigger replacement supplies for that investigative study site.
6.2.2
Allocation of Subjects to Treatment
Subjects will be randomized 1:1 to the teduglutide or SOC treatment arm.  Randomization will 
be stratified according to the presence of a small bowel ostomy (e.g., end jejunostomy or 
ileostomy).  The actual treatment given to individual subjects is determined by a randomization 
schedule.
Subject numbers are assigned to all subjects as they consent to take part in the study.  Within 
each site (numbered uniquely within a protocol), the subject number is assigned to subjects 
according to the sequence of presentation for study participation.  
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined.
6.2.3
Dosing
The initial dose will be calculated based on body weight measured at baseline (Visit 0), and 
adjusted as needed, based on body weight measured at Week 12. No other adjustments to dose 
will be made during the teduglutide treatment period, unless discussed with the sponsor’s 
medical monitor. 
Following reconstitution, teduglutide will be administered by SC injection once daily (QD) into 
1 of the 4 quadrants of the abdomen (in subjects without a stoma) or into either the thigh or arm.  
For subjects with a stoma, the quadrant of the abdomen containing the stoma should not be used.  
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Teduglutide should be used as soon as possible after reconstitution, but no more than 3 hours 
later.
The subject should be dosed at approximately the same time each day. Consecutive doses should 
be separated by at least 12 hours.  Each day, the injection site should be alternated.  
Any subject who achieves complete independence from PN support at any time during the 
treatment period will continue to receive teduglutide treatment.
The first SC injection in teduglutide-naïve subjects should be administered under the supervision 
of the investigator or designee and the subject observed for hypersensitivity reactions for at least 
4 hours during their initial dosing visit.  The site of administration (arm, thigh, and abdomen) of 
the first teduglutide dose must be specified and recorded in the eCRF. 
Detailed instructions for reconstitution and injection of the investigational product can be found 
in the Instructions for Use. 
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up 
period until the end of study (Week 28/EOS) during which time subjects will receive standard 
medical therapy, but no investigational product will be administered.  At EOS all subjects 
regardless of treatment arm may enroll in an extension study that will capture long-term safety 
data and provide the opportunity for additional teduglutide treatment.  The follow-up period for 
subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed 
immediately to the EOS if at least one of the following “escape” criteria is met:
1. Increasing PN requirements following teduglutide discontinuation.
2. Deteriorating nutritional status (e.g., weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation.  
4. Severe diarrhea related to teduglutide discontinuation.
6.2.4
Unblinding the Treatment Assignment
Not applicable for this open-label study.
6.2.5
Dose Selection Rationale
Teduglutide is approved for adult and pediatric use in the EU at a dose of 0.05 mg/kg SC once 
daily.  A completed 12-week dose finding study (TED-C13-003) demonstrated that teduglutide 
dosing at 0.025 and 0.05 mg/kg/day was associated with a favorable benefit-risk profile most 
meaningful at the 0.05 mg/kg/day dose (Carter et al., 2017). 
Population pharmacokinetic modeling and simulations were conducted to determine the optimal 
dose to be used in pediatric subjects using data from 8 adult clinical studies including adult Phase 
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1 studies and Phases 2/3 studies as well as TED-C13-003 and suggested the same adult dose 
(0.05mg/kg) in pediatric subjects (aged between 1.67-14.7 years) (Marier et al., 2017).
To support dosing in the current age group, further PK simulation was conducted based on the 
population PK model previously established and a virtual population of 1000 pediatric patients 
created based on Centers for Disease Control (CDC) growth charts in the target age group (4 to 
12 months) and taking into consideration body weights of pediatric patients with SBS enrolled in 
study TED-C13-003 (approximately 15% lower than healthy subjects in the same age group).  
Monte Carlo simulations for all age groups were performed according to the SC dosing regimens 
of 0.0125, 0.025 and 0.05 mg/kg every 24 hours.  Rich concentration-time profiles were 
simulated with the customized population PK model to derive the exposure metrics area under 
the concentration curve at steady state (AUCss) and maximum concentration at steady state 
(Cmax,ss).  Following 0.05 mg/kg daily SC administration, the median Cmax,ss of teduglutide in 
neonate patients (24.9 ng/mL) was within 20% of that observed in the 2 to 4 and 4 to 6 years age 
groups (26.9 and 29.4 ng/mL, respectively); and approximately ~28% lower than that in adult 
patients with SBS.  The clinical package in conjunction with Cmax was considered to support 
teduglutide dose selection since AUCss was previously shown not to correlate with efficacy.  
Thus, the 0.05 mg/kg dose is proposed for testing in this age group.
6.3
Labeling, Packaging, and Storage
6.3.1
Labeling
The investigational product will be packaged, labeled, and shipped to the study site by the 
sponsor or designee.  Kits containing 7 vials of investigational product will be provided for this 
study.  The vials will be labeled in accordance with applicable regulatory requirements. 
Ancillary kits, containing supplies needed for the reconstitution and administration of the 
investigational product will also be provided and labeled in accordance with the applicable 
regulatory requirements. 
All investigational product used in this study will be manufactured, tested, labeled, and released 
according to current legal requirements and Good Manufacturing Practice.
6.3.2
Storage and Handling
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.
Investigational product must be kept in a locked area with access restricted to specific study 
personnel. Investigational product will be stored refrigerated at a temperature between 2-8°C 
(35.6-46.4°F) until dispensed to a subject. Once dispensed to a subject, the IP can be stored 
refrigerated or up to a controlled room temperature (acceptable range of 2-25°C, or 35.6-77°F). 
Parent/legal guardian will be instructed to keep the subject’s IP and sterile water diluent at 
controlled room temperature. If there are concerns that the controlled room temperature cannot 
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be maintained, the IP may be refrigerated. The IP is for single use only, and should be used 
within 3 hours following reconstitution.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (i.e., certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), e.g., fumigation of a 
storage room.
Investigational products are distributed by the pharmacy or nominated member of the study 
team. The pharmacist/nominated team member will enter the unique subject identifier on the 
investigational product bottle/carton labels, as they are distributed.
6.4
Drug Accountability
Investigational product will not be dispatched to the study site until the sponsor or 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 investigational product 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.  Kits will be shipped to the site once the 
subject is screened.
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects.  The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition.  Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for dispensing investigational product.  Where 
permissible, tasks may be delegated to a qualified designee (e.g., a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator.  
This delegation must be documented in the applicable study delegation of authority form.
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The investigator or his/her designee will dispense the investigational product only to subjects 
included in this study following the procedures set out in the study protocol.  Investigational 
product kits will be dispensed at each of the applicable study visits at which the subject is 
required to be at the clinic. Each investigational product kit is sufficient for a treatment period of 
1 week and enough kits will be supplied to cover the period until the next planned study visit.  
Additional study kits will be provided as necessary.
Each subject will be given the investigational product according to the protocol.  The 
investigator is to keep a current record of the inventory and dispensing of all clinical supplies.  
All dispensed medication will be documented on the eCRFs and/or other investigational product 
record.  The investigator is responsible for assuring the retrieval of all study supplies from 
subjects.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor.  If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.
At the end of the study, or as instructed by the sponsor, all unused stock, subject returned 
investigational product, and empty/used investigational product packaging are to be sent to the 
sponsor or designee.  The investigator is responsible for assuring the retrieval of all study 
supplies from subjects.
Returned investigational product must be counted and verified by clinical site personnel and the 
sponsor (or study monitor). Shipment return forms, when used, must be signed prior to shipment 
from the site.  Contact the sponsor for authorization to return any investigational product prior to 
shipment.  Shipment of all returned investigational product must comply with local, state, and 
national laws. 
Please see the Pharmacy Manual for additional information.
6.5
Subject Compliance
The parent(s)/guardian(s) of subjects must be instructed to bring unused investigational product 
and empty/used investigational product packaging to every visit. Drug accountability must be 
assessed and recorded at the container/packaging level for unused investigational product that is 
contained within the original tamper-evident sealed container (e.g., bottles, trays, vials) or at the 
individual count level for opened containers/packaging. 
Subject compliance will be checked by site personnel at every visit by reviewing the subject 
diaries and asking the subject or the subject’s parent or legally-authorized representative if they 
have administered the investigational product according to instructions. If any doses have been 
missed, the reason for missed dose should be documented in the subject’s source documentation 
including, as applicable, the eCRF.
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The investigator is responsible for contacting the sponsor or designee when the subject’s daily 
investigational product dosing regimen is interrupted. Attempts should be made to contact the 
sponsor or designee prior to dose interruption. Reasons for dosage interruption may include but 
are not limited to hospitalization and AEs, a lapse in investigational product delivery, etc.
Subjects who have received 80% of the planned doses administered will be assessed as being 
compliant with the study protocol.
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STUDY PROCEDURES
7.
7.1
Study Schedule
Detailed study procedures and assessments to be performed for subjects throughout the study are 
outlined in the study schedules (Table 1 and Table 2) and must be referred to in conjunction with 
the instructions provided in this section. 
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 24/EOT are to be performed as completely as possible.  Whenever possible, all 
discontinued subjects should also undergo the protocol-specified 4-week Follow-up Period.  
7.1.1
Screening
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent from the 
parent(s)/guardian(s) of the subject. The screening visit assessments and procedures, beginning 
with informed consent, will be performed as outlined in Table 1.
7.1.2
Treatment Period
The randomized Treatment Period will comprise Weeks 1 to 24, during which all assessments 
will be performed as outlined in Table 1 and Table 2.
7.1.3
Follow-up Period
The Follow-up Period will comprise Weeks 25 to 28, during which all assessments will be 
performed as outlined in Table 2.
7.2
Study Evaluations and Procedures
7.2.1
Demographics and Other Baseline Characteristics
Demographics and Medical History
Demographic and/or other baseline variables obtained at the screening and/or baseline visits are 
listed below. Abnormal findings of clinical significance (if any) will be recorded as past medical 
history.

Demography (including age, gestational age, sex, and race)

Medical history (including surgical history)

SBS history, including remnant anatomy
Upper Gastrointestinal Series with Small Bowel Follow-through
An upper GI contrast series with small bowel follow-through will be performed on all subjects 
during the screening period if one has not been done since the subject's last GI surgery. 
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It is acceptable to only enroll subjects who have already had an upper GI series with small bowel 
follow-through performed since the subject’s most recent surgery.  
7.2.2
Efficacy Assessments
Subject Diaries
All available diary data will be reviewed by the investigator or their designee at each clinic and 
telephone visit to assess clinical status and opportunity for PN reduction and advance in feeds.  
Parenteral support adjustments should be made after review of the intake and output diaries and 
the safety lab data according to the guidance for nutrition support adjustment provided in 
Appendix 2.
Intake Diary
Intake diaries will be used to collect and evaluate each subject’s nutritional support. The 
parent/legally authorized representative/study site staff will complete the appropriate fields of the 
PN and EN sections of the intake diary daily throughout the study.
The following data will be captured in the intake diaries:

Parenteral support volume and infusion duration

Enteral nutrition (formula) including volume and calories
Site personnel will determine the actual PN and EN daily calories based on diary entries.
Output Diary
Urine and stool output should be recorded in the output diary over a 48-hour period of nutritional 
stability before every clinic visit; in addition, output should be recorded for subjects within 
1 week of implementing a change in the PN prescription.
Urine data:

Measure and record the weight of all urine-only diapers. Urine volume will be calculated 
using the following formula: 1 g (scale weight) = 1 mL or 1 cc

At the discretion of the investigator, the parent or legal guardian/study site staff may be 
asked to collect the first void after the daily PN infusion to measure specific gravity
Stool data (includes diapers with mixed urine and stool):

Record the weight of diapers containing stool (including diapers with mixed urine and 
stool) as stool output and score the stool consistency (see Output diary). Stool volume 
will be calculated using the formula: 1 g (scale weight)=1 mL or 1 cc
All ostomy output volume should be recorded.  
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Native GLP-2
Blood samples for native GLP-2 should be collected postprandial.  Blood samples while subjects 
are receiving teduglutide should be drawn at least 14 hours after the previous dose.  Native 
GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject 
weight or at investigator discretion based on weekly/monthly total volume.  
7.2.3
Safety Assessments
Laboratory Evaluations
Safety laboratory tests to be performed at site visits consist of clinical chemistry, hematology, 
and urinalysis and will be performed as outlined in the study plan (Table 1 and Table 2). 
Scheduled laboratory testing will be processed by a central lab. All laboratory assays will be 
performed according to the central laboratory’s normal procedures. Reference ranges are to be 
supplied by the laboratory. The investigator should assess out-of-range clinical laboratory values 
for clinical significance, indicating if the value(s) is/are not clinically significant or clinically 
significant. Abnormal clinical laboratory values, which are unexpected or not explained by the 
subject’s clinical condition, may, at the discretion of the investigator or sponsor, be repeated as 
soon as possible until confirmed, explained, or resolved.
During the Treatment Period, subjects will also have safety labs within approximately 5 to7 days 
after a PN adjustment.  Safety labs performed after PN adjustment and between site visits will 
consist of clinical chemistry and urinalysis and may be processed by the central laboratory or a 
local laboratory.  Local lab results are not required to be entered in the eCRFs; however, if the 
local lab results indicate any new clinically significant changes, they must be reported as an 
adverse event (see Section 8). Urine specimen collection should be attempted as part of the 
safety labs, but lack of urinalysis will not constitute a protocol deviation.
At baseline, blood samples for safety labs and PK can be separated by 1 day if blood volumes are 
limiting.  
Safety labs at telephone visits will be collected at the discretion of the investigator.  
For all subjects in the teduglutide treatment arm, prothrombin time (PT) and international 
normalized ratio (INR), tested at baseline, will be repeated if clinically indicated.
New clinically significant labs should be reported as AEs.
Close monitoring criteria related to liver test abnormalities:  
The investigator should contact the medical monitor within 24 hours of their awareness if the 
subject develops any of the following changes in laboratory parameters:

ALT or AST >5x ULN and >2x baseline value
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
Total or direct bilirubin that is >2x baseline value or an absolute increase of  ≥3 mg/dL 
(51.3 µmol/L)
If such changes are observed, the labs should be repeated along with an INR, and an inquiry 
should be made as to the presence of clinical symptoms consistent with new liver injury. The 
subject should be followed closely to determine the trajectory of the laboratory abnormalities and 
appropriate evaluations should be made, such as abdominal ultrasound with Doppler imaging to 
exclude vascular causes and biliary obstruction, consideration of sepsis, liver hypoperfusion, 
acute viral hepatitis (such as hepatitis A, EBV, or HSV), exposure to hepatotoxic medications, 
mitochondrial hepatopathy, or metabolic liver disease (such as hereditary fructose intolerance or 
arginosuccinate synthetase deficiency).  Further evaluations can be performed at the discretion of 
the investigator in consultation with the Shire medical monitor.
The following clinical laboratory assessments will be performed according to the study 
schedules:
Table 4:
List of Laboratory Tests
Biochemistry:

Albumin 

Alkaline phosphatase 

Alanine aminotransferase 

Amylase

Aspartate aminotransferase 

Bicarbonate

Bilirubin (total and indirect)

Blood urea nitrogen 

Calcium (total)

Chloride

Cholesterol

C-reactive protein 

Creatinine

Estimated Glomerular Filtration Rate 
(Schwartz formula)

Gamma-glutamyl transferase 

Glucose

Lipase

Magnesium

Phosphorus

Potassium 

Sodium 

Triglycerides
Hematologya:

Hematocrit 

Hemoglobin 

Platelet count

Red blood cell count 

Red blood cell morphology, if needed

White blood cell count with differential
Coagulationb:

Prothrombin time

International normalized ratio
Urinalysis: 

Specific gravity  

Urine Sodium
a Hematology is not collected at Week 1 or at telephone visits.
b For all subjects in the teduglutide treatment arm, PT and INR will be tested at baseline and repeated only if clinically indicated.
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Antibodies to Teduglutide 
Blood samples will be drawn to test for antibodies to teduglutide.  Samples will be taken before 
teduglutide administration at the screening visit (Visit -1) and at least 14 hours after the previous 
dose at Week 12 (Visit 12); samples may be drawn from a central line or peripheral access. One 
additional sample will be collected at the EOS 4 weeks after the EOT (i.e., Week 28 or EOS).  
Volume of Blood
Efforts will be made to minimize the amount of blood drawn from all pediatric subjects 
participating in this study. The volumes of blood to be drawn from each subject will vary 
depending on clinical status. Approximate volumes of blood to be drawn from each subject are 
shown in Table 5.
Table 5:
Approximate Volume of Blood to be Drawn from Each Subject 
Assessment
Sample 
Volume (mL)
No. 
Samples 
Total 
Volume (mL)
Notes
Subjects Receiving Teduglutide Treatment
Biochemistry 
0.6
12
7.2
Hematology
0.6
11
6.6
Coagulation 
Parameters
0.6
1
0.6
PT and INR tested at baseline 
only, repeat while on study 
only if clinically indicated.
Antibodies
1.5
5
7.5
Pharmacokinetics
1.5
4
6.0
Baseline: 3 timepoints
Week 7: 1 timepoint OR
Week 12: 1 timepoint
Native GLP-2
1.5
3
4.5
Total mL:
6.3
36
32.4
Subjects Receiving Standard of Care
Biochemistry 
0.6
12
7.2
Hematology
0.6
11
6.6
Native GLP-2
1.5
3
4.5
Total mL:
2.7
26
18.3
GLP=glucagon-like peptide; INR=international normalized ratio; PT=prothrombin time
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment. When more than 1 blood assessment is to be done at the time 
point/period, if they require the same type of tube, the assessments should be combined. Blood 
volume estimates do not include safety labs performed after PN adjustment, and anti-teduglutide 
antibody testing during no-teduglutide treatment.
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Physical Examinations, Vital Signs, Weight, Length, and Head Circumference
Physical examinations will be performed according to the study schedules (Table 1 and Table 2). 
Any new clinically significant findings noted during physical examinations should be recorded 
on the appropriate AE page of the eCRF.
Vital signs will be measured according to the study schedules. Measurements will include 
systolic and diastolic blood pressure (mmHg), pulse (beats per minute), and body temperature 
(°C/°F). Blood pressure should be determined by the appropriate size cuff (using the same 
method, the same leg, and in the supine position throughout the study, when possible).  Blood 
pressure measurements should be attempted as part of the vital signs, but lack of blood pressure 
results will not constitute a protocol deviation.  New clinically significant vital sign 
abnormalities should be recorded on the appropriate AE page of the eCRF.
Body weight will also be recorded in the eCRF; subjects should be weighed on the same scale 
at each study visit. Length and head circumference will be measured at selected visits. A height 
z-score, weight Z-score, and weight/length ratio will be calculated by the sponsor using the 
site-provided height and weight data collected at each site visit.
7.2.4
Pharmacokinetic Assessments
Subjects will have blood samples taken for teduglutide PK analysis predose, and 1 hour
±10 minutes and 4 hours ±10 minutes postdose at baseline (Visit 0). Subjects also will have 
blood samples taken for teduglutide PK analysis 2 hours ±10 minutes postdose at Week 7 
(Visit 7) or Week 12 (Visit 12) of the treatment period. Blood for PK sampling should be 
collected via peripheral IV or venipuncture, not from a central line. The site of teduglutide 
administration prior to PK blood draws (arm, thigh, abdomen) must be specified. 
7.2.5
Health Economics and Outcomes Research
Hospitalizations
Each hospitalization that occurs during the study will be recorded, including date of admission, 
date of discharge, reasons for hospitalization, discharge diagnosis, and discharge status. 
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ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.3. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, 
then each symptom should be listed individually. All AEs should be captured on the appropriate 
AE pages in the eCRF and in source documents. In addition to untoward AEs, unexpected 
benefits outside the investigational product indication should also be captured on the AE eCRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
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8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of 
the investigational product is compelling and/or follows a known or 
suspected response pattern to that product, and the event cannot be 
explained by the subject’s medical condition, other therapies, or 
accident.
Not Related
The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident and no 
plausible temporal or biologic relationship exists between the 
investigational product and the event.
AEs that are related to IP that are not resolved at EOS will be followed until the event resolves or 
stabilizes, as judged by the investigator.
Laboratory values, vital signs, and clinical findings at the scheduled physical examinations must 
be reported as AEs if the investigator considers the finding to be a clinically significant change 
from the baseline.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the eCRF. Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved with Sequelae 

Recovering/Resolving

Unknown
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8.1.4
Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE. It is assumed that some of the infants participating in this study may be 
hospitalized for planned surgery(ies) that will occur during their participation in the study.  Such 
pre-planned, elective surgeries, do not need to be reported as SAEs for this protocol.  
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory or vital sign can represent an AE if the change is 
clinically relevant or if, during the study, a shift of a parameter is observed from a normal value 
to an abnormal value, or a further worsening of an already abnormal value. When evaluating 
such changes, the extent of deviation from the reference range, the duration until return to the 
reference range, either while continuing treatment or after the end of treatment with the 
investigational product, and the range of variation of the respective parameter within its 
reference range, must be taken into consideration.
If, during the study, there are abnormal clinical laboratory values or vital signs which were not 
present at the beginning of the study, further investigations should be performed until the values 
return to within the reference range or until a plausible explanation (e.g., concomitant disease) is 
found for the abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory or vital sign is clinically significant and 
therefore represents an AE.
8.1.6
Pregnancy
Not applicable.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for 
a non-medical purpose (e.g., to alter one’s state of consciousness or get high) in a manner 
that may be detrimental to the individual and/or society.
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
Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol).

Overdose – Administration of a dose greater than the allocated dose of the study 
medication or at a frequency greater than the dosing interval specified by the protocol.

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product. For studies, medication errors are reportable to the sponsor 
only as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error. 
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally-authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator brochure which the sponsor 
has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Drug Safety Department and the Shire Medical Monitor within 24 hours of the first awareness of 
the event. Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, 
misuse, overdose, or medication errors (see Section 8.1.7) unless they result in an SAE.
All Adverse Events of Special Interest, as defined in Section 8.3, must be reported by the 
investigator to the Shire Global Drug Safety Department and the Shire Medical Monitor within 
24 hours of the first awareness of the event even if the event does not fulfill seriousness criterion.
The investigator must complete, sign, and date the Shire Clinical Study Adverse Event Form for 
SAEs and Non-serious AEs as Required by Protocol, and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested). Fax or e-mail the completed form to the Shire Global Drug Safety 
Department. A copy of the completed Shire Clinical Study Adverse Event Form for Serious 
Adverse Events (SAEs) and Non-serious AEs as Required by Protocol (and any applicable 
follow-up reports) must also be sent to the Shire medical monitor or designee using the details 
specified in the emergency contact information section of the protocol.
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8.2.3
Serious Adverse Event Definition
A SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose: 

Results in death

Is life-threatening. Note: The term 'life-threatening' in the definition of "serious" refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for pre 
existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse. 
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.3, and must be reported 
to the Shire Global Drug Safety Department and the Shire Medical Monitor within 24 hours of 
the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Drug Safety Department within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
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In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (i.e., the SAE was noted as the primary cause of 
death) must have fatal checked as an outcome with the date of death recorded as the resolution 
date. For all other events ongoing at the time of death that did not contribute to the subject’s 
death, the outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (e.g., drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death.  
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting 
The Sponsor and/or Clinical Contract Research Organization (CRO) is responsible for notifying 
the relevant regulatory authorities, and US central Institutional Review Boards (IRBs)/EU central 
ethics committees (ECs), of related, unexpected SAEs.
In addition, the Clinical CRO is responsible for notifying active sites of all related, unexpected 
SAEs occurring during all interventional studies across the SHP633 program.
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
8.3
Adverse Events of Special Interest
An AE of special interest is an AE (serious or nonserious) of scientific and medical concern 
specific to the sponsor’s product or program and for which ongoing monitoring and immediate 
notification by the investigator to the sponsor is required.
The AEs of special interest that require expedited regulatory reporting include the following:

Growth of pre-existing polyps of the colon

Benign neoplasia of the GI tract including the hepatobiliary system

Tumor-promoting ability (e.g., benign and/or malignant neoplasia of any kind, not 
limited to those of the GI or hepatobiliary system)
For AEs of special interest, the sponsor must be informed within 24 hours of first awareness as 
per the SAE notification instructions described in Section 8.2.2 even if the event does not fulfill 
the seriousness criteria.
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8.4
Dose Interruption Criteria
The investigator is responsible for contacting the sponsor/designee when the subject’s 
teduglutide dosing regimen is interrupted. The length of dose interruption, and whether 
teduglutide administration resumes or is permanently discontinued, depends on the clinical 
situation.
Investigational product must be interrupted if any of the following events occur:

An adverse event of special interest (see Section 8.3) 

Intestinal obstruction

Biliary obstruction

Pancreatic duct obstruction
Investigational product must be permanently discontinued if any of the following events occur: 

Severe hypersensitivity, such as anaphylaxis, determined by the 
investigator to be related to IP. 

Any malignancy 
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DATA MANAGEMENT AND STATISTICAL METHODS
9.
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the eCRF.  A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy.  Discrepancies 
between source data and data entered on the eCRF will be addressed by qualified site personnel.  
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel.  Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting.  Once a subject is randomized, it is expected that site 
personnel will complete the eCRF entry within approximately 3 business days of the subject’s 
visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the data management plan. Quality 
control and data validation procedures are applied to ensure the validity and accuracy of the 
clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Statistical Analysis Process
The study will be analyzed by the sponsor or designee. All statistical analyses will be performed 
using SAS® (SAS Institute, Cary, NC, US) version 9.3 or higher.
The statistical analysis plan (SAP) will provide the definitions and statistical methods  for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed.
9.4
Planned Interim Analysis, and Data Monitoring Committee 
No interim analyses is planned for this the study. 
A data monitoring committee (DMC) will be involved in the management of this study. The 
DMC members will review the data approximately every 3 months according to the DMC 
Charter. The DMC review will include all cumulative safety data (i.e., AEs, laboratory 
assessments, physical examinations, etc.) from study assessments through each cutoff period. 
Further details regarding the DMC can be found in the DMC charter, which will be available 
prior to the administration of investigational product. 
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The DMC for this study will be conducted in accordance with the FDA Guidance for Clinical 
Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees 
(March 2006).
The DMC will be an external, independent board comprised of physicians with relevant training. 
The DMC will be restricted to individuals free of significant conflicts of interest, including, but 
not limited to, financial, scientific, or regulatory in nature. The DMC will be governed by a 
Charter agreed to by members of the Board and the sponsor. Members of the Board may not be 
study investigators or be employed at the same institution as a study investigator, individuals 
employed by the sponsor, independent contractors hired by the sponsor, or members of 
regulatory agencies. The DMC may make recommendations to the sponsor regarding study 
aspects including stopping, modifying or continuing the study; however, the sponsor will have 
the final responsibility to determine whether the study should be modified or temporarily or 
permanently stopped. 
9.5
Sample Size Calculation and Power Considerations
The sample size is determined based on enrollment feasibility for this rare condition and the age 
of the study population. 
9.6
Study Population
Intent to treat (ITT) population: All subjects randomized in the study.
Safety analysis population: The safety analysis set will contain all subjects who meet the 
following criteria:

Teduglutide treatment arm: subjects who receive at least 1 dose of teduglutide and 
have undergone at least 1 post-baseline safety assessment; analyses will be performed 
according to dose group as appropriate.   

Standard of care treatment arm: subjects who have undergone at least 1 post-baseline
safety assessment.
Per-protocol population: All subjects in the ITT population without any major protocol deviation 
that affects interpretation of efficacy results.
Pharmacokinetic analysis population: All subjects who received at least 1 dose of teduglutide 
and have at least 1 evaluable postdose PK concentration value.   
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9.7
Efficacy Analyses
9.7.1
Efficacy Endpoints
Efficacy endpoints consist of the following:
9.7.1.1
Primary Efficacy Endpoint 

Reduction in weight-normalized PN fluid volume by at least 20% from baseline at 
Week 24/EOT
9.7.1.2
Secondary Efficacy Endpoints

Reduction in weight-normalized parenteral calories by at least 20% from baseline to 
Week 24/EOT

Achievement of enteral autonomy by Week 24

Change in weight-normalized parenteral fluid volume from baseline to each visit

Change in weight-normalized parenteral calories from baseline to each visit

Change in weight-normalized enteral fluid volume from baseline to each visit

Change in weight-normalized enteral caloric intake from baseline to each visit

Increase in weight-normalized enteral fluid intake by at least 20% from baseline to week 
24/EOT

Increase in weight-normalized enteral caloric intake by at least 20% from baseline to 
week 24/EOT
9.7.2
Method of Analysis-Efficacy Endpoints
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 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.
Analyses of weekly PN support will be based on 2 data sources: the subject diary data (also 
referred to as actual data) and the investigator prescribed data.  
The number and percentage of subjects who achieve at least a 20% reduction from baseline in 
weight-normalized average daily PN volume at Week 24/EOT and the number and percentage of 
subjects who achieve at least a 20% reduction from baseline in weight-normalized parenteral 
calories at Week 24/EOT will be summarized by treatment arm.
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During the treatment period, a subject will be considered to have achieved enteral autonomy 
(completely weaned off PN) at a given visit if the investigator prescribes no PN at that visit and 
for the remainder of the treatment period, and there is no use of PN recorded in the subject diary 
during the week prior to that visit and for the remainder of the treatment period. During the 
follow-up period, a subject will be considered to have achieved enteral autonomy at a given visit 
if the investigator prescribes no PN at that visit and for the remainder of the follow-up period and 
there is no use of PN recorded in the subject diary during the week prior to that visit and for the 
remainder of the follow-up period. The number and percentage of subjects who achieve enteral 
autonomy at each scheduled visit, as well as at EOT, will be summarized by treatment arm.
The absolute and percent change in weight-normalized weekly PN volume, parenteral calories, 
enteral fluid volume, and enteral caloric intake, from baseline to each scheduled visit, as well as 
at EOT, will be summarized by treatment arm using descriptive statistics.
The number and percentage of subjects who demonstrate an increase in weight-normalized 
enteral fluid intake by at least 20% from baseline to Week 24/EOT and the number and 
percentage of subjects who demonstrate an increase in weight-normalized enteral caloric intake 
by at least 20% from baseline to week 24/EOT will be summarized by treatment arm.
9.8
Safety Analyses
9.8.1
Safety Endpoints
Safety endpoints consist of the following:

Adverse events

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for 
gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output

Stool (including mixed) output

Antibodies to teduglutide
9.8.2
Method of Analysis-Safety Endpoints
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Treatment-emergent AEs will be summarized by system organ class and preferred 
term using descriptive statistics (e.g., number and percentage of subjects).  Adverse events will 
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be summarized by severity and relationship to treatment.  In addition, SAEs will also be 
tabulated by overall and treatment-related events.  AEs leading to treatment discontinuation and 
death will also be summarized.
For laboratory tests; vital signs; urine and stool output; weight, length, and head circumference 
Z-scores, and descriptive statistics (e.g., n, mean, standard deviation, median, minimum and 
maximum values, and the number and percentage of subjects in specified categories) will be 
used to summarize the absolute values and change from baseline at each visit.
The number and percentage of subjects classified as having antibodies to teduglutide will be used 
to summarize the presence of antibodies.  
9.9
Health Economics and Outcomes Research Analyses
Health economics and outcomes research endpoints consist of the following:

Cumulative number of hospitalization days during the study
Health economics and outcomes research endpoints will be summarized using descriptive 
statistics (number, mean and standard deviation) at nominal time points.  
9.10
Pharmacokinetics Analyses
Plasma concentrations will be summarized using descriptive statistics (number, mean, standard 
deviation, geometric mean, coefficient of variation, minimum, median, and maximum ) at 
nominal time points. 
Pharmacokinetic parameters will be estimated using a population PK modeling approach as 
appropriate and reported separately.
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SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES
10.
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements. 
The name and address of each third-party vendor (e.g., CRO) used in this study will be 
maintained in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996), EU 
Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines.  If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study.  An insurance certificate is supplied as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
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10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of the end of 
the study completion date for pediatric studies and within 1 year for non-pediatric studies as per 
guidance.  The sponsor will provide the ECs with a copy of the same summary.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.  The sponsor will make an end-of-study declaration to the relevant competent 
authority as required by Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator will be appointed to review the final clinical study report 
for multicenter studies.  Agreement with the final clinical study report is documented by the 
signed and dated signature of the principal investigator (single-site study) or coordinating 
principal investigator (multicenter study), in compliance with Directive 2001/83/EC as amended 
by Directive 2003/63/EC and ICH Guidance E3 (1995).
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10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.2.1
Documentation and Retention of Records
10.2.2.2
Electronic Case Report Forms
Electronic case report forms are supplied by the sponsor or designee and should be handled in 
accordance with instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Electronic case report forms 
must be completed by the investigator or designee as stated in the site delegation log.  All data 
will have separate source documentation; no data will be recorded directly onto the eCRF.
All data sent to the sponsor must be endorsed by the investigator.  
The study monitor will verify the contents against the source data per the monitoring plan. If the 
data are unclear or contradictory, queries are sent for corrections or verification of data.
10.2.2.3
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject diaries, and original clinical laboratory reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
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The study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF entries 
against the source documents. The consent form includes a statement by which the 
parent/guardian agrees to the monitor/auditor from the sponsor or its representatives, national or 
local regulatory authorities, or the IRB/EC, having access to source data (e.g., subject’s medical 
file, appointment books, original laboratory reports, X-rays etc). Non-study site personnel will 
not disclose any personal information or personal medical information.
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (e.g., the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.2.4
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the European Medicines Agency (EMA), the 
Medicines and Healthcare products Regulatory Agency, other regulatory authorities, the sponsor 
or its representatives, and the IRB/EC for each site.
10.2.2.5
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent, where applicable, 
from the parent(s)/guardian(s) of all study subjects prior to any study-related procedures 
including screening assessments. All consent documentation must be in accordance with 
applicable regulations and GCP. Each subject’s legally authorized representative is requested to 
sign and date the subject informed consent form or a certified translation if applicable, after the 
subject’s parent or guardian has received and read (or been read) the written subject information 
and received an explanation of what the study involves, including but not limited to: the 
objectives, potential benefits and risk, inconveniences, and the subject’s rights and 
responsibilities. A copy of the informed consent documentation (i.e., a complete set of subject 
information sheets and fully executed signature pages) must be given to the subject’s legally 
authorized representative, as applicable. This document may require translation into the local 
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language. Signed consent forms must remain in each subject’s study file and must be available 
for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form  that was 
reviewed by the IRB/EC and received their favorable opinion/approval. A copy of the IRB/EC’s 
written favorable opinion/approval of these documents must be provided to the sponsor prior to 
the start of the study unless it is agreed to and documented (abiding by regulatory guidelines and 
national provisions) prior to study start that another party (i.e., sponsor or coordinating principal 
investigator) is responsible for this action. Additionally, if the IRB/EC requires modification of 
the sample subject information and consent document provided by the sponsor, the 
documentation supporting this requirement must be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the sponsor/designee has received 
written IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB/EC informed of any serious and 
significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996.  A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the sponsor/designee.
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The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market teduglutide; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (e.g., to confirm 
that laboratory results have been assigned to the correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines 
(e.g., Good Publication Practices 2) when forming a publication steering committee, which is 
done for large, multicenter Phase 2 to 4 and certain other studies as determined by Shire. The 
purpose of the publication steering committee is to act as a non-commercial body that advises or 
decides on dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, royalty 
free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
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medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.
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REFERENCES
11.
Beattie, L. M., Barclay, A. R. & Wilson, D. C. 2010. Short bowel syndrome and intestinal failure 
in infants and children. Paediatrics and Child Health, 20, 485-491.
Carter, Cohran, Cole, Corkins, Dimmitt, Duggan, Hill, Horslen, Lim, Mercer, Merritt, Nichol, 
Sigurdsson, Teitelbaum, Thompson, Vanderpool, Vaughan, Li, Youssef, Venick & 
Kocoshis 2017. Outcomes from a 12-Week, Open-Label, Multicenter Clinical Trial of 
Teduglutide in Pediatric Short Bowel Syndrome. Journal of Pediatrics, The, 181, 102-
111.e5.
Gonzalez-Hernandez, Prajapati, Ogola, Channabasappa, Drews & Piper 2017. Predicting time to 
full enteral nutrition in children after significant bowel resection. Journal of Pediatric 
Surgery, 52, 764-767.
Goulet, O. & Ruemmele, F. 2006. Causes and Management of Intestinal Failure in Children. 
Gastroenterology, 130, S16-S28.
Huisman-de Waal, G., Schoonhoven, L., Jansen, J., Wanten, G. & van Achterberg, T. 2007. The 
impact of home parenteral nutrition on daily life-A review. Clinical Nutrition, 26, 275-
288.
Khan, F. A., Squires, R. H., Litman, H. J., Balint, J., Carter, B. A., Fisher, J. G., Horslen, S. P., 
Jaksic, T., Kocoshis, S., Martinez, J. A., Mercer, D., Rhee, S., Rudolph, J. A., Soden, J., 
Sudan, D., Superina, R. A., Teitelbaum, D. H., Venick, R., Wales, P. W. & Duggan, C. 
2015. Predictors of Enteral Autonomy in Children with Intestinal Failure: A Multicenter 
Cohort Study. J Pediatr, 167, 29-34.e1.
Marier, J., Kassir, N., Martin, P. & Wang, Y. 2017. Population pharmacokinetic modeling of 
teduglutide to support dosing in pediatric patients with short bowel syndrome. Clinical 
Pharmacology & Therapeutics, 101, S91.
Martin, G.-R., Beck, P.-L. & Sigalet, D.-L. 2006. Gut hormones, and short bowel syndrome: the 
enigmatic role of glucagon-like peptide-2 in the regulation of intestinal adaptation. World 
Journal of Gastroenterology, 12, 4117-29.
O'Keefe, S. J., Buchman, A. L., Fishbein, T. M., Jeejeebhoy, K. N., Jeppesen, P. B. & Shaffer, J. 
2006. Short bowel syndrome and intestinal failure: consensus definitions and overview. 
Clin Gastroenterol Hepatol, 4, 6-10.
Sigalet, D. L., Martin, G., Meddings, J., Hartman, B. & Holst, J. J. 2004. GLP-2 levels in infants 
with intestinal dysfunction. Pediatr Res, 56, 371-6.
Spencer, A. U., Neaga, A., West, B., Safran, J., Brown, P., Btaiche, I., Kuzma-O'Reilly, B. & 
Teitelbaum, D. H. 2005. Pediatric Short Bowel Syndrome: Redefining Predictors of 
Success. Annals of Surgery, 242, 403-412.
Squires, R. H., Duggan, C., Teitelbaum, D. H., Wales, P. W., Balint, J., Venick, R., Rhee, S., 
Sudan, D., Mercer, D., Martinez, J. A., Carter, B. A., Soden, J., Horslen, S., Rudolph, J. 
A., Kocoshis, S., Superina, R., Lawlor, S., Haller, T., Kurs-Lasky, M. & Belle, S. H. 
2012. Natural history of pediatric intestinal failure: initial report from the Pediatric 
Intestinal Failure Consortium. J Pediatr, 161, 723-8.e2.
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Tappenden, K. A., Edelman, J. & Joelsson, B. 2013. Teduglutide enhances structural adaptation 
of the small intestinal mucosa in patients with short bowel syndrome. J Clin 
Gastroenterol, 47, 602-7.
Thymann, T., Stoll, B., Mecklenburg, L., Burrin, D. G., Vegge, A., Qvist, N., Eriksen, T., 
Jeppesen, P. B. & Sangild, P. T. 2014. Acute effects of the glucagon-like peptide 2 
analogue, teduglutide, on intestinal adaptation in short bowel syndrome. J Pediatr 
Gastroenterol Nutr, 58, 694-702.
Wales, P. W., de Silva, N., Kim, J., Lecce, L., To, T. & Moore, A. 2004. Neonatal short bowel 
syndrome: population-based estimates of incidence and mortality rates. J Pediatr Surg,
39, 690-5.
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APPENDICES
12.
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Appendix 1
Protocol History
Document
Date
Global/Country/Site Specific
Original Protocol
03 Oct 2017
Global
Amendment 1
18 Jan 2018
Global
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Appendix 2
Guidelines for Nutritional Support Management During the Study
The nutritional support adjustment guidelines are designed to standardize management of 
parenteral and enteral nutritional support in this study. Adjustments to nutritional support should 
be considered at every scheduled clinic visit. Adjustments at phone visits may also be performed, 
but nutritional assessments at phone visits serve primarily to confirm that nutritional adjustments 
at prior clinic visits were tolerated.
All attempts should be made to follow the guidelines, but departure from the guidelines will not 
constitute a protocol deviation.
Clinical judgment is required within the algorithm. Each decision point requires integrating 
multiple sources of information into a yes/no decision. When individual data points are 
conflicting, the investigator must use their best judgment in the assessment.
If intestinal adaptation is occurring, reductions in parenteral support volume and calories are 
expected to be in decrements of 5 to 10% relative to baseline values. Parenteral support 
components are at the discretion of the investigator, but care should be taken to balance 
carbohydrate, fat, and protein. Likewise, if intestinal adaptation is occurring, enteral nutrition 
volume and calories should be increased in increments of approximately 10% relative to baseline 
values.
Assessment of the severity of malabsorption may require estimation of stool output for children 
who have mixed stool and urine output.
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.
During the 48-hour output measurement period prior to the subject’s scheduled visit, no further 
changes to the prescribed nutritional support should be made.
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Figure A-1:
Parenteral Nutrition/Intravenous Adjustment Algorithm for All Subjects  
BUN=blood urea nitrogen; Cr=creatinine; PN=parenteral nutrition; UNa=urine sodium; UOP=urine output; USpGr=Urine specific gravity; VS=vital signs; vol=volume
Adequately hydrated?
•
Normal exam and VS
•
Weight stable
•
UOP > 1 ml/kg/h
•
USpGr < 1.020
•
UNa > 20 meq/L
•
Stable, normal BUN/Cr
yes
no
Adequate weight gain 
and linear growth?
↑ PN kcal or no change
↓PN vol and kcal
↑ PN vol +/- kcal
yes
no
Assess severity of malabsorption and adjust EN as appropriate
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PROTOCOL: SHP633-301
TITLE:
A Randomized, Open-label, 24-Week Safety, Efficacy, and 
Pharmacokinetic Study of Teduglutide in Infants 4 to 12 Months of Age 
with Short Bowel Syndrome Who are Dependent on Parenteral Support
NUMBER
SHP633-301
PHASE
3 
DRUG:
Teduglutide
INDICATION:
Short bowel syndrome
EUDRACT NO.:
2017-003606-40
SPONSOR: 
Shire Human Genetic Therapies, Inc.
300 Shire Way
Lexington, MA 02421 USA
PROTOCOL 
HISTORY:
Original Protocol: 03 Oct 2017
Amendment 1: 18 Jan 2018
Amendment 1.1: 07 Aug 2018 (France-specific) 
Confidentiality Statement
This document contains confidential and proprietary information of Shire and is disclosed 
pursuant to confidentiality and non-disclosure obligations. This information should be used 
solely for the purposes for which it was provided and should not be copied, shared with, or 
disclosed to any third party without the express written consent of Shire.
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Page2 
PROTOCOL SIGNATURE PAGE 
Sponsor's (Shire) Approval 
ment 
Investigator's Acknowledgement 
I have read this protocol for Shire Study SHP633-301. 
Title: A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic Study of 
Teduglutide in Infants 4 to 12 Months of Age with Short Bowel Syndrome Who are Dependent 
on Parenteral Support 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) guidelines on Good Clinical Practice (GCP) and with the 
applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution ofthe study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Address: 
(please hand print or type) 
Signature: --------------------------------- Date: 
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EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Adverse Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as 
Required by Protocol within 24 hours to the Shire Global Drug Safety Department. Applicable 
fax numbers and e-mail address can be found on the form (sent under separate cover).  A copy of 
this form must also be sent to the Shire Medical Monitor by fax or e-mail:  
Fax:
,  Email: 
For protocol- or safety-related issues, the investigator must contact IQVIA Medical Support:
Primary Contact
Backup Contact 
, MD
, MD
Mobile:  
Mobile: 
US Toll Free Number: 
Phone: 
Phone: 
 
(medical emergencies)
Phone: 
 
(medical emergencies)
Email:  
Email: 
In addition, the investigator may also contact Shire:
, MD, PhD 
Phone: 
Mobile: 
Email: 
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PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (e.g., inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (e.g., wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
European Union and Rest of World
Telephone numbers (provided for reference, if needed): 
Shire (USA)
 
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SUMMARY OF CHANGES FROM PREVIOUS VERSION
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1.1
Amendment Date
07 Aug 2018
France-specific
Description of Change and Rationale
Section(s) Affected by Change
The Shire contact was updated to 
.
Emergency Contact 
Information
Added an exclusion criterion for Gilbert’s disease and liver 
failure based on the values of the transaminases and of total 
bilirubin as requested by Agence Nationale de Sécurité du 
Medicament et des Produits de Santé (ANSM).
Synopsis, Section 4.2
Added an exclusion criterion for hypersensitivity to trace 
residues of tetracycline to be consistent with the European 
Summary of Product Characteristics of teduglutide as 
requested by ANSM.
Synopsis, Section 4.2
Added text to specify that efforts to minimize pain and 
discomfort during procedures such as peripheral venipuncture 
will be implemented.
Section 7.2.3
See Appendix 1 for protocol history, including all amendments.  
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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
PRODUCT QUALITY COMPLAINTS..........................................................................................4
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................5
TABLE OF CONTENTS.................................................................................................................6
LIST OF TABLES.........................................................................................................................10
LIST OF FIGURES .......................................................................................................................10
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..................................................11
STUDY SYNOPSIS ......................................................................................................................12
STUDY SCHEDULES ..................................................................................................................17
BACKGROUND INFORMATION .......................................................................................21
1.
1.1
Short Bowel Syndrome..................................................................................21
1.2
Teduglutide....................................................................................................22
OBJECTIVES.........................................................................................................................23
2.
2.1
Rationale for the Study..................................................................................23
2.2
Study Objectives............................................................................................23
STUDY DESIGN ...................................................................................................................24
3.
3.1
Study Design and Flow Chart........................................................................24
3.1.1
Screening Period ...............................................................................................24
3.1.2
Treatment Period...............................................................................................24
3.1.3
Follow-up Period...............................................................................................25
3.2
Study Duration...............................................................................................25
3.3
Sites and Regions ..........................................................................................26
STUDY POPULATION.........................................................................................................27
4.
4.1
Inclusion Criteria...........................................................................................27
4.2
Exclusion Criteria..........................................................................................27
4.3
Reproductive Potential ..................................................................................29
4.4
Discontinuation of Subjects...........................................................................29
4.4.1
Reasons for Discontinuation .............................................................................30
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit ............................30
PRIOR AND CONCOMITANT TREATMENT ...................................................................31
5.
5.1
Prior Medications and Procedures.................................................................31
5.2
Concomitant Medications and Procedures ....................................................31
5.3
Permitted Treatment ......................................................................................31
5.4
Prohibited Treatment.....................................................................................31
INVESTIGATIONAL PRODUCT ........................................................................................32
6.
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6.1
Identity of Investigational Product ................................................................32
6.2
Administration of Investigational Product ....................................................32
6.2.1
Interactive Response Technology for Investigational Product 
Management......................................................................................................32
6.2.2
Allocation of Subjects to Treatment .................................................................32
6.2.3
Dosing ...............................................................................................................32
6.2.4
Unblinding the Treatment Assignment .............................................................33
6.2.5
Dose Selection Rationale ..................................................................................33
6.3
Labeling, Packaging, and Storage .................................................................34
6.3.1
Labeling.............................................................................................................34
6.3.2
Storage and Handling........................................................................................34
6.4
Drug Accountability ......................................................................................35
6.5
Subject Compliance.......................................................................................36
STUDY PROCEDURES........................................................................................................38
7.
7.1
Study Schedule ..............................................................................................38
7.1.1
Screening...........................................................................................................38
7.1.2
Treatment Period...............................................................................................38
7.1.3
Follow-up Period...............................................................................................38
7.2
Study Evaluations and Procedures ................................................................38
7.2.1
Demographics and Other Baseline Characteristics ...........................................38
7.2.2
Efficacy Assessments........................................................................................39
7.2.3
Safety Assessments ...........................................................................................40
7.2.4
Pharmacokinetic Assessments ..........................................................................43
7.2.5
Health Economics and Outcomes Research......................................................43
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................44
8.
8.1
Definition of Adverse Events, Period of Observation, Recording of 
Adverse Events..............................................................................................44
8.1.1
Severity Categorization.....................................................................................44
8.1.2
Relationship Categorization..............................................................................45
8.1.3
Outcome Categorization....................................................................................45
8.1.4
Symptoms of the Disease under Study..............................................................46
8.1.5
Clinical Laboratory and Other Safety Evaluations ...........................................46
8.1.6
Pregnancy..........................................................................................................46
8.1.7
Abuse, Misuse, Overdose, and Medication Error .............................................46
8.2
Serious Adverse Event Procedures................................................................47
8.2.1
Reference Safety Information ...........................................................................47
8.2.2
Reporting Procedures........................................................................................47
8.2.3
Serious Adverse Event Definition.....................................................................48
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8.2.4
Serious Adverse Event Collection Time Frame................................................48
8.2.5
Serious Adverse Event Onset and Resolution Dates ........................................48
8.2.6
Fatal Outcome...................................................................................................49
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and 
Site Reporting ...................................................................................................49
8.3
Adverse Events of Special Interest................................................................49
8.4
Dose Interruption Criteria..............................................................................50
DATA MANAGEMENT AND STATISTICAL METHODS ...............................................51
9.
9.1
Data Collection..............................................................................................51
9.2
Clinical Data Management............................................................................51
9.3
Statistical Analysis Process ...........................................................................51
9.4
Planned Interim Analysis, and Data Monitoring Committee ........................51
9.5
Sample Size Calculation and Power Considerations.....................................52
9.6
Study Population ...........................................................................................52
9.7
Efficacy Analyses..........................................................................................53
9.7.1
Efficacy Endpoints............................................................................................53
9.7.1.1
Primary Efficacy Endpoint.....................................................................53
9.7.1.2
Secondary Efficacy Endpoints ...............................................................53
9.7.2
Method of Analysis-Efficacy Endpoints...........................................................53
9.8
Safety Analyses .............................................................................................54
9.8.1
Safety Endpoints ...............................................................................................54
9.8.2
Method of Analysis-Safety Endpoints ..............................................................54
9.9
Health Economics and Outcomes Research Analyses ..................................55
9.10
Pharmacokinetics Analyses ...........................................................................55
SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES ............................................56
10.
10.1
Sponsor’s Responsibilities.............................................................................56
10.1.1
Good Clinical Practice Compliance..................................................................56
10.1.2
Indemnity/Liability and Insurance ....................................................................56
10.1.3
Public Posting of Study Information.................................................................56
10.1.4
Submission of Summary of Clinical Study Report to Competent 
Authorities of Member States Concerned and Ethics Committees...................57
10.1.5
Study Suspension, Termination, and Completion.............................................57
10.2
Investigator’s Responsibilities.......................................................................57
10.2.1
Good Clinical Practice Compliance..................................................................57
10.2.2
Protocol Adherence and Investigator Agreement .............................................58
10.2.2.1
Documentation and Retention of Records .............................................58
10.2.2.2
Electronic Case Report Forms................................................................58
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10.2.2.3
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................58
10.2.2.4
Audit/Inspection .....................................................................................59
10.2.2.5
Financial Disclosure...............................................................................59
10.3
Ethical Considerations...................................................................................59
10.3.1
Informed Consent..............................................................................................59
10.3.2
Institutional Review Board or Ethics Committee .............................................60
10.4
Privacy and Confidentiality...........................................................................60
10.5
Study Results/Publication Policy ..................................................................61
REFERENCES .......................................................................................................................63
11.
APPENDICES ........................................................................................................................65
12.
Appendix 1
Protocol History.............................................................................................66
Appendix 2
Guidelines for Nutritional Support Management During the Study .............69
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LIST OF TABLES
Table 1:
Study Schedule: Visits -1 to 12 .....................................................................17
Table 2:
Study Schedule: Visits 13-28 ........................................................................19
Table 3:
Prohibited Treatment.....................................................................................31
Table 4:
List of Laboratory Tests ................................................................................41
Table 5:
Approximate Volume of Blood to be Drawn from Each Subject .................42
LIST OF FIGURES
Figure 1:
Study Schematic ............................................................................................24
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation
Definition
AE
adverse event
AUCss
area under the concentration-time curve at steady-state 
Cmax,ss
maximum plasma concentration at steady state
CRO
contract research organization
eCRF
electronic case report form
DMC
data monitoring committee
EDC
electronic data capture
EMA
European Medicines Agency
EN
enteral nutrition
EOS
end of study
EOT
end of treatment
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
gastrointestinal 
GLP
glucagon-like peptide
HIPAA
Health Insurance Portability and Accountability Act
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for
Human Use
ICMJE
International Committee of Medicinal Journal Editors
I/O
oral fluid intake and urine output
IP
Investigational product
IRB
Institutional Review Board
ITT
intent-to-treat
MedDRA
Medical Dictionary for Regulatory Activities
PK
pharmacokinetics
PN
parenteral nutrition
SAE
serious adverse event
SAP
statistical analysis plan
SBS
short bowel syndrome
SC
subcutaneous
SD
standard deviation
SOC
standard of care
ULN
upper limit of normal 
US
United States
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STUDY SYNOPSIS
Protocol number: SHP633-301
Drug: Teduglutide
Title of the study: A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic Study of 
Teduglutide in Infants 4 to 12 Months of Age with Short Bowel Syndrome Who are Dependent on Parenteral 
Support
Number of subjects (total and for each treatment arm):
At least 10 subjects will be randomized: at least 5 subjects in a teduglutide treatment arm and at least 5 subjects in 
a standard of care (SOC) comparator arm
Investigator(s): Multicenter study
Site(s) and Region(s): 
This study is planned to be conducted in approximately 5 to 10 sites globally.
Study period (planned):
2017-2020
Clinical phase:
3
Objectives:
The objectives of this clinical study are to evaluate the safety, efficacy/pharmacodynamics and pharmacokinetics 
(PK) of teduglutide treatment in infants with short bowel syndrome (SBS) dependent on parenteral support.
Investigational product, dose, and mode of administration:
Teduglutide 0.05 mg/kg by subcutaneous (SC) injection once daily into 1 of the 4 quadrants of the abdomen or 
either thigh or arm.
Methodology:
This is a randomized, multicenter, open-label study, consisting of a 2 to 4 week screening period, a 24-week 
treatment period, and a 4-week follow-up period. 
* At EOS all subjects regardless of treatment arm may enroll in an extension study that will capture long-term 
safety data and provide the opportunity for additional teduglutide treatment.  The follow-up period for subjects in 
the teduglutide treatment arm may be interrupted and the subjects may proceed immediately to the EOS if at least 
Extension 
study* 
1
24
1
3
5
7
9
12
16
20
28
2 to 4
Weeks
Screening
Teduglutide 0.05 mg/kg SC once daily for 24 weeks
Site Visit 
Telephone Visit
Standard of care for 24 weeks
Baseline: treatment 
randomization
0
24
3
5
7
9
12
16
20
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one “escape” criteria is met.
Study eligibility will be confirmed during the screening period (minimum: 2 weeks; maximum 4 weeks). At the 
baseline visit (Week 0), subjects will be randomized 1:1 to the teduglutide or SOC treatment arm. Randomization 
will be stratified according to the presence of a small bowel ostomy (e.g., end jejunostomy or ileostomy). During 
the 24-week treatment period, subjects in the SOC treatment arm will receive standard medical therapy for SBS; 
while those in the teduglutide arm will receive 0.05 mg/kg SC once daily in addition to standard medical therapy. 
Subjects in both arms will follow the same visit schedule and assessments. Subjects will be monitored weekly 
with phone or clinic visits. Clinic visits will occur at Weeks 1, 3, 5, 7, 9, 12, 16, 20, 24, and 28. At all site visits 
and telephone contacts, safety will be monitored and nutritional support will be reviewed and adjusted as needed. 
To maintain consistency across centers, guidance and training will be provided to help sites follow the nutritional 
support adjustment guidelines (developed with SBS expert input and provided in the protocol) related to decisions 
for parenteral nutrition (PN) reduction and advances in enteral feeds based on weight gain, urine and stool output, 
and clinical stability. Deviations from the guidelines are not considered a protocol deviation.
Sparse PK sampling, in the teduglutide treatment arm only, will occur at baseline (predose and 1 hour 
±10 minutes and 4 hours ±10 minutes postdose) and at Week 7 or 12 (2 hours±10 minutes postdose).
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up period until the end 
of study (Week 28/EOS) during which time subjects will receive standard medical therapy, but no investigational 
product will be administered.  At EOS all subjects regardless of treatment arm may enroll in an extension study 
that will capture long-term safety data and provide the opportunity for additional teduglutide treatment.  The 
follow-up period for subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed 
immediately to the EOS if at least one of the following “escape” criteria is met:
1.
Increasing PN requirements following discontinuation of teduglutide.
2.
Deteriorating nutritional status (e.g., weight loss or growth failure) despite maximal tolerated enteral 
nutrition (EN) following teduglutide discontinuation.
3.
Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and electrolyte intake 
following teduglutide discontinuation.
4.
Severe diarrhea related to teduglutide discontinuation.
Inclusion and Exclusion Criteria:
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1.
Informed consent by the parent or legal guardian. 
2.
Male or female infant 4 to 12 months corrected gestational age at screening.
3.
Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and baseline.
4.
Short bowel syndrome with dependence on parenteral support to provide at least 50% of fluid or caloric 
needs.
5.
Stable PN requirements for at least 1 month prior to screening, defined as a ≤10% change in the weight-
normalized parenteral total fluid and caloric intake, despite attempts to wean PN, notwithstanding 
transient instability for events such as sepsis or interruption of central venous access.
6.
Lack of terminal ileum and ileocecal valve
7.
Parent or legal guardian understands and is willing and able to fully adhere to study requirements as 
defined in this protocol.
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Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1.
Previous treatment with teduglutide.
2.
Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus inclusion disease, 
etc.
3.
Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility, that is the primary contributing factor to feeding intolerance and 
inability to reduce parenteral support, prior to screening.  Dysmotility is defined as severe if it is 
expected to limit the advancement of enteral feeding.
4.
Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral aversion in the 
absence of a feeding tube.
5.
Intestinal obstruction or clinically significant intestinal stenosis.
6.
Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or major intestinal 
resection or anastomosis, within 3 months prior to screening or planned during the study period.
7.
Unstable cardiac disease.
8.
Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
9.
Biliary obstruction, stenosis, or malformation. 
10. Clinically significant pancreatic disease. 
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b.
Platelet count <100×10^3/µl due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d.
Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 2-week period
13. More than 3 serious complications of intestinal failure (e.g., catheter-associated bloodstream infections, 
interruption of nutrition due to feeding intolerance, catheter-associated thrombosis, severe fluid or 
electrolyte disturbances) within 1 month prior to or during screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile polyposis or Beckwith-
Wiedemann syndrome, or first degree relative with early onset of gastrointestinal cancer (including 
hepatobiliary and pancreatic cancers). 
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 (GLP-2); insulin-
like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs of these hormones; or 
glutamine. 
16. Participation in a clinical study using an experimental drug within 3 months or 5.5 half-lives of the 
experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, closely-related 
compounds, or any of the stated ingredients.
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts the subject at any 
undue risk, prevents completion of the study, or interferes with analysis of the study results.
19. Hypersensitivity to trace residues of tetracycline.
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20. Signs of active severe or unstable, clinically significant hepatic impairment shown by any of the below 
laboratory test results at screening:
a. Total bilirubin ≥2 x upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥5 x ULN
c. Alanine aminotransferase (ALT) ≥5 x ULN
For subjects with Gilbert’s disease:
d. Indirect (unconjugated) bilirubin ≥2 x ULN
Maximum Duration of Subject Involvement in the Study:
The study consists of a 2 to 4 week screening period, a 24-week treatment period, and a 4-week follow-up period. 
The maximum duration of participation for each subject is 32 weeks.
Study completion is defined as the last subject, last visit. This is the visit date at which the last subject on the 
study has his or her last follow-up visit on the study (whether during the 24-week treatment period or the 4-week 
follow-up period).
Endpoints:
Efficacy
Efficacy endpoints consist of the following:
Primary

Reduction in weight-normalized PN fluid volume by at least 20% from baseline at Week 24/EOT
Secondary

Reduction in weight-normalized parenteral calories by at least 20% from baseline to Week 24/EOT

Achievement of enteral autonomy by Week 24

Change in weight-normalized parenteral fluid volume from baseline to each visit

Change in weight-normalized parenteral calories from baseline to each visit

Change in weight-normalized enteral fluid volume from baseline to each visit

Change in weight-normalized enteral caloric intake from baseline to each visit

Increase in weight-normalized enteral fluid intake by at least 20% from baseline to Week 24/EOT

Increase in weight-normalized enteral caloric intake by at least 20% from baseline to Week 24/EOT
Pharmacokinetics
The pharmacokinetic endpoint is plasma teduglutide concentration at nominal time point.
Safety
Safety endpoints consist of the following:

Adverse events (AEs)

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output

Stool (including mixed) output  

Antibodies to teduglutide 
Health Economics and Outcomes Research
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Health economics and outcomes research (HEOR) endpoints include the following:

Cumulative number of hospitalization days during the study
Statistical Methods:
Efficacy
Analyses of weekly PN support will be based on 2 data sources: the subject diary data (also referred to as actual 
data) and the investigator prescribed data.  
The number and percentage of subjects who achieve at least a 20% reduction from baseline in weight-normalized 
average daily PN volume at Week 24/EOT and the number and percentage of subjects who achieve at least a 20% 
reduction from baseline in weight-normalized parenteral calories at Week 24/EOT will be summarized by 
treatment arm.
During the treatment period, a subject will be considered to have achieved enteral autonomy (completely weaned 
off PN) at a given visit if the investigator prescribes no PN at that visit and for the remainder of the treatment 
period, and there is no use of PN recorded in the subject diary during the week prior to that visit and for the 
remainder of the treatment period. During the follow-up period, a subject will be considered to have achieved 
enteral autonomy at a given visit if the investigator prescribes no PN at that visit and for the remainder of the 
follow-up period and there is no use of PN recorded in the subject diary during the week prior to that visit and for 
the remainder of the follow-up period. The number and percentage of subjects who achieve enteral autonomy at 
each scheduled visit, as well as at EOT, will be summarized by treatment arm. 
The absolute and percent change in weight-normalized weekly PN volume, parenteral calories, enteral fluid 
volume, and enteral caloric intake, from baseline to each scheduled visit, as well as at EOT, will be summarized 
by treatment arm using descriptive statistics.
The number and percentage of subjects who demonstrate an increase in weight-normalized enteral fluid intake by 
at least 20% from baseline to Week 24/EOT and the number and percentage of subjects who demonstrate an 
increase in weight-normalized enteral caloric intake by at least 20% from baseline to week 24/EOT will be 
summarized by treatment arm.
Pharmacokinetics
Plasma concentrations will be summarized using descriptive statistics (number, mean, standard deviation, 
geometric mean, coefficient of variation, minimum, median, and maximum) at nominal time points. 
Pharmacokinetic parameters will be estimated using a population PK modeling approach as appropriate and 
reported separately.
Safety
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Treatment-emergent AEs will be summarized by system organ class and preferred term using descriptive statistics 
(e.g., number and percentage of subjects). Adverse events will be summarized by severity and relationship to 
treatment. In addition, serious adverse events  will also be tabulated by overall and treatment-related events. AEs 
leading to treatment discontinuation and death will also be summarized.
For laboratory tests; vital signs; urine and stool output; weight, length, and head circumference Z-scores; and 
descriptive statistics (e.g., n, mean, standard deviation, median, minimum and maximum values, and the number 
and percentage of subjects in specified categories) will be used to summarize the absolute values and change from 
baseline at each visit.
The number and percentage of subjects classified as having antibodies to teduglutide will be used to summarize 
the presence of antibodies.  
Health Economics and Outcomes Research
The HEOR endpoints will be summarized descriptively.  
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STUDY SCHEDULES
Table 1:
Study Schedule: Visits -1 to 12
Procedures
Screening
Baseline 
(Week 0)
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
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit type
Site
Site
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Tel
Site
Study day
-14
0
7
14
21
28
35
42
49
56
63
70
77
84
±window (days)
-2 weeks
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Informed consent
X
Eligibility
X
X
Randomization
X
Demographics 
X
SBS history
X
Medical and surgical history
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications and 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, vital signs, 
weight
X
X
X
X
X
X
X
X
Length and head circumference
X
X
X
X
UGI/SBFT
X
Safety labs and urinalysisb, c
X
Xb
X
(X)
X
(X)
X
(X)
X
(X)
X
(X)
(X)
X
PK samplinga
X
 
[X]d
[X]d
Antibodies to teduglutidea,e
X
Xe
Native GLP-2f
X
Provide intake and output 
diariesg
X
X
X
X
X
X
X
X
Review diaries and nutritional 
support
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional support as 
neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense IPa, i
X
X
X
X
X
X
X
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Table 1:
Study Schedule: Visits -1 to 12
Procedures
Screening
Baseline 
(Week 0)
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
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit type
Site
Site
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Tel
Site
Study day
-14
0
7
14
21
28
35
42
49
56
63
70
77
84
±window (days)
-2 weeks
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Adjust IP dosej
X
EN=enteral nutrition; GLP-2=glucagon-like peptide 2; INR=international normalized ratio; IP=investigational product; PK=pharmacokinetics; PN=parenteral nutrition; PT=prothrombin time; 
UGI/SBFT=upper GI series with small bowel follow-through 
a Applicable to the teduglutide treatment arm only. 
b At baseline, safety labs (Table 4) and PK can be separated by 1 day if blood volumes are limiting. Safety labs at telephone visits will be collected at the discretion of the investigator. For all subjects in 
the teduglutide treatment arm, PT and INR will be tested at baseline, and repeated if clinically indicated.
c Urinalysis will consist of urine sodium and specific gravity. Urine collection should be attempted, but inability to obtain urinalysis is not a protocol deviation.
d Subjects will have blood samples taken for teduglutide PK analysis predose and 1 hour ±10 minutes and 4 hours ±10 minutes postdose at baseline (Visit 0). Subjects also will have blood samples taken 
for teduglutide PK analysis 2 hours ±10 minutes postdose at Week 7 (Visit 7) or Week 12 (Visit 12) of the treatment period.
e Samples for antibody analysis will be drawn at the baseline and Week 12 visits.  Blood samples while subjects are receiving teduglutide should be drawn at least 14 hours after the previous dose.
f Blood samples for native GLP-2 should be collected postprandial.  Native GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at investigator 
discretion based on weekly/monthly total volume.  
g Intake diaries will collect actual PN volume and hours per day and EN volume and calories. Intake diaries should be completed daily throughout the study. Urine and stool output should be recorded in 
the output diary over a 48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PN prescription. 
h Parenteral support adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment provided in Appendix 2.
i The initial dose will be calculated based on body weight measured at baseline (Visit 0).
j  The dose will be adjusted as needed, based on body weight measured at Week 12 visit.
Note: (X) denotes optional assessments; [X] denotes possible PK sampling time point (Refer to footnote “e”.)
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Table 2:
Study Schedule: Visits 13-28
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 
(EOT/ET)
Week 
25
Week 
26
Week 
27
Week 
28 
(EOS)a
Visit number
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit type
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Study day
91
98
105
112
119
126
133
140
147
154
161
168
175
182
189
196
±window (days)
±3
±3
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications
and procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, vital 
signs, weight
X
X
X
X
Length and head 
circumference
X
X
X
X
Safety labs and 
urinalysisb,c
(X)
(X)
(X)
X
(X)
(X)
(X)
X
(X)
(X)
(X)
X
(X)
(X)
(X)
X
Antibodies to 
teduglutided,e
X
Native GLP-2f
X
Provide intake and output 
diaries
X
X
X
Review diaries and 
nutritional supportg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional support 
as neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess follow-up period 
escape criteriad
Xi
Xi
Xi
X
Dispense IPd
X
X
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Table 2:
Study Schedule: Visits 13-28
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 
(EOT/ET)
Week 
25
Week 
26
Week 
27
Week 
28 
(EOS)a
Visit number
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit type
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Study day
91
98
105
112
119
126
133
140
147
154
161
168
175
182
189
196
±window (days)
±3
±3
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
EN=enteral nutrition; EOS=end of study; EOT=end of treatment; ET=early termination; GLP-2=glucagon-like peptide 2; INR=international normalized ratio; IP=investigational product; PN=parenteral 
nutrition; PT=prothrombin time; UGI/SBFT=upper GI series with small bowel follow-through
a At EOS subjects may enroll in an extension study, if subjects require treatment before the end of the 4-week follow-up they may enter the extension study immediately.  
b Safety labs at telephone visits will be collected at the discretion of the investigator. For all subjects in the teduglutide treatment arm, PT and INR are tested if clinically indicated.
c Urinalysis will consist of urine sodium and specific gravity.  
d Applicable to the teduglutide treatment arm only. 
e Samples for antibody analysis will be drawn at the EOS (Week 28) visit.
f Blood samples for native GLP-2 should be collected postprandial.  Blood samples drawn while subjects are receiving teduglutide should be drawn at least 14 hours after the previous dose. Native GLP-
2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at investigator discretion based on weekly/monthly total volume.  
g Intake diaries will collect actual PN volume and hours per day and EN volume and calories. Intake diaries should be completed daily throughout the study. Urine and stool output should be recorded in 
the output diary over a 48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PN prescription. 
h Parenteral support adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment provided in Appendix 2.
Note: (X) denotes optional assessments.
i If a subject treated with teduglutide meets the escape criteria, the assessments scheduled for the EOS visit should be conducted.
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BACKGROUND INFORMATION
1.
1.1
Short Bowel Syndrome
Short bowel syndrome (SBS) is a rare disorder resulting from congenital abnormalities or severe 
intestinal diseases that result in major surgical resections of the small intestine (O'Keefe et al., 
2006).  Unlike the adult population, the majority of cases of SBS in pediatric subjects are due to 
congenital anomalies or catastrophic events that occur during infancy such as necrotizing 
enterocolitis, gastroschisis, intestinal atresia, midgut volvulus, or long-segment Hirschsprung 
disease (Beattie et al., 2010; Goulet and Ruemmele, 2006).  A Canadian population-based study 
in neonates estimates an overall incidence of SBS to be 24.5 cases per 100,000 live births (Wales 
et al., 2004).  
The small intestine is capable of remarkable adaptation, but excessive loss of absorptive surface 
area or specialized functions can lead to dependence on parenteral nutrition (PN)1 fluids 
(O'Keefe et al., 2006).  Although PN is life-sustaining in intestinal failure, it is associated with 
serious complications, including liver disease, life-threatening catheter-related blood stream 
infections, and central venous thrombosis (Beattie et al., 2010; Goulet and Ruemmele, 2006).  
Dependence on PN is also associated with reduced quality of life in both patients and caregivers 
and has an extremely high cost of care (Huisman-de Waal et al., 2007).  About 30% of infants 
with SBS become independent of PN requirements within 12 months of the initial insult, and an 
additional 10% wean off PN within 24 months. After this time, linear intestinal growth slows.  It 
is estimated that 42% to 86% of pediatric patients with SBS are able to become independent of 
PN within 1 to 3 years (Gonzalez-Hernandez et al., 2017; Khan et al., 2015; Squires et al., 2012).  
Nevertheless, despite optimal medical management, some children remain dependent on PN for 
many years (Squires et al., 2012).  Infants who have less than 10% of expected small intestinal 
length for their gestational age have a low likelihood of ever achieving enteral autonomy (i.e., 
independence from parenteral support).  Providing the maximum tolerated amount of enteral 
nutrition (EN) has been the primary strategy to promote enteral adaptation (Spencer et al., 2005).  
Accelerating the adaptive process and achieving enteral autonomy is an urgent goal for all 
patients with SBS who are dependent on PN (Khan et al., 2015; Squires et al., 2012).  The 
adaptive process is in part controlled by glucagon-like peptide 2 (GLP-2), a 33 amino acid 
peptide hormone secreted from L-type enteroendocrine cells in the terminal ileum and colon in 
response to luminal nutrients and bile acids (Martin et al., 2006).  The post-prandial plasma 
concentration of GLP-2 in infants with SBS correlates with length of the remaining small 
intestine (Sigalet et al., 2004).  Infants who lack terminal ileum may have impaired adaptation 
due to inadequate production of GLP-2.
                                                
1 For the purpose of the study the terms parenteral support (PS) and parenteral nutrition (PN) are used 
interchangeably.
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1.2
Teduglutide
Teduglutide is a novel, recombinant analog of naturally occurring human GLP-2 that regulates 
the functional and structural integrity of the cells lining the gastrointestinal (GI) tract. 
Teduglutide is a 33-amino acid peptide that differs from native GLP-2 in the substitution of 
glycine for alanine at the second position at the N-terminus.  As a result, teduglutide 
demonstrates resistance to degradation by dipeptidyl peptidase 4 (DPP-4) and therefore 
maintains a longer elimination half-life (t1/2), approximately 2 hours in healthy adult subjects, 
1.3 hours in adult SBS subjects, and 0.22 hours in pediatric SBS subjects, compared to the native 
peptide, which has a t1/2 of approximately 7 minutes.  Teduglutide has been shown in animal 
studies and previous human clinical trials to increase villus height and crypt depth in the 
intestinal epithelium, thereby increasing the absorptive surface area of the intestines (Tappenden 
et al., 2013; Thymann et al., 2014). 
A Phase 3 study, TED-C13-003, has been completed in pediatric SBS subjects.  In this study, 
teduglutide was administered to 3 cohorts of pediatric subjects from ages 1-17 years.  
Thirty-seven pediatric subjects received teduglutide at doses of 0.0125, 0.025, or 0.05 mg/kg/day 
for 12 weeks.  Five additional pediatric subjects were enrolled in an observational standard of 
care (SOC) cohort.  There were clear dose-dependent effects of teduglutide seen at the 0.025 and 
0.05 mg/kg/day doses compared to SOC and the 0.0125 mg/kg/day dose.  In the 
0.025 mg/kg/day cohort there was a reduction in PN volume at Week 12 of 37%, including 
complete independence from PN support in 1 subject, and a reduction of 3.94 hours per day 
infusion time.  In the 0.05 mg/kg/day cohort there was a reduction in PN volume at Week 12 of 
39%, including complete independence from PN support in 3 subjects, and a reduction of 
4.18 hours per day infusion time.  Teduglutide was generally safe and well tolerated by pediatric 
subjects in all dosing cohorts.  There were no deaths during the study and no treatment-emergent 
serious adverse events (SAEs) related to teduglutide were reported.  No discontinuations from 
study were due to adverse events (AEs).  Additional studies in pediatric patients with SBS are 
ongoing.
Teduglutide (0.05 mg/kg/day) is currently approved for the treatment of adult patients with SBS 
in >30 countries.  On 29 Jun 2016, the European Commission granted an extension of the Market 
Authorization for teduglutide for the treatment of patients aged 1 year and above with SBS.  
Always refer to the latest version of the investigator’s brochure for the overall risk/benefit 
assessment and the most accurate and current information regarding the drug metabolism, 
pharmacokinetics, efficacy and safety of teduglutide (SHP633).
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OBJECTIVES
2.
2.1
Rationale for the Study 
There is no approved pharmacological therapy to improve intestinal adaptation in infants with 
SBS who are dependent on parenteral support.  This study will evaluate whether teduglutide is 
safe and effective in this patient population.  
2.2
Study Objectives
The objectives of this study are to evaluate the safety, efficacy/pharmacodynamics and 
pharmacokinetics (PK) of teduglutide treatment in infants with SBS dependent on parenteral 
support.
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STUDY DESIGN
3.
3.1
Study Design and Flow Chart
This is a randomized, multicenter, open-label study, consisting of a 2 to 4-week screening period, 
a 24-week treatment period and a 4-week follow-up period.  A schematic representation of the 
study design is presented in Figure 1.
Figure 1:
Study Schematic
*At EOS all subjects regardless of treatment arm may enroll in an extension study that will capture long-term safety data and 
provide the opportunity for additional teduglutide treatment.  The follow-up period for subjects in the teduglutide treatment arm 
may be interrupted and the subjects may proceed immediately to the EOS if at least one “escape” criteria is met.
3.1.1
Screening Period 
Study eligibility will be confirmed during the screening period (minimum: 2 weeks; maximum: 
4 weeks).  The schedule of evaluations to be conducted during the Screening Period can be found 
in Table 1.
3.1.2
Treatment Period
At the baseline visit (Week 0), subjects will randomized 1:1 to the teduglutide or SOC treatment 
arm. Randomization will be stratified according to the presence of a small bowel ostomy (e.g., 
end jejunostomy or ileostomy). During the 24-week treatment period, subjects in the SOC 
treatment arm will receive standard medical therapy for SBS, while those in the teduglutide arm 
will receive 0.05 mg/kg by subcutaneous (SC) injection once daily in addition to standard 
medical therapy. 
Extension 
study* 
1
24
1
3
5
7
9
12
16
20
28
2 to 4
Weeks
Screening
Teduglutide 0.05 mg/kg SC once daily for 24 weeks
Site Visit 
Telephone Visit
Standard of care for 24 weeks
Baseline: treatment 
randomization
0
24
3
5
7
9
12
16
20
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Subjects in both arms will follow the same visit schedule and assessments. Subjects will be 
monitored weekly with phone or clinic visits. Clinic visits will occur at Weeks 1, 3, 5, 7, 9, 12, 
16, 20, 24, and 28. At all site visits and telephone contacts, safety will be monitored and 
nutritional support will be reviewed and adjusted as needed. To maintain consistency across 
centers, guidance and training will be provided to help sites follow the nutritional support 
adjustment guidelines (developed with SBS expert input and provided in the protocol) related to 
decisions for PN reduction and advances in enteral feeds based on weight gain, urine and stool 
output, and clinical stability (Appendix 2). Deviations from the guidelines are not considered a 
protocol deviation.
Sparse PK sampling, in the teduglutide treatment arm only, will occur at baseline (predose and 
1 hour ±10 minutes and 4 hours ±10 minutes postdose) and at Week 7 or 12 (2 hours±10 minutes 
postdose).
The schedule of evaluations for the Treatment Period can be found in Table 1 (Visits -1 to 12) 
and Table 2 (Visits 13 to 28).  
3.1.3
Follow-up Period
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up 
period until the end of study (Week 28/EOS) during which time subjects will receive standard 
medical therapy, but no investigational product (IP) will be administered. At EOS, all subjects 
regardless of treatment arm may enroll in an extension study that will capture long-term safety 
data and provide the opportunity for additional teduglutide treatment. The follow-up period for 
subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed 
immediately to the EOS visit if at least one of the following “escape” criteria is met:
1. Increasing PN requirements following discontinuation of teduglutide.
2. Deteriorating nutritional status (e.g., weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation.  
4. Severe diarrhea related to teduglutide discontinuation.
The schedule of evaluations for the Follow-up Period can be found in Table 2 (Visits 13 to 28).
3.2
Study Duration
The study consists of a 2 to 4-week screening period, a 24-week treatment period and a 4-week 
follow-up period.  The maximum duration of participation for each subject is 32 weeks.
Study completion is defined as the last subject, last visit. This is the visit date at which the last 
subject on the study has his or her last follow-up visit on the study (whether during the 24-week 
treatment period or the 4-week follow-up period).
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3.3
Sites and Regions
This study is planned to be conducted at approximately 5 to 10 sites globally.
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STUDY POPULATION
4.
At least 10 subjects will be randomized: at least 5 subjects in a teduglutide treatment arm and at 
least 5 subjects in an SOC comparator arm.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1. Informed consent by the parent or legal guardian. 
2. Male or female infant 4 to 12 months corrected gestational age at screening.
3. Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and baseline.
4. Short bowel syndrome with dependence on parenteral support to provide at least 50% of fluid 
or caloric needs.
5. Stable PN requirements for at least 1 month prior to screening, defined as a ≤10% change in 
the weight-normalized parenteral total fluid and caloric intake, despite attempts to wean PN, 
notwithstanding transient instability for events such as sepsis or interruption of central 
venous access.
6. Lack of terminal ileum and ileocecal valve.
7. Parent or legal guardian understands and is willing and able to fully adhere to study 
requirements as defined in this protocol.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1. Previous treatment with teduglutide.
2. Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus 
inclusion disease, etc.
3. Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility, that is the primary contributing factor to feeding intolerance 
and inability to reduce parenteral support, prior to screening.  Dysmotility is defined as 
severe if it is expected to limit the advancement of enteral feeding.
4. Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral 
aversion in the absence of a feeding tube.
5. Intestinal obstruction or clinically significant intestinal stenosis.
6. Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or major 
intestinal resection or anastomosis, within 3 months prior to screening or planned during the 
study period.
7. Unstable cardiac disease.
8. Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
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9. Biliary obstruction, stenosis, or malformation. 
10. Clinically significant pancreatic disease. 
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following 
parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b. Platelet count <100×10^3/µL due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d. Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 2 week 
period.
13. More than 3 serious complications of intestinal failure (e.g., catheter-associated bloodstream 
infections, interruption of nutrition due to feeding intolerance, catheter-associated 
thrombosis, severe fluid or electrolyte disturbances) within 1 month prior to or during 
screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile polyposis or
Beckwith-Wiedemann syndrome, or first degree relative with early onset of gastrointestinal 
cancer (including hepatobiliary and pancreatic cancers). 
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 (GLP-
2); insulin-like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs of these 
hormones; or glutamine. 
16. Participation in a clinical study using an experimental drug within 3 months or 5.5 half-lives 
of the experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, closely-
related compounds, or any of the stated ingredients.  
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts the 
subject at any undue risk, prevents completion of the study, or interferes with analysis of the 
study results.
19. Hypersensitivity to trace residues of tetracycline.
20. Signs of active severe or unstable, clinically significant hepatic impairment shown by any of 
the below laboratory test results at screening:
a.Total bilirubin ≥2 x upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥5 x ULN
c.
Alanine aminotransferase (ALT) ≥5 x ULN
For subjects with Gilbert’s disease:
d. Indirect (unconjugated) bilirubin ≥2 x ULN
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4.3
Reproductive Potential 
Not applicable; this study will enroll infants.
4.4
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution.  The investigator or sponsor may 
withdraw the subject at any time (e.g., in the interest of subject safety).  The investigator should 
discuss withdrawal of a subject from investigational product with the medical monitor as soon as 
possible.
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 24/EOT/early termination are to be performed as completely as possible. Whenever 
possible, all discontinued subjects should also undergo the protocol-specified 4-week Follow-up 
Period. Comments (spontaneous or elicited) or complaints pertaining to IP discontinuation made 
by the subject must be recorded in the source documents. The reason for discontinuation, the 
date and the total amount of investigational product administered must be recorded in the
electronic case report form (eCRF) and source documents.
Subjects who discontinue will not be replaced. 
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4.4.1
Reasons for Discontinuation
The reason(s) for permanent discontinuation of treatment and/or withdrawal from the study must 
be determined by the investigator, and recorded in the subject’s medical record and in the eCRF.  
If a subject is withdrawn for more than 1 reason, each reason should be documented in the source 
document, and the most clinically relevant reason should be entered in the eCRF.
Reasons for discontinuation include, but are not limited to:

Adverse event

Death

Lost to follow-up

Physician decision

Protocol deviation

Study terminated by sponsor

Withdrawal by parent/guardian

Lack of efficacy

Other
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact the parent(s)/guardian(s) of any 
subject lost to follow-up at any time point prior to the last scheduled contact (office visit or 
telephone contact). At least 1 of these documented attempts must include a written 
communication sent to the subject’s last known address via courier or mail (with an 
acknowledgement of receipt request) asking that they return to the site for final safety 
evaluations and return any unused investigational product.
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PRIOR AND CONCOMITANT TREATMENT
5.
5.1
Prior Medications and Procedures
Prior treatment includes all treatment and procedures (including but not limited to prescription 
treatments, herbal treatments, vitamins, non-pharmacological treatment, as appropriate) received 
within 14 days prior to the screening visit (Visit -1) (or pharmacokinetic equivalent of 5 half 
lives, whichever is longer, must be recorded on the appropriate eCRF page.
5.2
Concomitant Medications and Procedures
The administration of all medications including concomitant medications (including prescription 
and nonprescription medications, dietary and nutritional supplements, and vitamins) and PN 
must be recorded from the first dose of investigational product and for the duration of the study 
in the appropriate sections of the eCRF.  Any diagnostic, surgical or other therapeutic treatments 
received by a subject during the course of the study will also be recorded on the eCRF.
The mechanism of action of teduglutide may increase enteral absorption of oral drugs (e.g., 
drugs used for management of SBS such as motility medication, opioids, psychotropics, 
metronidazole), so consideration should be given to modifying concomitant enteral medication 
regimens. Titration of concomitant enteral medications should be considered when drugs, 
especially those with a narrow therapeutic index (e.g., warfarin, digoxin, psychotropics) are 
given.
5.3
Permitted Treatment
Standard medical therapy for SBS should be continued.
5.4
Prohibited Treatment
The following medications are prohibited during teduglutide treatment and within the provided 
timeframe prior to the pretreatment visit (Table 3):
Table 3:
Prohibited Treatment
Prior Therapy
Time Restriction Prior to 
the Pretreatment Visit
Teduglutide
Any
GLP-2, human growth hormone, or analogs of these hormones
6 months
Octreotide, GLP-1 analogs, and enteral glutamine
30 days
GLP=glucagon-like peptide
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INVESTIGATIONAL PRODUCT
6.
6.1
Identity of Investigational Product
The SOC treatment arm will receive standard medical therapy for SBS; while those in the 
teduglutide arm will receive 0.05 mg/kg SC once daily in addition to standard medical therapy.
Teduglutide will be provided in sterile, single-use 3 mL vials containing 1.25 mg teduglutide as a 
white lyophilized powder to be reconstituted before use with 0.5 mL sterile water for injection. 
In addition to the active ingredient (teduglutide), each vial of teduglutide contains L-histidine, 
mannitol, monobasic sodium phosphate monohydrate, and dibasic sodium phosphate as 
excipients. Additional information is provided in the current investigator’s brochure.
6.2
Administration of Investigational Product
6.2.1
Interactive Response Technology for Investigational Product Management
All investigative study sites will be initially provided with sufficient investigational product to 
randomly assign a subject into the study (for either of the proposed treatment groups).  
Randomization will occur through an interactive response system. Random assignment of a 
subject will trigger replacement supplies for that investigative study site.
6.2.2
Allocation of Subjects to Treatment
Subjects will be randomized 1:1 to the teduglutide or SOC treatment arm.  Randomization will 
be stratified according to the presence of a small bowel ostomy (e.g., end jejunostomy or 
ileostomy).  The actual treatment given to individual subjects is determined by a randomization 
schedule.
Subject numbers are assigned to all subjects as they consent to take part in the study.  Within 
each site (numbered uniquely within a protocol), the subject number is assigned to subjects 
according to the sequence of presentation for study participation.  
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined.
6.2.3
Dosing
The initial dose will be calculated based on body weight measured at baseline (Visit 0), and 
adjusted as needed, based on body weight measured at Week 12.  No other adjustments to dose 
will be made during the teduglutide treatment period, unless discussed with the sponsor’s 
medical monitor. 
Following reconstitution, teduglutide will be administered by SC injection once daily (QD) into 
1 of the 4 quadrants of the abdomen (in subjects without a stoma) or into either the thigh or arm.  
For subjects with a stoma, the quadrant of the abdomen containing the stoma should not be used.  
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Teduglutide should be used as soon as possible after reconstitution, but no more than 3 hours 
later.
The subject should be dosed at approximately the same time each day. Consecutive doses should 
be separated by at least 12 hours.  Each day, the injection site should be alternated.  
Any subject who achieves complete independence from PN support at any time during the 
treatment period will continue to receive teduglutide treatment.
The first SC injection in teduglutide-naïve subjects should be administered under the supervision 
of the investigator or designee and the subject observed for hypersensitivity reactions for at least 
4 hours during their initial dosing visit.  The site of administration (arm, thigh, and abdomen) of 
the first teduglutide dose must be specified and recorded in the eCRF. 
Detailed instructions for reconstitution and injection of the investigational product can be found 
in the Instructions for Use. 
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up 
period until the end of study (Week 28/EOS) during which time subjects will receive standard 
medical therapy, but no investigational product will be administered.  At EOS all subjects 
regardless of treatment arm may enroll in an extension study that will capture long-term safety 
data and provide the opportunity for additional teduglutide treatment.  The follow-up period for 
subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed 
immediately to the EOS if at least one of the following “escape” criteria is met:
1. Increasing PN requirements following teduglutide discontinuation.
2. Deteriorating nutritional status (e.g., weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation.  
4. Severe diarrhea related to teduglutide discontinuation.
6.2.4
Unblinding the Treatment Assignment
Not applicable for this open-label study.
6.2.5
Dose Selection Rationale
Teduglutide is approved for adult and pediatric use in the EU at a dose of 0.05 mg/kg SC once 
daily.  A completed 12-week dose finding study (TED-C13-003) demonstrated that teduglutide 
dosing at 0.025 and 0.05 mg/kg/day was associated with a favorable benefit-risk profile most 
meaningful at the 0.05 mg/kg/day dose (Carter et al., 2017). 
Population pharmacokinetic modeling and simulations were conducted to determine the optimal 
dose to be used in pediatric subjects using data from 8 adult clinical studies including adult Phase 
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1 studies and Phases 2/3 studies as well as TED-C13-003 and suggested the same adult dose 
(0.05mg/kg) in pediatric subjects (aged between 1.67-14.7 years) (Marier et al., 2017).
To support dosing in the current age group, further PK simulation was conducted based on the 
population PK model previously established and a virtual population of 1000 pediatric patients 
created based on Centers for Disease Control (CDC) growth charts in the target age group (4 to 
12 months) and taking into consideration body weights of pediatric patients with SBS enrolled in 
study TED-C13-003 (approximately 15% lower than healthy subjects in the same age group).  
Monte Carlo simulations for all age groups were performed according to the SC dosing regimens 
of 0.0125, 0.025 and 0.05 mg/kg every 24 hours.  Rich concentration-time profiles were 
simulated with the customized population PK model to derive the exposure metrics area under 
the concentration curve at steady state (AUCss) and maximum concentration at steady state 
(Cmax,ss).  Following 0.05 mg/kg daily SC administration, the median Cmax,ss of teduglutide in 
neonate patients (24.9 ng/mL) was within 20% of that observed in the 2 to 4 and 4 to 6 years age 
groups (26.9 and 29.4 ng/mL, respectively); and approximately ~28% lower than that in adult 
patients with SBS.  The clinical package in conjunction with Cmax was considered to support 
teduglutide dose selection since AUCss was previously shown not to correlate with efficacy.  
Thus, the 0.05 mg/kg dose is proposed for testing in this age group.
6.3
Labeling, Packaging, and Storage
6.3.1
Labeling
The investigational product will be packaged, labeled, and shipped to the study site by the 
sponsor or designee.  Kits containing 7 vials of investigational product will be provided for this 
study.  The vials will be labeled in accordance with applicable regulatory requirements. 
Ancillary kits, containing supplies needed for the reconstitution and administration of the 
investigational product will also be provided and labeled in accordance with the applicable 
regulatory requirements. 
All investigational product used in this study will be manufactured, tested, labeled, and released 
according to current legal requirements and Good Manufacturing Practice.
6.3.2
Storage and Handling
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.
Investigational product must be kept in a locked area with access restricted to specific study 
personnel. Investigational product will be stored refrigerated at a temperature between 2-8°C 
(35.6-46.4°F) until dispensed to a subject. Once dispensed to a subject, the IP can be stored 
refrigerated or up to a controlled room temperature (acceptable range of 2-25°C, or 35.6-77°F). 
Parent/legal guardian will be instructed to keep the subject’s IP and sterile water diluent at 
controlled room temperature. If there are concerns that the controlled room temperature cannot 
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be maintained, the IP may be refrigerated. The IP is for single use only, and should be used 
within 3 hours following reconstitution.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (i.e., certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), e.g., fumigation of a 
storage room.
Investigational products are distributed by the pharmacy or nominated member of the study 
team. The pharmacist/nominated team member will enter the unique subject identifier on the 
investigational product bottle/carton labels, as they are distributed.
6.4
Drug Accountability
Investigational product will not be dispatched to the study site until the sponsor or 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 investigational product 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.  Kits will be shipped to the site once the 
subject is screened.
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects.  The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition.  Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for dispensing investigational product.  Where 
permissible, tasks may be delegated to a qualified designee (e.g., a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator.  
This delegation must be documented in the applicable study delegation of authority form.
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The investigator or his/her designee will dispense the investigational product only to subjects 
included in this study following the procedures set out in the study protocol.  Investigational 
product kits will be dispensed at each of the applicable study visits at which the subject is 
required to be at the clinic.  Each investigational product kit is sufficient for a treatment period of 
1 week and enough kits will be supplied to cover the period until the next planned study visit.  
Additional study kits will be provided as necessary.
Each subject will be given the investigational product according to the protocol.  The 
investigator is to keep a current record of the inventory and dispensing of all clinical supplies.  
All dispensed medication will be documented on the eCRFs and/or other investigational product 
record.  The investigator is responsible for assuring the retrieval of all study supplies from 
subjects.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor.  If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.
At the end of the study, or as instructed by the sponsor, all unused stock, subject returned 
investigational product, and empty/used investigational product packaging are to be sent to the 
sponsor or designee.  The investigator is responsible for assuring the retrieval of all study 
supplies from subjects.
Returned investigational product must be counted and verified by clinical site personnel and the 
sponsor (or study monitor). Shipment return forms, when used, must be signed prior to shipment 
from the site.  Contact the sponsor for authorization to return any investigational product prior to 
shipment.  Shipment of all returned investigational product must comply with local, state, and 
national laws. 
Please see the Pharmacy Manual for additional information.
6.5
Subject Compliance
The parent(s)/guardian(s) of subjects must be instructed to bring unused investigational product 
and empty/used investigational product packaging to every visit. Drug accountability must be 
assessed and recorded at the container/packaging level for unused investigational product that is 
contained within the original tamper-evident sealed container (e.g., bottles, trays, vials) or at the 
individual count level for opened containers/packaging. 
Subject compliance will be checked by site personnel at every visit by reviewing the subject 
diaries and asking the subject or the subject’s parent or legally-authorized representative if they 
have administered the investigational product according to instructions. If any doses have been 
missed, the reason for missed dose should be documented in the subject’s source documentation 
including, as applicable, the eCRF.
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The investigator is responsible for contacting the sponsor or designee when the subject’s daily 
investigational product dosing regimen is interrupted. Attempts should be made to contact the 
sponsor or designee prior to dose interruption. Reasons for dosage interruption may include but 
are not limited to hospitalization and AEs, a lapse in investigational product delivery, etc.
Subjects who have received 80% of the planned doses administered will be assessed as being 
compliant with the study protocol.
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STUDY PROCEDURES
7.
7.1
Study Schedule
Detailed study procedures and assessments to be performed for subjects throughout the study are 
outlined in the study schedules (Table 1 and Table 2) and must be referred to in conjunction with 
the instructions provided in this section. 
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 24/EOT are to be performed as completely as possible.  Whenever possible, all 
discontinued subjects should also undergo the protocol-specified 4-week Follow-up Period.  
7.1.1
Screening
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent from the 
parent(s)/guardian(s) of the subject. The screening visit assessments and procedures, beginning 
with informed consent, will be performed as outlined in Table 1.
7.1.2
Treatment Period
The randomized Treatment Period will comprise Weeks 1 to 24, during which all assessments 
will be performed as outlined in Table 1 and Table 2.
7.1.3
Follow-up Period
The Follow-up Period will comprise Weeks 25 to 28, during which all assessments will be 
performed as outlined in Table 2.
7.2
Study Evaluations and Procedures
7.2.1
Demographics and Other Baseline Characteristics
Demographics and Medical History
Demographic and/or other baseline variables obtained at the screening and/or baseline visits are 
listed below. Abnormal findings of clinical significance (if any) will be recorded as past medical 
history.

Demography (including age, gestational age, sex, and race)

Medical history (including surgical history)

SBS history, including remnant anatomy
Upper Gastrointestinal Series with Small Bowel Follow-through
An upper GI contrast series with small bowel follow-through will be performed on all subjects 
during the screening period if one has not been done since the subject's last GI surgery. 
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It is acceptable to only enroll subjects who have already had an upper GI series with small bowel 
follow-through performed since the subject’s most recent surgery.  
7.2.2
Efficacy Assessments
Subject Diaries
All available diary data will be reviewed by the investigator or their designee at each clinic and 
telephone visit to assess clinical status and opportunity for PN reduction and advance in feeds.  
Parenteral support adjustments should be made after review of the intake and output diaries and 
the safety lab data according to the guidance for nutrition support adjustment provided in 
Appendix 2.
Intake Diary
Intake diaries will be used to collect and evaluate each subject’s nutritional support. The 
parent/legally authorized representative/study site staff will complete the appropriate fields of the 
PN and EN sections of the intake diary daily throughout the study.
The following data will be captured in the intake diaries:

Parenteral support volume and infusion duration

Enteral nutrition (formula) including volume and calories
Site personnel will determine the actual PN and EN daily calories based on diary entries.
Output Diary
Urine and stool output should be recorded in the output diary over a 48-hour period of nutritional 
stability before every clinic visit; in addition, output should be recorded for subjects within 
1 week of implementing a change in the PN prescription.
Urine data:

Measure and record the weight of all urine-only diapers. Urine volume will be calculated 
using the following formula: 1 g (scale weight) = 1 mL or 1 cc

At the discretion of the investigator, the parent or legal guardian/study site staff may be 
asked to collect the first void after the daily PN infusion to measure specific gravity
Stool data (includes diapers with mixed urine and stool):

Record the weight of diapers containing stool (including diapers with mixed urine and 
stool) as stool output and score the stool consistency (see Output diary). Stool volume 
will be calculated using the formula: 1 g (scale weight)=1 mL or 1 cc
All ostomy output volume should be recorded.  
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Native GLP-2
Blood samples for native GLP-2 should be collected postprandial.  Blood samples while subjects 
are receiving teduglutide should be drawn at least 14 hours after the previous dose.  Native 
GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject 
weight or at investigator discretion based on weekly/monthly total volume.  
7.2.3
Safety Assessments
Laboratory Evaluations
Safety laboratory tests to be performed at site visits consist of clinical chemistry, hematology, 
and urinalysis and will be performed as outlined in the study plan (Table 1 and Table 2). 
Scheduled laboratory testing will be processed by a central lab. All laboratory assays will be 
performed according to the central laboratory’s normal procedures. Reference ranges are to be 
supplied by the laboratory. The investigator should assess out-of-range clinical laboratory values 
for clinical significance, indicating if the value(s) is/are not clinically significant or clinically 
significant. Abnormal clinical laboratory values, which are unexpected or not explained by the 
subject’s clinical condition, may, at the discretion of the investigator or sponsor, be repeated as 
soon as possible until confirmed, explained, or resolved.
During the Treatment Period, subjects will also have safety labs within approximately 5 to7 days 
after a PN adjustment.  Safety labs performed after PN adjustment and between site visits will 
consist of clinical chemistry and urinalysis and may be processed by the central laboratory or a 
local laboratory.  Local lab results are not required to be entered in the eCRFs; however, if the 
local lab results indicate any new clinically significant changes, they must be reported as an 
adverse event (see Section 8). Urine specimen collection should be attempted as part of the 
safety labs, but lack of urinalysis will not constitute a protocol deviation.
At baseline, blood samples for safety labs and PK can be separated by 1 day if blood volumes are 
limiting.  
Safety labs at telephone visits will be collected at the discretion of the investigator.  
For all subjects in the teduglutide treatment arm, prothrombin time (PT) and international 
normalized ratio (INR), tested at baseline, will be repeated if clinically indicated.
New clinically significant labs should be reported as AEs.
Close monitoring criteria related to liver test abnormalities:  
The investigator should contact the medical monitor within 24 hours of their awareness if the 
subject develops any of the following changes in laboratory parameters:

ALT or AST >5x ULN and >2x baseline value
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
Total or direct bilirubin that is >2x baseline value or an absolute increase of  ≥3 mg/dL 
(51.3 µmol/L)
If such changes are observed, the labs should be repeated along with an INR, and an inquiry 
should be made as to the presence of clinical symptoms consistent with new liver injury. The 
subject should be followed closely to determine the trajectory of the laboratory abnormalities and 
appropriate evaluations should be made, such as abdominal ultrasound with Doppler imaging to 
exclude vascular causes and biliary obstruction, consideration of sepsis, liver hypoperfusion, 
acute viral hepatitis (such as hepatitis A, EBV, or HSV), exposure to hepatotoxic medications, 
mitochondrial hepatopathy, or metabolic liver disease (such as hereditary fructose intolerance or 
arginosuccinate synthetase deficiency).  Further evaluations can be performed at the discretion of 
the investigator in consultation with the Shire medical monitor.
The following clinical laboratory assessments will be performed according to the study 
schedules:
Table 4:
List of Laboratory Tests
Biochemistry:

Albumin 

Alkaline phosphatase 

Alanine aminotransferase 

Amylase

Aspartate aminotransferase 

Bicarbonate

Bilirubin (total and indirect)

Blood urea nitrogen 

Calcium (total)

Chloride

Cholesterol

C-reactive protein 

Creatinine

Estimated Glomerular Filtration Rate 
(Schwartz formula)

Gamma-glutamyl transferase 

Glucose

Lipase

Magnesium

Phosphorus

Potassium 

Sodium 

Triglycerides
Hematologya:

Hematocrit 

Hemoglobin 

Platelet count

Red blood cell count 

Red blood cell morphology, if needed

White blood cell count with differential
Coagulationb:

Prothrombin time

International normalized ratio
Urinalysis: 

Specific gravity  

Urine Sodium
a Hematology is not collected at Week 1 or at telephone visits.
b For all subjects in the teduglutide treatment arm, PT and INR will be tested at baseline and repeated only if clinically indicated.
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Antibodies to Teduglutide 
Blood samples will be drawn to test for antibodies to teduglutide.  Samples will be taken before 
teduglutide administration at the screening visit (Visit -1) and at least 14 hours after the previous 
dose at Week 12 (Visit 12); samples may be drawn from a central line or peripheral access. One 
additional sample will be collected at the EOS 4 weeks after the EOT (i.e., Week 28 or EOS).  
Volume of Blood
Efforts will be made to minimize the amount of blood drawn from all pediatric subjects 
participating in this study. The volumes of blood to be drawn from each subject will vary 
depending on clinical status. Approximate volumes of blood to be drawn from each subject are 
shown in Table 5.
Table 5:
Approximate Volume of Blood to be Drawn from Each Subject 
Assessment
Sample 
Volume (mL)
No. 
Samples 
Total 
Volume (mL)
Notes
Subjects Receiving Teduglutide Treatment
Biochemistry 
0.6
12
7.2
Hematology
0.6
11
6.6
Coagulation 
Parameters
0.6
1
0.6
PT and INR tested at baseline 
only, repeat while on study 
only if clinically indicated.
Antibodies
1.5
5
7.5
Pharmacokinetics
1.5
4
6.0
Baseline: 3 timepoints
Week 7: 1 timepoint OR
Week 12: 1 timepoint
Native GLP-2
1.5
3
4.5
Total mL:
6.3
36
32.4
Subjects Receiving Standard of Care
Biochemistry 
0.6
12
7.2
Hematology
0.6
11
6.6
Native GLP-2
1.5
3
4.5
Total mL:
2.7
26
18.3
GLP=glucagon-like peptide; INR=international normalized ratio; PT=prothrombin time
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment. When more than 1 blood assessment is to be done at the time 
point/period, if they require the same type of tube, the assessments should be combined. Blood 
volume estimates do not include safety labs performed after PN adjustment, and anti-teduglutide 
antibody testing during no-teduglutide treatment.
Consistent with standard medical practice, efforts to minimize pain and discomfort during 
procedures such as peripheral venipuncture should be implemented as applicable. This may 
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include oral sucrose solutions, a pacifier, distraction techniques, and the use of topical anesthetic 
such as EMLA.   
Physical Examinations, Vital Signs, Weight, Length, and Head Circumference
Physical examinations will be performed according to the study schedules (Table 1 and Table 2). 
Any new clinically significant findings noted during physical examinations should be recorded 
on the appropriate AE page of the eCRF.
Vital signs will be measured according to the study schedules. Measurements will include 
systolic and diastolic blood pressure (mmHg), pulse (beats per minute), and body temperature 
(°C/°F). Blood pressure should be determined by the appropriate size cuff (using the same 
method, the same leg, and in the supine position throughout the study, when possible).  Blood 
pressure measurements should be attempted as part of the vital signs, but lack of blood pressure 
results will not constitute a protocol deviation.  New clinically significant vital sign 
abnormalities should be recorded on the appropriate AE page of the eCRF.
Body weight will also be recorded in the eCRF; subjects should be weighed on the same scale 
at each study visit. Length and head circumference will be measured at selected visits. A height 
z-score, weight Z-score, and weight/length ratio will be calculated by the sponsor using the 
site-provided height and weight data collected at each site visit.
7.2.4
Pharmacokinetic Assessments
Subjects will have blood samples taken for teduglutide PK analysis predose, and 1 hour 
±10 minutes and 4 hours ±10 minutes postdose at baseline (Visit 0).  Subjects also will have 
blood samples taken for teduglutide PK analysis 2 hours ±10 minutes postdose at Week 7 
(Visit 7) or Week 12 (Visit 12) of the treatment period. Blood for PK sampling should be 
collected via peripheral IV or venipuncture, not from a central line. The site of teduglutide 
administration prior to PK blood draws (arm, thigh, abdomen) must be specified. 
7.2.5
Health Economics and Outcomes Research
Hospitalizations
Each hospitalization that occurs during the study will be recorded, including date of admission, 
date of discharge, reasons for hospitalization, discharge diagnosis, and discharge status. 
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ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.3. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, 
then each symptom should be listed individually. All AEs should be captured on the appropriate 
AE pages in the eCRF and in source documents. In addition to untoward AEs, unexpected 
benefits outside the investigational product indication should also be captured on the AE eCRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
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8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of 
the investigational product is compelling and/or follows a known or 
suspected response pattern to that product, and the event cannot be 
explained by the subject’s medical condition, other therapies, or 
accident.
Not Related
The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident and no 
plausible temporal or biologic relationship exists between the 
investigational product and the event.
AEs that are related to IP that are not resolved at EOS will be followed until the event resolves or 
stabilizes, as judged by the investigator.
Laboratory values, vital signs, and clinical findings at the scheduled physical examinations must 
be reported as AEs if the investigator considers the finding to be a clinically significant change 
from the baseline.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the eCRF. Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved with Sequelae 

Recovering/Resolving

Unknown
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8.1.4
Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE. It is assumed that some of the infants participating in this study may be 
hospitalized for planned surgery(ies) that will occur during their participation in the study.  Such 
pre-planned, elective surgeries, do not need to be reported as SAEs for this protocol.  
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory or vital sign can represent an AE if the change is 
clinically relevant or if, during the study, a shift of a parameter is observed from a normal value 
to an abnormal value, or a further worsening of an already abnormal value. When evaluating 
such changes, the extent of deviation from the reference range, the duration until return to the 
reference range, either while continuing treatment or after the end of treatment with the 
investigational product, and the range of variation of the respective parameter within its 
reference range, must be taken into consideration.
If, during the study, there are abnormal clinical laboratory values or vital signs which were not 
present at the beginning of the study, further investigations should be performed until the values 
return to within the reference range or until a plausible explanation (e.g., concomitant disease) is 
found for the abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory or vital sign is clinically significant and 
therefore represents an AE.
8.1.6
Pregnancy
Not applicable.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for 
a non-medical purpose (e.g., to alter one’s state of consciousness or get high) in a manner 
that may be detrimental to the individual and/or society.
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
Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol).

Overdose – Administration of a dose greater than the allocated dose of the study 
medication or at a frequency greater than the dosing interval specified by the protocol.

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product. For studies, medication errors are reportable to the sponsor 
only as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error. 
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally-authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator brochure which the sponsor 
has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Drug Safety Department and the Shire Medical Monitor within 24 hours of the first awareness of 
the event. Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, 
misuse, overdose, or medication errors (see Section 8.1.7) unless they result in an SAE.
All Adverse Events of Special Interest, as defined in Section 8.3, must be reported by the 
investigator to the Shire Global Drug Safety Department and the Shire Medical Monitor within 
24 hours of the first awareness of the event even if the event does not fulfill seriousness criterion.
The investigator must complete, sign, and date the Shire Clinical Study Adverse Event Form for 
SAEs and Non-serious AEs as Required by Protocol, and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested). Fax or e-mail the completed form to the Shire Global Drug Safety 
Department. A copy of the completed Shire Clinical Study Adverse Event Form for Serious 
Adverse Events (SAEs) and Non-serious AEs as Required by Protocol (and any applicable 
follow-up reports) must also be sent to the Shire medical monitor or designee using the details 
specified in the emergency contact information section of the protocol.
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8.2.3
Serious Adverse Event Definition
A SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose: 

Results in death

Is life-threatening. Note: The term 'life-threatening' in the definition of "serious" refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for pre 
existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse. 
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.3, and must be reported 
to the Shire Global Drug Safety Department and the Shire Medical Monitor within 24 hours of 
the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Drug Safety Department within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
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In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (i.e., the SAE was noted as the primary cause of 
death) must have fatal checked as an outcome with the date of death recorded as the resolution 
date. For all other events ongoing at the time of death that did not contribute to the subject’s 
death, the outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (e.g., drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death.  
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting 
The Sponsor and/or Clinical Contract Research Organization (CRO) is responsible for notifying 
the relevant regulatory authorities, and US central Institutional Review Boards (IRBs)/EU central 
ethics committees (ECs), of related, unexpected SAEs.
In addition, the Clinical CRO is responsible for notifying active sites of all related, unexpected 
SAEs occurring during all interventional studies across the SHP633 program.
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
8.3
Adverse Events of Special Interest
An AE of special interest is an AE (serious or nonserious) of scientific and medical concern 
specific to the sponsor’s product or program and for which ongoing monitoring and immediate 
notification by the investigator to the sponsor is required.
The AEs of special interest that require expedited regulatory reporting include the following:

Growth of pre-existing polyps of the colon

Benign neoplasia of the GI tract including the hepatobiliary system

Tumor-promoting ability (e.g., benign and/or malignant neoplasia of any kind, not 
limited to those of the GI or hepatobiliary system)
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For AEs of special interest, the sponsor must be informed within 24 hours of first awareness as 
per the SAE notification instructions described in Section 8.2.2 even if the event does not fulfill 
the seriousness criteria.
8.4
Dose Interruption Criteria
The investigator is responsible for contacting the sponsor/designee when the subject’s 
teduglutide dosing regimen is interrupted. The length of dose interruption, and whether 
teduglutide administration resumes or is permanently discontinued, depends on the clinical 
situation.
Investigational product must be interrupted if any of the following events occur:

An adverse event of special interest (see Section 8.3) 

Intestinal obstruction

Biliary obstruction

Pancreatic duct obstruction
Investigational product must be permanently discontinued if any of the following events occur: 

Severe hypersensitivity, such as anaphylaxis, determined by the 
investigator to be related to IP. 

Any malignancy 
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DATA MANAGEMENT AND STATISTICAL METHODS
9.
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the eCRF.  A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy.  Discrepancies 
between source data and data entered on the eCRF will be addressed by qualified site personnel.  
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel.  Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting.  Once a subject is randomized, it is expected that site 
personnel will complete the eCRF entry within approximately 3 business days of the subject’s 
visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the data management plan. Quality 
control and data validation procedures are applied to ensure the validity and accuracy of the 
clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Statistical Analysis Process
The study will be analyzed by the sponsor or designee. All statistical analyses will be performed 
using SAS® (SAS Institute, Cary, NC, US) version 9.3 or higher.
The statistical analysis plan (SAP) will provide the definitions and statistical methods  for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed.
9.4
Planned Interim Analysis, and Data Monitoring Committee 
No interim analyses is planned for this the study. 
A data monitoring committee (DMC) will be involved in the management of this study. The 
DMC members will review the data approximately every 3 months according to the DMC 
Charter. The DMC review will include all cumulative safety data (i.e., AEs, laboratory 
assessments, physical examinations, etc.) from study assessments through each cutoff period. 
Further details regarding the DMC can be found in the DMC charter, which will be available 
prior to the administration of investigational product. 
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The DMC for this study will be conducted in accordance with the FDA Guidance for Clinical 
Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees 
(March 2006).
The DMC will be an external, independent board comprised of physicians with relevant training. 
The DMC will be restricted to individuals free of significant conflicts of interest, including, but 
not limited to, financial, scientific, or regulatory in nature. The DMC will be governed by a 
Charter agreed to by members of the Board and the sponsor. Members of the Board may not be 
study investigators or be employed at the same institution as a study investigator, individuals 
employed by the sponsor, independent contractors hired by the sponsor, or members of 
regulatory agencies. The DMC may make recommendations to the sponsor regarding study 
aspects including stopping, modifying or continuing the study; however, the sponsor will have 
the final responsibility to determine whether the study should be modified or temporarily or 
permanently stopped. 
9.5
Sample Size Calculation and Power Considerations
The sample size is determined based on enrollment feasibility for this rare condition and the age 
of the study population. 
9.6
Study Population
Intent to treat (ITT) population: All subjects randomized in the study.
Safety analysis population: The safety analysis set will contain all subjects who meet the 
following criteria:

Teduglutide treatment arm: subjects who receive at least 1 dose of teduglutide and 
have undergone at least 1 post-baseline safety assessment; analyses will be performed 
according to dose group as appropriate.   

Standard of care treatment arm: subjects who have undergone at least 1 post-baseline 
safety assessment.
Per-protocol population: All subjects in the ITT population without any major protocol deviation 
that affects interpretation of efficacy results.
Pharmacokinetic analysis population: All subjects who received at least 1 dose of teduglutide 
and have at least 1 evaluable postdose PK concentration value.   
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9.7
Efficacy Analyses
9.7.1
Efficacy Endpoints
Efficacy endpoints consist of the following:
9.7.1.1
Primary Efficacy Endpoint 

Reduction in weight-normalized PN fluid volume by at least 20% from baseline at 
Week 24/EOT
9.7.1.2
Secondary Efficacy Endpoints

Reduction in weight-normalized parenteral calories by at least 20% from baseline to 
Week 24/EOT

Achievement of enteral autonomy by Week 24

Change in weight-normalized parenteral fluid volume from baseline to each visit

Change in weight-normalized parenteral calories from baseline to each visit

Change in weight-normalized enteral fluid volume from baseline to each visit

Change in weight-normalized enteral caloric intake from baseline to each visit

Increase in weight-normalized enteral fluid intake by at least 20% from baseline to week 
24/EOT

Increase in weight-normalized enteral caloric intake by at least 20% from baseline to 
week 24/EOT
9.7.2
Method of Analysis-Efficacy Endpoints
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 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.
Analyses of weekly PN support will be based on 2 data sources: the subject diary data (also 
referred to as actual data) and the investigator prescribed data.  
The number and percentage of subjects who achieve at least a 20% reduction from baseline in 
weight-normalized average daily PN volume at Week 24/EOT and the number and percentage of 
subjects who achieve at least a 20% reduction from baseline in weight-normalized parenteral 
calories at Week 24/EOT will be summarized by treatment arm.
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During the treatment period, a subject will be considered to have achieved enteral autonomy 
(completely weaned off PN) at a given visit if the investigator prescribes no PN at that visit and 
for the remainder of the treatment period, and there is no use of PN recorded in the subject diary 
during the week prior to that visit and for the remainder of the treatment period. During the 
follow-up period, a subject will be considered to have achieved enteral autonomy at a given visit 
if the investigator prescribes no PN at that visit and for the remainder of the follow-up period and 
there is no use of PN recorded in the subject diary during the week prior to that visit and for the 
remainder of the follow-up period. The number and percentage of subjects who achieve enteral 
autonomy at each scheduled visit, as well as at EOT, will be summarized by treatment arm.
The absolute and percent change in weight-normalized weekly PN volume, parenteral calories, 
enteral fluid volume, and enteral caloric intake, from baseline to each scheduled visit, as well as 
at EOT, will be summarized by treatment arm using descriptive statistics.
The number and percentage of subjects who demonstrate an increase in weight-normalized 
enteral fluid intake by at least 20% from baseline to Week 24/EOT and the number and 
percentage of subjects who demonstrate an increase in weight-normalized enteral caloric intake 
by at least 20% from baseline to week 24/EOT will be summarized by treatment arm.
9.8
Safety Analyses
9.8.1
Safety Endpoints
Safety endpoints consist of the following:

Adverse events

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for 
gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output

Stool (including mixed) output

Antibodies to teduglutide
9.8.2
Method of Analysis-Safety Endpoints
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Treatment-emergent AEs will be summarized by system organ class and preferred 
term using descriptive statistics (e.g., number and percentage of subjects).  Adverse events will 
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be summarized by severity and relationship to treatment.  In addition, SAEs will also be 
tabulated by overall and treatment-related events.  AEs leading to treatment discontinuation and 
death will also be summarized.
For laboratory tests; vital signs; urine and stool output; weight, length, and head circumference 
Z-scores, and descriptive statistics (e.g., n, mean, standard deviation, median, minimum and 
maximum values, and the number and percentage of subjects in specified categories) will be 
used to summarize the absolute values and change from baseline at each visit.
The number and percentage of subjects classified as having antibodies to teduglutide will be used 
to summarize the presence of antibodies.  
9.9
Health Economics and Outcomes Research Analyses
Health economics and outcomes research endpoints consist of the following:

Cumulative number of hospitalization days during the study
Health economics and outcomes research endpoints will be summarized using descriptive 
statistics (number, mean and standard deviation) at nominal time points.  
9.10
Pharmacokinetics Analyses
Plasma concentrations will be summarized using descriptive statistics (number, mean, standard 
deviation, geometric mean, coefficient of variation, minimum, median, and maximum ) at 
nominal time points. 
Pharmacokinetic parameters will be estimated using a population PK modeling approach as 
appropriate and reported separately.
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SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES
10.
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements. 
The name and address of each third-party vendor (e.g., CRO) used in this study will be 
maintained in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996), EU 
Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines.  If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study.  An insurance certificate is supplied as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
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10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of the end of 
the study completion date for pediatric studies and within 1 year for non-pediatric studies as per 
guidance.  The sponsor will provide the ECs with a copy of the same summary.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.  The sponsor will make an end-of-study declaration to the relevant competent 
authority as required by Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator will be appointed to review the final clinical study report 
for multicenter studies.  Agreement with the final clinical study report is documented by the 
signed and dated signature of the principal investigator (single-site study) or coordinating 
principal investigator (multicenter study), in compliance with Directive 2001/83/EC as amended 
by Directive 2003/63/EC and ICH Guidance E3 (1995).
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10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.2.1
Documentation and Retention of Records
10.2.2.2
Electronic Case Report Forms
Electronic case report forms are supplied by the sponsor or designee and should be handled in 
accordance with instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Electronic case report forms 
must be completed by the investigator or designee as stated in the site delegation log.  All data 
will have separate source documentation; no data will be recorded directly onto the eCRF.
All data sent to the sponsor must be endorsed by the investigator.  
The study monitor will verify the contents against the source data per the monitoring plan. If the 
data are unclear or contradictory, queries are sent for corrections or verification of data.
10.2.2.3
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject diaries, and original clinical laboratory reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
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The study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF entries 
against the source documents. The consent form includes a statement by which the 
parent/guardian agrees to the monitor/auditor from the sponsor or its representatives, national or 
local regulatory authorities, or the IRB/EC, having access to source data (e.g., subject’s medical 
file, appointment books, original laboratory reports, X-rays etc). Non-study site personnel will 
not disclose any personal information or personal medical information.
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (e.g., the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.2.4
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the European Medicines Agency (EMA), the 
Medicines and Healthcare products Regulatory Agency, other regulatory authorities, the sponsor 
or its representatives, and the IRB/EC for each site.
10.2.2.5
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent, where applicable, 
from the parent(s)/guardian(s) of all study subjects prior to any study-related procedures 
including screening assessments. All consent documentation must be in accordance with 
applicable regulations and GCP. Each subject’s legally authorized representative is requested to 
sign and date the subject informed consent form or a certified translation if applicable, after the 
subject’s parent or guardian has received and read (or been read) the written subject information 
and received an explanation of what the study involves, including but not limited to: the 
objectives, potential benefits and risk, inconveniences, and the subject’s rights and 
responsibilities. A copy of the informed consent documentation (i.e., a complete set of subject 
information sheets and fully executed signature pages) must be given to the subject’s legally 
authorized representative, as applicable. This document may require translation into the local 
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language. Signed consent forms must remain in each subject’s study file and must be available 
for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form  that was 
reviewed by the IRB/EC and received their favorable opinion/approval. A copy of the IRB/EC’s 
written favorable opinion/approval of these documents must be provided to the sponsor prior to 
the start of the study unless it is agreed to and documented (abiding by regulatory guidelines and 
national provisions) prior to study start that another party (i.e., sponsor or coordinating principal 
investigator) is responsible for this action. Additionally, if the IRB/EC requires modification of 
the sample subject information and consent document provided by the sponsor, the 
documentation supporting this requirement must be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the sponsor/designee has received 
written IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB/EC informed of any serious and 
significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996.  A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the sponsor/designee.
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The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market teduglutide; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (e.g., to confirm 
that laboratory results have been assigned to the correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines 
(e.g., Good Publication Practices 2) when forming a publication steering committee, which is 
done for large, multicenter Phase 2 to 4 and certain other studies as determined by Shire. The 
purpose of the publication steering committee is to act as a non-commercial body that advises or 
decides on dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, royalty 
free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
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medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.
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REFERENCES
11.
Beattie, L. M., Barclay, A. R. & Wilson, D. C. 2010. Short bowel syndrome and intestinal failure 
in infants and children. Paediatrics and Child Health, 20, 485-491.
Carter, Cohran, Cole, Corkins, Dimmitt, Duggan, Hill, Horslen, Lim, Mercer, Merritt, Nichol, 
Sigurdsson, Teitelbaum, Thompson, Vanderpool, Vaughan, Li, Youssef, Venick & 
Kocoshis 2017. Outcomes from a 12-Week, Open-Label, Multicenter Clinical Trial of 
Teduglutide in Pediatric Short Bowel Syndrome. Journal of Pediatrics, The, 181, 102-
111.e5.
Gonzalez-Hernandez, Prajapati, Ogola, Channabasappa, Drews & Piper 2017. Predicting time to 
full enteral nutrition in children after significant bowel resection. Journal of Pediatric 
Surgery, 52, 764-767.
Goulet, O. & Ruemmele, F. 2006. Causes and Management of Intestinal Failure in Children. 
Gastroenterology, 130, S16-S28.
Huisman-de Waal, G., Schoonhoven, L., Jansen, J., Wanten, G. & van Achterberg, T. 2007. The 
impact of home parenteral nutrition on daily life-A review. Clinical Nutrition, 26, 275-
288.
Khan, F. A., Squires, R. H., Litman, H. J., Balint, J., Carter, B. A., Fisher, J. G., Horslen, S. P., 
Jaksic, T., Kocoshis, S., Martinez, J. A., Mercer, D., Rhee, S., Rudolph, J. A., Soden, J., 
Sudan, D., Superina, R. A., Teitelbaum, D. H., Venick, R., Wales, P. W. & Duggan, C. 
2015. Predictors of Enteral Autonomy in Children with Intestinal Failure: A Multicenter 
Cohort Study. J Pediatr, 167, 29-34.e1.
Marier, J., Kassir, N., Martin, P. & Wang, Y. 2017. Population pharmacokinetic modeling of 
teduglutide to support dosing in pediatric patients with short bowel syndrome. Clinical 
Pharmacology & Therapeutics, 101, S91.
Martin, G.-R., Beck, P.-L. & Sigalet, D.-L. 2006. Gut hormones, and short bowel syndrome: the 
enigmatic role of glucagon-like peptide-2 in the regulation of intestinal adaptation. World 
Journal of Gastroenterology, 12, 4117-29.
O'Keefe, S. J., Buchman, A. L., Fishbein, T. M., Jeejeebhoy, K. N., Jeppesen, P. B. & Shaffer, J. 
2006. Short bowel syndrome and intestinal failure: consensus definitions and overview. 
Clin Gastroenterol Hepatol, 4, 6-10.
Sigalet, D. L., Martin, G., Meddings, J., Hartman, B. & Holst, J. J. 2004. GLP-2 levels in infants 
with intestinal dysfunction. Pediatr Res, 56, 371-6.
Spencer, A. U., Neaga, A., West, B., Safran, J., Brown, P., Btaiche, I., Kuzma-O'Reilly, B. & 
Teitelbaum, D. H. 2005. Pediatric Short Bowel Syndrome: Redefining Predictors of 
Success. Annals of Surgery, 242, 403-412.
Squires, R. H., Duggan, C., Teitelbaum, D. H., Wales, P. W., Balint, J., Venick, R., Rhee, S., 
Sudan, D., Mercer, D., Martinez, J. A., Carter, B. A., Soden, J., Horslen, S., Rudolph, J. 
A., Kocoshis, S., Superina, R., Lawlor, S., Haller, T., Kurs-Lasky, M. & Belle, S. H. 
2012. Natural history of pediatric intestinal failure: initial report from the Pediatric 
Intestinal Failure Consortium. J Pediatr, 161, 723-8.e2.
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Tappenden, K. A., Edelman, J. & Joelsson, B. 2013. Teduglutide enhances structural adaptation 
of the small intestinal mucosa in patients with short bowel syndrome. J Clin 
Gastroenterol, 47, 602-7.
Thymann, T., Stoll, B., Mecklenburg, L., Burrin, D. G., Vegge, A., Qvist, N., Eriksen, T., 
Jeppesen, P. B. & Sangild, P. T. 2014. Acute effects of the glucagon-like peptide 2 
analogue, teduglutide, on intestinal adaptation in short bowel syndrome. J Pediatr 
Gastroenterol Nutr, 58, 694-702.
Wales, P. W., de Silva, N., Kim, J., Lecce, L., To, T. & Moore, A. 2004. Neonatal short bowel 
syndrome: population-based estimates of incidence and mortality rates. J Pediatr Surg,
39, 690-5.
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APPENDICES
12.
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Appendix 1
Protocol History
Document
Date
Global/Country/Site Specific
Original Protocol
03 Oct 2017
Global
Amendment 1
18 Jan 2018
Global
Amendment 1.1
07 Aug 2018
France-specific
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change and Rationale
Section(s) Affected by Change
Updated emergency contact information to reflect the change 
of the Contract Research Organization’s name.
Emergency Contact 
Information
Clarified the duration of the screening period and total time 
on study.  
Provided a clear definition of study completion.
Synopsis, Section 3.1, 
Section 3.2
Updated the study schematic to reflect the study design 
changes.
Revised the telephone and clinic visit schedule to assure 
laboratory measurement could be collected without exceeding 
weekly/monthly total blood volume restrictions.  
Synopsis, Table 1, 
Section 3.1.2
Moved the PK sampling from Week 6 to Week 7 so that the 
samples could be collected without exceeding 
weekly/monthly total blood volume restrictions.
Synopsis, Table 1, 
Section 3.1.2, Section 7.2.4, 
Table 5
Clarified that blood for pharmacokinetic samples of postdose 
may be taken within ± 10 minutes of the time pre-specified.
Clarified that end jejunostomy or ileostomy are examples  of 
small bowel ostomy rather than the stratification factors.
Synopsis, Section 3.1.2, 
Section 6.2.2
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change and Rationale
Section(s) Affected by Change
Clarified that all subjects regardless of treatment arm are 
eligible for the extension study.
Synopsis, Section 3.1.3
Clarified that if a subject treated with teduglutide meets the 
escape criteria, the assessments scheduled for the EOS visit 
should be conducted.
Synopsis, Table 2, 
Section 3.1.3, Section 6.2.3
Clarified that subjects must be 4 to 12 months corrected 
gestational age at screening.
Synopsis, Section 4.1
Changed dose adjustments to Week 12 rather than at every 
clinic visit to reduce site burden.
Synopsis, Table 1, 
Section 6.2.3
Clarified the definition of enteral autonomy.
Synopsis, Section 9.7.2
Updated the pharmacokinetic endpoint and analysis to reflect 
that only descriptive statistics will be calculated on plasma 
teduglutide concentration values. Pharmacokinetic parameters 
will be estimated using a population PK modeling approach 
as appropriate and reported separately.
Synopsis, Section 9.10
Removed assessment of the 5-level EuroQol five dimensions 
questionnaire to reduce caregiver burden.
Synopsis, Table 1, 
Section 7.2.5, Section 9.9
Clarified that native GLP-2 samples drawn while subjects are 
receiving teduglutide should be drawn at least 14 hours after 
the previous dose.
Table 2, Section 7.2.2
Inserted a footnote to clarify that parenteral support and 
parenteral nutrition are used interchangeably.
Section 1.1
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change and Rationale
Section(s) Affected by Change
Removed the 5 mg vial of teduglutide as this size vial will not 
be supplied for this study.
Section 6.1
Clarified the procedures for assessing subject compliance. 
Section 6.5
Specified that it is acceptable to only enroll subjects who 
have already had an upper GI series with small bowel follow 
through performed since the subject’s most recent surgery.  
Section 7.2.1
Corrected the volume of blood to be collected for native 
GLP-2.
Table 5
Removed references to subject assent as assent is not possible 
in a study of infants. 
Section 7.1.1, Section 10.3.1
Clarified the definitions of the analysis sets.
Section 9.6
Clarified that an adjustment to enteral nutrition as appropriate
is part of the PN/IV adjustment algorithm.
Figure A-1
Minor editorial changes and corrections to typographical 
errors (which do not modify content and/or intent of the 
original document) were made.
Throughout protocol.
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Appendix 2
Guidelines for Nutritional Support Management During the Study
The nutritional support adjustment guidelines are designed to standardize management of 
parenteral and enteral nutritional support in this study. Adjustments to nutritional support should 
be considered at every scheduled clinic visit. Adjustments at phone visits may also be performed, 
but nutritional assessments at phone visits serve primarily to confirm that nutritional adjustments 
at prior clinic visits were tolerated.
All attempts should be made to follow the guidelines, but departure from the guidelines will not 
constitute a protocol deviation.
Clinical judgment is required within the algorithm. Each decision point requires integrating 
multiple sources of information into a yes/no decision. When individual data points are 
conflicting, the investigator must use their best judgment in the assessment.
If intestinal adaptation is occurring, reductions in parenteral support volume and calories are 
expected to be in decrements of 5 to 10% relative to baseline values. Parenteral support 
components are at the discretion of the investigator, but care should be taken to balance 
carbohydrate, fat, and protein. Likewise, if intestinal adaptation is occurring, enteral nutrition 
volume and calories should be increased in increments of approximately 10% relative to baseline 
values.
Assessment of the severity of malabsorption may require estimation of stool output for children 
who have mixed stool and urine output.
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.
During the 48-hour output measurement period prior to the subject’s scheduled visit, no further 
changes to the prescribed nutritional support should be made.
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Figure A-1:
Parenteral Nutrition/Intravenous Adjustment Algorithm for All Subjects  
BUN=blood urea nitrogen; Cr=creatinine; PN=parenteral nutrition; UNa=urine sodium; UOP=urine output; USpGr=Urine specific gravity; VS=vital signs; vol=volume
Adequately hydrated?
•
Normal exam and VS
•
Weight stable
•
UOP > 1 ml/kg/h
•
USpGr < 1.020
•
UNa > 20 meq/L
•
Stable, normal BUN/Cr
yes
no
Adequate weight gain 
and linear growth?
↑ PN kcal or no change
↓PN vol and kcal
↑ PN vol +/- kcal
yes
no
Assess severity of malabsorption and adjust EN as appropriate
For non-commercial use only


 
 
 
cc: SHP633-301 TMF Main Study File  
 
 
 
 
Protocol Administrative Amendment 
MEMORANDUM 
To: 
SHP633-301 Trial Master File (TMF), SHP633-301 Study Sites 
From:  
, MD 
Date: 
3 Oct 2018 
Subject:  Protocol Administrative Amendment: Change in Medical Monitor 
EUDRACT NO: 2017-003606-40 
 
 
Protocol Title:  
A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic Study of Teduglutide in Infants 4 to 12 
Months of Age with Short Bowel Syndrome Who are Dependent on Parenteral Support 
Protocol Version:  
Original Protocol 03 Oct 2017 
The following Administrative Amendment is for Protocol SHP633-301, Protocol Amendment 1 dated 18 Jan 2018.  These changes are considered 
administrative in nature and the clarifications do not compromise the scope, design, or integrity of the study.  These changes do not compromise subject 
safety in any way.   
 
Administrative  Change : A revision to the protocol that does not affect the overall study design. Examples include, but are not limited to: clarification , 
addition or removal of procedural details that do not affect the overall design, safety or scientific quality of the study (e.g., clarifying discrepancies 
between synopsis and methodology section of protocol); typographical, grammatical or minor logistical changes (e.g. change to name of medical 
monitor, change to contact information, change in personnel/vendors) . Administrative changes are documented (e.g., by memorandum , letter, note to 
file) and do not necessitate a protocol amendment. 
 
The following revisions meet the definition of Administrative Change as noted above and will be incorporated into any subsequent amendment to the 
protocol. 
 
Clarification in screening procedures: 
 
Current Language:  
Screening 
Prior to performing any study-related procedures (including those related to screening), the investigator or his/her designee must obtain written 
informed consent from the parent(s)/guardian(s) of the subject. The screening visit assessments and procedures, beginning with informed 
consent, will be performed as outlined in Error! Reference source not found.. 
New Language:  
Screening 
Prior to performing any study-related procedures (including those related to screening), the investigator or his/her designee must obtain written 
informed consent from the parent(s)/guardian(s) of the subject. The screening visit assessments and procedures, beginning with informed 
consent, will be performed as outlined in Error! Reference source not found.. Rescreening will not be allowed. 
 
Impacted Section(s): 
 
                 Section 7.1.1 Screening 
 
 
Copies of this letter shall be distributed to the Principal Investigators of the study and should be forwarded to the site Ethics Committees as necessary. 
 
If you have further questions, please do not hesitate to contact your CRA or Shire directly. 
 
 
I have reviewed the above Memorandum and am in agreement with the specified administrative clarifications. 
 
Thank you, 
____                                    
, MD 
Date 
—Teduglutide 
SHP633-301 Medical Monitor 
 
 
 
 
 
For non-commercial use only


PROTOCOL: SHP633-301
TITLE:
A Randomized, Open-label, 24-Week Safety, Efficacy, and 
Pharmacokinetic Study of Teduglutide in Infants 4 to 12 Months of Age 
with Short Bowel Syndrome Who are Dependent on Parenteral Support
NUMBER
SHP633-301
PHASE
3 
DRUG:
Teduglutide
INDICATION:
Short bowel syndrome
EUDRACT NO.:
2017-003606-40
SPONSOR: 
Shire Human Genetic Therapies, Inc.
300 Shire Way
Lexington, MA 02421 USA
PROTOCOL 
HISTORY:
Original Protocol: 03 Oct 2017
Amendment 1: 18 Jan 2018
Amendment 2 : 04 Dec 2018
Confidentiality Statement
This document contains confidential and proprietary information of Shire and is disclosed 
pursuant to confidentiality and non-disclosure obligations. This information should be used 
solely for the purposes for which it was provided and should not be copied, shared with, or 
disclosed to any third party without the express written consent of Shire.
For non-commercial use only


Sponsor's (Shire) Approval 
Signature: 
, Global Clinical Development 
Investigator's Acknowledgement 
I have read this protocol for Shire Study SHP633-301. 
Title: A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic Study of 
Teduglutide in Infants 4 to 12 Months of Age with Shott Bowel Syndrome Who are Dependent 
on Parenteral Suppmt 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disClosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to patticipate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) guidelines on Good Clinical Practice (GCP) and with the 
applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my patticipation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Address: 
(please hand print or type) 
Signature: --------------------------------- Date: 
Shire
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PROTOCOL SIGNATURE PAGE
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EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Adverse Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as 
Required by Protocol within 24 hours to the Shire Global Drug Safety Department. Applicable 
fax numbers and e-mail address can be found on the form (sent under separate cover).  A copy of 
this form must also be sent to the Shire Medical Monitor by e-mail at 
.
For protocol- or safety-related issues, the investigator must contact IQVIA Medical Support:
Primary Contact
Backup Contact 
, MD
, MD, PhD
Mobile:  
Mobile: 
Phone: 
(medical emergencies)
Phone: 
 (medical emergencies)
Email:  
Email: 
In addition, the investigator may also contact Shire:
, MD
Mobile Phone: 
Email: 
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PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (e.g., inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (e.g., wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please use the E-mail address below to report the Product Quality Complaint:
Telephone numbers (provided for reference, if needed): 
Shire (USA)
 
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SUMMARY OF CHANGES FROM PREVIOUS VERSION
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2
Amendment Date
04 Dec 2018
Global
Description of Change and Rationale
Section(s) Affected by Change
The fax number currently used to send the Shire Medical 
Monitor a copy of the Shire Clinical Study Adverse Event 
Form for Serious Adverse Events (SAEs) and Non-serious 
AEs as Required by Protocol is now retired; a copy of the 
form must be sent by email only.
Updated emergency contact information to reflect the change 
of Shire medical monitor to 
, IQVIA back 
up medical support to 
, and IQVIA phone 
number for medical emergencies.
Emergency Contact 
Information
A single email address (
) is now used to 
report a Product Quality Complaint, independently from 
where it has originated.   
Product Quality Complaints
Added the new secondary efficacy endpoint “Time to achieve 
enteral autonomy” and statistical methodology to be used.
Synopsis, Section 9.7.1.2, 
Section 9.7.2
Updated  the information on the clinical studies with 
teduglutide in pediatric subjects to include the results of TED-
C14-006.
Section 1.2
Clarified that teduglutide is the investigational product for 
this study.
Section 6.1
Updated the dose selection rationale with results from a 
simulation work using the previous population 
pharmacokinetic model. Based on the totality of clinical data, 
0.05 mg/kg once daily is expected to provide comparable Cmax
concentrations in infants as compared to pediatric patients 
with SBS and was recommended as an evaluation dosing 
regimen in Study SHP633-301.
Section 6.2.5
Clarified that rescreening of subjects in the study will not be 
allowed. (Administrative amendment dated 03 Oct 2018)
Section 7.1.1
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2
Amendment Date
04 Dec 2018
Global
Description of Change and Rationale
Section(s) Affected by Change
Clarifications were made to the definition of adverse events.
Section 8.1, Section 8.1.5, 
Section 8.2.4
Added heart failure with severe fluid overload, determined by 
the sponsor or investigator to be related to the investigational 
product, to the list of events leading to interruption of 
investigational product administration. This addition is in 
alignment with the warnings and special precautions listed in 
the investigator brochure.
Section 8.4
As recommended by the FDA, specified that if the DMC 
recommends termination of this pediatric study, the 
recommendations will be communicated to the relevant 
regulatory agencies within 7 calendar days.
Section 9.4
Minor editorial changes and corrections to typographical 
errors (which do not modify content and/or intent of the 
original document) were made.
Throughout the protocol
See Appendix 1 for protocol history, including all amendments.  
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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
PRODUCT QUALITY COMPLAINTS..........................................................................................4
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................5
TABLE OF CONTENTS.................................................................................................................7
LIST OF TABLES.........................................................................................................................11
LIST OF FIGURES .......................................................................................................................11
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..................................................12
STUDY SYNOPSIS ......................................................................................................................13
STUDY SCHEDULES ..................................................................................................................18
BACKGROUND INFORMATION .......................................................................................22
1.
1.1
Short Bowel Syndrome ......................................................................................22
1.2
Teduglutide.........................................................................................................23
OBJECTIVES.........................................................................................................................25
2.
2.1
Rationale for the Study.......................................................................................25
2.2
Study Objectives ................................................................................................25
STUDY DESIGN ...................................................................................................................26
3.
3.1
Study Design and Flow Chart ............................................................................26
3.1.1
Screening Period ....................................................................................................26
3.1.2
Treatment Period....................................................................................................26
3.1.3
Follow-up Period ...................................................................................................27
3.2
Study Duration ...................................................................................................27
3.3
Sites and Regions ...............................................................................................27
STUDY POPULATION.........................................................................................................28
4.
4.1
Inclusion Criteria................................................................................................28
4.2
Exclusion Criteria...............................................................................................28
4.3
Reproductive Potential .......................................................................................29
4.4
Discontinuation of Subjects ...............................................................................29
4.4.1
Reasons for Discontinuation..................................................................................30
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit .................................30
PRIOR AND CONCOMITANT TREATMENT ...................................................................31
5.
5.1
Prior Medications and Procedures......................................................................31
5.2
Concomitant Medications and Procedures.........................................................31
5.3
Permitted Treatment...........................................................................................31
5.4
Prohibited Treatment..........................................................................................31
INVESTIGATIONAL PRODUCT ........................................................................................32
6.
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6.1
Identity of Investigational Product.....................................................................32
6.2
Administration of Investigational Product .........................................................32
6.2.1
Interactive Response Technology for Investigational Product Management ........32
6.2.2
Allocation of Subjects to Treatment ......................................................................32
6.2.3
Dosing....................................................................................................................32
6.2.4
Unblinding the Treatment Assignment..................................................................33
6.2.5
Dose Selection Rationale .......................................................................................33
6.3
Labeling, Packaging, and Storage ......................................................................34
6.3.1
Labeling .................................................................................................................34
6.3.2
Storage and Handling.............................................................................................35
6.4
Drug Accountability...........................................................................................35
6.5
Subject Compliance............................................................................................37
STUDY PROCEDURES........................................................................................................38
7.
7.1
Study Schedule...................................................................................................38
7.1.1
Screening................................................................................................................38
7.1.2
Treatment Period....................................................................................................38
7.1.3
Follow-up Period ...................................................................................................38
7.2
Study Evaluations and Procedures .....................................................................38
7.2.1
Demographics and Other Baseline Characteristics................................................38
7.2.2
Efficacy Assessments.............................................................................................39
7.2.3
Safety Assessments................................................................................................40
7.2.4
Pharmacokinetic Assessments ...............................................................................43
7.2.5
Health Economics and Outcomes Research ..........................................................43
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................44
8.
8.1
Definition of Adverse Events, Period of Observation, Recording of 
Adverse Events...................................................................................................44
8.1.1
Severity Categorization..........................................................................................44
8.1.2
Relationship Categorization...................................................................................45
8.1.3
Outcome Categorization ........................................................................................45
8.1.4
Symptoms of the Disease under Study ..................................................................46
8.1.5
Clinical Laboratory and Other Safety Evaluations ................................................46
8.1.6
Pregnancy...............................................................................................................46
8.1.7
Abuse, Misuse, Overdose, and Medication Error ..................................................46
8.2
Serious Adverse Event Procedures ....................................................................47
8.2.1
Reference Safety Information ................................................................................47
8.2.2
Reporting Procedures.............................................................................................47
8.2.3
Serious Adverse Event Definition .........................................................................48
8.2.4
Serious Adverse Event Collection Time Frame.....................................................48
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8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................48
8.2.6
Fatal Outcome........................................................................................................49
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................49
8.3
Adverse Events of Special Interest.....................................................................49
8.4
Dose Interruption Criteria ..................................................................................50
DATA MANAGEMENT AND STATISTICAL METHODS ...............................................51
9.
9.1
Data Collection...................................................................................................51
9.2
Clinical Data Management.................................................................................51
9.3
Statistical Analysis Process................................................................................51
9.4
Planned Interim Analysis, and Data Monitoring Committee.............................51
9.5
Sample Size Calculation and Power Considerations..........................................52
9.6
Study Population ................................................................................................52
9.7
Efficacy Analyses...............................................................................................53
9.7.1
Efficacy Endpoints.................................................................................................53
9.7.1.1
Primary Efficacy Endpoint.....................................................................53
9.7.1.2
Secondary Efficacy Endpoints ...............................................................53
9.7.2
Method of Analysis-Efficacy Endpoints................................................................53
9.8
Safety Analyses ..................................................................................................54
9.8.1
Safety Endpoints ....................................................................................................54
9.8.2
Method of Analysis-Safety Endpoints...................................................................55
9.9
Health Economics and Outcomes Research Analyses .......................................55
9.10
Pharmacokinetics Analyses................................................................................55
SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES ............................................56
10.
10.1
Sponsor’s Responsibilities .................................................................................56
10.1.1 Good Clinical Practice Compliance.......................................................................56
10.1.2 Indemnity/Liability and Insurance.........................................................................56
10.1.3 Public Posting of Study Information......................................................................56
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................56
10.1.5 Study Suspension, Termination, and Completion..................................................57
10.2
Investigator’s Responsibilities ...........................................................................57
10.2.1 Good Clinical Practice Compliance.......................................................................57
10.2.2 Protocol Adherence and Investigator Agreement ..................................................57
10.2.3 Documentation and Retention of Records .............................................................58
10.2.3.1
Electronic Case Report Forms................................................................58
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................58
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10.2.3.3
Audit/Inspection .....................................................................................59
10.2.3.4
Financial Disclosure...............................................................................59
10.3
Ethical Considerations........................................................................................59
10.3.1 Informed Consent...................................................................................................59
10.3.2 Institutional Review Board or Ethics Committee ..................................................60
10.4
Privacy and Confidentiality................................................................................60
10.5
Study Results/Publication Policy .......................................................................61
REFERENCES .......................................................................................................................63
11.
APPENDICES ........................................................................................................................65
12.
Appendix 1 Protocol History .................................................................................................66
Appendix 2 Guidelines for Nutritional Support Management During the Study ..................69
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LIST OF TABLES
Table 1:
Study Schedule: Visits -1 to 12 .....................................................................18
Table 2:
Study Schedule: Visits 13-28 ........................................................................20
Table 3:
Prohibited Treatment.....................................................................................31
Table 4:
List of Laboratory Tests ................................................................................41
Table 5:
Approximate Volume of Blood to be Drawn from Each Subject .................42
LIST OF FIGURES
Figure 1:
Study Schematic ............................................................................................26
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation
Definition
AE
adverse event
AUCss
area under the concentration-time curve at steady-state 
Cmax,ss
maximum plasma concentration at steady state
CRO
contract research organization
eCRF
electronic case report form
DMC
data monitoring committee
EDC
electronic data capture
EMA
European Medicines Agency
EN
enteral nutrition
EOS
end of study
EOT
end of treatment
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
gastrointestinal 
GLP
glucagon-like peptide
HIPAA
Health Insurance Portability and Accountability Act
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use
ICMJE
International Committee of Medicinal Journal Editors
I/O
oral fluid intake and urine output
IP
Investigational product
IRB
Institutional Review Board
ITT
intent-to-treat
MedDRA
Medical Dictionary for Regulatory Activities
PK
pharmacokinetics
PN
parenteral nutrition
SAE
serious adverse event
SAP
statistical analysis plan
SBS
short bowel syndrome
SC
subcutaneous
SD
standard deviation
SOC
standard of care
ULN
upper limit of normal 
US
United States
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STUDY SYNOPSIS
Protocol number: SHP633-301
Drug: Teduglutide
Title of the study: A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic Study of 
Teduglutide in Infants 4 to 12 Months of Age with Short Bowel Syndrome Who are Dependent on Parenteral 
Support
Number of subjects (total and for each treatment arm):
At least 10 subjects will be randomized: at least 5 subjects in a teduglutide treatment arm and at least 5 subjects in 
a standard of care (SOC) comparator arm
Investigator(s): Multicenter study
Site(s) and Region(s): 
This study is planned to be conducted in approximately 5 to 10 sites globally.
Study period (planned):
2017-2020
Clinical phase:
3
Objectives:
The objectives of this clinical study are to evaluate the safety, efficacy/pharmacodynamics and pharmacokinetics 
(PK) of teduglutide treatment in infants with short bowel syndrome (SBS) dependent on parenteral support.
Investigational product, dose, and mode of administration:
Teduglutide 0.05 mg/kg by subcutaneous (SC) injection once daily into 1 of the 4 quadrants of the abdomen or 
either thigh or arm.
Methodology:
This is a randomized, multicenter, open-label study, consisting of a 2 to 4 week screening period, a 24-week 
treatment period, and a 4-week follow-up period. 
* At EOS all subjects regardless of treatment arm may enroll in an extension study that will 
capture long-term safety data and provide the opportunity for additional teduglutide treatment.  
Extension 
study* 
1
24
1
3
5
7
9
12
16
20
28
2 to 4
Weeks
Screening
Teduglutide 0.05 mg/kg SC once daily for 24 weeks
Site Visit 
Telephone Visit
Standard of care for 24 weeks
Baseline: treatment 
randomization
0
24
3
5
7
9
12
16
20
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The follow-up period for subjects in the teduglutide treatment arm may be interrupted and the 
subjects may proceed immediately to the EOS if at least one “escape” criteria is met.
Study eligibility will be confirmed during the screening period (minimum: 2 weeks; maximum 4 weeks). At the 
baseline visit (Week 0), subjects will be randomized 1:1 to the teduglutide or SOC treatment arm. Randomization 
will be stratified according to the presence of a small bowel ostomy (e.g., end jejunostomy or ileostomy). During 
the 24-week treatment period, subjects in the SOC treatment arm will receive standard medical therapy for SBS; 
while those in the teduglutide arm will receive 0.05 mg/kg SC once daily in addition to standard medical therapy. 
Subjects in both arms will follow the same visit schedule and assessments. Subjects will be monitored weekly 
with phone or clinic visits. Clinic visits will occur at Weeks 1, 3, 5, 7, 9, 12, 16, 20, 24, and 28. At all site visits 
and telephone contacts, safety will be monitored and nutritional support will be reviewed and adjusted as needed. 
To maintain consistency across centers, guidance and training will be provided to help sites follow the nutritional 
support adjustment guidelines (developed with SBS expert input and provided in the protocol) related to decisions 
for parenteral nutrition (PN) reduction and advances in enteral feeds based on weight gain, urine and stool output, 
and clinical stability. Deviations from the guidelines are not considered a protocol deviation.
Sparse PK sampling, in the teduglutide treatment arm only, will occur at baseline (predose and 1 hour 
±10 minutes and 4 hours ±10 minutes postdose) and at Week 7 or 12 (2 hours±10 minutes postdose).
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up period until the end 
of study (Week 28/EOS) during which time subjects will receive standard medical therapy, but no investigational 
product will be administered. At EOS all subjects regardless of treatment arm may enroll in an extension study 
that will capture long-term safety data and provide the opportunity for additional teduglutide treatment.  The 
follow-up period for subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed 
immediately to the EOS if at least one of the following “escape” criteria is met:
1.
Increasing PN requirements following discontinuation of teduglutide.
2.
Deteriorating nutritional status (e.g., weight loss or growth failure) despite maximal tolerated enteral 
nutrition (EN) following teduglutide discontinuation.
3.
Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and electrolyte intake 
following teduglutide discontinuation.
4.
Severe diarrhea related to teduglutide discontinuation.
Inclusion and Exclusion Criteria:
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1.
Informed consent by the parent or legal guardian. 
2.
Male or female infant 4 to 12 months corrected gestational age at screening.
3.
Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and baseline.
4.
Short bowel syndrome with dependence on parenteral support to provide at least 50% of fluid or caloric 
needs.
5.
Stable PN requirements for at least 1 month prior to screening, defined as a ≤10% change in the weight-
normalized parenteral total fluid and caloric intake, despite attempts to wean PN, notwithstanding 
transient instability for events such as sepsis or interruption of central venous access.
6.
Lack of terminal ileum and ileocecal valve
7.
Parent or legal guardian understands and is willing and able to fully adhere to study requirements as 
defined in this protocol.
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Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1.
Previous treatment with teduglutide.
2.
Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus inclusion disease, 
etc.
3.
Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility, that is the primary contributing factor to feeding intolerance and 
inability to reduce parenteral support, prior to screening.  Dysmotility is defined as severe if it is 
expected to limit the advancement of enteral feeding.
4.
Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral aversion in the 
absence of a feeding tube.
5.
Intestinal obstruction or clinically significant intestinal stenosis.
6.
Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or major intestinal 
resection or anastomosis, within 3 months prior to screening or planned during the study period.
7.
Unstable cardiac disease.
8.
Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
9.
Biliary obstruction, stenosis, or malformation. 
10. Clinically significant pancreatic disease. 
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b.
Platelet count <100×10^3/µl due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d.
Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 2-week period
13. More than 3 serious complications of intestinal failure (e.g., catheter-associated bloodstream infections, 
interruption of nutrition due to feeding intolerance, catheter-associated thrombosis, severe fluid or 
electrolyte disturbances) within 1 month prior to or during screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile polyposis or Beckwith-
Wiedemann syndrome, or first degree relative with early onset of gastrointestinal cancer (including 
hepatobiliary and pancreatic cancers). 
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 (GLP-2); insulin-
like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs of these hormones; or 
glutamine. 
16. Participation in a clinical study using an experimental drug within 3 months or 5.5 half-lives of the 
experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, closely-related 
compounds, or any of the stated ingredients.
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts the subject at any 
undue risk, prevents completion of the study, or interferes with analysis of the study results.
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Maximum Duration of Subject Involvement in the Study:
The study consists of a 2 to 4 week screening period, a 24-week treatment period, and a 4-week follow-up period. 
The maximum duration of participation for each subject is 32 weeks.
Study completion is defined as the last subject, last visit. This is the visit date at which the last subject on the 
study has his or her last follow-up visit on the study (whether during the 24-week treatment period or the 4-week 
follow-up period).
Endpoints:
Efficacy
Efficacy endpoints consist of the following:
Primary

Reduction in weight-normalized PN fluid volume by at least 20% from baseline at Week 24/EOT
Secondary

Reduction in weight-normalized parenteral calories by at least 20% from baseline to Week 24/EOT

Achievement of enteral autonomy by week 24

Time to achieve enteral autonomy

Change in weight-normalized parenteral fluid volume from baseline to each visit

Change in weight-normalized parenteral calories from baseline to each visit

Change in weight-normalized enteral fluid volume from baseline to each visit

Change in weight-normalized enteral caloric intake from baseline to each visit

Increase in weight-normalized enteral fluid intake by at least 20% from baseline to Week 24/EOT

Increase in weight-normalized enteral caloric intake by at least 20% from baseline to Week 24/EOT
Pharmacokinetics
The pharmacokinetic endpoint is plasma teduglutide concentration at nominal time point.
Safety
Safety endpoints consist of the following:

Adverse events (AEs)

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output

Stool (including mixed) output  

Antibodies to teduglutide 
Health Economics and Outcomes Research
Health economics and outcomes research (HEOR) endpoints include the following:

Cumulative number of hospitalization days during the study
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Statistical Methods:
Efficacy
Analyses of weekly PN support will be based on 2 data sources: the subject diary data (also referred to as actual 
data) and the investigator prescribed data.  
The number and percentage of subjects who achieve at least a 20% reduction from baseline in weight-normalized 
average daily PN volume at Week 24/EOT and the number and percentage of subjects who achieve at least a 20% 
reduction from baseline in weight-normalized parenteral calories at Week 24/EOT will be summarized by 
treatment arm.
During the treatment period, a subject will be considered to have achieved enteral autonomy (completely weaned 
off PN) at a given visit if the investigator prescribes no PN at that visit and for the remainder of the treatment 
period, and there is no use of PN recorded in the subject diary during the week prior to that visit and for the 
remainder of the treatment period. During the follow-up period, a subject will be considered to have achieved 
enteral autonomy at a given visit if the investigator prescribes no PN at that visit and for the remainder of the 
follow-up period and there is no use of PN recorded in the subject diary during the week prior to that visit and for 
the remainder of the follow-up period. The number and percentage of subjects who achieve enteral autonomy at 
each scheduled visit, as well as at EOT, will be summarized by treatment arm. Descriptive statistics will be used 
to summarize time to achievement of enteral autonomy by treatment arm.
The absolute and percent change in weight-normalized weekly PN volume, parenteral calories, enteral fluid 
volume, and enteral caloric intake, from baseline to each scheduled visit, as well as at EOT, will be summarized 
by treatment arm using descriptive statistics.
The number and percentage of subjects who demonstrate an increase in weight-normalized enteral fluid intake by 
at least 20% from baseline to Week 24/EOT and the number and percentage of subjects who demonstrate an 
increase in weight-normalized enteral caloric intake by at least 20% from baseline to week 24/EOT will be 
summarized by treatment arm.
Pharmacokinetics
Plasma concentrations will be summarized using descriptive statistics (number, mean, standard deviation, 
geometric mean, coefficient of variation, minimum, median, and maximum) at nominal time points. 
Pharmacokinetic parameters will be estimated using a population PK modeling approach as appropriate and 
reported separately.
Safety
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Treatment-emergent AEs will be summarized by system organ class and preferred term using descriptive statistics 
(e.g., number and percentage of subjects). Adverse events will be summarized by severity and relationship to 
treatment. In addition, serious adverse events  will also be tabulated by overall and treatment-related events. AEs 
leading to treatment discontinuation and death will also be summarized.
For laboratory tests; vital signs; urine and stool output; weight, length, and head circumference Z-scores; and 
descriptive statistics (e.g., n, mean, standard deviation, median, minimum and maximum values, and the number 
and percentage of subjects in specified categories) will be used to summarize the absolute values and change from 
baseline at each visit.
The number and percentage of subjects classified as having antibodies to teduglutide will be used to summarize 
the presence of antibodies.  
Health Economics and Outcomes Research
The HEOR endpoints will be summarized descriptively.  
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STUDY SCHEDULES
Table 1:
Study Schedule: Visits -1 to 12
Procedures
Screening
Baseline 
(Week 0)
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
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit type
Site
Site
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Tel
Site
Study day
-14
0
7
14
21
28
35
42
49
56
63
70
77
84
±window (days)
-2 weeks
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Informed consent
X
Eligibility
X
X
Randomization
X
Demographics 
X
SBS history
X
Medical and surgical history
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications and 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, vital signs, 
weight
X
X
X
X
X
X
X
X
Length and head circumference
X
X
X
X
UGI/SBFT
X
Safety labs and urinalysisb, c
X
Xb
X
(X)
X
(X)
X
(X)
X
(X)
X
(X)
(X)
X
PK samplinga
X
 
[X]d
[X]d
Antibodies to teduglutidea,e
X
Xe
Native GLP-2f
X
Provide intake and output 
diariesg
X
X
X
X
X
X
X
X
Review diaries and nutritional 
support
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional support as 
neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense IPa, i
X
X
X
X
X
X
X
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Table 1:
Study Schedule: Visits -1 to 12
Procedures
Screening
Baseline 
(Week 0)
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
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit type
Site
Site
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Tel
Site
Study day
-14
0
7
14
21
28
35
42
49
56
63
70
77
84
±window (days)
-2 weeks
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Adjust IP dosej
X
EN=enteral nutrition; GLP-2=glucagon-like peptide 2; INR=international normalized ratio; IP=investigational product; PK=pharmacokinetics; PN=parenteral nutrition; PT=prothrombin time; 
UGI/SBFT=upper GI series with small bowel follow-through 
a Applicable to the teduglutide treatment arm only. 
b At baseline, safety labs (Table 4) and PK can be separated by 1 day if blood volumes are limiting. Safety labs at telephone visits will be collected at the discretion of the investigator. For all subjects in 
the teduglutide treatment arm, PT and INR will be tested at baseline, and repeated if clinically indicated.
c Urinalysis will consist of urine sodium and specific gravity. Urine collection should be attempted, but inability to obtain urinalysis is not a protocol deviation.
d Subjects will have blood samples taken for teduglutide PK analysis predose and 1 hour ±10 minutes and 4 hours ±10 minutes postdose at baseline (Visit 0). Subjects also will have blood samples taken 
for teduglutide PK analysis 2 hours ±10 minutes postdose at Week 7 (Visit 7) or Week 12 (Visit 12) of the treatment period.
e Samples for antibody analysis will be drawn at the baseline and Week 12 visits.  Blood samples while subjects are receiving teduglutide should be drawn at least 14 hours after the previous dose.
f Blood samples for native GLP-2 should be collected postprandial.  Native GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at investigator 
discretion based on weekly/monthly total volume.  
g Intake diaries will collect actual PN volume and hours per day and EN volume and calories. Intake diaries should be completed daily throughout the study. Urine and stool output should be recorded in 
the output diary over a 48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PN prescription. 
h Parenteral support adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment provided in Appendix 2.
i The initial dose will be calculated based on body weight measured at baseline (Visit 0).
j  The dose will be adjusted as needed, based on body weight measured at Week 12 visit.
Note: (X) denotes optional assessments; [X] denotes possible PK sampling time point (Refer to footnote “e”.)
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Table 2:
Study Schedule: Visits 13-28
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 
(EOT/ET)
Week 
25
Week 
26
Week 
27
Week 
28 
(EOS)a
Visit number
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit type
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Study day
91
98
105
112
119
126
133
140
147
154
161
168
175
182
189
196
±window (days)
±3
±3
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications 
and procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, vital 
signs, weight
X
X
X
X
Length and head 
circumference
X
X
X
X
Safety labs and 
urinalysisb,c
(X)
(X)
(X)
X
(X)
(X)
(X)
X
(X)
(X)
(X)
X
(X)
(X)
(X)
X
Antibodies to 
teduglutided,e
X
Native GLP-2f
X
Provide intake and output 
diaries
X
X
X
Review diaries and 
nutritional supportg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional support 
as neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess follow-up period 
escape criteriad
Xi
Xi
Xi
X
Dispense IPd
X
X
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Table 2:
Study Schedule: Visits 13-28
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 
(EOT/ET)
Week 
25
Week 
26
Week 
27
Week 
28 
(EOS)a
Visit number
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit type
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Study day
91
98
105
112
119
126
133
140
147
154
161
168
175
182
189
196
±window (days)
±3
±3
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
EN=enteral nutrition; EOS=end of study; EOT=end of treatment; ET=early termination; GLP-2=glucagon-like peptide 2; INR=international normalized ratio; IP=investigational product; PN=parenteral 
nutrition; PT=prothrombin time; UGI/SBFT=upper GI series with small bowel follow-through
a At EOS subjects may enroll in an extension study, if subjects require treatment before the end of the 4-week follow-up they may enter the extension study immediately.  
bSafety labs at telephone visits will be collected at the discretion of the investigator. For all subjects in the teduglutide treatment arm, PT and INR are tested if clinically indicated.
c Urinalysis will consist of urine sodium and specific gravity.  
d Applicable to the teduglutide treatment arm only. 
e Samples for antibody analysis will be drawn at the EOS (Week 28) visit.
f Blood samples for native GLP-2 should be collected postprandial.  Blood samples drawn while subjects are receiving teduglutide should be drawn at least 14 hours after the previous dose. Native GLP-
2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at investigator discretion based on weekly/monthly total volume.  
g Intake diaries will collect actual PN volume and hours per day and EN volume and calories. Intake diaries should be completed daily throughout the study. Urine and stool output should be recorded in 
the output diary over a 48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PN prescription. 
h Parenteral support adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment provided in Appendix 2.
Note: (X) denotes optional assessments.
i If a subject treated with teduglutide meets the escape criteria, the assessments scheduled for the EOS visit should be conducted.
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BACKGROUND INFORMATION
1.
1.1
Short Bowel Syndrome
Short bowel syndrome (SBS) is a rare disorder resulting from congenital abnormalities or severe 
intestinal diseases that result in major surgical resections of the small intestine (O'Keefe et al., 
2006).  Unlike the adult population, the majority of cases of SBS in pediatric subjects are due to 
congenital anomalies or catastrophic events that occur during infancy such as necrotizing 
enterocolitis, gastroschisis, intestinal atresia, midgut volvulus, or long-segment Hirschsprung 
disease (Beattie et al., 2010; Goulet and Ruemmele, 2006).  A Canadian population-based study 
in neonates estimates an overall incidence of SBS to be 24.5 cases per 100,000 live births (Wales 
et al., 2004).  
The small intestine is capable of remarkable adaptation, but excessive loss of absorptive surface 
area or specialized functions can lead to dependence on parenteral nutrition (PN)1 fluids 
(O'Keefe et al., 2006).  Although PN is life-sustaining in intestinal failure, it is associated with 
serious complications, including liver disease, life-threatening catheter-related blood stream 
infections, and central venous thrombosis (Beattie et al., 2010; Goulet and Ruemmele, 2006).  
Dependence on PN is also associated with reduced quality of life in both patients and caregivers 
and has an extremely high cost of care (Huisman-de Waal et al., 2007).  About 30% of infants 
with SBS become independent of PN requirements within 12 months of the initial insult, and an 
additional 10% wean off PN within 24 months. After this time, linear intestinal growth slows.  It 
is estimated that 42% to 86% of pediatric patients with SBS are able to become independent of 
PN within 1 to 3 years (Gonzalez-Hernandez et al., 2017; Khan et al., 2015; Squires et al., 2012).  
Nevertheless, despite optimal medical management, some children remain dependent on PN for 
many years (Squires et al., 2012).  Infants who have less than 10% of expected small intestinal 
length for their gestational age have a low likelihood of ever achieving enteral autonomy (i.e., 
independence from parenteral support).  Providing the maximum tolerated amount of enteral 
nutrition (EN) has been the primary strategy to promote enteral adaptation (Spencer et al., 2005).  
Accelerating the adaptive process and achieving enteral autonomy is an urgent goal for all 
patients with SBS who are dependent on PN (Khan et al., 2015; Squires et al., 2012).  The 
adaptive process is in part controlled by glucagon-like peptide 2 (GLP-2), a 33 amino acid 
peptide hormone secreted from L-type enteroendocrine cells in the terminal ileum and colon in 
response to luminal nutrients and bile acids (Martin et al., 2006).  The post-prandial plasma 
concentration of GLP-2 in infants with SBS correlates with length of the remaining small 
intestine (Sigalet et al., 2004).  Infants who lack terminal ileum may have impaired adaptation 
due to inadequate production of GLP-2.
                                                
1 For the purpose of the study the terms parenteral support (PS) and parenteral nutrition (PN) are used 
interchangeably.
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1.2
Teduglutide
Teduglutide is a novel, recombinant analog of naturally occurring human GLP-2 that regulates 
the functional and structural integrity of the cells lining the gastrointestinal (GI) tract. 
Teduglutide is a 33-amino acid peptide that differs from native GLP-2 in the substitution of 
glycine for alanine at the second position at the N-terminus.  As a result, teduglutide 
demonstrates resistance to degradation by dipeptidyl peptidase 4 (DPP-4) and therefore 
maintains a longer elimination half-life (t1/2), approximately 2 hours in healthy adult subjects, 
1.3 hours in adult SBS subjects, and 0.22 hours in pediatric SBS subjects, compared to the native 
peptide, which has a t1/2 of approximately 7 minutes.  Teduglutide has been shown in animal 
studies and previous human clinical trials to increase villus height and crypt depth in the 
intestinal epithelium, thereby increasing the absorptive surface area of the intestines (Tappenden 
et al., 2013; Thymann et al., 2014). 
A Phase 3 study, TED-C13-003, has been completed in pediatric SBS subjects.  In this study, 
teduglutide was administered to 3 cohorts of pediatric subjects from ages 1-17 years.  
Thirty-seven pediatric subjects received teduglutide at doses of 0.0125, 0.025, or 0.05 mg/kg/day 
for 12 weeks.  Five additional pediatric subjects were enrolled in an observational standard of 
care (SOC) cohort.  There were clear dose-dependent effects of teduglutide seen at the 0.025 and 
0.05 mg/kg/day doses compared to SOC and the 0.0125 mg/kg/day dose.  In the 
0.025 mg/kg/day cohort there was a reduction in PN volume at Week 12 of 37%, including 
complete independence from PN support in 1 subject, and a reduction of 3.94 hours per day 
infusion time.  In the 0.05 mg/kg/day cohort there was a reduction in PN volume at Week 12 of 
39%, including complete independence from PN support in 3 subjects, and a reduction of 
4.18 hours per day infusion time.  Teduglutide was generally safe and well tolerated by pediatric 
subjects in all dosing cohorts.  There were no deaths during the study and no treatment-emergent 
serious adverse events (SAEs) related to teduglutide were reported.  No discontinuations from 
study were due to adverse events (AEs).  Additional studies in pediatric patients with SBS are 
ongoing.
TED-C14-006 is a recently completed study of pediatric subjects through 17 years which 
included 2 treatment arms: a teduglutide treatment arm and a SOC treatment arm. Subjects in 
both arms participated in a 2-week minimum screening period, a 24-week treatment period, and a 
4-week follow-up period. During the screening period, subjects chose into which arm to enroll. 
During the 24-week treatment period, subjects in the SOC treatment arm received standard 
medical therapy for SBS; while those in the teduglutide treatment arm received daily 
subcutaneous (SC) injections of teduglutide (study drug) in addition to standard medical therapy. 
The subjects enrolling in the teduglutide treatment arm were randomized 1:1 in a double-blinded 
manner into 2 parallel dose groups: 0.025 mg/kg/day or 0.05 mg/kg/day of teduglutide 
administered subcutaneously for 24 weeks. Compared to the SOC, treatment of pediatric subjects 
with SBS with teduglutide resulted in clinically meaningful reductions in PN/IV volume, 
calories, days per week, and hours per day. A total 10% of subjects who received teduglutide 
achieved enteral autonomy within 24 weeks despite prior dependence on PN/IV for several 
years. Teduglutide treatment also resulted in increases in EN volume and caloric intake as well 
as plasma citrulline. Although the differences in efficacy between the 0.025 and 0.05 mg/kg dose 
groups were small, a consistently greater effect was seen in the 0.05 mg/kg dose in all efficacy 
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parameters. The pharmacokinetic (PK) properties were well characterized in this population and 
were consistent with the prior 12 week pediatric study. Teduglutide was generally well tolerated 
by pediatric subjects with SBS. The safety profile was favorable and consistent with the prior 
pediatric study, the underlying disease, and previous experience with teduglutide in adult 
subjects with SBS.
Teduglutide (0.05 mg/kg/day) is currently approved for the treatment of adult patients with SBS 
in >30 countries.  On 29 Jun 2016, the European Commission granted an extension of the Market 
Authorization for teduglutide for the treatment of patients aged 1 year and above with SBS.  
Always refer to the latest version of the investigator’s brochure for the overall risk/benefit 
assessment and the most accurate and current information regarding the drug metabolism, 
pharmacokinetics, efficacy and safety of teduglutide (SHP633).
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OBJECTIVES
2.
2.1
Rationale for the Study 
There is no approved pharmacological therapy to improve intestinal adaptation in infants with 
SBS who are dependent on parenteral support.  This study will evaluate whether teduglutide is 
safe and effective in this patient population.  
2.2
Study Objectives
The objectives of this study are to evaluate the safety, efficacy/pharmacodynamics and 
pharmacokinetics (PK) of teduglutide treatment in infants with SBS dependent on parenteral 
support.
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STUDY DESIGN
3.
3.1
Study Design and Flow Chart
This is a randomized, multicenter, open-label study, consisting of a 2 to 4-week screening period, 
a 24-week treatment period and a 4-week follow-up period.  A schematic representation of the 
study design is presented in Figure 1.
Figure 1:
Study Schematic
*At EOS all subjects regardless of treatment arm may enroll in an extension study that will capture long-term safety data and 
provide the opportunity for additional teduglutide treatment.  The follow-up period for subjects in the teduglutide treatment arm 
may be interrupted and the subjects may proceed immediately to the EOS if at least one “escape” criteria is met.
3.1.1
Screening Period 
Study eligibility will be confirmed during the screening period (minimum: 2 weeks; maximum: 
4 weeks).  The schedule of evaluations to be conducted during the Screening Period can be found 
in Table 1.
3.1.2
Treatment Period
At the baseline visit (Week 0), subjects will randomized 1:1 to the teduglutide or SOC treatment 
arm. Randomization will be stratified according to the presence of a small bowel ostomy (e.g., 
end jejunostomy or ileostomy). During the 24-week treatment period, subjects in the SOC 
treatment arm will receive standard medical therapy for SBS, while those in the teduglutide arm 
will receive 0.05 mg/kg by SC injection once daily in addition to standard medical therapy. 
Subjects in both arms will follow the same visit schedule and assessments. Subjects will be 
monitored weekly with phone or clinic visits. Clinic visits will occur at Weeks 1, 3, 5, 7, 9, 12, 
Extension 
study* 
1
24
1
3
5
7
9
12
16
20
28
2 to 4
Weeks
Screening
Teduglutide 0.05 mg/kg SC once daily for 24 weeks
Site Visit 
Telephone Visit
Standard of care for 24 weeks
Baseline: treatment 
randomization
0
24
3
5
7
9
12
16
20
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16, 20, 24, and 28. At all site visits and telephone contacts, safety will be monitored and 
nutritional support will be reviewed and adjusted as needed. To maintain consistency across 
centers, guidance and training will be provided to help sites follow the nutritional support 
adjustment guidelines (developed with SBS expert input and provided in the protocol) related to 
decisions for PN reduction and advances in enteral feeds based on weight gain, urine and stool 
output, and clinical stability (Appendix 2). Deviations from the guidelines are not considered a 
protocol deviation.
Sparse PK sampling, in the teduglutide treatment arm only, will occur at baseline (predose and 
1 hour ±10 minutes and 4 hours ±10 minutes postdose) and at Week 7 or 12 (2 hours±10 minutes 
postdose).
The schedule of evaluations for the Treatment Period can be found in Table 1 (Visits -1 to 12) 
and Table 2 (Visits 13 to 28).  
3.1.3
Follow-up Period
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up 
period until the end of study (Week 28/EOS) during which time subjects will receive standard 
medical therapy, but no investigational product (IP) will be administered. At EOS, all subjects
regardless of treatment arm may enroll in an extension study that will capture long-term safety 
data and provide the opportunity for additional teduglutide treatment. The follow-up period for 
subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed 
immediately to the EOS visit if at least one of the following “escape” criteria is met:
1. Increasing PN requirements following discontinuation of teduglutide.
2. Deteriorating nutritional status (e.g., weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation.  
4. Severe diarrhea related to teduglutide discontinuation.
The schedule of evaluations for the Follow-up Period can be found in Table 2 (Visits 13 to 28).
3.2
Study Duration
The study consists of a 2 to 4-week screening period, a 24-week treatment period and a 4-week 
follow-up period.  The maximum duration of participation for each subject is 32 weeks.
Study completion is defined as the last subject, last visit. This is the visit date at which the last 
subject on the study has his or her last follow-up visit on the study (whether during the 24-week 
treatment period or the 4-week follow-up period).
3.3
Sites and Regions
This study is planned to be conducted at approximately 5 to 10 sites globally.
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STUDY POPULATION
4.
At least 10 subjects will be randomized: at least 5 subjects in a teduglutide treatment arm and at 
least 5 subjects in an SOC comparator arm.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1. Informed consent by the parent or legal guardian. 
2. Male or female infant 4 to 12 months corrected gestational age at screening.
3. Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and 
baseline.
4. Short bowel syndrome with dependence on parenteral support to provide at least 50% of 
fluid or caloric needs.
5. Stable PN requirements for at least 1 month prior to screening, defined as a ≤10% change 
in the weight-normalized parenteral total fluid and caloric intake, despite attempts to 
wean PN, notwithstanding transient instability for events such as sepsis or interruption of 
central venous access.
6. Lack of terminal ileum and ileocecal valve.
7. Parent or legal guardian understands and is willing and able to fully adhere to study 
requirements as defined in this protocol.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1. Previous treatment with teduglutide.
2. Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus 
inclusion disease, etc.
3. Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, 
active gastroschisis-related dysmotility, that is the primary contributing factor to feeding 
intolerance and inability to reduce parenteral support, prior to screening.  Dysmotility is 
defined as severe if it is expected to limit the advancement of enteral feeding.
4. Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral 
aversion in the absence of a feeding tube.
5. Intestinal obstruction or clinically significant intestinal stenosis.
6. Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or 
major intestinal resection or anastomosis, within 3 months prior to screening or planned 
during the study period.
7. Unstable cardiac disease.
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8. Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
9. Biliary obstruction, stenosis, or malformation. 
10. Clinically significant pancreatic disease. 
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following 
parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b. Platelet count <100×10^3/µL due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d. Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 
2 week period.
13. More than 3 serious complications of intestinal failure (e.g., catheter-associated 
bloodstream infections, interruption of nutrition due to feeding intolerance, 
catheter-associated thrombosis, severe fluid or electrolyte disturbances) within 1 month 
prior to or during screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile 
polyposis or Beckwith-Wiedemann syndrome, or first degree relative with early onset of 
gastrointestinal cancer (including hepatobiliary and pancreatic cancers). 
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 
(GLP-2); insulin-like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs 
of these hormones; or glutamine. 
16. Participation in a clinical study using an experimental drug within 3 months or 
5.5 half-lives of the experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, 
closely-related compounds, or any of the stated ingredients.  
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts 
the subject at any undue risk, prevents completion of the study, or interferes with analysis 
of the study results.
4.3
Reproductive Potential 
Not applicable; this study will enroll infants.
4.4
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution.  The investigator or sponsor may 
withdraw the subject at any time (e.g., in the interest of subject safety).  The investigator should 
discuss withdrawal of a subject from investigational product with the medical monitor as soon as 
possible.
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If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 24/EOT/early termination are to be performed as completely as possible. Whenever 
possible, all discontinued subjects should also undergo the protocol-specified 4-week Follow-up 
Period. Comments (spontaneous or elicited) or complaints pertaining to IP discontinuation made 
by the subject must be recorded in the source documents. The reason for discontinuation, the 
date and the total amount of investigational product administered must be recorded in the 
electronic case report form (eCRF) and source documents.
Subjects who discontinue will not be replaced. 
4.4.1
Reasons for Discontinuation
The reason(s) for permanent discontinuation of treatment and/or withdrawal from the study must 
be determined by the investigator, and recorded in the subject’s medical record and in the eCRF.  
If a subject is withdrawn for more than 1 reason, each reason should be documented in the source 
document, and the most clinically relevant reason should be entered in the eCRF.
Reasons for discontinuation include, but are not limited to:

Adverse event

Death

Lost to follow-up

Physician decision

Protocol deviation

Study terminated by sponsor

Withdrawal by parent/guardian

Lack of efficacy

Other
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact the parent(s)/guardian(s) of any 
subject lost to follow-up at any time point prior to the last scheduled contact (office visit or 
telephone contact). At least 1 of these documented attempts must include a written 
communication sent to the subject’s last known address via courier or mail (with an 
acknowledgement of receipt request) asking that they return to the site for final safety 
evaluations and return any unused investigational product.
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PRIOR AND CONCOMITANT TREATMENT
5.
5.1
Prior Medications and Procedures
Prior treatment includes all treatment and procedures (including but not limited to prescription 
treatments, herbal treatments, vitamins, non-pharmacological treatment, as appropriate) received 
within 14 days prior to the screening visit (Visit -1) (or pharmacokinetic equivalent of 5 half 
lives, whichever is longer, must be recorded on the appropriate eCRF page.
5.2
Concomitant Medications and Procedures
The administration of all medications including concomitant medications (including prescription 
and nonprescription medications, dietary and nutritional supplements, and vitamins) and PN 
must be recorded from the first dose of investigational product and for the duration of the study 
in the appropriate sections of the eCRF.  Any diagnostic, surgical or other therapeutic treatments 
received by a subject during the course of the study will also be recorded on the eCRF.
The mechanism of action of teduglutide may increase enteral absorption of oral drugs (e.g., 
drugs used for management of SBS such as motility medication, opioids, psychotropics, 
metronidazole), so consideration should be given to modifying concomitant enteral medication 
regimens. Titration of concomitant enteral medications should be considered when drugs, 
especially those with a narrow therapeutic index (e.g., warfarin, digoxin, psychotropics) are 
given.
5.3
Permitted Treatment
Standard medical therapy for SBS should be continued.
5.4
Prohibited Treatment
The following medications are prohibited during teduglutide treatment and within the provided 
timeframe prior to the pretreatment visit (Table 3):
Table 3:
Prohibited Treatment
Prior Therapy
Time Restriction Prior to 
the Pretreatment Visit
Teduglutide
Any
GLP-2, human growth hormone, or analogs of these hormones
6 months
Octreotide, GLP-1 analogs, and enteral glutamine
30 days
GLP=glucagon-like peptide
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INVESTIGATIONAL PRODUCT
6.
6.1
Identity of Investigational Product
The SOC treatment arm will receive standard medical therapy for SBS; while those in the 
teduglutide arm will receive 0.05 mg/kg SC once daily in addition to standard medical therapy.
The investigational product is teduglutide, which will be provided in sterile, single-use 3 mL 
vials containing 1.25 mg teduglutide as a white lyophilized powder to be reconstituted before use 
with 0.5 mL sterile water for injection. In addition to the active ingredient (teduglutide), each 
vial of teduglutide contains L-histidine, mannitol, monobasic sodium phosphate monohydrate, 
and dibasic sodium phosphate as excipients. Additional information is provided in the current 
investigator’s brochure.
6.2
Administration of Investigational Product
6.2.1
Interactive Response Technology for Investigational Product Management
All investigative study sites will be initially provided with sufficient investigational product to 
randomly assign a subject into the study (for either of the proposed treatment groups).  
Randomization will occur through an interactive response system. Random assignment of a 
subject will trigger replacement supplies for that investigative study site.
6.2.2
Allocation of Subjects to Treatment
Subjects will be randomized 1:1 to the teduglutide or SOC treatment arm.  Randomization will 
be stratified according to the presence of a small bowel ostomy (e.g., end jejunostomy or 
ileostomy).  The actual treatment given to individual subjects is determined by a randomization 
schedule.
Subject numbers are assigned to all subjects as they consent to take part in the study.  Within 
each site (numbered uniquely within a protocol), the subject number is assigned to subjects 
according to the sequence of presentation for study participation.  
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined.
6.2.3
Dosing
The initial dose will be calculated based on body weight measured at baseline (Visit 0), and 
adjusted as needed, based on body weight measured at Week 12. No other adjustments to dose 
will be made during the teduglutide treatment period, unless discussed with the sponsor’s 
medical monitor. 
Following reconstitution, teduglutide will be administered by SC injection once daily (QD) into 
1 of the 4 quadrants of the abdomen (in subjects without a stoma) or into either the thigh or arm.  
For subjects with a stoma, the quadrant of the abdomen containing the stoma should not be used.  
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Teduglutide should be used as soon as possible after reconstitution, but no more than 3 hours 
later.
The subject should be dosed at approximately the same time each day. Consecutive doses should 
be separated by at least 12 hours.  Each day, the injection site should be alternated.  
Any subject who achieves complete independence from PN support at any time during the 
treatment period will continue to receive teduglutide treatment.
The first SC injection in teduglutide-naïve subjects should be administered under the supervision 
of the investigator or designee and the subject observed for hypersensitivity reactions for at least 
4 hours during their initial dosing visit.  The site of administration (arm, thigh, and abdomen) of 
the first teduglutide dose must be specified and recorded in the eCRF. 
Detailed instructions for reconstitution and injection of the investigational product can be found 
in the Instructions for Use. 
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up 
period until the end of study (Week 28/EOS) during which time subjects will receive standard 
medical therapy, but no investigational product will be administered.  At EOS all subjects 
regardless of treatment arm may enroll in an extension study that will capture long-term safety 
data and provide the opportunity for additional teduglutide treatment.  The follow-up period for 
subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed 
immediately to the EOS if at least one of the following “escape” criteria is met:
1. Increasing PN requirements following teduglutide discontinuation.
2. Deteriorating nutritional status (e.g., weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation.  
4. Severe diarrhea related to teduglutide discontinuation.
6.2.4
Unblinding the Treatment Assignment
Not applicable for this open-label study.
6.2.5
Dose Selection Rationale
Teduglutide is approved for adult and pediatric use in the EU at a dose of 0.05 mg/kg SC once 
daily.  A completed 12-week dose finding study (TED-C13-003) demonstrated that teduglutide 
dosing at 0.025 and 0.05 mg/kg/day was associated with a favorable benefit-risk profile most 
meaningful at the 0.05 mg/kg/day dose (Carter et al., 2017). 
Population pharmacokinetic modeling and simulations were conducted to determine the optimal 
dose to be used in pediatric subjects using data from 8 adult clinical studies including adult Phase 
1 studies and Phases 2/3 studies as well as TED-C13-003 and suggested the same adult dose 
(0.05mg/kg) in pediatric subjects (aged between 1.67-14.7 years) (Marier et al., 2017).
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To support dosing in the current age group, further PK simulation was conducted based on the 
population PK model previously established and a virtual population of 1000 pediatric patients 
created based on Centers for Disease Control (CDC) growth charts in the target age group (4 to 
12 months) and taking into consideration body weights of pediatric patients with SBS enrolled in 
study TED-C13-003 and TED-C14-006 (approximately 15% lower than healthy subjects in the 
same age group). The model was customized by including a maturation function on clearance 
(CL/F) as a function of estimated glomerular filtration rate. Monte Carlo simulations for all age 
groups were performed according to the SC dosing regimens of 0.0125, 0.025 and 0.05 mg/kg 
every 24 hours.  Rich concentration-time profiles were simulated with the customized population 
PK model to derive the exposure metrics area under the concentration curve at steady state 
(AUCss) and maximum concentration at steady state (Cmax,ss). Exposure parameters in infant 
patients were compared to those derived in pediatric (1-17 years) and adult (≥18 years) patients 
with SBS using a Bayesian approach. Based on the clinical observations, Cmax is considered to be 
associated with clinical responses. Following 0.05 mg/kg daily SC administration, the median 
Cmax,ss of teduglutide in neonate patients (24.9 ng/mL) was within 20% of that observed in the 2 
to 4 and 4 to 6 years age groups (26.9 and 29.4 ng/mL, respectively); and approximately ~28% 
lower than that in adult patients with SBS. The median Cmax,ss of teduglutide in infant patients 4 
to 12 months (41.9 ng/mL) following 0.05 mg/kg once daily was within 8% of that previously 
observed in adult patients with SBS (39.0 ng/mL, refer to the attached Simulation Report). In 
addition, individual simulated Cmax,ss values of teduglutide in infant patients 4 to 12 months (25.6 
to 65.1 ng/mL) were contained within the range of Cmax,ss previously observed in pediatric 
patients 1 to 17 years (20.7 to 77.4 ng/mL). The clinical package in conjunction with Cmax was 
considered to support teduglutide dose selection since AUCss was previously shown not to 
correlate with efficacy. Individual simulated AUCss values of teduglutide in infant patients 4 to 
12 months (66.9 to 160 ng.h/mL) following 0.05 mg/kg once daily were contained within the 
range of AUCss values previously observed in pediatric patients 1 to 17 years (63.5 to 
421 ng.h/mL). Based on the totality of clinical data, 0.05 mg/kg once daily is expected to provide 
comparable Cmax concentrations in infants as compared to pediatric patients with SBS and was 
recommended as an evaluation dosing regimen in Study SHP633-301.
6.3
Labeling, Packaging, and Storage
6.3.1
Labeling
The investigational product will be packaged, labeled, and shipped to the study site by the 
sponsor or designee.  Kits containing 7 vials of investigational product will be provided for this 
study.  The vials will be labeled in accordance with applicable regulatory requirements. 
Ancillary kits, containing supplies needed for the reconstitution and administration of the 
investigational product will also be provided and labeled in accordance with the applicable 
regulatory requirements. 
All investigational product used in this study will be manufactured, tested, labeled, and released 
according to current legal requirements and Good Manufacturing Practice.
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6.3.2
Storage and Handling
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.
Investigational product must be kept in a locked area with access restricted to specific study 
personnel. Investigational product will be stored refrigerated at a temperature between 2-8°C 
(35.6-46.4°F) until dispensed to a subject. Once dispensed to a subject, the IP can be stored 
refrigerated or up to a controlled room temperature (acceptable range of 2-25°C, or 35.6-77°F). 
Parent/legal guardian will be instructed to keep the subject’s IP and sterile water diluent at 
controlled room temperature. If there are concerns that the controlled room temperature cannot 
be maintained, the IP may be refrigerated. The IP is for single use only, and should be used 
within 3 hours following reconstitution.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (i.e., certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), e.g., fumigation of a 
storage room.
Investigational products are distributed by the pharmacy or nominated member of the study 
team. The pharmacist/nominated team member will enter the unique subject identifier on the 
investigational product bottle/carton labels, as they are distributed.
6.4
Drug Accountability
Investigational product will not be dispatched to the study site until the sponsor or 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 investigational product 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.  Kits will be shipped to the site once the 
subject is screened.
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Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects.  The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition.  Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for dispensing investigational product.  Where 
permissible, tasks may be delegated to a qualified designee (e.g., a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator.  
This delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee will dispense the investigational product only to subjects 
included in this study following the procedures set out in the study protocol.  Investigational 
product kits will be dispensed at each of the applicable study visits at which the subject is 
required to be at the clinic.  Each investigational product kit is sufficient for a treatment period of 
1 week and enough kits will be supplied to cover the period until the next planned study visit.  
Additional study kits will be provided as necessary.
Each subject will be given the investigational product according to the protocol.  The 
investigator is to keep a current record of the inventory and dispensing of all clinical supplies.  
All dispensed medication will be documented on the eCRFs and/or other investigational product 
record.  The investigator is responsible for assuring the retrieval of all study supplies from 
subjects.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor.  If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.
At the end of the study, or as instructed by the sponsor, all unused stock, subject returned 
investigational product, and empty/used investigational product packaging are to be sent to the 
sponsor or designee.  The investigator is responsible for assuring the retrieval of all study 
supplies from subjects.
Returned investigational product must be counted and verified by clinical site personnel and the 
sponsor (or study monitor). Shipment return forms, when used, must be signed prior to shipment 
from the site.  Contact the sponsor for authorization to return any investigational product prior to 
shipment.  Shipment of all returned investigational product must comply with local, state, and 
national laws. 
Please see the Pharmacy Manual for additional information.
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6.5
Subject Compliance
The parent(s)/guardian(s) of subjects must be instructed to bring unused investigational product 
and empty/used investigational product packaging to every visit. Drug accountability must be 
assessed and recorded at the container/packaging level for unused investigational product that is 
contained within the original tamper-evident sealed container (e.g., bottles, trays, vials) or at the 
individual count level for opened containers/packaging. 
Subject compliance will be checked by site personnel at every visit by reviewing the subject 
diaries and asking the subject or the subject’s parent or legally-authorized representative if they 
have administered the investigational product according to instructions. If any doses have been 
missed, the reason for missed dose should be documented in the subject’s source documentation 
including, as applicable, the eCRF.
The investigator is responsible for contacting the sponsor or designee when the subject’s daily 
investigational product dosing regimen is interrupted. Attempts should be made to contact the 
sponsor or designee prior to dose interruption. Reasons for dosage interruption may include but 
are not limited to hospitalization and AEs, a lapse in investigational product delivery, etc.
Subjects who have received 80% of the planned doses administered will be assessed as being 
compliant with the study protocol.
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STUDY PROCEDURES
7.
7.1
Study Schedule
Detailed study procedures and assessments to be performed for subjects throughout the study are 
outlined in the study schedules (Table 1 and Table 2) and must be referred to in conjunction with 
the instructions provided in this section. 
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 24/EOT are to be performed as completely as possible.  Whenever possible, all 
discontinued subjects should also undergo the protocol-specified 4-week Follow-up Period.  
7.1.1
Screening
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent from the 
parent(s)/guardian(s) of the subject. The screening visit assessments and procedures, beginning 
with informed consent, will be performed as outlined in Table 1. Rescreening will not be 
allowed.
7.1.2
Treatment Period
The randomized Treatment Period will comprise Weeks 1 to 24, during which all assessments 
will be performed as outlined in Table 1 and Table 2.
7.1.3
Follow-up Period
The Follow-up Period will comprise Weeks 25 to 28, during which all assessments will be 
performed as outlined in Table 2.
7.2
Study Evaluations and Procedures
7.2.1
Demographics and Other Baseline Characteristics
Demographics and Medical History
Demographic and/or other baseline variables obtained at the screening and/or baseline visits are 
listed below. Abnormal findings of clinical significance (if any) will be recorded as past medical 
history.

Demography (including age, gestational age, sex, and race)

Medical history (including surgical history)

SBS history, including remnant anatomy
Upper Gastrointestinal Series with Small Bowel Follow-through
An upper GI contrast series with small bowel follow-through will be performed on all subjects 
during the screening period if one has not been done since the subject's last GI surgery. 
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It is acceptable to only enroll subjects who have already had an upper GI series with small bowel 
follow-through performed since the subject’s most recent surgery.  
7.2.2
Efficacy Assessments
Subject Diaries
All available diary data will be reviewed by the investigator or their designee at each clinic and 
telephone visit to assess clinical status and opportunity for PN reduction and advance in feeds.  
Parenteral support adjustments should be made after review of the intake and output diaries and 
the safety lab data according to the guidance for nutrition support adjustment provided in 
Appendix 2.
Intake Diary
Intake diaries will be used to collect and evaluate each subject’s nutritional support. The 
parent/legally authorized representative/study site staff will complete the appropriate fields of the 
PN and EN sections of the intake diary daily throughout the study.
The following data will be captured in the intake diaries:

Parenteral support volume and infusion duration

Enteral nutrition (formula) including volume and calories
Site personnel will determine the actual PN and EN daily calories based on diary entries.
Output Diary
Urine and stool output should be recorded in the output diary over a 48-hour period of nutritional 
stability before every clinic visit; in addition, output should be recorded for subjects within 
1 week of implementing a change in the PN prescription.
Urine data:

Measure and record the weight of all urine-only diapers. Urine volume will be calculated 
using the following formula: 1 g (scale weight) = 1 mL or 1 cc

At the discretion of the investigator, the parent or legal guardian/study site staff may be 
asked to collect the first void after the daily PN infusion to measure specific gravity
Stool data (includes diapers with mixed urine and stool):

Record the weight of diapers containing stool (including diapers with mixed urine and 
stool) as stool output and score the stool consistency (see Output diary). Stool volume 
will be calculated using the formula: 1 g (scale weight)=1 mL or 1 cc
All ostomy output volume should be recorded.  
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Native GLP-2
Blood samples for native GLP-2 should be collected postprandial.  Blood samples while subjects 
are receiving teduglutide should be drawn at least 14 hours after the previous dose.  Native 
GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject 
weight or at investigator discretion based on weekly/monthly total volume.  
7.2.3
Safety Assessments
Laboratory Evaluations
Safety laboratory tests to be performed at site visits consist of clinical chemistry, hematology, 
and urinalysis and will be performed as outlined in the study plan (Table 1 and Table 2). 
Scheduled laboratory testing will be processed by a central lab. All laboratory assays will be 
performed according to the central laboratory’s normal procedures. Reference ranges are to be 
supplied by the laboratory. The investigator should assess out-of-range clinical laboratory values 
for clinical significance, indicating if the value(s) is/are not clinically significant or clinically 
significant. Abnormal clinical laboratory values, which are unexpected or not explained by the 
subject’s clinical condition, may, at the discretion of the investigator or sponsor, be repeated as 
soon as possible until confirmed, explained, or resolved.
During the Treatment Period, subjects will also have safety labs within approximately 5 to7 days 
after a PN adjustment.  Safety labs performed after PN adjustment and between site visits will 
consist of clinical chemistry and urinalysis and may be processed by the central laboratory or a 
local laboratory.  Local lab results are not required to be entered in the eCRFs; however, if the 
local lab results indicate any new clinically significant changes, they must be reported as an 
adverse event (see Section 8). Urine specimen collection should be attempted as part of the 
safety labs, but lack of urinalysis will not constitute a protocol deviation.
At baseline, blood samples for safety labs and PK can be separated by 1 day if blood volumes are 
limiting.  
Safety labs at telephone visits will be collected at the discretion of the investigator.  
For all subjects in the teduglutide treatment arm, prothrombin time (PT) and international 
normalized ratio (INR), tested at baseline, will be repeated if clinically indicated.
New clinically significant labs should be reported as AEs.
Close Monitoring Criteria Related To Liver Test Abnormalities:  
The investigator should contact the medical monitor within 24 hours of their awareness if the 
subject develops any of the following changes in laboratory parameters:

ALT or AST >5x ULN and >2x baseline value

Total or direct bilirubin that is >2x baseline value or an absolute increase of  ≥3 mg/dL 
(51.3 µmol/L)
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If such changes are observed, the labs should be repeated along with an INR, and an inquiry 
should be made as to the presence of clinical symptoms consistent with new liver injury. The 
subject should be followed closely to determine the trajectory of the laboratory abnormalities and 
appropriate evaluations should be made, such as abdominal ultrasound with Doppler imaging to 
exclude vascular causes and biliary obstruction, consideration of sepsis, liver hypoperfusion, 
acute viral hepatitis (such as hepatitis A, EBV, or HSV), exposure to hepatotoxic medications, 
mitochondrial hepatopathy, or metabolic liver disease (such as hereditary fructose intolerance or 
arginosuccinate synthetase deficiency).  Further evaluations can be performed at the discretion of 
the investigator in consultation with the Shire medical monitor.
The following clinical laboratory assessments will be performed according to the study 
schedules:
Table 4:
List of Laboratory Tests
Biochemistry:

Albumin 

Alkaline phosphatase 

Alanine aminotransferase 

Amylase

Aspartate aminotransferase 

Bicarbonate

Bilirubin (total and indirect)

Blood urea nitrogen 

Calcium (total)

Chloride

Cholesterol

C-reactive protein 

Creatinine

Estimated Glomerular Filtration Rate 
(Schwartz formula)

Gamma-glutamyl transferase 

Glucose

Lipase

Magnesium

Phosphorus

Potassium 

Sodium 

Triglycerides
Hematologya:

Hematocrit 

Hemoglobin 

Platelet count

Red blood cell count 

Red blood cell morphology, if needed

White blood cell count with differential
Coagulationb:

Prothrombin time

International normalized ratio
Urinalysis: 

Specific gravity  

Urine Sodium
a Hematology is not collected at Week 1 or at telephone visits.
b For all subjects in the teduglutide treatment arm, PT and INR will be tested at baseline and repeated only if clinically indicated.
Antibodies to Teduglutide 
Blood samples will be drawn to test for antibodies to teduglutide.  Samples will be taken before 
teduglutide administration at the screening visit (Visit -1) and at least 14 hours after the previous 
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dose at Week 12 (Visit 12); samples may be drawn from a central line or peripheral access. One 
additional sample will be collected at the EOS 4 weeks after the EOT (i.e., Week 28 or EOS).  
Volume of Blood
Efforts will be made to minimize the amount of blood drawn from all pediatric subjects 
participating in this study. The volumes of blood to be drawn from each subject will vary 
depending on clinical status. Approximate volumes of blood to be drawn from each subject are 
shown in Table 5.
Table 5:
Approximate Volume of Blood to be Drawn from Each Subject 
Assessment
Sample 
Volume (mL)
No. 
Samples 
Total 
Volume (mL)
Notes
Subjects Receiving Teduglutide Treatment
Biochemistry 
0.6
12
7.2
Hematology
0.6
11
6.6
Coagulation 
Parameters
0.6
1
0.6
PT and INR tested at baseline 
only, repeat while on study 
only if clinically indicated.
Antibodies
1.5
5
7.5
Pharmacokinetics
1.5
4
6.0
Baseline: 3 timepoints
Week 7: 1 timepoint OR
Week 12: 1 timepoint
Native GLP-2
1.5
3
4.5
Total mL:
6.3
36
32.4
Subjects Receiving Standard of Care
Biochemistry 
0.6
12
7.2
Hematology
0.6
11
6.6
Native GLP-2
1.5
3
4.5
Total mL:
2.7
26
18.3
GLP=glucagon-like peptide; INR=international normalized ratio; PT=prothrombin time
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment. When more than 1 blood assessment is to be done at the time 
point/period, if they require the same type of tube, the assessments should be combined. Blood 
volume estimates do not include safety labs performed after PN adjustments.
Physical Examinations, Vital Signs, Weight, Length, and Head Circumference
Physical examinations will be performed according to the study schedules (Table 1 and Table 2). 
Any new clinically significant findings noted during physical examinations should be recorded 
on the appropriate AE page of the eCRF.
Vital signs will be measured according to the study schedules. Measurements will include 
systolic and diastolic blood pressure (mmHg), pulse (beats per minute), and body temperature 
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(°C/°F). Blood pressure should be determined by the appropriate size cuff (using the same 
method, the same leg, and in the supine position throughout the study, when possible).  Blood 
pressure measurements should be attempted as part of the vital signs, but lack of blood pressure 
results will not constitute a protocol deviation.  New clinically significant vital sign 
abnormalities should be recorded on the appropriate AE page of the eCRF.
Body weight will also be recorded in the eCRF; subjects should be weighed on the same scale 
at each study visit. Length and head circumference will be measured at selected visits. A height 
z-score, weight Z-score, and weight/length ratio will be calculated by the sponsor using the 
site-provided height and weight data collected at each site visit.
7.2.4
Pharmacokinetic Assessments
Subjects will have blood samples taken for teduglutide PK analysis predose, and 1 hour
±10 minutes and 4 hours ±10 minutes postdose at baseline (Visit 0). Subjects also will have 
blood samples taken for teduglutide PK analysis 2 hours ±10 minutes postdose at Week 7 
(Visit 7) or Week 12 (Visit 12) of the treatment period. Blood for PK sampling should be 
collected via peripheral IV or venipuncture, not from a central line. The site of teduglutide 
administration prior to PK blood draws (arm, thigh, abdomen) must be specified. 
7.2.5
Health Economics and Outcomes Research
Hospitalizations
Each hospitalization that occurs during the study will be recorded, including date of admission, 
date of discharge, reasons for hospitalization, discharge diagnosis, and discharge status. 
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ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.3. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, or 
a symptom is more severe or prolonged than expected given the diagnosis, then symptom(s) 
should be listed individually. All AEs should be captured on the appropriate AE pages in the 
eCRF and in source documents. In addition to untoward AEs, unexpected benefits outside the 
investigational product indication should also be captured on the AE eCRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
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clinical status, or may require intensive therapeutic intervention.
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of 
the investigational product is compelling and/or follows a known or 
suspected response pattern to that product, and the event cannot be 
explained by the subject’s medical condition, other therapies, or 
accident.
Not Related
The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident and no 
plausible temporal or biologic relationship exists between the 
investigational product and the event.
AEs that are related to IP that are not resolved at EOS will be followed until the event resolves or 
stabilizes, as judged by the investigator.
Laboratory values, vital signs, and clinical findings at the scheduled physical examinations must 
be reported as AEs if the investigator considers the finding to be a clinically significant change 
from the baseline.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the eCRF. Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved with Sequelae 

Recovering/Resolving

Unknown
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8.1.4
Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE. It is assumed that some of the infants participating in this study may be 
hospitalized for planned surgery(ies) that will occur during their participation in the study.  Such 
pre-planned, elective surgeries, do not need to be reported as SAEs for this protocol.  
8.1.5
Clinical Laboratory and Other Safety Evaluations
An untoward change in the value of a clinical laboratory parameter, vital sign measure, or ECG
assessment can represent an AE if the change is clinically relevant or if, during administration of 
investigational product, a shift of a parameter is observed from a value in the normative range to 
a value that is outside the normal range and considered clinically significant, or a further waning 
of an already clinically significant value. Clinical significance is defined as any abnormal finding 
that results in further clinical investigation(s), treatment(s), or the diagnosis of new or 
progression of established condition. When evaluating such changes, the extent of deviation from 
the reference range, the duration until return to the reference range, either while continuing 
administration or after the end of administration with the investigational product, and the range 
of variation of the respective parameter within its reference range, should also be considered.
If, at the end of the treatment phase, there are abnormal clinical laboratory (such as hematology 
panel or clinical chemistry panel), vital sign, or ECG values which were not present at the 
beginning of the pretreatment evaluation observed closest to the start of study treatment, further 
investigations should be performed until the values return to within the reference range or until a 
plausible explanation (eg, concomitant disease or expected disease evolution) is found for the 
abnormal values.
The investigator should assess, based on the above criteria and the clinical condition of a subject, 
whether a change in a clinical laboratory value, vital sign, or ECG parameter is clinically 
significant and represents an AE.
8.1.6
Pregnancy
Not applicable.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for 
a non-medical purpose (e.g., to alter one’s state of consciousness or get high) in a manner 
that may be detrimental to the individual and/or society.
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
Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol).

Overdose – Administration of a dose greater than the allocated dose of the study 
medication or at a frequency greater than the dosing interval specified by the protocol.

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product. For studies, medication errors are reportable to the sponsor 
only as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error. 
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally-authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator brochure which the sponsor 
has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Drug Safety Department and the Shire Medical Monitor within 24 hours of the first awareness of 
the event. Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, 
misuse, overdose, or medication errors (see Section 8.1.7) unless they result in an SAE.
All Adverse Events of Special Interest, as defined in Section 8.3, must be reported by the 
investigator to the Shire Global Drug Safety Department and the Shire Medical Monitor within 
24 hours of the first awareness of the event even if the event does not fulfill seriousness criterion.
The investigator must complete, sign, and date the Shire Clinical Study Adverse Event Form for 
SAEs and Non-serious AEs as Required by Protocol, and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested). Fax or e-mail the completed form to the Shire Global Drug Safety 
Department. A copy of the completed Shire Clinical Study Adverse Event Form for Serious 
Adverse Events (SAEs) and Non-serious AEs as Required by Protocol (and any applicable 
follow-up reports) must also be sent to the Shire medical monitor or designee using the details 
specified in the emergency contact information section of the protocol.
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8.2.3
Serious Adverse Event Definition
A SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose: 

Results in death

Is life-threatening. Note: The term 'life-threatening' in the definition of "serious" refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for pre 
existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse. 
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to investigational product) are collected from the time the 
subject signs the informed consent until the defined follow-up period stated in Section 7.1.3, and 
must be reported to the Shire Global Drug Safety Department and the Shire Medical Monitor 
within 24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Drug Safety Department within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
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In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (i.e., the SAE was noted as the primary cause of 
death) must have fatal checked as an outcome with the date of death recorded as the resolution 
date. For all other events ongoing at the time of death that did not contribute to the subject’s 
death, the outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (e.g., drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death.  
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting 
The Sponsor and/or Clinical Contract Research Organization (CRO) is responsible for notifying 
the relevant regulatory authorities, and US central Institutional Review Boards (IRBs)/EU central 
ethics committees (ECs), of related, unexpected SAEs.
In addition, the Clinical CRO is responsible for notifying active sites of all related, unexpected 
SAEs occurring during all interventional studies across the SHP633 program.
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
8.3
Adverse Events of Special Interest
An AE of special interest is an AE (serious or nonserious) of scientific and medical concern 
specific to the sponsor’s product or program and for which ongoing monitoring and immediate 
notification by the investigator to the sponsor is required.
The AEs of special interest that require expedited regulatory reporting include the following:

Growth of pre-existing polyps of the colon

Benign neoplasia of the GI tract including the hepatobiliary system

Tumor-promoting ability (e.g., benign and/or malignant neoplasia of any kind, not
limited to those of the GI or hepatobiliary system)
For AEs of special interest, the sponsor must be informed within 24 hours of first awareness as 
per the SAE notification instructions described in Section 8.2.2 even if the event does not fulfill 
the seriousness criteria.
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8.4
Dose Interruption Criteria
The investigator is responsible for contacting the sponsor/designee when the subject’s 
teduglutide dosing regimen is interrupted. The length of dose interruption, and whether 
teduglutide administration resumes or is permanently discontinued, depends on the clinical 
situation.
Investigational product must be interrupted if any of the following events occur:

An adverse event of special interest (see Section 8.3) 

Intestinal obstruction

Biliary obstruction

Pancreatic duct obstruction

Heart failure with severe fluid overload determined by the sponsor or investigator to 
be related to IP.
Investigational product must be permanently discontinued if any of the following events occur: 

Severe hypersensitivity, such as anaphylaxis, determined by the investigator to be 
related to IP. 

Any malignancy 
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DATA MANAGEMENT AND STATISTICAL METHODS
9.
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the eCRF.  A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy.  Discrepancies 
between source data and data entered on the eCRF will be addressed by qualified site personnel.  
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel.  Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting.  Once a subject is randomized, it is expected that site 
personnel will complete the eCRF entry within approximately 3 business days of the subject’s 
visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the data management plan. Quality 
control and data validation procedures are applied to ensure the validity and accuracy of the 
clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Statistical Analysis Process
The study will be analyzed by the sponsor or designee. All statistical analyses will be performed 
using SAS® (SAS Institute, Cary, NC, US) version 9.3 or higher.
The statistical analysis plan (SAP) will provide the definitions and statistical methods  for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed.
9.4
Planned Interim Analysis, and Data Monitoring Committee 
No interim analyses is planned for this the study. 
A data monitoring committee (DMC) will be involved in the management of this study. The 
DMC members will review the data approximately every 3 months according to the DMC 
Charter. The DMC review will include all cumulative safety data (i.e., AEs, laboratory 
assessments, physical examinations, etc.) from study assessments through each cutoff period. 
Further details regarding the DMC can be found in the DMC charter, which will be available 
prior to the administration of investigational product. 
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The DMC for this study will be conducted in accordance with the FDA Guidance for Clinical 
Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees 
(March 2006).
The DMC will be an external, independent board comprised of physicians with relevant training. 
The DMC will be restricted to individuals free of significant conflicts of interest, including, but 
not limited to, financial, scientific, or regulatory in nature. The DMC will be governed by a 
Charter agreed to by members of the Board and the sponsor. Members of the Board may not be 
study investigators or be employed at the same institution as a study investigator, individuals 
employed by the sponsor, independent contractors hired by the sponsor, or members of 
regulatory agencies. The DMC may make recommendations to the sponsor regarding study 
aspects including stopping, modifying or continuing the study; however, the sponsor will have 
the final responsibility to determine whether the study should be modified or temporarily or 
permanently stopped. If the DMC recommends termination of this pediatric study, the 
recommendations will be communicated to the relevant regulatory agencies within 7 calendar 
days.
9.5
Sample Size Calculation and Power Considerations
The sample size is determined based on enrollment feasibility for this rare condition and the age 
of the study population. 
9.6
Study Population
Intent to treat (ITT) population: All subjects randomized in the study.
Safety analysis population: The safety analysis set will contain all subjects who meet the 
following criteria:

Teduglutide treatment arm: subjects who receive at least 1 dose of teduglutide and 
have undergone at least 1 post-baseline safety assessment; analyses will be performed 
according to dose group as appropriate.   

Standard of care treatment arm: subjects who have undergone at least 1 post-baseline
safety assessment.
Per-protocol population: All subjects in the ITT population without any major protocol deviation 
that affects interpretation of efficacy results.
Pharmacokinetic analysis population: All subjects who received at least 1 dose of teduglutide 
and have at least 1 evaluable postdose PK concentration value.   
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9.7
Efficacy Analyses
9.7.1
Efficacy Endpoints
Efficacy endpoints consist of the following:
9.7.1.1
Primary Efficacy Endpoint 

Reduction in weight-normalized PN fluid volume by at least 20% from baseline at 
Week 24/EOT
9.7.1.2
Secondary Efficacy Endpoints

Reduction in weight-normalized parenteral calories by at least 20% from baseline to 
Week 24/EOT

Achievement of enteral autonomy by Week 24

Time to achieve enteral autonomy

Change in weight-normalized parenteral fluid volume from baseline to each visit

Change in weight-normalized parenteral calories from baseline to each visit

Change in weight-normalized enteral fluid volume from baseline to each visit

Change in weight-normalized enteral caloric intake from baseline to each visit

Increase in weight-normalized enteral fluid intake by at least 20% from baseline to week 
24/EOT

Increase in weight-normalized enteral caloric intake by at least 20% from baseline to 
week 24/EOT
9.7.2
Method of Analysis-Efficacy Endpoints
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 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.
Analyses of weekly PN support will be based on 2 data sources: the subject diary data (also 
referred to as actual data) and the investigator prescribed data.  
The number and percentage of subjects who achieve at least a 20% reduction from baseline in 
weight-normalized average daily PN volume at Week 24/EOT and the number and percentage of 
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subjects who achieve at least a 20% reduction from baseline in weight-normalized parenteral 
calories at Week 24/EOT will be summarized by treatment arm.
During the treatment period, a subject will be considered to have achieved enteral autonomy 
(completely weaned off PN) at a given visit if the investigator prescribes no PN at that visit and 
for the remainder of the treatment period, and there is no use of PN recorded in the subject diary 
during the week prior to that visit and for the remainder of the treatment period. During the 
follow-up period, a subject will be considered to have achieved enteral autonomy at a given visit 
if the investigator prescribes no PN at that visit and for the remainder of the follow-up period and 
there is no use of PN recorded in the subject diary during the week prior to that visit and for the 
remainder of the follow-up period. The number and percentage of subjects who achieve enteral 
autonomy at each scheduled visit, as well as at EOT, will be summarized by treatment arm.
Descriptive statistics will be used to summarize time to achievement of enteral autonomy by 
treatment arm.
The absolute and percent change in weight-normalized weekly PN volume, parenteral calories, 
enteral fluid volume, and enteral caloric intake, from baseline to each scheduled visit, as well as 
at EOT, will be summarized by treatment arm using descriptive statistics.
The number and percentage of subjects who demonstrate an increase in weight-normalized 
enteral fluid intake by at least 20% from baseline to Week 24/EOT and the number and 
percentage of subjects who demonstrate an increase in weight-normalized enteral caloric intake 
by at least 20% from baseline to week 24/EOT will be summarized by treatment arm.
9.8
Safety Analyses
9.8.1
Safety Endpoints
Safety endpoints consist of the following:

Adverse events

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for 
gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output

Stool (including mixed) output

Antibodies to teduglutide
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9.8.2
Method of Analysis-Safety Endpoints
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Treatment-emergent AEs will be summarized by system organ class and preferred 
term using descriptive statistics (e.g., number and percentage of subjects).  Adverse events will
be summarized by severity and relationship to treatment.  In addition, SAEs will also be 
tabulated by overall and treatment-related events.  AEs leading to treatment discontinuation and 
death will also be summarized.
For laboratory tests; vital signs; urine and stool output; weight, length, and head circumference 
Z-scores, and descriptive statistics (e.g., n, mean, standard deviation, median, minimum and 
maximum values, and the number and percentage of subjects in specified categories) will be 
used to summarize the absolute values and change from baseline at each visit.
The number and percentage of subjects classified as having antibodies to teduglutide will be used 
to summarize the presence of antibodies.  
9.9
Health Economics and Outcomes Research Analyses
Health economics and outcomes research endpoints consist of the following:

Cumulative number of hospitalization days during the study
Health economics and outcomes research endpoints will be summarized using descriptive 
statistics (number, mean and standard deviation) at nominal time points.  
9.10
Pharmacokinetics Analyses
Plasma concentrations will be summarized using descriptive statistics (number, mean, standard 
deviation, geometric mean, coefficient of variation, minimum, median, and maximum ) at 
nominal time points. 
Pharmacokinetic parameters will be estimated using a population PK modeling approach as 
appropriate and reported separately.
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SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES
10.
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements. 
The name and address of each third-party vendor (e.g., CRO) used in this study will be 
maintained in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996), EU 
Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines.  If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study.  An insurance certificate is supplied as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of the end of 
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the study completion date for pediatric studies and within 1 year for non-pediatric studies as per 
guidance.  The sponsor will provide the ECs with a copy of the same summary.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.  The sponsor will make an end-of-study declaration to the relevant competent 
authority as required by Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator will be appointed to review the final clinical study report 
for multicenter studies.  Agreement with the final clinical study report is documented by the 
signed and dated signature of the principal investigator (single-site study) or coordinating 
principal investigator (multicenter study), in compliance with Directive 2001/83/EC as amended 
by Directive 2003/63/EC and ICH Guidance E3 (1995).
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
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investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Electronic Case Report Forms
Electronic case report forms are supplied by the sponsor or designee and should be handled in 
accordance with instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Electronic case report forms 
must be completed by the investigator or designee as stated in the site delegation log.  All data 
will have separate source documentation; no data will be recorded directly onto the eCRF.
All data sent to the sponsor must be endorsed by the investigator.  
The study monitor will verify the contents against the source data per the monitoring plan. If the 
data are unclear or contradictory, queries are sent for corrections or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject diaries, and original clinical laboratory reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF entries 
against the source documents. The consent form includes a statement by which the 
parent/guardian agrees to the monitor/auditor from the sponsor or its representatives, national or 
local regulatory authorities, or the IRB/EC, having access to source data (e.g., subject’s medical 
file, appointment books, original laboratory reports, X-rays etc). Non-study site personnel will 
not disclose any personal information or personal medical information.
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (e.g., the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
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Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the European Medicines Agency (EMA), the 
Medicines and Healthcare products Regulatory Agency, other regulatory authorities, the sponsor 
or its representatives, and the IRB/EC for each site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent, where applicable, 
from the parent(s)/guardian(s) of all study subjects prior to any study-related procedures 
including screening assessments. All consent documentation must be in accordance with 
applicable regulations and GCP. Each subject’s legally authorized representative is requested to 
sign and date the subject informed consent form or a certified translation if applicable, after the 
subject’s parent or guardian has received and read (or been read) the written subject information 
and received an explanation of what the study involves, including but not limited to: the 
objectives, potential benefits and risk, inconveniences, and the subject’s rights and 
responsibilities. A copy of the informed consent documentation (i.e., a complete set of subject 
information sheets and fully executed signature pages) must be given to the subject’s legally 
authorized representative, as applicable. This document may require translation into the local 
language. Signed consent forms must remain in each subject’s study file and must be available 
for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form  that was 
reviewed by the IRB/EC and received their favorable opinion/approval. A copy of the IRB/EC’s 
written favorable opinion/approval of these documents must be provided to the sponsor prior to 
the start of the study unless it is agreed to and documented (abiding by regulatory guidelines and 
national provisions) prior to study start that another party (i.e., sponsor or coordinating principal 
investigator) is responsible for this action. Additionally, if the IRB/EC requires modification of 
the sample subject information and consent document provided by the sponsor, the 
documentation supporting this requirement must be provided to the sponsor.
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10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the sponsor/designee has received 
written IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB/EC informed of any serious and 
significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996.  A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the sponsor/designee.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market teduglutide; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
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Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (e.g., to confirm 
that laboratory results have been assigned to the correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines 
(e.g., Good Publication Practices 2) when forming a publication steering committee, which is 
done for large, multicenter Phase 2 to 4 and certain other studies as determined by Shire. The 
purpose of the publication steering committee is to act as a non-commercial body that advises or 
decides on dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, royalty 
free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
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If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.
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REFERENCES
11.
Beattie, L. M., Barclay, A. R. & Wilson, D. C. 2010. Short bowel syndrome and intestinal failure 
in infants and children. Paediatrics and Child Health, 20, 485-491.
Carter, Cohran, Cole, Corkins, Dimmitt, Duggan, Hill, Horslen, Lim, Mercer, Merritt, Nichol, 
Sigurdsson, Teitelbaum, Thompson, Vanderpool, Vaughan, Li, Youssef, Venick & 
Kocoshis 2017. Outcomes from a 12-Week, Open-Label, Multicenter Clinical Trial of 
Teduglutide in Pediatric Short Bowel Syndrome. Journal of Pediatrics, The, 181, 102-
111.e5.
Gonzalez-Hernandez, Prajapati, Ogola, Channabasappa, Drews & Piper 2017. Predicting time to 
full enteral nutrition in children after significant bowel resection. Journal of Pediatric 
Surgery, 52, 764-767.
Goulet, O. & Ruemmele, F. 2006. Causes and Management of Intestinal Failure in Children. 
Gastroenterology, 130, S16-S28.
Huisman-de Waal, G., Schoonhoven, L., Jansen, J., Wanten, G. & van Achterberg, T. 2007. The 
impact of home parenteral nutrition on daily life-A review. Clinical Nutrition, 26, 275-
288.
Khan, F. A., Squires, R. H., Litman, H. J., Balint, J., Carter, B. A., Fisher, J. G., Horslen, S. P., 
Jaksic, T., Kocoshis, S., Martinez, J. A., Mercer, D., Rhee, S., Rudolph, J. A., Soden, J., 
Sudan, D., Superina, R. A., Teitelbaum, D. H., Venick, R., Wales, P. W. & Duggan, C. 
2015. Predictors of Enteral Autonomy in Children with Intestinal Failure: A Multicenter 
Cohort Study. J Pediatr, 167, 29-34.e1.
Marier, J., Kassir, N., Martin, P. & Wang, Y. 2017. Population pharmacokinetic modeling of 
teduglutide to support dosing in pediatric patients with short bowel syndrome. Clinical 
Pharmacology & Therapeutics, 101, S91.
Martin, G.-R., Beck, P.-L. & Sigalet, D.-L. 2006. Gut hormones, and short bowel syndrome: the 
enigmatic role of glucagon-like peptide-2 in the regulation of intestinal adaptation. World 
Journal of Gastroenterology, 12, 4117-29.
O'Keefe, S. J., Buchman, A. L., Fishbein, T. M., Jeejeebhoy, K. N., Jeppesen, P. B. & Shaffer, J. 
2006. Short bowel syndrome and intestinal failure: consensus definitions and overview. 
Clin Gastroenterol Hepatol, 4, 6-10.
Sigalet, D. L., Martin, G., Meddings, J., Hartman, B. & Holst, J. J. 2004. GLP-2 levels in infants 
with intestinal dysfunction. Pediatr Res, 56, 371-6.
Spencer, A. U., Neaga, A., West, B., Safran, J., Brown, P., Btaiche, I., Kuzma-O'Reilly, B. & 
Teitelbaum, D. H. 2005. Pediatric Short Bowel Syndrome: Redefining Predictors of 
Success. Annals of Surgery, 242, 403-412.
Squires, R. H., Duggan, C., Teitelbaum, D. H., Wales, P. W., Balint, J., Venick, R., Rhee, S., 
Sudan, D., Mercer, D., Martinez, J. A., Carter, B. A., Soden, J., Horslen, S., Rudolph, J. 
A., Kocoshis, S., Superina, R., Lawlor, S., Haller, T., Kurs-Lasky, M. & Belle, S. H. 
2012. Natural history of pediatric intestinal failure: initial report from the Pediatric 
Intestinal Failure Consortium. J Pediatr, 161, 723-8.e2.
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Tappenden, K. A., Edelman, J. & Joelsson, B. 2013. Teduglutide enhances structural adaptation 
of the small intestinal mucosa in patients with short bowel syndrome. J Clin 
Gastroenterol, 47, 602-7.
Thymann, T., Stoll, B., Mecklenburg, L., Burrin, D. G., Vegge, A., Qvist, N., Eriksen, T., 
Jeppesen, P. B. & Sangild, P. T. 2014. Acute effects of the glucagon-like peptide 2 
analogue, teduglutide, on intestinal adaptation in short bowel syndrome. J Pediatr 
Gastroenterol Nutr, 58, 694-702.
Wales, P. W., de Silva, N., Kim, J., Lecce, L., To, T. & Moore, A. 2004. Neonatal short bowel 
syndrome: population-based estimates of incidence and mortality rates. J Pediatr Surg,
39, 690-5.
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APPENDICES
12.
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Appendix 1
Protocol History
Document
Date
Global/Country/Site Specific
Original Protocol
03 Oct 2017
Global
Amendment 1
18 Jan 2018
Global
Amendment 2
04 Dec 2018
Global
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change
Section(s) Affected by 
Change
Updated emergency contact information to reflect the change 
of the Contract Research Organization’s name.
Emergency Contact 
Information
Clarified the duration of the screening period and total time 
on study.  
Provided a clear definition of study completion.
Synopsis, Section 3.1, 
Section 3.2
Updated the study schematic to reflect the study design 
changes.
Revised the telephone and clinic visit schedule to assure 
laboratory measurement could be collected without exceeding 
weekly/monthly total blood volume restrictions.  
Synopsis, Table 1,
Section 3.1.2
Moved the PK sampling from Week 6 to Week 7 so that the 
samples could be collected without exceeding 
weekly/monthly total blood volume restrictions.
Synopsis, Table 1, 
Section 3.1.2, Section 7.2.4, 
Table 5
Clarified that blood for pharmacokinetic samples of postdose 
may be taken within ± 10 minutes of the time pre-specified.
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change
Section(s) Affected by 
Change
Clarified that end jejunostomy or ileostomy are examples  of 
small bowel ostomy rather than the stratification factors.
Synopsis, Section 3.1.2, 
Section 6.2.2
Clarified that all subjects regardless of treatment arm are 
eligible for the extension study.
Synopsis, Section 3.1.3
Clarified that if a subject treated with teduglutide meets the 
escape criteria, the assessments scheduled for the EOS visit 
should be conducted.
Synopsis, Table 2, 
Section 3.1.3, Section 6.2.3
Clarified that subjects must be 4 to 12 months corrected 
gestational age at screening.
Synopsis, Section 4.1
Changed dose adjustments to Week 12 rather than at every 
clinic visit to reduce site burden.
Synopsis, Table 1, 
Section 6.2.3
Clarified the definition of enteral autonomy.
Synopsis, Section 9.7.2
Updated the pharmacokinetic endpoint and analysis to reflect 
that only descriptive statistics will be calculated on plasma 
teduglutide concentration values. Pharmacokinetic parameters 
will be estimated using a population PK modeling approach 
as appropriate and reported separately.
Synopsis, Section 9.10
Removed assessment of the 5-level EuroQol five dimensions 
questionnaire to reduce caregiver burden.
Synopsis, Table 1, 
Section 7.2.5, Section 9.9
Clarified that native GLP-2 samples drawn while subjects are 
receiving teduglutide should be drawn at least 14 hours after 
Table 2, Section 7.2.2
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change
Section(s) Affected by 
Change
the previous dose.
Inserted a footnote to clarify that parenteral support and 
parenteral nutrition are used interchangeably.
Section 1.1
Removed the 5 mg vial of teduglutide as this size vial will not 
be supplied for this study.
Section 6.1
Clarified the procedures for assessing subject compliance. 
Section 6.5
Specified that it is acceptable to only enroll subjects who 
have already had an upper GI series with small bowel follow 
through performed since the subject’s most recent surgery.  
Section 7.2.1
Corrected the volume of blood to be collected for native 
GLP-2.
Table 5
Removed references to subject assent as assent is not possible 
in a study of infants. 
Section 7.1.1, Section 10.3.1
Clarified the definitions of the analysis sets.
Section 9.6
Clarified that an adjustment to enteral nutrition as appropriate
is part of the PN/IV adjustment algorithm.
Figure A-1
Minor editorial changes and corrections to typographical 
errors (which do not modify content and/or intent of the 
original document) were made.
Throughout protocol.
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Appendix 2
Guidelines for Nutritional Support Management During the Study
The nutritional support adjustment guidelines are designed to standardize management of 
parenteral and enteral nutritional support in this study. Adjustments to nutritional support should 
be considered at every scheduled clinic visit. Adjustments at phone visits may also be performed, 
but nutritional assessments at phone visits serve primarily to confirm that nutritional adjustments 
at prior clinic visits were tolerated.
All attempts should be made to follow the guidelines, but departure from the guidelines will not 
constitute a protocol deviation.
Clinical judgment is required within the algorithm. Each decision point requires integrating 
multiple sources of information into a yes/no decision. When individual data points are 
conflicting, the investigator must use their best judgment in the assessment.
If intestinal adaptation is occurring, reductions in parenteral support volume and calories are 
expected to be in decrements of 5 to 10% relative to baseline values. Parenteral support 
components are at the discretion of the investigator, but care should be taken to balance 
carbohydrate, fat, and protein. Likewise, if intestinal adaptation is occurring, enteral nutrition 
volume and calories should be increased in increments of approximately 10% relative to baseline 
values.
Assessment of the severity of malabsorption may require estimation of stool output for children 
who have mixed stool and urine output.
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.
During the 48-hour output measurement period prior to the subject’s scheduled visit, no further 
changes to the prescribed nutritional support should be made.
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Figure A-1:
Parenteral Nutrition/Intravenous Adjustment Algorithm for All Subjects  
BUN=blood urea nitrogen; Cr=creatinine; PN=parenteral nutrition; UNa=urine sodium; UOP=urine output; USpGr=Urine specific gravity; VS=vital signs; vol=volume
Adequately hydrated?
•
Normal exam and VS
•
Weight stable
•
UOP > 1 ml/kg/h
•
USpGr < 1.020
•
UNa > 20 meq/L
•
Stable, normal BUN/Cr
yes
no
Adequate weight gain 
and linear growth?
↑ PN kcal or no change
↓PN vol and kcal
↑ PN vol +/- kcal
yes
no
Assess severity of malabsorption and adjust EN as appropriate
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PROTOCOL: SHP633-301
TITLE:
A Randomized, Open-label, 24-Week Safety, Efficacy, and 
Pharmacokinetic Study of Teduglutide in Infants 4 to 12 Months of Age 
with Short Bowel Syndrome Who are Dependent on Parenteral Support
NUMBER
SHP633-301
PHASE
3 
DRUG:
Teduglutide
INDICATION:
Short bowel syndrome
EUDRACT NO.:
2017-003606-40
SPONSOR: 
Shire Human Genetic Therapies, Inc.
300 Shire Way
Lexington, MA 02421 USA
PROTOCOL 
HISTORY:
Original Protocol: 03 Oct 2017
Amendment 1: 18 Jan 2018
Amendment 1.1: 07 Aug 2018 (France-specific) 
Amendment 2.1: 04 Dec 2018 (France-specific)
Confidentiality Statement
This document contains confidential and proprietary information of Shire and is disclosed 
pursuant to confidentiality and non-disclosure obligations. This information should be used 
solely for the purposes for which it was provided and should not be copied, shared with, or 
disclosed to any third party without the express written consent of Shire.
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SHP633-301 Protocol Amendment 2.1 (France-specific) 
Teduglutide 
PROTOCOL SIGNATURE PAGE 
Sponsor's (Shire) Approval 
TDate-: 
I 
I 
Signature: 
.. 
, Global Clinical Develo ment 
Investigator's Acknowledgement 
I have read this protocol for Shire Study SHP633-301. 
Page2 
04 Dec 2018 
-] 
Title: A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic Study of 
Teduglutide in Infants 4 to 12 Months of Age with Short Bowel Syndrome Who are Dependent 
on Parenteral Supp01i 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) guidelines on Good Clinical Practice (GCP) and with the 
applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my patiicipation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Address: 
(please hand print or type) 
Signature: 
Date: 
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EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Adverse Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as 
Required by Protocol within 24 hours to the Shire Global Drug Safety Department. Applicable 
fax numbers and e-mail address can be found on the form (sent under separate cover).  A copy of 
this form must also be sent to the Shire Medical Monitor by e-mail at 
.
For protocol- or safety-related issues, the investigator must contact IQVIA Medical Support:
Primary Contact
Backup Contact 
, MD
, MD, PhD
Mobile:  
Mobile: 
Phone: 
(medical emergencies)
Phone: 
 (medical emergencies)
Email:  
Email: 
In addition, the investigator may also contact Shire:
, MD 
Mobile Phone: 
Email: 
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PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (e.g., inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (e.g., wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please use the E-mail address below to report the Product Quality Complaint:
Telephone numbers (provided for reference, if needed): 
Shire (USA)
 
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SUMMARY OF CHANGES FROM PREVIOUS VERSION
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2.1
Amendment Date
04 Dec 2018
France-specific
Description of Change and Rationale
Section(s) Affected by Change
The fax number currently used to send the Shire Medical 
Monitor a copy of the Shire Clinical Study Adverse Event 
Form for Serious Adverse Events (SAEs) and Non-serious 
AEs as Required by Protocol is now retired; a copy of the 
form must be sent by email only.
Updated emergency contact information to reflect the change 
of Shire medical monitor to 
, IQVIA back 
up medical support to 
, and IQVIA phone 
number for medical emergencies.
Emergency Contact 
Information
A single email address (
) is now used to 
report a Product Quality Complaint, independently from 
where it has originated.   
Product Quality Complaints
Added the new secondary efficacy endpoint “Time to achieve 
enteral autonomy” and statistical methodology to be used.
Synopsis, Section 9.7.1.2, 
Section 9.7.2
Updated  the information on the clinical studies with 
teduglutide in pediatric subjects to include the results of TED-
C14-006.
Section 1.2
Clarified that teduglutide is the investigational product for 
this study.
Section 6.1
Updated the dose selection rationale with results from a 
simulation work using the previous population 
pharmacokinetic model. Based on the totality of clinical data, 
0.05 mg/kg once daily is  expected to provide comparable 
Cmax concentrations in infants as compared to pediatric 
patients with SBS and was recommended as an evaluation 
dosing regimen in Study SHP633-301.
Section 6.2.5
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2.1
Amendment Date
04 Dec 2018
France-specific
Description of Change and Rationale
Section(s) Affected by Change
Clarified that rescreening of subjects in the study will not be 
allowed. (Administrative amendment dated 03 Oct 2018)
Section 7.1.1
Clarifications were made to the definition of adverse events.
Section 8.1, Section 8.1.5, 
Section 8.2.4
Added heart failure with severe fluid overload, determined by 
the sponsor or investigator to be related to the investigational 
product, to the list of events leading to interruption of 
investigational product administration. This addition is in 
alignment with the warnings and special precautions listed in 
the investigator brochure.
Section 8.4
As recommended by the FDA, specified that if the DMC 
recommends termination of this pediatric study, the 
recommendations will be communicated to the relevant 
regulatory agencies within 7 calendar days.
Section 9.4
Minor editorial changes and corrections to typographical 
errors (which do not modify content and/or intent of the 
original document) were made.
Throughout the protocol
See Appendix 1 for protocol history, including all amendments.  
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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
PRODUCT QUALITY COMPLAINTS..........................................................................................4
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................5
TABLE OF CONTENTS.................................................................................................................7
LIST OF TABLES.........................................................................................................................11
LIST OF FIGURES .......................................................................................................................11
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..................................................12
STUDY SYNOPSIS ......................................................................................................................13
STUDY SCHEDULES ..................................................................................................................18
BACKGROUND INFORMATION .......................................................................................22
1.
1.1
Short Bowel Syndrome ............................................................................................22
1.2
Teduglutide...............................................................................................................23
OBJECTIVES.........................................................................................................................25
2.
2.1
Rationale for the Study.............................................................................................25
2.2
Study Objectives ......................................................................................................25
STUDY DESIGN ...................................................................................................................26
3.
3.1
Study Design and Flow Chart ..................................................................................26
3.1.1
Screening Period ........................................................................................26
3.1.2
Treatment Period........................................................................................26
3.1.3
Follow-up Period .......................................................................................27
3.2
Study Duration .........................................................................................................27
3.3
Sites and Regions .....................................................................................................28
STUDY POPULATION.........................................................................................................29
4.
4.1
Inclusion Criteria......................................................................................................29
4.2
Exclusion Criteria.....................................................................................................29
4.3
Reproductive Potential .............................................................................................31
4.4
Discontinuation of Subjects .....................................................................................31
4.4.1
Reasons for Discontinuation......................................................................31
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit .....................32
PRIOR AND CONCOMITANT TREATMENT ...................................................................33
5.
5.1
Prior Medications and Procedures............................................................................33
5.2
Concomitant Medications and Procedures...............................................................33
5.3
Permitted Treatment.................................................................................................33
5.4
Prohibited Treatment................................................................................................33
INVESTIGATIONAL PRODUCT ........................................................................................34
6.
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6.1
Identity of Investigational Product...........................................................................34
6.2
Administration of Investigational Product ...............................................................34
6.2.1
Interactive Response Technology for Investigational Product 
Management...............................................................................................34
6.2.2
Allocation of Subjects to Treatment ..........................................................34
6.2.3
Dosing........................................................................................................34
6.2.4
Unblinding the Treatment Assignment......................................................35
6.2.5
Dose Selection Rationale ...........................................................................35
6.3
Labeling, Packaging, and Storage ............................................................................36
6.3.1
Labeling .....................................................................................................36
6.3.2
Storage and Handling.................................................................................37
6.4
Drug Accountability.................................................................................................37
6.5
Subject Compliance..................................................................................................39
STUDY PROCEDURES........................................................................................................40
7.
7.1
Study Schedule.........................................................................................................40
7.1.1
Screening....................................................................................................40
7.1.2
Treatment Period........................................................................................40
7.1.3
Follow-up Period .......................................................................................40
7.2
Study Evaluations and Procedures ...........................................................................40
7.2.1
Demographics and Other Baseline Characteristics....................................40
7.2.2
Efficacy Assessments.................................................................................41
7.2.3
Safety Assessments....................................................................................42
7.2.4
Pharmacokinetic Assessments ...................................................................45
7.2.5
Health Economics and Outcomes Research ..............................................45
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................46
8.
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................46
8.1.1
Severity Categorization..............................................................................46
8.1.2
Relationship Categorization.......................................................................47
8.1.3
Outcome Categorization ............................................................................47
8.1.4
Symptoms of the Disease under Study ......................................................48
8.1.5
Clinical Laboratory and Other Safety Evaluations ....................................48
8.1.6
Pregnancy...................................................................................................48
8.1.7
Abuse, Misuse, Overdose, and Medication Error ......................................48
8.2
Serious Adverse Event Procedures ..........................................................................49
8.2.1
Reference Safety Information ....................................................................49
8.2.2
Reporting Procedures.................................................................................49
8.2.3
Serious Adverse Event Definition .............................................................50
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8.2.4
Serious Adverse Event Collection Time Frame.........................................50
8.2.5
Serious Adverse Event Onset and Resolution Dates .................................50
8.2.6
Fatal Outcome............................................................................................51
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, 
and Site Reporting......................................................................................51
8.3
Adverse Events of Special Interest...........................................................................51
8.4
Dose Interruption Criteria ........................................................................................52
DATA MANAGEMENT AND STATISTICAL METHODS ...............................................53
9.
9.1
Data Collection.........................................................................................................53
9.2
Clinical Data Management.......................................................................................53
9.3
Statistical Analysis Process......................................................................................53
9.4
Planned Interim Analysis, and Data Monitoring Committee ...................................53
9.5
Sample Size Calculation and Power Considerations................................................54
9.6
Study Population ......................................................................................................54
9.7
Efficacy Analyses.....................................................................................................55
9.7.1
Efficacy Endpoints.....................................................................................55
9.7.1.1
Primary Efficacy Endpoint.....................................................................55
9.7.1.2
Secondary Efficacy Endpoints ...............................................................55
9.7.2
Method of Analysis-Efficacy Endpoints....................................................55
9.8
Safety Analyses ........................................................................................................56
9.8.1
Safety Endpoints ........................................................................................56
9.8.2
Method of Analysis-Safety Endpoints.......................................................57
9.9
Health Economics and Outcomes Research Analyses .............................................57
9.10
Pharmacokinetics Analyses......................................................................................57
SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES ............................................58
10.
10.1
Sponsor’s Responsibilities .......................................................................................58
10.1.1
Good Clinical Practice Compliance...........................................................58
10.1.2
Indemnity/Liability and Insurance.............................................................58
10.1.3
Public Posting of Study Information..........................................................58
10.1.4
Submission of Summary of Clinical Study Report to Competent 
Authorities of Member States Concerned and Ethics Committees............58
10.1.5
Study Suspension, Termination, and Completion......................................59
10.2
Investigator’s Responsibilities .................................................................................59
10.2.1
Good Clinical Practice Compliance...........................................................59
10.2.2
Protocol Adherence and Investigator Agreement ......................................59
10.2.3
Documentation and Retention of Records .................................................60
10.2.3.1
Electronic Case Report Forms................................................................60
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10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................60
10.2.3.3
Audit/Inspection .....................................................................................61
10.2.3.4
Financial Disclosure...............................................................................61
10.3
Ethical Considerations..............................................................................................61
10.3.1
Informed Consent.......................................................................................61
10.3.2
Institutional Review Board or Ethics Committee ......................................62
10.4
Privacy and Confidentiality......................................................................................62
10.5
Study Results/Publication Policy .............................................................................63
REFERENCES .......................................................................................................................65
11.
APPENDICES ........................................................................................................................67
12.
Appendix 1
Protocol History.........................................................................................68
Appendix 2
Guidelines for Nutritional Support Management During the Study ..........72
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LIST OF TABLES
Table 1:
Study Schedule: Visits -1 to 12 .....................................................................18
Table 2:
Study Schedule: Visits 13-28 ........................................................................20
Table 3:
Prohibited Treatment.....................................................................................33
Table 4:
List of Laboratory Tests ................................................................................43
Table 5:
Approximate Volume of Blood to be Drawn from Each Subject .................44
LIST OF FIGURES
Figure 1:
Study Schematic ............................................................................................26
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation
Definition
AE
adverse event
AUCss
area under the concentration-time curve at steady-state 
Cmax,ss
maximum plasma concentration at steady state
CRO
contract research organization
eCRF
electronic case report form
DMC
data monitoring committee
EDC
electronic data capture
EMA
European Medicines Agency
EN
enteral nutrition
EOS
end of study
EOT
end of treatment
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
gastrointestinal 
GLP
glucagon-like peptide
HIPAA
Health Insurance Portability and Accountability Act
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use
ICMJE
International Committee of Medicinal Journal Editors
I/O
oral fluid intake and urine output
IP
Investigational product
IRB
Institutional Review Board
ITT
intent-to-treat
MedDRA
Medical Dictionary for Regulatory Activities
PK
pharmacokinetics
PN
parenteral nutrition
SAE
serious adverse event
SAP
statistical analysis plan
SBS
short bowel syndrome
SC
subcutaneous
SD
standard deviation
SOC
standard of care
ULN
upper limit of normal 
US
United States
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STUDY SYNOPSIS
Protocol number: SHP633-301
Drug: Teduglutide
Title of the study: A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic Study of 
Teduglutide in Infants 4 to 12 Months of Age with Short Bowel Syndrome Who are Dependent on Parenteral 
Support
Number of subjects (total and for each treatment arm):
At least 10 subjects will be randomized: at least 5 subjects in a teduglutide treatment arm and at least 5 subjects in 
a standard of care (SOC) comparator arm
Investigator(s): Multicenter study
Site(s) and Region(s): 
This study is planned to be conducted in approximately 5 to 10 sites globally.
Study period (planned):
2017-2020
Clinical phase:
3
Objectives:
The objectives of this clinical study are to evaluate the safety, efficacy/pharmacodynamics and pharmacokinetics 
(PK) of teduglutide treatment in infants with short bowel syndrome (SBS) dependent on parenteral support.
Investigational product, dose, and mode of administration:
Teduglutide 0.05 mg/kg by subcutaneous (SC) injection once daily into 1 of the 4 quadrants of the abdomen or 
either thigh or arm.
Methodology:
This is a randomized, multicenter, open-label study, consisting of a 2 to 4 week screening period, a 24-week 
treatment period, and a 4-week follow-up period. 
* At EOS all subjects regardless of treatment arm may enroll in an extension study that will capture long-term 
safety data and provide the opportunity for additional teduglutide treatment.  The follow-up period for subjects in 
the teduglutide treatment arm may be interrupted and the subjects may proceed immediately to the EOS if at least 
one “escape” criteria is met.
Extension 
study* 
1
24
1
3
5
7
9
12
16
20
28
2 to 4
Weeks
Screening
Teduglutide 0.05 mg/kg SC once daily for 24 weeks
Site Visit 
Telephone Visit
Standard of care for 24 weeks
Baseline: treatment 
randomization
0
24
3
5
7
9
12
16
20
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Study eligibility will be confirmed during the screening period (minimum: 2 weeks; maximum 4 weeks). At the 
baseline visit (Week 0), subjects will be randomized 1:1 to the teduglutide or SOC treatment arm. Randomization 
will be stratified according to the presence of a small bowel ostomy (e.g., end jejunostomy or ileostomy). During 
the 24-week treatment period, subjects in the SOC treatment arm will receive standard medical therapy for SBS; 
while those in the teduglutide arm will receive 0.05 mg/kg SC once daily in addition to standard medical therapy. 
Subjects in both arms will follow the same visit schedule and assessments. Subjects will be monitored weekly 
with phone or clinic visits. Clinic visits will occur at Weeks 1, 3, 5, 7, 9, 12, 16, 20, 24, and 28. At all site visits 
and telephone contacts, safety will be monitored and nutritional support will be reviewed and adjusted as needed. 
To maintain consistency across centers, guidance and training will be provided to help sites follow the nutritional 
support adjustment guidelines (developed with SBS expert input and provided in the protocol) related to decisions 
for parenteral nutrition (PN) reduction and advances in enteral feeds based on weight gain, urine and stool output, 
and clinical stability. Deviations from the guidelines are not considered a protocol deviation.
Sparse PK sampling, in the teduglutide treatment arm only, will occur at baseline (predose and 1 hour 
±10 minutes and 4 hours ±10 minutes postdose) and at Week 7 or 12 (2 hours±10 minutes postdose).
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up period until the end 
of study (Week 28/EOS) during which time subjects will receive standard medical therapy, but no investigational 
product will be administered.  At EOS all subjects regardless of treatment arm may enroll in an extension study 
that will capture long-term safety data and provide the opportunity for additional teduglutide treatment.  The 
follow-up period for subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed 
immediately to the EOS if at least one of the following “escape” criteria is met:
1.
Increasing PN requirements following discontinuation of teduglutide.
2.
Deteriorating nutritional status (e.g., weight loss or growth failure) despite maximal tolerated enteral 
nutrition (EN) following teduglutide discontinuation.
3.
Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and electrolyte intake 
following teduglutide discontinuation.
4.
Severe diarrhea related to teduglutide discontinuation.
Inclusion and Exclusion Criteria:
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1.
Informed consent by the parent or legal guardian. 
2.
Male or female infant 4 to 12 months corrected gestational age at screening.
3.
Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and baseline.
4.
Short bowel syndrome with dependence on parenteral support to provide at least 50% of fluid or caloric 
needs.
5.
Stable PN requirements for at least 1 month prior to screening, defined as a ≤10% change in the 
weight-normalized parenteral total fluid and caloric intake, despite attempts to wean PN, 
notwithstanding transient instability for events such as sepsis or interruption of central venous access.
6.
Lack of terminal ileum and ileocecal valve
7.
Parent or legal guardian understands and is willing and able to fully adhere to study requirements as
defined in this protocol.
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Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1.
Previous treatment with teduglutide.
2.
Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus inclusion disease, 
etc.
3.
Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility, that is the primary contributing factor to feeding intolerance and 
inability to reduce parenteral support, prior to screening.  Dysmotility is defined as severe if it is 
expected to limit the advancement of enteral feeding.
4.
Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral aversion in the 
absence of a feeding tube.
5.
Intestinal obstruction or clinically significant intestinal stenosis.
6.
Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or major intestinal 
resection or anastomosis, within 3 months prior to screening or planned during the study period.
7.
Unstable cardiac disease.
8.
Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
9.
Biliary obstruction, stenosis, or malformation. 
10. Clinically significant pancreatic disease. 
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b.
Platelet count <100×10^3/µl due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d.
Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 2-week period
13. More than 3 serious complications of intestinal failure (e.g., catheter-associated bloodstream infections, 
interruption of nutrition due to feeding intolerance, catheter-associated thrombosis, severe fluid or 
electrolyte disturbances) within 1 month prior to or during screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile polyposis or 
Beckwith-Wiedemann syndrome, or first degree relative with early onset of gastrointestinal cancer 
(including hepatobiliary and pancreatic cancers). 
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 (GLP-2); 
insulin-like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs of these hormones; or 
glutamine. 
16. Participation in a clinical study using an experimental drug within 3 months or 5.5 half-lives of the 
experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, closely-related 
compounds, or any of the stated ingredients.
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts the subject at any 
undue risk, prevents completion of the study, or interferes with analysis of the study results.
19. Hypersensitivity to trace residues of tetracycline.
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20. Signs of active severe or unstable, clinically significant hepatic impairment shown by any of the below 
laboratory test results at screening:
a. Total bilirubin ≥2 x upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥5 x ULN
c. Alanine aminotransferase (ALT) ≥5 x ULN
For subjects with Gilbert’s disease:
d. Indirect (unconjugated) bilirubin ≥2 x ULN
Maximum Duration of Subject Involvement in the Study:
The study consists of a 2 to 4 week screening period, a 24-week treatment period, and a 4-week follow-up period. 
The maximum duration of participation for each subject is 32 weeks.
Study completion is defined as the last subject, last visit. This is the visit date at which the last subject on the 
study has his or her last follow-up visit on the study (whether during the 24-week treatment period or the 4-week 
follow-up period).
Endpoints:
Efficacy
Efficacy endpoints consist of the following:
Primary

Reduction in weight-normalized PN fluid volume by at least 20% from baseline at Week 24/EOT
Secondary

Reduction in weight-normalized parenteral calories by at least 20% from baseline to Week 24/EOT

Achievement of enteral autonomy by Week 24

Time to achieve enteral autonomy

Change in weight-normalized parenteral fluid volume from baseline to each visit

Change in weight-normalized parenteral calories from baseline to each visit

Change in weight-normalized enteral fluid volume from baseline to each visit

Change in weight-normalized enteral caloric intake from baseline to each visit

Increase in weight-normalized enteral fluid intake by at least 20% from baseline to Week 24/EOT

Increase in weight-normalized enteral caloric intake by at least 20% from baseline to Week 24/EOT
Pharmacokinetics
The pharmacokinetic endpoint is plasma teduglutide concentration at nominal time point.
Safety
Safety endpoints consist of the following:

Adverse events (AEs)

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output

Stool (including mixed) output  

Antibodies to teduglutide 
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Health Economics and Outcomes Research
Health economics and outcomes research (HEOR) endpoints include the following:

Cumulative number of hospitalization days during the study
Statistical Methods:
Efficacy
Analyses of weekly PN support will be based on 2 data sources: the subject diary data (also referred to as actual 
data) and the investigator prescribed data.  
The number and percentage of subjects who achieve at least a 20% reduction from baseline in weight-normalized 
average daily PN volume at Week 24/EOT and the number and percentage of subjects who achieve at least a 20% 
reduction from baseline in weight-normalized parenteral calories at Week 24/EOT will be summarized by 
treatment arm.
During the treatment period, a subject will be considered to have achieved enteral autonomy (completely weaned 
off PN) at a given visit if the investigator prescribes no PN at that visit and for the remainder of the treatment 
period, and there is no use of PN recorded in the subject diary during the week prior to that visit and for the 
remainder of the treatment period. During the follow-up period, a subject will be considered to have achieved 
enteral autonomy at a given visit if the investigator prescribes no PN at that visit and for the remainder of the 
follow-up period and there is no use of PN recorded in the subject diary during the week prior to that visit and for 
the remainder of the follow-up period. The number and percentage of subjects who achieve enteral autonomy at 
each scheduled visit, as well as at EOT, will be summarized by treatment arm. Descriptive statistics will be used 
to summarize time to achievement of enteral autonomy by treatment arm.
The absolute and percent change in weight-normalized weekly PN volume, parenteral calories, enteral fluid 
volume, and enteral caloric intake, from baseline to each scheduled visit, as well as at EOT, will be summarized 
by treatment arm using descriptive statistics.
The number and percentage of subjects who demonstrate an increase in weight-normalized enteral fluid intake by 
at least 20% from baseline to Week 24/EOT and the number and percentage of subjects who demonstrate an 
increase in weight-normalized enteral caloric intake by at least 20% from baseline to week 24/EOT will be 
summarized by treatment arm.
Pharmacokinetics
Plasma concentrations will be summarized using descriptive statistics (number, mean, standard deviation, 
geometric mean, coefficient of variation, minimum, median, and maximum) at nominal time points. 
Pharmacokinetic parameters will be estimated using a population PK modeling approach as appropriate and 
reported separately.
Safety
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Treatment-emergent AEs will be summarized by system organ class and preferred term using descriptive statistics 
(e.g., number and percentage of subjects). Adverse events will be summarized by severity and relationship to 
treatment. In addition, serious adverse events  will also be tabulated by overall and treatment-related events. AEs 
leading to treatment discontinuation and death will also be summarized.
For laboratory tests; vital signs; urine and stool output; weight, length, and head circumference Z-scores; and 
descriptive statistics (e.g., n, mean, standard deviation, median, minimum and maximum values, and the number 
and percentage of subjects in specified categories) will be used to summarize the absolute values and change from 
baseline at each visit.
The number and percentage of subjects classified as having antibodies to teduglutide will be used to summarize 
the presence of antibodies.  
Health Economics and Outcomes Research
The HEOR endpoints will be summarized descriptively.  
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STUDY SCHEDULES
Table 1:
Study Schedule: Visits -1 to 12
Procedures
Screening
Baseline 
(Week 0)
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
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit type
Site
Site
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Tel
Site
Study day
-14
0
7
14
21
28
35
42
49
56
63
70
77
84
±window (days)
-2 weeks
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Informed consent
X
Eligibility
X
X
Randomization
X
Demographics 
X
SBS history
X
Medical and surgical history
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications and 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, vital signs, 
weight
X
X
X
X
X
X
X
X
Length and head circumference
X
X
X
X
UGI/SBFT
X
Safety labs and urinalysisb, c
X
Xb
X
(X)
X
(X)
X
(X)
X
(X)
X
(X)
(X)
X
PK samplinga
X
 
[X]d
[X]d
Antibodies to teduglutidea,e
X
Xe
Native GLP-2f
X
Provide intake and output 
diariesg
X
X
X
X
X
X
X
X
Review diaries and nutritional 
support
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional support as 
neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense IPa, i
X
X
X
X
X
X
X
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Table 1:
Study Schedule: Visits -1 to 12
Procedures
Screening
Baseline 
(Week 0)
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
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit type
Site
Site
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Tel
Site
Study day
-14
0
7
14
21
28
35
42
49
56
63
70
77
84
±window (days)
-2 weeks
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Adjust IP dosej
X
EN=enteral nutrition; GLP-2=glucagon-like peptide 2; INR=international normalized ratio; IP=investigational product; PK=pharmacokinetics; PN=parenteral nutrition; PT=prothrombin time; 
UGI/SBFT=upper GI series with small bowel follow-through 
a Applicable to the teduglutide treatment arm only. 
b At baseline, safety labs (Table 4) and PK can be separated by 1 day if blood volumes are limiting. Safety labs at telephone visits will be collected at the discretion of the investigator. For all subjects in 
the teduglutide treatment arm, PT and INR will be tested at baseline, and repeated if clinically indicated.
c Urinalysis will consist of urine sodium and specific gravity. Urine collection should be attempted, but inability to obtain urinalysis is not a protocol deviation.
d Subjects will have blood samples taken for teduglutide PK analysis predose and 1 hour ±10 minutes and 4 hours ±10 minutes postdose at baseline (Visit 0). Subjects also will have blood samples taken 
for teduglutide PK analysis 2 hours ±10 minutes postdose at Week 7 (Visit 7) or Week 12 (Visit 12) of the treatment period.
e Samples for antibody analysis will be drawn at the baseline and Week 12 visits.  Blood samples while subjects are receiving teduglutide should be drawn at least 14 hours after the previous dose.
f Blood samples for native GLP-2 should be collected postprandial.  Native GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at investigator 
discretion based on weekly/monthly total volume.  
g Intake diaries will collect actual PN volume and hours per day and EN volume and calories. Intake diaries should be completed daily throughout the study. Urine and stool output should be recorded in 
the output diary over a 48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PN prescription. 
h Parenteral support adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment provided in Appendix 2.
i The initial dose will be calculated based on body weight measured at baseline (Visit 0).
j  The dose will be adjusted as needed, based on body weight measured at Week 12 visit.
Note: (X) denotes optional assessments; [X] denotes possible PK sampling time point (Refer to footnote “e”.)
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Table 2:
Study Schedule: Visits 13-28
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 
(EOT/ET)
Week 
25
Week 
26
Week 
27
Week 
28 
(EOS)a
Visit number
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit type
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Study day
91
98
105
112
119
126
133
140
147
154
161
168
175
182
189
196
±window (days)
±3
±3
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications
and procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, vital 
signs, weight
X
X
X
X
Length and head 
circumference
X
X
X
X
Safety labs and 
urinalysisb,c
(X)
(X)
(X)
X
(X)
(X)
(X)
X
(X)
(X)
(X)
X
(X)
(X)
(X)
X
Antibodies to 
teduglutided,e
X
Native GLP-2f
X
Provide intake and output 
diaries
X
X
X
Review diaries and 
nutritional supportg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional support 
as neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess follow-up period 
escape criteriad
Xi
Xi
Xi
X
Dispense IPd
X
X
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Table 2:
Study Schedule: Visits 13-28
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 
(EOT/ET)
Week 
25
Week 
26
Week 
27
Week 
28 
(EOS)a
Visit number
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit type
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Study day
91
98
105
112
119
126
133
140
147
154
161
168
175
182
189
196
±window (days)
±3
±3
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
EN=enteral nutrition; EOS=end of study; EOT=end of treatment; ET=early termination; GLP-2=glucagon-like peptide 2; INR=international normalized ratio; IP=investigational product; PN=parenteral 
nutrition; PT=prothrombin time; UGI/SBFT=upper GI series with small bowel follow-through
a At EOS subjects may enroll in an extension study, if subjects require treatment before the end of the 4-week follow-up they may enter the extension study immediately.  
b Safety labs at telephone visits will be collected at the discretion of the investigator. For all subjects in the teduglutide treatment arm, PT and INR are tested if clinically indicated.
c Urinalysis will consist of urine sodium and specific gravity.  
d Applicable to the teduglutide treatment arm only. 
e Samples for antibody analysis will be drawn at the EOS (Week 28) visit.
f Blood samples for native GLP-2 should be collected postprandial.  Blood samples drawn while subjects are receiving teduglutide should be drawn at least 14 hours after the previous dose. Native GLP-
2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at investigator discretion based on weekly/monthly total volume.  
g Intake diaries will collect actual PN volume and hours per day and EN volume and calories. Intake diaries should be completed daily throughout the study. Urine and stool output should be recorded in 
the output diary over a 48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PN prescription. 
h Parenteral support adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment provided in Appendix 2.
Note: (X) denotes optional assessments.
i If a subject treated with teduglutide meets the escape criteria, the assessments scheduled for the EOS visit should be conducted.
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BACKGROUND INFORMATION
1.
1.1
Short Bowel Syndrome
Short bowel syndrome (SBS) is a rare disorder resulting from congenital abnormalities or severe 
intestinal diseases that result in major surgical resections of the small intestine (O'Keefe et al., 
2006).  Unlike the adult population, the majority of cases of SBS in pediatric subjects are due to 
congenital anomalies or catastrophic events that occur during infancy such as necrotizing 
enterocolitis, gastroschisis, intestinal atresia, midgut volvulus, or long-segment Hirschsprung 
disease (Beattie et al., 2010; Goulet and Ruemmele, 2006).  A Canadian population-based study 
in neonates estimates an overall incidence of SBS to be 24.5 cases per 100,000 live births (Wales 
et al., 2004).  
The small intestine is capable of remarkable adaptation, but excessive loss of absorptive surface 
area or specialized functions can lead to dependence on parenteral nutrition (PN)1 fluids 
(O'Keefe et al., 2006).  Although PN is life-sustaining in intestinal failure, it is associated with 
serious complications, including liver disease, life-threatening catheter-related blood stream 
infections, and central venous thrombosis (Beattie et al., 2010; Goulet and Ruemmele, 2006).  
Dependence on PN is also associated with reduced quality of life in both patients and caregivers 
and has an extremely high cost of care (Huisman-de Waal et al., 2007).  About 30% of infants 
with SBS become independent of PN requirements within 12 months of the initial insult, and an 
additional 10% wean off PN within 24 months. After this time, linear intestinal growth slows.  It 
is estimated that 42% to 86% of pediatric patients with SBS are able to become independent of 
PN within 1 to 3 years (Gonzalez-Hernandez et al., 2017; Khan et al., 2015; Squires et al., 2012).  
Nevertheless, despite optimal medical management, some children remain dependent on PN for 
many years (Squires et al., 2012).  Infants who have less than 10% of expected small intestinal 
length for their gestational age have a low likelihood of ever achieving enteral autonomy (i.e., 
independence from parenteral support).  Providing the maximum tolerated amount of enteral 
nutrition (EN) has been the primary strategy to promote enteral adaptation (Spencer et al., 2005).  
Accelerating the adaptive process and achieving enteral autonomy is an urgent goal for all 
patients with SBS who are dependent on PN (Khan et al., 2015; Squires et al., 2012).  The 
adaptive process is in part controlled by glucagon-like peptide 2 (GLP-2), a 33 amino acid 
peptide hormone secreted from L-type enteroendocrine cells in the terminal ileum and colon in 
response to luminal nutrients and bile acids (Martin et al., 2006).  The post-prandial plasma 
concentration of GLP-2 in infants with SBS correlates with length of the remaining small 
intestine (Sigalet et al., 2004).  Infants who lack terminal ileum may have impaired adaptation 
due to inadequate production of GLP-2.
                                                
1 For the purpose of the study the terms parenteral support (PS) and parenteral nutrition (PN) are used 
interchangeably.
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1.2
Teduglutide
Teduglutide is a novel, recombinant analog of naturally occurring human GLP-2 that regulates 
the functional and structural integrity of the cells lining the gastrointestinal (GI) tract. 
Teduglutide is a 33-amino acid peptide that differs from native GLP-2 in the substitution of 
glycine for alanine at the second position at the N-terminus.  As a result, teduglutide 
demonstrates resistance to degradation by dipeptidyl peptidase 4 (DPP-4) and therefore 
maintains a longer elimination half-life (t1/2), approximately 2 hours in healthy adult subjects, 
1.3 hours in adult SBS subjects, and 0.22 hours in pediatric SBS subjects, compared to the native 
peptide, which has a t1/2 of approximately 7 minutes.  Teduglutide has been shown in animal 
studies and previous human clinical trials to increase villus height and crypt depth in the 
intestinal epithelium, thereby increasing the absorptive surface area of the intestines (Tappenden 
et al., 2013; Thymann et al., 2014). 
A Phase 3 study, TED-C13-003, has been completed in pediatric SBS subjects.  In this study, 
teduglutide was administered to 3 cohorts of pediatric subjects from ages 1-17 years.  
Thirty-seven pediatric subjects received teduglutide at doses of 0.0125, 0.025, or 0.05 mg/kg/day 
for 12 weeks.  Five additional pediatric subjects were enrolled in an observational standard of 
care (SOC) cohort.  There were clear dose-dependent effects of teduglutide seen at the 0.025 and 
0.05 mg/kg/day doses compared to SOC and the 0.0125 mg/kg/day dose.  In the 
0.025 mg/kg/day cohort there was a reduction in PN volume at Week 12 of 37%, including 
complete independence from PN support in 1 subject, and a reduction of 3.94 hours per day 
infusion time.  In the 0.05 mg/kg/day cohort there was a reduction in PN volume at Week 12 of 
39%, including complete independence from PN support in 3 subjects, and a reduction of 
4.18 hours per day infusion time.  Teduglutide was generally safe and well tolerated by pediatric 
subjects in all dosing cohorts.  There were no deaths during the study and no treatment-emergent 
serious adverse events (SAEs) related to teduglutide were reported.  No discontinuations from 
study were due to adverse events (AEs).  Additional studies in pediatric patients with SBS are 
ongoing.
TED-C14-006 is a recently completed study of pediatric subjects through 17 years which 
included 2 treatment arms: a teduglutide treatment arm and a SOC treatment arm. Subjects 
in both arms participated in a 2-week minimum screening period, a 24-week treatment 
period, and a 4-week follow-up period. During the screening period, subjects chose into 
which arm to enroll. During the 24-week treatment period, subjects in the SOC treatment 
arm received standard medical therapy for SBS; while those in the teduglutide treatment 
arm received daily subcutaneous (SC) injections of teduglutide (study drug) in addition to 
standard medical therapy. The subjects enrolling in the teduglutide treatment arm were 
randomized 1:1 in a double-blinded manner into 2 parallel dose groups: 0.025 mg/kg/day or 
0.05 mg/kg/day of teduglutide administered subcutaneously for 24 weeks. Compared to the 
SOC, treatment of pediatric subjects with SBS with teduglutide resulted in clinically 
meaningful reductions in PN/IV volume, calories, days per week, and hours per day. A total 
10% of subjects who received teduglutide achieved enteral autonomy within 24 weeks 
despite prior dependence on PN/IV for several years. Teduglutide treatment also resulted in 
increases in EN volume and caloric intake as well as plasma citrulline. 
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Although the differences in efficacy between the 0.025 and 0.05 mg/kg dose groups were small, 
a consistently greater effect was seen in the 0.05 mg/kg dose in all efficacy parameters. The 
pharmacokinetic (PK) properties were well characterized in this population and were consistent 
with the prior 12 week pediatric study. Teduglutide was generally well tolerated by pediatric 
subjects with SBS. The safety profile was favorable and consistent with the prior pediatric study, 
the underlying disease, and previous experience with teduglutide in adult subjects with SBS.
Teduglutide (0.05 mg/kg/day) is currently approved for the treatment of adult patients with SBS 
in >30 countries.  On 29 Jun 2016, the European Commission granted an extension of the Market 
Authorization for teduglutide for the treatment of patients aged 1 year and above with SBS.  
Always refer to the latest version of the investigator’s brochure for the overall risk/benefit 
assessment and the most accurate and current information regarding the drug metabolism, 
pharmacokinetics, efficacy and safety of teduglutide (SHP633).
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OBJECTIVES
2.
2.1
Rationale for the Study 
There is no approved pharmacological therapy to improve intestinal adaptation in infants with 
SBS who are dependent on parenteral support.  This study will evaluate whether teduglutide is 
safe and effective in this patient population.  
2.2
Study Objectives
The objectives of this study are to evaluate the safety, efficacy/pharmacodynamics and 
pharmacokinetics (PK) of teduglutide treatment in infants with SBS dependent on parenteral
support.
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STUDY DESIGN
3.
3.1
Study Design and Flow Chart
This is a randomized, multicenter, open-label study, consisting of a 2 to 4-week screening period, 
a 24-week treatment period and a 4-week follow-up period.  A schematic representation of the 
study design is presented in Figure 1.
Figure 1:
Study Schematic
*At EOS all subjects regardless of treatment arm may enroll in an extension study that will capture long-term safety data and 
provide the opportunity for additional teduglutide treatment.  The follow-up period for subjects in the teduglutide treatment arm 
may be interrupted and the subjects may proceed immediately to the EOS if at least one “escape” criteria is met.
3.1.1
Screening Period 
Study eligibility will be confirmed during the screening period (minimum: 2 weeks; maximum: 
4 weeks).  The schedule of evaluations to be conducted during the Screening Period can be found 
in Table 1.
3.1.2
Treatment Period
At the baseline visit (Week 0), subjects will randomized 1:1 to the teduglutide or SOC treatment 
arm. Randomization will be stratified according to the presence of a small bowel ostomy (e.g., 
end jejunostomy or ileostomy). During the 24-week treatment period, subjects in the SOC 
treatment arm will receive standard medical therapy for SBS, while those in the teduglutide arm 
will receive 0.05 mg/kg by SC injection once daily in addition to standard medical therapy. 
Extension 
study* 
1
24
1
3
5
7
9
12
16
20
28
2 to 4
Weeks
Screening
Teduglutide 0.05 mg/kg SC once daily for 24 weeks
Site Visit 
Telephone Visit
Standard of care for 24 weeks
Baseline: treatment 
randomization
0
24
3
5
7
9
12
16
20
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Subjects in both arms will follow the same visit schedule and assessments. Subjects will be 
monitored weekly with phone or clinic visits. Clinic visits will occur at Weeks 1, 3, 5, 7, 9, 12, 
16, 20, 24, and 28. At all site visits and telephone contacts, safety will be monitored and 
nutritional support will be reviewed and adjusted as needed. To maintain consistency across 
centers, guidance and training will be provided to help sites follow the nutritional support 
adjustment guidelines (developed with SBS expert input and provided in the protocol) related to 
decisions for PN reduction and advances in enteral feeds based on weight gain, urine and stool 
output, and clinical stability (Appendix 2). Deviations from the guidelines are not considered a 
protocol deviation.
Sparse PK sampling, in the teduglutide treatment arm only, will occur at baseline (predose and 
1 hour ±10 minutes and 4 hours ±10 minutes postdose) and at Week 7 or 12 (2 hours±10 minutes 
postdose).
The schedule of evaluations for the Treatment Period can be found in Table 1 (Visits -1 to 12) 
and Table 2 (Visits 13 to 28).  
3.1.3
Follow-up Period
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up 
period until the end of study (Week 28/EOS) during which time subjects will receive standard 
medical therapy, but no investigational product (IP) will be administered. At EOS, all subjects 
regardless of treatment arm may enroll in an extension study that will capture long-term safety 
data and provide the opportunity for additional teduglutide treatment. The follow-up period for 
subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed 
immediately to the EOS visit if at least one of the following “escape” criteria is met:
1. Increasing PN requirements following discontinuation of teduglutide.
2. Deteriorating nutritional status (e.g., weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation.  
4. Severe diarrhea related to teduglutide discontinuation.
The schedule of evaluations for the Follow-up Period can be found in Table 2 (Visits 13 to 28).
3.2
Study Duration
The study consists of a 2 to 4-week screening period, a 24-week treatment period and a 4-week 
follow-up period.  The maximum duration of participation for each subject is 32 weeks.
Study completion is defined as the last subject, last visit. This is the visit date at which the last 
subject on the study has his or her last follow-up visit on the study (whether during the 24-week 
treatment period or the 4-week follow-up period).
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3.3
Sites and Regions
This study is planned to be conducted at approximately 5 to 10 sites globally.
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STUDY POPULATION
4.
At least 10 subjects will be randomized: at least 5 subjects in a teduglutide treatment arm and at 
least 5 subjects in an SOC comparator arm.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1. Informed consent by the parent or legal guardian. 
2. Male or female infant 4 to 12 months corrected gestational age at screening.
3. Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and baseline.
4. Short bowel syndrome with dependence on parenteral support to provide at least 50% of fluid 
or caloric needs.
5. Stable PN requirements for at least 1 month prior to screening, defined as a ≤10% change in 
the weight-normalized parenteral total fluid and caloric intake, despite attempts to wean PN, 
notwithstanding transient instability for events such as sepsis or interruption of central 
venous access.
6. Lack of terminal ileum and ileocecal valve.
7. Parent or legal guardian understands and is willing and able to fully adhere to study 
requirements as defined in this protocol.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1. Previous treatment with teduglutide.
2. Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus 
inclusion disease, etc.
3. Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility, that is the primary contributing factor to feeding intolerance 
and inability to reduce parenteral support, prior to screening.  Dysmotility is defined as 
severe if it is expected to limit the advancement of enteral feeding.
4. Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral 
aversion in the absence of a feeding tube.
5. Intestinal obstruction or clinically significant intestinal stenosis.
6. Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or major 
intestinal resection or anastomosis, within 3 months prior to screening or planned during the 
study period.
7. Unstable cardiac disease.
8. Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
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9. Biliary obstruction, stenosis, or malformation. 
10. Clinically significant pancreatic disease. 
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following 
parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b. Platelet count <100×10^3/µL due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d. Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 2 week 
period.
13. More than 3 serious complications of intestinal failure (e.g., catheter-associated bloodstream 
infections, interruption of nutrition due to feeding intolerance, catheter-associated 
thrombosis, severe fluid or electrolyte disturbances) within 1 month prior to or during 
screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile polyposis or 
Beckwith-Wiedemann syndrome, or first degree relative with early onset of gastrointestinal 
cancer (including hepatobiliary and pancreatic cancers). 
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 
(GLP-2); insulin-like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs of 
these hormones; or glutamine. 
16. Participation in a clinical study using an experimental drug within 3 months or 5.5 half-lives 
of the experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, 
closely-related compounds, or any of the stated ingredients.  
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts the 
subject at any undue risk, prevents completion of the study, or interferes with analysis of the 
study results.
19. Hypersensitivity to trace residues of tetracycline.
20. Signs of active severe or unstable, clinically significant hepatic impairment shown by any of 
the below laboratory test results at screening:
a.Total bilirubin ≥2 x upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥5 x ULN
c.
Alanine aminotransferase (ALT) ≥5 x ULN
For subjects with Gilbert’s disease:
d. Indirect (unconjugated) bilirubin ≥2 x ULN
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4.3
Reproductive Potential 
Not applicable; this study will enroll infants.
4.4
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution.  The investigator or sponsor may 
withdraw the subject at any time (e.g., in the interest of subject safety).  The investigator should 
discuss withdrawal of a subject from investigational product with the medical monitor as soon as 
possible.
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 24/EOT/early termination are to be performed as completely as possible. Whenever 
possible, all discontinued subjects should also undergo the protocol-specified 4-week Follow-up 
Period. Comments (spontaneous or elicited) or complaints pertaining to IP discontinuation made 
by the subject must be recorded in the source documents. The reason for discontinuation, the 
date and the total amount of investigational product administered must be recorded in the 
electronic case report form (eCRF) and source documents.
Subjects who discontinue will not be replaced. 
4.4.1
Reasons for Discontinuation
The reason(s) for permanent discontinuation of treatment and/or withdrawal from the study must 
be determined by the investigator, and recorded in the subject’s medical record and in the eCRF.  
If a subject is withdrawn for more than 1 reason, each reason should be documented in the source 
document, and the most clinically relevant reason should be entered in the eCRF.
Reasons for discontinuation include, but are not limited to:

Adverse event

Death

Lost to follow-up

Physician decision

Protocol deviation

Study terminated by sponsor

Withdrawal by parent/guardian

Lack of efficacy

Other
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4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact the parent(s)/guardian(s) of any 
subject lost to follow-up at any time point prior to the last scheduled contact (office visit or 
telephone contact). At least 1 of these documented attempts must include a written 
communication sent to the subject’s last known address via courier or mail (with an 
acknowledgement of receipt request) asking that they return to the site for final safety 
evaluations and return any unused investigational product.
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PRIOR AND CONCOMITANT TREATMENT
5.
5.1
Prior Medications and Procedures
Prior treatment includes all treatment and procedures (including but not limited to prescription 
treatments, herbal treatments, vitamins, non-pharmacological treatment, as appropriate) received 
within 14 days prior to the screening visit (Visit -1) (or pharmacokinetic equivalent of 5 half 
lives, whichever is longer, must be recorded on the appropriate eCRF page.
5.2
Concomitant Medications and Procedures
The administration of all medications including concomitant medications (including prescription 
and nonprescription medications, dietary and nutritional supplements, and vitamins) and PN 
must be recorded from the first dose of investigational product and for the duration of the study 
in the appropriate sections of the eCRF.  Any diagnostic, surgical or other therapeutic treatments 
received by a subject during the course of the study will also be recorded on the eCRF.
The mechanism of action of teduglutide may increase enteral absorption of oral drugs (e.g., 
drugs used for management of SBS such as motility medication, opioids, psychotropics, 
metronidazole), so consideration should be given to modifying concomitant enteral medication 
regimens. Titration of concomitant enteral medications should be considered when drugs, 
especially those with a narrow therapeutic index (e.g., warfarin, digoxin, psychotropics) are
given.
5.3
Permitted Treatment
Standard medical therapy for SBS should be continued.
5.4
Prohibited Treatment
The following medications are prohibited during teduglutide treatment and within the provided 
timeframe prior to the pretreatment visit (Table 3):
Table 3:
Prohibited Treatment
Prior Therapy
Time Restriction Prior to 
the Pretreatment Visit
Teduglutide
Any
GLP-2, human growth hormone, or analogs of these hormones
6 months
Octreotide, GLP-1 analogs, and enteral glutamine
30 days
GLP=glucagon-like peptide
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INVESTIGATIONAL PRODUCT
6.
6.1
Identity of Investigational Product
The SOC treatment arm will receive standard medical therapy for SBS; while those in the 
teduglutide arm will receive 0.05 mg/kg SC once daily in addition to standard medical therapy.
The investigational product is teduglutide, which will be provided in sterile, single-use 3 mL 
vials containing 1.25 mg teduglutide as a white lyophilized powder to be reconstituted before use 
with 0.5 mL sterile water for injection. In addition to the active ingredient (teduglutide), each 
vial of teduglutide contains L-histidine, mannitol, monobasic sodium phosphate monohydrate, 
and dibasic sodium phosphate as excipients. Additional information is provided in the current 
investigator’s brochure.
6.2
Administration of Investigational Product
6.2.1
Interactive Response Technology for Investigational Product Management
All investigative study sites will be initially provided with sufficient investigational product to 
randomly assign a subject into the study (for either of the proposed treatment groups).  
Randomization will occur through an interactive response system. Random assignment of a 
subject will trigger replacement supplies for that investigative study site.
6.2.2
Allocation of Subjects to Treatment
Subjects will be randomized 1:1 to the teduglutide or SOC treatment arm.  Randomization will 
be stratified according to the presence of a small bowel ostomy (e.g., end jejunostomy or 
ileostomy).  The actual treatment given to individual subjects is determined by a randomization 
schedule.
Subject numbers are assigned to all subjects as they consent to take part in the study.  Within 
each site (numbered uniquely within a protocol), the subject number is assigned to subjects 
according to the sequence of presentation for study participation.  
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined.
6.2.3
Dosing
The initial dose will be calculated based on body weight measured at baseline (Visit 0), and 
adjusted as needed, based on body weight measured at Week 12.  No other adjustments to dose 
will be made during the teduglutide treatment period, unless discussed with the sponsor’s 
medical monitor. 
Following reconstitution, teduglutide will be administered by SC injection once daily (QD) into 
1 of the 4 quadrants of the abdomen (in subjects without a stoma) or into either the thigh or arm.  
For subjects with a stoma, the quadrant of the abdomen containing the stoma should not be used.  
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Teduglutide should be used as soon as possible after reconstitution, but no more than 3 hours 
later.
The subject should be dosed at approximately the same time each day. Consecutive doses should 
be separated by at least 12 hours.  Each day, the injection site should be alternated.  
Any subject who achieves complete independence from PN support at any time during the 
treatment period will continue to receive teduglutide treatment.
The first SC injection in teduglutide-naïve subjects should be administered under the supervision 
of the investigator or designee and the subject observed for hypersensitivity reactions for at least 
4 hours during their initial dosing visit.  The site of administration (arm, thigh, and abdomen) of 
the first teduglutide dose must be specified and recorded in the eCRF. 
Detailed instructions for reconstitution and injection of the investigational product can be found 
in the Instructions for Use. 
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up 
period until the end of study (Week 28/EOS) during which time subjects will receive standard 
medical therapy, but no investigational product will be administered.  At EOS all subjects 
regardless of treatment arm may enroll in an extension study that will capture long-term safety 
data and provide the opportunity for additional teduglutide treatment.  The follow-up period for 
subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed 
immediately to the EOS if at least one of the following “escape” criteria is met:
1. Increasing PN requirements following teduglutide discontinuation.
2. Deteriorating nutritional status (e.g., weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation.  
4. Severe diarrhea related to teduglutide discontinuation.
6.2.4
Unblinding the Treatment Assignment
Not applicable for this open-label study.
6.2.5
Dose Selection Rationale
Teduglutide is approved for adult and pediatric use in the EU at a dose of 0.05 mg/kg SC once 
daily.  A completed 12-week dose finding study (TED-C13-003) demonstrated that teduglutide 
dosing at 0.025 and 0.05 mg/kg/day was associated with a favorable benefit-risk profile most 
meaningful at the 0.05 mg/kg/day dose (Carter et al., 2017). 
Population pharmacokinetic modeling and simulations were conducted to determine the optimal 
dose to be used in pediatric subjects using data from 8 adult clinical studies including adult Phase 
1 studies and Phases 2/3 studies as well as TED-C13-003 and suggested the same adult dose 
(0.05mg/kg) in pediatric subjects (aged between 1.67-14.7 years) (Marier et al., 2017).
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To support dosing in the current age group, further PK simulation was conducted based on the 
population PK model previously established and a virtual population of 1000 pediatric patients 
created based on Centers for Disease Control (CDC) growth charts in the target age group (4 to 
12 months) and taking into consideration body weights of pediatric patients with SBS enrolled in 
study TED-C13-003 and TED-C14-006 (approximately 15% lower than healthy subjects in the 
same age group). The model was customized by including a maturation function on clearance 
(CL/F) as a function of estimated glomerular filtration rate. Monte Carlo simulations for all age 
groups were performed according to the SC dosing regimens of 0.0125, 0.025 and 0.05 mg/kg 
every 24 hours.  Rich concentration-time profiles were simulated with the customized population 
PK model to derive the exposure metrics area under the concentration curve at steady state 
(AUCss) and maximum concentration at steady state (Cmax,ss). Exposure parameters in infant 
patients were compared to those derived in pediatric (1-17 years) and adult (≥18 years) patients 
with SBS using a Bayesian approach. Based on the clinical observations, Cmax is considered to be 
associated with clinical responses. Following 0.05 mg/kg daily SC administration, the median 
Cmax,ss of teduglutide in neonate patients (24.9 ng/mL) was within 20% of that observed in the 
2 to 4 and 4 to 6 years age groups (26.9 and 29.4 ng/mL, respectively); and approximately ~28% 
lower than that in adult patients with SBS. The median Cmax,ss of teduglutide in infant patients 4
to 12 months (41.9 ng/mL) following 0.05 mg/kg once daily was within 8% of that previously 
observed in adult patients with SBS (39.0 ng/mL, refer to the attached Simulation Report). In 
addition, individual simulated Cmax,ss values of teduglutide in infant patients 4 to 12 months 
(25.6 to 65.1 ng/mL) were contained within the range of Cmax,ss previously observed in pediatric 
patients 1 to 17 years (20.7 to 77.4 ng/mL). The clinical package in conjunction with Cmax was 
considered to support teduglutide dose selection since AUCss was previously shown not to 
correlate with efficacy. Individual simulated AUCss values of teduglutide in infant patients 4 to 
12 months (66.9 to 160 ng.h/mL) following 0.05 mg/kg once daily were contained within the 
range of AUCss values previously observed in pediatric patients 1 to 17 years (63.5 to 
421 ng.h/mL). Based on the totality of clinical data, 0.05 mg/kg once daily is expected to provide 
comparable Cmax concentrations in infants as compared to pediatric patients with SBS and was 
recommended as an evaluation dosing regimen in Study SHP633-301.
6.3
Labeling, Packaging, and Storage
6.3.1
Labeling
The investigational product will be packaged, labeled, and shipped to the study site by the 
sponsor or designee.  Kits containing 7 vials of investigational product will be provided for this 
study.  The vials will be labeled in accordance with applicable regulatory requirements. 
Ancillary kits, containing supplies needed for the reconstitution and administration of the 
investigational product will also be provided and labeled in accordance with the applicable 
regulatory requirements. 
All investigational product used in this study will be manufactured, tested, labeled, and released 
according to current legal requirements and Good Manufacturing Practice.
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6.3.2
Storage and Handling
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.
Investigational product must be kept in a locked area with access restricted to specific study 
personnel. Investigational product will be stored refrigerated at a temperature between 2-8°C 
(35.6-46.4°F) until dispensed to a subject. Once dispensed to a subject, the IP can be stored 
refrigerated or up to a controlled room temperature (acceptable range of 2-25°C, or 35.6-77°F). 
Parent/legal guardian will be instructed to keep the subject’s IP and sterile water diluent at 
controlled room temperature. If there are concerns that the controlled room temperature cannot 
be maintained, the IP may be refrigerated. The IP is for single use only, and should be used 
within 3 hours following reconstitution.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (i.e., certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), e.g., fumigation of a 
storage room.
Investigational products are distributed by the pharmacy or nominated member of the study 
team. The pharmacist/nominated team member will enter the unique subject identifier on the 
investigational product bottle/carton labels, as they are distributed.
6.4
Drug Accountability
Investigational product will not be dispatched to the study site until the sponsor or 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 investigational product 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.  Kits will be shipped to the site once the 
subject is screened.
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Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects.  The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition.  Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for dispensing investigational product.  Where 
permissible, tasks may be delegated to a qualified designee (e.g., a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator.  
This delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee will dispense the investigational product only to subjects 
included in this study following the procedures set out in the study protocol.  Investigational 
product kits will be dispensed at each of the applicable study visits at which the subject is 
required to be at the clinic.  Each investigational product kit is sufficient for a treatment period of 
1 week and enough kits will be supplied to cover the period until the next planned study visit.  
Additional study kits will be provided as necessary.
Each subject will be given the investigational product according to the protocol.  The 
investigator is to keep a current record of the inventory and dispensing of all clinical supplies.  
All dispensed medication will be documented on the eCRFs and/or other investigational product 
record. The investigator is responsible for assuring the retrieval of all study supplies from 
subjects.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor.  If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.
At the end of the study, or as instructed by the sponsor, all unused stock, subject returned 
investigational product, and empty/used investigational product packaging are to be sent to the 
sponsor or designee.  The investigator is responsible for assuring the retrieval of all study 
supplies from subjects.
Returned investigational product must be counted and verified by clinical site personnel and the 
sponsor (or study monitor). Shipment return forms, when used, must be signed prior to shipment 
from the site.  Contact the sponsor for authorization to return any investigational product prior to 
shipment.  Shipment of all returned investigational product must comply with local, state, and 
national laws. 
Please see the Pharmacy Manual for additional information.
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6.5
Subject Compliance
The parent(s)/guardian(s) of subjects must be instructed to bring unused investigational product 
and empty/used investigational product packaging to every visit. Drug accountability must be 
assessed and recorded at the container/packaging level for unused investigational product that is 
contained within the original tamper-evident sealed container (e.g., bottles, trays, vials) or at the 
individual count level for opened containers/packaging. 
Subject compliance will be checked by site personnel at every visit by reviewing the subject 
diaries and asking the subject or the subject’s parent or legally-authorized representative if they 
have administered the investigational product according to instructions. If any doses have been 
missed, the reason for missed dose should be documented in the subject’s source documentation 
including, as applicable, the eCRF.
The investigator is responsible for contacting the sponsor or designee when the subject’s daily 
investigational product dosing regimen is interrupted. Attempts should be made to contact the 
sponsor or designee prior to dose interruption. Reasons for dosage interruption may include but 
are not limited to hospitalization and AEs, a lapse in investigational product delivery, etc.
Subjects who have received 80% of the planned doses administered will be assessed as being 
compliant with the study protocol.
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STUDY PROCEDURES
7.
7.1
Study Schedule
Detailed study procedures and assessments to be performed for subjects throughout the study are 
outlined in the study schedules (Table 1 and Table 2) and must be referred to in conjunction with 
the instructions provided in this section. 
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 24/EOT are to be performed as completely as possible.  Whenever possible, all 
discontinued subjects should also undergo the protocol-specified 4-week Follow-up Period.  
7.1.1
Screening
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent from the 
parent(s)/guardian(s) of the subject. The screening visit assessments and procedures, beginning 
with informed consent, will be performed as outlined in Table 1. Rescreening will not be 
allowed.
7.1.2
Treatment Period
The randomized Treatment Period will comprise Weeks 1 to 24, during which all assessments 
will be performed as outlined in Table 1 and Table 2.
7.1.3
Follow-up Period
The Follow-up Period will comprise Weeks 25 to 28, during which all assessments will be 
performed as outlined in Table 2.
7.2
Study Evaluations and Procedures
7.2.1
Demographics and Other Baseline Characteristics
Demographics and Medical History
Demographic and/or other baseline variables obtained at the screening and/or baseline visits are 
listed below. Abnormal findings of clinical significance (if any) will be recorded as past medical 
history.

Demography (including age, gestational age, sex, and race)

Medical history (including surgical history)

SBS history, including remnant anatomy
Upper Gastrointestinal Series with Small Bowel Follow-through
An upper GI contrast series with small bowel follow-through will be performed on all subjects 
during the screening period if one has not been done since the subject's last GI surgery. 
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It is acceptable to only enroll subjects who have already had an upper GI series with small bowel 
follow-through performed since the subject’s most recent surgery.  
7.2.2
Efficacy Assessments
Subject Diaries
All available diary data will be reviewed by the investigator or their designee at each clinic and 
telephone visit to assess clinical status and opportunity for PN reduction and advance in feeds.  
Parenteral support adjustments should be made after review of the intake and output diaries and 
the safety lab data according to the guidance for nutrition support adjustment provided in 
Appendix 2.
Intake Diary
Intake diaries will be used to collect and evaluate each subject’s nutritional support. The 
parent/legally authorized representative/study site staff will complete the appropriate fields of the 
PN and EN sections of the intake diary daily throughout the study.
The following data will be captured in the intake diaries:

Parenteral support volume and infusion duration

Enteral nutrition (formula) including volume and calories
Site personnel will determine the actual PN and EN daily calories based on diary entries.
Output Diary
Urine and stool output should be recorded in the output diary over a 48-hour period of nutritional 
stability before every clinic visit; in addition, output should be recorded for subjects within 
1 week of implementing a change in the PN prescription.
Urine data:

Measure and record the weight of all urine-only diapers. Urine volume will be calculated 
using the following formula: 1 g (scale weight) = 1 mL or 1 cc

At the discretion of the investigator, the parent or legal guardian/study site staff may be 
asked to collect the first void after the daily PN infusion to measure specific gravity
Stool data (includes diapers with mixed urine and stool):

Record the weight of diapers containing stool (including diapers with mixed urine and 
stool) as stool output and score the stool consistency (see Output diary). Stool volume 
will be calculated using the formula: 1 g (scale weight)=1 mL or 1 cc
All ostomy output volume should be recorded.  
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Native GLP-2
Blood samples for native GLP-2 should be collected postprandial.  Blood samples while subjects 
are receiving teduglutide should be drawn at least 14 hours after the previous dose.  Native 
GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject 
weight or at investigator discretion based on weekly/monthly total volume.  
7.2.3
Safety Assessments
Laboratory Evaluations
Safety laboratory tests to be performed at site visits consist of clinical chemistry, hematology, 
and urinalysis and will be performed as outlined in the study plan (Table 1 and Table 2). 
Scheduled laboratory testing will be processed by a central lab. All laboratory assays will be 
performed according to the central laboratory’s normal procedures. Reference ranges are to be 
supplied by the laboratory. The investigator should assess out-of-range clinical laboratory values 
for clinical significance, indicating if the value(s) is/are not clinically significant or clinically 
significant. Abnormal clinical laboratory values, which are unexpected or not explained by the 
subject’s clinical condition, may, at the discretion of the investigator or sponsor, be repeated as 
soon as possible until confirmed, explained, or resolved.
During the Treatment Period, subjects will also have safety labs within approximately 5 to7 days 
after a PN adjustment.  Safety labs performed after PN adjustment and between site visits will 
consist of clinical chemistry and urinalysis and may be processed by the central laboratory or a 
local laboratory.  Local lab results are not required to be entered in the eCRFs; however, if the 
local lab results indicate any new clinically significant changes, they must be reported as an 
adverse event (see Section 8). Urine specimen collection should be attempted as part of the 
safety labs, but lack of urinalysis will not constitute a protocol deviation.
At baseline, blood samples for safety labs and PK can be separated by 1 day if blood volumes are 
limiting.  
Safety labs at telephone visits will be collected at the discretion of the investigator.  
For all subjects in the teduglutide treatment arm, prothrombin time (PT) and international 
normalized ratio (INR), tested at baseline, will be repeated if clinically indicated.
New clinically significant labs should be reported as AEs.
Close Monitoring Criteria Related To Liver Test Abnormalities:  
The investigator should contact the medical monitor within 24 hours of their awareness if the 
subject develops any of the following changes in laboratory parameters:

ALT or AST >5x ULN and >2x baseline value

Total or direct bilirubin that is >2x baseline value or an absolute increase of  ≥3 mg/dL 
(51.3 µmol/L)
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If such changes are observed, the labs should be repeated along with an INR, and an inquiry 
should be made as to the presence of clinical symptoms consistent with new liver injury. The 
subject should be followed closely to determine the trajectory of the laboratory abnormalities and 
appropriate evaluations should be made, such as abdominal ultrasound with Doppler imaging to 
exclude vascular causes and biliary obstruction, consideration of sepsis, liver hypoperfusion, 
acute viral hepatitis (such as hepatitis A, EBV, or HSV), exposure to hepatotoxic medications, 
mitochondrial hepatopathy, or metabolic liver disease (such as hereditary fructose intolerance or 
arginosuccinate synthetase deficiency).  Further evaluations can be performed at the discretion of 
the investigator in consultation with the Shire medical monitor.
The following clinical laboratory assessments will be performed according to the study 
schedules:
Table 4:
List of Laboratory Tests
Biochemistry:

Albumin 

Alkaline phosphatase 

Alanine aminotransferase 

Amylase

Aspartate aminotransferase 

Bicarbonate

Bilirubin (total and indirect)

Blood urea nitrogen 

Calcium (total)

Chloride

Cholesterol

C-reactive protein 

Creatinine

Estimated Glomerular Filtration Rate 
(Schwartz formula)

Gamma-glutamyl transferase 

Glucose

Lipase

Magnesium

Phosphorus

Potassium 

Sodium 

Triglycerides
Hematologya:

Hematocrit 

Hemoglobin 

Platelet count

Red blood cell count 

Red blood cell morphology, if needed

White blood cell count with differential
Coagulationb:

Prothrombin time

International normalized ratio
Urinalysis: 

Specific gravity  

Urine Sodium
a Hematology is not collected at Week 1 or at telephone visits.
b For all subjects in the teduglutide treatment arm, PT and INR will be tested at baseline and repeated only if clinically indicated.
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Antibodies to Teduglutide 
Blood samples will be drawn to test for antibodies to teduglutide.  Samples will be taken before 
teduglutide administration at the screening visit (Visit -1) and at least 14 hours after the previous 
dose at Week 12 (Visit 12); samples may be drawn from a central line or peripheral access. One 
additional sample will be collected at the EOS 4 weeks after the EOT (i.e., Week 28 or EOS).  
Volume of Blood
Efforts will be made to minimize the amount of blood drawn from all pediatric subjects 
participating in this study. The volumes of blood to be drawn from each subject will vary 
depending on clinical status. Approximate volumes of blood to be drawn from each subject are 
shown in Table 5.
Table 5:
Approximate Volume of Blood to be Drawn from Each Subject 
Assessment
Sample 
Volume (mL)
No. 
Samples 
Total 
Volume (mL)
Notes
Subjects Receiving Teduglutide Treatment
Biochemistry 
0.6
12
7.2
Hematology
0.6
11
6.6
Coagulation 
Parameters
0.6
1
0.6
PT and INR tested at baseline 
only, repeat while on study 
only if clinically indicated.
Antibodies
1.5
5
7.5
Pharmacokinetics
1.5
4
6.0
Baseline: 3 timepoints
Week 7: 1 timepoint OR
Week 12: 1 timepoint
Native GLP-2
1.5
3
4.5
Total mL:
6.3
36
32.4
Subjects Receiving Standard of Care
Biochemistry 
0.6
12
7.2
Hematology
0.6
11
6.6
Native GLP-2
1.5
3
4.5
Total mL:
2.7
26
18.3
GLP=glucagon-like peptide; INR=international normalized ratio; PT=prothrombin time
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment. When more than 1 blood assessment is to be done at the time 
point/period, if they require the same type of tube, the assessments should be combined. Blood 
volume estimates do not include safety labs performed after PN adjustments.
Consistent with standard medical practice, efforts to minimize pain and discomfort during 
procedures such as peripheral venipuncture should be implemented as applicable. This may 
include oral sucrose solutions, a pacifier, distraction techniques, and the use of topical anesthetic 
such as EMLA.   
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Physical Examinations, Vital Signs, Weight, Length, and Head Circumference
Physical examinations will be performed according to the study schedules (Table 1 and Table 2). 
Any new clinically significant findings noted during physical examinations should be recorded 
on the appropriate AE page of the eCRF.
Vital signs will be measured according to the study schedules. Measurements will include 
systolic and diastolic blood pressure (mmHg), pulse (beats per minute), and body temperature 
(°C/°F). Blood pressure should be determined by the appropriate size cuff (using the same 
method, the same leg, and in the supine position throughout the study, when possible).  Blood 
pressure measurements should be attempted as part of the vital signs, but lack of blood pressure 
results will not constitute a protocol deviation.  New clinically significant vital sign 
abnormalities should be recorded on the appropriate AE page of the eCRF.
Body weight will also be recorded in the eCRF; subjects should be weighed on the same scale 
at each study visit. Length and head circumference will be measured at selected visits. A height 
z-score, weight Z-score, and weight/length ratio will be calculated by the sponsor using the 
site-provided height and weight data collected at each site visit.
7.2.4
Pharmacokinetic Assessments
Subjects will have blood samples taken for teduglutide PK analysis predose, and 1 hour 
±10 minutes and 4 hours ±10 minutes postdose at baseline (Visit 0).  Subjects also will have 
blood samples taken for teduglutide PK analysis 2 hours ±10 minutes postdose at Week 7 
(Visit 7) or Week 12 (Visit 12) of the treatment period. Blood for PK sampling should be 
collected via peripheral IV or venipuncture, not from a central line. The site of teduglutide 
administration prior to PK blood draws (arm, thigh, abdomen) must be specified. 
7.2.5
Health Economics and Outcomes Research
Hospitalizations
Each hospitalization that occurs during the study will be recorded, including date of admission, 
date of discharge, reasons for hospitalization, discharge diagnosis, and discharge status. 
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ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.3. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, or 
a symptom is more severe or prolonged than expected given the diagnosis, then symptom(s)
should be listed individually. All AEs should be captured on the appropriate AE pages in the 
eCRF and in source documents. In addition to untoward AEs, unexpected benefits outside the 
investigational product indication should also be captured on the AE eCRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
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8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of 
the investigational product is compelling and/or follows a known or 
suspected response pattern to that product, and the event cannot be 
explained by the subject’s medical condition, other therapies, or 
accident.
Not Related
The event can be readily explained by other factors such as the subject’s
underlying medical condition, concomitant therapy, or accident and no 
plausible temporal or biologic relationship exists between the 
investigational product and the event.
AEs that are related to IP that are not resolved at EOS will be followed until the event resolves or 
stabilizes, as judged by the investigator.
Laboratory values, vital signs, and clinical findings at the scheduled physical examinations must 
be reported as AEs if the investigator considers the finding to be a clinically significant change 
from the baseline.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the eCRF. Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved with Sequelae 

Recovering/Resolving

Unknown
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8.1.4
Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE. It is assumed that some of the infants participating in this study may be 
hospitalized for planned surgery(ies) that will occur during their participation in the study.  Such 
pre-planned, elective surgeries, do not need to be reported as SAEs for this protocol.  
8.1.5
Clinical Laboratory and Other Safety Evaluations
An untoward change in the value of a clinical laboratory parameter, vital sign measure, or ECG 
assessment can represent an AE if the change is clinically relevant or if, during administration of 
investigational product, a shift of a parameter is observed from a value in the normative range to 
a value that is outside the normal range and considered clinically significant, or a further waning 
of an already clinically significant value. Clinical significance is defined as any abnormal finding 
that results in further clinical investigation(s), treatment(s), or the diagnosis of new or 
progression of established condition. When evaluating such changes, the extent of deviation from 
the reference range, the duration until return to the reference range, either while continuing 
administration or after the end of administration with the investigational product, and the range 
of variation of the respective parameter within its reference range, should also be considered.
If, at the end of the treatment phase, there are abnormal clinical laboratory (such as hematology 
panel or clinical chemistry panel),  vital sign, or ECG values which were not present at the 
beginning of the pretreatment evaluation observed closest to the start of study treatment, further 
investigations should be performed until the values return to within the reference range or until a 
plausible explanation (eg, concomitant disease or expected disease evolution) is found for the 
abnormal values.
The investigator should assess, based on the above criteria and the clinical condition of a subject, 
whether a change in a clinical laboratory value, vital sign, or ECG parameter is clinically 
significant and represents an AE.
8.1.6
Pregnancy
Not applicable.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for 
a non-medical purpose (e.g., to alter one’s state of consciousness or get high) in a manner 
that may be detrimental to the individual and/or society.
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
Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol).

Overdose – Administration of a dose greater than the allocated dose of the study 
medication or at a frequency greater than the dosing interval specified by the protocol.

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product. For studies, medication errors are reportable to the sponsor 
only as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error. 
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally-authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator brochure which the sponsor 
has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Drug Safety Department and the Shire Medical Monitor within 24 hours of the first awareness of 
the event. Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, 
misuse, overdose, or medication errors (see Section 8.1.7) unless they result in an SAE.
All Adverse Events of Special Interest, as defined in Section 8.3, must be reported by the 
investigator to the Shire Global Drug Safety Department and the Shire Medical Monitor within 
24 hours of the first awareness of the event even if the event does not fulfill seriousness criterion.
The investigator must complete, sign, and date the Shire Clinical Study Adverse Event Form for 
SAEs and Non-serious AEs as Required by Protocol, and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested). Fax or e-mail the completed form to the Shire Global Drug Safety 
Department. A copy of the completed Shire Clinical Study Adverse Event Form for Serious 
Adverse Events (SAEs) and Non-serious AEs as Required by Protocol (and any applicable 
follow-up reports) must also be sent to the Shire medical monitor or designee using the details 
specified in the emergency contact information section of the protocol.
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8.2.3
Serious Adverse Event Definition
A SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose: 

Results in death

Is life-threatening. Note: The term 'life-threatening' in the definition of "serious" refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for pre 
existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse. 
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to investigational product) are collected from the time the 
subject signs the informed consent until the defined follow-up period stated in Section 7.1.3, and 
must be reported to the Shire Global Drug Safety Department and the Shire Medical Monitor 
within 24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Drug Safety Department within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
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In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (i.e., the SAE was noted as the primary cause of 
death) must have fatal checked as an outcome with the date of death recorded as the resolution 
date. For all other events ongoing at the time of death that did not contribute to the subject’s 
death, the outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (e.g., drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death.  
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting 
The Sponsor and/or Clinical Contract Research Organization (CRO) is responsible for notifying 
the relevant regulatory authorities, and US central Institutional Review Boards (IRBs)/EU central 
ethics committees (ECs), of related, unexpected SAEs.
In addition, the Clinical CRO is responsible for notifying active sites of all related, unexpected 
SAEs occurring during all interventional studies across the SHP633 program.
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
8.3
Adverse Events of Special Interest
An AE of special interest is an AE (serious or nonserious) of scientific and medical concern 
specific to the sponsor’s product or program and for which ongoing monitoring and immediate 
notification by the investigator to the sponsor is required.
The AEs of special interest that require expedited regulatory reporting include the following:

Growth of pre-existing polyps of the colon

Benign neoplasia of the GI tract including the hepatobiliary system

Tumor-promoting ability (e.g., benign and/or malignant neoplasia of any kind, not 
limited to those of the GI or hepatobiliary system)
For AEs of special interest, the sponsor must be informed within 24 hours of first awareness as 
per the SAE notification instructions described in Section 8.2.2 even if the event does not fulfill 
the seriousness criteria.
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8.4
Dose Interruption Criteria
The investigator is responsible for contacting the sponsor/designee when the subject’s 
teduglutide dosing regimen is interrupted. The length of dose interruption, and whether 
teduglutide administration resumes or is permanently discontinued, depends on the clinical 
situation.
Investigational product must be interrupted if any of the following events occur:

An adverse event of special interest (see Section 8.3) 

Intestinal obstruction

Biliary obstruction

Pancreatic duct obstruction

Heart failure with severe fluid overload determined by the sponsor or investigator to 
be related to IP.
Investigational product must be permanently discontinued if any of the following events occur: 

Severe hypersensitivity, such as anaphylaxis, determined by the investigator to be 
related to IP. 

Any malignancy 
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DATA MANAGEMENT AND STATISTICAL METHODS
9.
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the eCRF.  A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy.  Discrepancies 
between source data and data entered on the eCRF will be addressed by qualified site personnel.  
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel.  Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting.  Once a subject is randomized, it is expected that site 
personnel will complete the eCRF entry within approximately 3 business days of the subject’s 
visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the data management plan. Quality 
control and data validation procedures are applied to ensure the validity and accuracy of the 
clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Statistical Analysis Process
The study will be analyzed by the sponsor or designee. All statistical analyses will be performed 
using SAS® (SAS Institute, Cary, NC, US) version 9.3 or higher.
The statistical analysis plan (SAP) will provide the definitions and statistical methods  for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The
SAP will also include a description of how missing, unused and spurious data will be addressed.
9.4
Planned Interim Analysis, and Data Monitoring Committee 
No interim analyses is planned for this the study. 
A data monitoring committee (DMC) will be involved in the management of this study. The 
DMC members will review the data approximately every 3 months according to the DMC 
Charter. The DMC review will include all cumulative safety data (i.e., AEs, laboratory 
assessments, physical examinations, etc.) from study assessments through each cutoff period. 
Further details regarding the DMC can be found in the DMC charter, which will be available 
prior to the administration of investigational product. 
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The DMC for this study will be conducted in accordance with the FDA Guidance for Clinical 
Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees 
(March 2006).
The DMC will be an external, independent board comprised of physicians with relevant training. 
The DMC will be restricted to individuals free of significant conflicts of interest, including, but 
not limited to, financial, scientific, or regulatory in nature. The DMC will be governed by a 
Charter agreed to by members of the Board and the sponsor. Members of the Board may not be 
study investigators or be employed at the same institution as a study investigator, individuals 
employed by the sponsor, independent contractors hired by the sponsor, or members of 
regulatory agencies. The DMC may make recommendations to the sponsor regarding study 
aspects including stopping, modifying or continuing the study; however, the sponsor will have 
the final responsibility to determine whether the study should be modified or temporarily or 
permanently stopped. If the DMC recommends termination of this pediatric study, the 
recommendations will be communicated to the relevant regulatory agencies within 7 calendar 
days.
9.5
Sample Size Calculation and Power Considerations
The sample size is determined based on enrollment feasibility for this rare condition and the age 
of the study population. 
9.6
Study Population
Intent to treat (ITT) population: All subjects randomized in the study.
Safety analysis population: The safety analysis set will contain all subjects who meet the 
following criteria:

Teduglutide treatment arm: subjects who receive at least 1 dose of teduglutide and 
have undergone at least 1 post-baseline safety assessment; analyses will be performed 
according to dose group as appropriate.   

Standard of care treatment arm: subjects who have undergone at least 1 post-baseline 
safety assessment.
Per-protocol population: All subjects in the ITT population without any major protocol deviation 
that affects interpretation of efficacy results.
Pharmacokinetic analysis population: All subjects who received at least 1 dose of teduglutide 
and have at least 1 evaluable postdose PK concentration value.   
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9.7
Efficacy Analyses
9.7.1
Efficacy Endpoints
Efficacy endpoints consist of the following:
9.7.1.1
Primary Efficacy Endpoint 

Reduction in weight-normalized PN fluid volume by at least 20% from baseline at 
Week 24/EOT
9.7.1.2
Secondary Efficacy Endpoints

Reduction in weight-normalized parenteral calories by at least 20% from baseline to 
Week 24/EOT

Achievement of enteral autonomy by Week 24

Time to achieve enteral autonomy

Change in weight-normalized parenteral fluid volume from baseline to each visit

Change in weight-normalized parenteral calories from baseline to each visit

Change in weight-normalized enteral fluid volume from baseline to each visit

Change in weight-normalized enteral caloric intake from baseline to each visit

Increase in weight-normalized enteral fluid intake by at least 20% from baseline to week 
24/EOT

Increase in weight-normalized enteral caloric intake by at least 20% from baseline to 
week 24/EOT
9.7.2
Method of Analysis-Efficacy Endpoints
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 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.
Analyses of weekly PN support will be based on 2 data sources: the subject diary data (also 
referred to as actual data) and the investigator prescribed data.  
The number and percentage of subjects who achieve at least a 20% reduction from baseline in 
weight-normalized average daily PN volume at Week 24/EOT and the number and percentage of 
subjects who achieve at least a 20% reduction from baseline in weight-normalized parenteral 
calories at Week 24/EOT will be summarized by treatment arm.
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During the treatment period, a subject will be considered to have achieved enteral autonomy 
(completely weaned off PN) at a given visit if the investigator prescribes no PN at that visit and 
for the remainder of the treatment period, and there is no use of PN recorded in the subject diary 
during the week prior to that visit and for the remainder of the treatment period. During the 
follow-up period, a subject will be considered to have achieved enteral autonomy at a given visit 
if the investigator prescribes no PN at that visit and for the remainder of the follow-up period and 
there is no use of PN recorded in the subject diary during the week prior to that visit and for the 
remainder of the follow-up period. The number and percentage of subjects who achieve enteral 
autonomy at each scheduled visit, as well as at EOT, will be summarized by treatment arm.
Descriptive statistics will be used to summarize time to achievement of enteral autonomy by 
treatment arm.
The absolute and percent change in weight-normalized weekly PN volume, parenteral calories, 
enteral fluid volume, and enteral caloric intake, from baseline to each scheduled visit, as well as 
at EOT, will be summarized by treatment arm using descriptive statistics.
The number and percentage of subjects who demonstrate an increase in weight-normalized 
enteral fluid intake by at least 20% from baseline to Week 24/EOT and the number and 
percentage of subjects who demonstrate an increase in weight-normalized enteral caloric intake 
by at least 20% from baseline to week 24/EOT will be summarized by treatment arm.
9.8
Safety Analyses
9.8.1
Safety Endpoints
Safety endpoints consist of the following:

Adverse events

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for 
gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output

Stool (including mixed) output

Antibodies to teduglutide
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9.8.2
Method of Analysis-Safety Endpoints
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Treatment-emergent AEs will be summarized by system organ class and preferred 
term using descriptive statistics (e.g., number and percentage of subjects).  Adverse events will 
be summarized by severity and relationship to treatment.  In addition, SAEs will also be 
tabulated by overall and treatment-related events.  AEs leading to treatment discontinuation and 
death will also be summarized.
For laboratory tests; vital signs; urine and stool output; weight, length, and head circumference 
Z-scores, and descriptive statistics (e.g., n, mean, standard deviation, median, minimum and 
maximum values, and the number and percentage of subjects in specified categories) will be 
used to summarize the absolute values and change from baseline at each visit.
The number and percentage of subjects classified as having antibodies to teduglutide will be used 
to summarize the presence of antibodies.  
9.9
Health Economics and Outcomes Research Analyses
Health economics and outcomes research endpoints consist of the following:

Cumulative number of hospitalization days during the study
Health economics and outcomes research endpoints will be summarized using descriptive 
statistics (number, mean and standard deviation) at nominal time points.  
9.10
Pharmacokinetics Analyses
Plasma concentrations will be summarized using descriptive statistics (number, mean, standard 
deviation, geometric mean, coefficient of variation, minimum, median, and maximum ) at 
nominal time points. 
Pharmacokinetic parameters will be estimated using a population PK modeling approach as 
appropriate and reported separately.
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SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES
10.
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements. 
The name and address of each third-party vendor (e.g., CRO) used in this study will be 
maintained in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996), EU 
Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines.  If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study.  An insurance certificate is supplied as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. 
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This requirement will be fulfilled within 6 months of the end of the study completion date for 
pediatric studies and within 1 year for non-pediatric studies as per guidance.  The sponsor will 
provide the ECs with a copy of the same summary.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.  The sponsor will make an end-of-study declaration to the relevant competent 
authority as required by Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator will be appointed to review the final clinical study report 
for multicenter studies.  Agreement with the final clinical study report is documented by the 
signed and dated signature of the principal investigator (single-site study) or coordinating 
principal investigator (multicenter study), in compliance with Directive 2001/83/EC as amended 
by Directive 2003/63/EC and ICH Guidance E3 (1995).
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
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If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Electronic Case Report Forms
Electronic case report forms are supplied by the sponsor or designee and should be handled in 
accordance with instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Electronic case report forms 
must be completed by the investigator or designee as stated in the site delegation log.  All data 
will have separate source documentation; no data will be recorded directly onto the eCRF.
All data sent to the sponsor must be endorsed by the investigator.  
The study monitor will verify the contents against the source data per the monitoring plan. If the 
data are unclear or contradictory, queries are sent for corrections or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject diaries, and original clinical laboratory reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF entries 
against the source documents. The consent form includes a statement by which the 
parent/guardian agrees to the monitor/auditor from the sponsor or its representatives, national or 
local regulatory authorities, or the IRB/EC, having access to source data (e.g., subject’s medical 
file, appointment books, original laboratory reports, X-rays etc). Non-study site personnel will 
not disclose any personal information or personal medical information.
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (e.g., the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
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Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the European Medicines Agency (EMA), the 
Medicines and Healthcare products Regulatory Agency, other regulatory authorities, the sponsor 
or its representatives, and the IRB/EC for each site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent, where applicable, 
from the parent(s)/guardian(s) of all study subjects prior to any study-related procedures 
including screening assessments. All consent documentation must be in accordance with 
applicable regulations and GCP. Each subject’s legally authorized representative is requested to 
sign and date the subject informed consent form or a certified translation if applicable, after the 
subject’s parent or guardian has received and read (or been read) the written subject information 
and received an explanation of what the study involves, including but not limited to: the 
objectives, potential benefits and risk, inconveniences, and the subject’s rights and 
responsibilities. A copy of the informed consent documentation (i.e., a complete set of subject 
information sheets and fully executed signature pages) must be given to the subject’s legally 
authorized representative, as applicable. This document may require translation into the local 
language. Signed consent forms must remain in each subject’s study file and must be available 
for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form  that was 
reviewed by the IRB/EC and received their favorable opinion/approval. A copy of the IRB/EC’s 
written favorable opinion/approval of these documents must be provided to the sponsor prior to 
the start of the study unless it is agreed to and documented (abiding by regulatory guidelines and 
national provisions) prior to study start that another party (i.e., sponsor or coordinating principal 
investigator) is responsible for this action. Additionally, if the IRB/EC requires modification of 
the sample subject information and consent document provided by the sponsor, the 
documentation supporting this requirement must be provided to the sponsor.
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10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the sponsor/designee has received 
written IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB/EC informed of any serious and 
significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996.  A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the sponsor/designee.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market teduglutide; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
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Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (e.g., to confirm 
that laboratory results have been assigned to the correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines 
(e.g., Good Publication Practices 2) when forming a publication steering committee, which is 
done for large, multicenter Phase 2 to 4 and certain other studies as determined by Shire. The 
purpose of the publication steering committee is to act as a non-commercial body that advises or 
decides on dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, royalty 
free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
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If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.
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REFERENCES
11.
Beattie, L. M., Barclay, A. R. & Wilson, D. C. 2010. Short bowel syndrome and intestinal failure 
in infants and children. Paediatrics and Child Health, 20, 485-491.
Carter, Cohran, Cole, Corkins, Dimmitt, Duggan, Hill, Horslen, Lim, Mercer, Merritt, Nichol, 
Sigurdsson, Teitelbaum, Thompson, Vanderpool, Vaughan, Li, Youssef, Venick & 
Kocoshis 2017. Outcomes from a 12-Week, Open-Label, Multicenter Clinical Trial of 
Teduglutide in Pediatric Short Bowel Syndrome. Journal of Pediatrics, The, 181, 102-
111.e5.
Gonzalez-Hernandez, Prajapati, Ogola, Channabasappa, Drews & Piper 2017. Predicting time to 
full enteral nutrition in children after significant bowel resection. Journal of Pediatric 
Surgery, 52, 764-767.
Goulet, O. & Ruemmele, F. 2006. Causes and Management of Intestinal Failure in Children. 
Gastroenterology, 130, S16-S28.
Huisman-de Waal, G., Schoonhoven, L., Jansen, J., Wanten, G. & van Achterberg, T. 2007. The 
impact of home parenteral nutrition on daily life-A review. Clinical Nutrition, 26, 275-
288.
Khan, F. A., Squires, R. H., Litman, H. J., Balint, J., Carter, B. A., Fisher, J. G., Horslen, S. P., 
Jaksic, T., Kocoshis, S., Martinez, J. A., Mercer, D., Rhee, S., Rudolph, J. A., Soden, J., 
Sudan, D., Superina, R. A., Teitelbaum, D. H., Venick, R., Wales, P. W. & Duggan, C. 
2015. Predictors of Enteral Autonomy in Children with Intestinal Failure: A Multicenter 
Cohort Study. J Pediatr, 167, 29-34.e1.
Marier, J., Kassir, N., Martin, P. & Wang, Y. 2017. Population pharmacokinetic modeling of 
teduglutide to support dosing in pediatric patients with short bowel syndrome. Clinical 
Pharmacology & Therapeutics, 101, S91.
Martin, G.-R., Beck, P.-L. & Sigalet, D.-L. 2006. Gut hormones, and short bowel syndrome: the 
enigmatic role of glucagon-like peptide-2 in the regulation of intestinal adaptation. World 
Journal of Gastroenterology, 12, 4117-29.
O'Keefe, S. J., Buchman, A. L., Fishbein, T. M., Jeejeebhoy, K. N., Jeppesen, P. B. & Shaffer, J. 
2006. Short bowel syndrome and intestinal failure: consensus definitions and overview. 
Clin Gastroenterol Hepatol, 4, 6-10.
Sigalet, D. L., Martin, G., Meddings, J., Hartman, B. & Holst, J. J. 2004. GLP-2 levels in infants 
with intestinal dysfunction. Pediatr Res, 56, 371-6.
Spencer, A. U., Neaga, A., West, B., Safran, J., Brown, P., Btaiche, I., Kuzma-O'Reilly, B. & 
Teitelbaum, D. H. 2005. Pediatric Short Bowel Syndrome: Redefining Predictors of 
Success. Annals of Surgery, 242, 403-412.
Squires, R. H., Duggan, C., Teitelbaum, D. H., Wales, P. W., Balint, J., Venick, R., Rhee, S., 
Sudan, D., Mercer, D., Martinez, J. A., Carter, B. A., Soden, J., Horslen, S., Rudolph, J. 
A., Kocoshis, S., Superina, R., Lawlor, S., Haller, T., Kurs-Lasky, M. & Belle, S. H. 
2012. Natural history of pediatric intestinal failure: initial report from the Pediatric 
Intestinal Failure Consortium. J Pediatr, 161, 723-8.e2.
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Tappenden, K. A., Edelman, J. & Joelsson, B. 2013. Teduglutide enhances structural adaptation 
of the small intestinal mucosa in patients with short bowel syndrome. J Clin 
Gastroenterol, 47, 602-7.
Thymann, T., Stoll, B., Mecklenburg, L., Burrin, D. G., Vegge, A., Qvist, N., Eriksen, T.,
Jeppesen, P. B. & Sangild, P. T. 2014. Acute effects of the glucagon-like peptide 2 
analogue, teduglutide, on intestinal adaptation in short bowel syndrome. J Pediatr 
Gastroenterol Nutr, 58, 694-702.
Wales, P. W., de Silva, N., Kim, J., Lecce, L., To, T. & Moore, A. 2004. Neonatal short bowel 
syndrome: population-based estimates of incidence and mortality rates. J Pediatr Surg,
39, 690-5.
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APPENDICES
12.
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Appendix 1
Protocol History
Document
Date
Global/Country/Site Specific
Original Protocol
03 Oct 2017
Global
Amendment 1
18 Jan 2018
Global
Amendment 1.1
07 Aug 2018
France-specific
Amendment 2.1
04 Dec 2018
France-specific
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1.1
Amendment Date
07 Aug 2018
France-specific
Description of Change and Rationale
Section(s) Affected by Change
The Shire contact was updated to 
.
Emergency Contact 
Information
Added an exclusion criterion for Gilbert’s disease and liver 
failure based on the values of the transaminases and of total 
bilirubin as requested by Agence Nationale de Sécurité du 
Medicament et des Produits de Santé (ANSM).
Synopsis, Section 4.2
Added an exclusion criterion for hypersensitivity to trace 
residues of tetracycline to be consistent with the European 
Summary of Product Characteristics of teduglutide as 
requested by ANSM.
Synopsis, Section 4.2
Added text to specify that efforts to minimize pain and 
discomfort during procedures such as peripheral venipuncture 
will be implemented.
Section 7.2.3
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change and Rationale
Section(s) Affected by Change
Updated emergency contact information to reflect the change 
of the Contract Research Organization’s name.
Emergency Contact 
Information
Clarified the duration of the screening period and total time 
on study.  
Provided a clear definition of study completion.
Synopsis, Section 3.1, 
Section 3.2
Updated the study schematic to reflect the study design 
changes.
Revised the telephone and clinic visit schedule to assure 
laboratory measurement could be collected without exceeding 
weekly/monthly total blood volume restrictions.  
Synopsis, Table 1, 
Section 3.1.2
Moved the PK sampling from Week 6 to Week 7 so that the 
samples could be collected without exceeding 
weekly/monthly total blood volume restrictions.
Synopsis, Table 1, 
Section 3.1.2, Section 7.2.4, 
Table 5
Clarified that blood for pharmacokinetic samples of postdose 
may be taken within ± 10 minutes of the time pre-specified.
Clarified that end jejunostomy or ileostomy are examples  of 
small bowel ostomy rather than the stratification factors.
Synopsis, Section 3.1.2, 
Section 6.2.2
Clarified that all subjects regardless of treatment arm are 
eligible for the extension study.
Synopsis, Section 3.1.3
Clarified that if a subject treated with teduglutide meets the 
escape criteria, the assessments scheduled for the EOS visit 
should be conducted.
Synopsis, Table 2, 
Section 3.1.3, Section 6.2.3
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change and Rationale
Section(s) Affected by Change
Clarified that subjects must be 4 to 12 months corrected 
gestational age at screening.
Synopsis, Section 4.1
Changed dose adjustments to Week 12 rather than at every 
clinic visit to reduce site burden.
Synopsis, Table 1, 
Section 6.2.3
Clarified the definition of enteral autonomy.
Synopsis, Section 9.7.2
Updated the pharmacokinetic endpoint and analysis to reflect 
that only descriptive statistics will be calculated on plasma 
teduglutide concentration values. Pharmacokinetic parameters 
will be estimated using a population PK modeling approach 
as appropriate and reported separately.
Synopsis, Section 9.10
Removed assessment of the 5-level EuroQol five dimensions 
questionnaire to reduce caregiver burden.
Synopsis, Table 1, 
Section 7.2.5, Section 9.9
Clarified that native GLP-2 samples drawn while subjects are 
receiving teduglutide should be drawn at least 14 hours after 
the previous dose.
Table 2, Section 7.2.2
Inserted a footnote to clarify that parenteral support and 
parenteral nutrition are used interchangeably.
Section 1.1
Removed the 5 mg vial of teduglutide as this size vial will not 
be supplied for this study.
Section 6.1
Clarified the procedures for assessing subject compliance. 
Section 6.5
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change and Rationale
Section(s) Affected by Change
Specified that it is acceptable to only enroll subjects who have 
already had an upper GI series with small bowel follow 
through performed since the subject’s most recent surgery.  
Section 7.2.1
Corrected the volume of blood to be collected for native 
GLP-2.
Table 5
Removed references to subject assent as assent is not possible 
in a study of infants. 
Section 7.1.1, Section 10.3.1
Clarified the definitions of the analysis sets.
Section 9.6
Clarified that an adjustment to enteral nutrition as appropriate 
is part of the PN/IV adjustment algorithm.
Figure A-1
Minor editorial changes and corrections to typographical 
errors (which do not modify content and/or intent of the 
original document) were made.
Throughout protocol.
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Appendix 2
Guidelines for Nutritional Support Management During the Study
The nutritional support adjustment guidelines are designed to standardize management of 
parenteral and enteral nutritional support in this study. Adjustments to nutritional support should 
be considered at every scheduled clinic visit. Adjustments at phone visits may also be performed, 
but nutritional assessments at phone visits serve primarily to confirm that nutritional adjustments 
at prior clinic visits were tolerated.
All attempts should be made to follow the guidelines, but departure from the guidelines will not 
constitute a protocol deviation.
Clinical judgment is required within the algorithm. Each decision point requires integrating 
multiple sources of information into a yes/no decision. When individual data points are 
conflicting, the investigator must use their best judgment in the assessment.
If intestinal adaptation is occurring, reductions in parenteral support volume and calories are 
expected to be in decrements of 5 to 10% relative to baseline values. Parenteral support 
components are at the discretion of the investigator, but care should be taken to balance 
carbohydrate, fat, and protein. Likewise, if intestinal adaptation is occurring, enteral nutrition 
volume and calories should be increased in increments of approximately 10% relative to baseline 
values.
Assessment of the severity of malabsorption may require estimation of stool output for children 
who have mixed stool and urine output.
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.
During the 48-hour output measurement period prior to the subject’s scheduled visit, no further 
changes to the prescribed nutritional support should be made.
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Figure A-1:
Parenteral Nutrition/Intravenous Adjustment Algorithm for All Subjects  
BUN=blood urea nitrogen; Cr=creatinine; PN=parenteral nutrition; UNa=urine sodium; UOP=urine output; USpGr=Urine specific gravity; VS=vital signs; vol=volume
Adequately hydrated?
•
Normal exam and VS
•
Weight stable
•
UOP > 1 ml/kg/h
•
USpGr < 1.020
•
UNa > 20 meq/L
•
Stable, normal BUN/Cr
yes
no
Adequate weight gain 
and linear growth?
↑ PN kcal or no change
↓PN vol and kcal
↑ PN vol +/- kcal
yes
no
Assess severity of malabsorption and adjust EN as appropriate
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PROTOCOL: SHP633-301
TITLE:
A Randomized, Open-label, 24-Week Safety, Efficacy, and 
Pharmacokinetic Study of Teduglutide in Infants 4 to 12 Months of Age 
with Short Bowel Syndrome Who are Dependent on Parenteral Support
NUMBER
SHP633-301
PHASE
3 
DRUG:
Teduglutide
INDICATION:
Short bowel syndrome
EUDRACT NO.:
2017-003606-40
SPONSOR: 
Shire Human Genetic Therapies, Inc.
300 Shire Way
Lexington, MA 02421 USA
PROTOCOL 
HISTORY:
Original Protocol: 03 Oct 2017
Amendment 1: 18 Jan 2018
Amendment 2: 04 Dec 2018
Amendment 3: 24 May 2019
Confidentiality Statement
This document contains confidential and proprietary information of Shire and is disclosed 
pursuant to confidentiality and non-disclosure obligations. This information should be used 
solely for the purposes for which it was provided and should not be copied, shared with, or 
disclosed to any third party without the express written consent of Shire.
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Page2 
SHP633-301 Protocol Amendment 3 
Teduglutide 
24 May 2019 
PROTOCOL SIGNATURE PAGE 
Sponsor's (Shire) Approval 
F •ture: 
, MD PhD
I 
I 
, Global Clinical Development 
J 
Investigator's Acknowledgement 
I have read this protocol for Shire Study SHP633-301. 
Title: A Randomized, Open-label, 24-Week Safety, Efficacy, and Phannacokinetic Study of 
Teduglutide in Infants 4 to 12 Months of Age with Short Bowel Syndrome Who are Dependent 
on Parenteral Suppo1t 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Council for Hannonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) guidelines on Good Clinical Practice (GCP) and with the 
applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my paiticipation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely te1minate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Address: 
(please hand print or type) 
Signature: 
Date: 
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EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Adverse Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as 
Required by Protocol within 24 hours to the Shire Global Drug Safety Department. Applicable 
fax numbers and e-mail address can be found on the form (sent under separate cover). A copy of 
this form must also be sent to the Shire Medical Monitor by e-mail at 
.
For protocol- or safety-related issues, the investigator must contact IQVIA Medical Support:
Primary Contact
Backup Contact 
, MD
, MD, PhD
Mobile:  
Mobile: 
Phone: 
(medical emergencies)
Phone: 
 (medical emergencies)
Email: 
Email: 
In addition, the investigator may also contact Shire:
, MD
Mobile Phone: 
Email: 
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PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please use the E-mail address below to report the Product Quality Complaint:
Telephone numbers (provided for reference, if needed): 
Shire (USA)
 
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SUMMARY OF CHANGES FROM PREVIOUS VERSION
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
3
Amendment Date
24 May 2019
Global
Description of Change and Rationale
Section(s) Affected by Change
Deleted Inclusion Criteria #6, Lack of terminal ileum and 
ileocecal valve, due to difficulties in enrollment. 
Synopsis, Section 4.1
Minor editorial changes and corrections to typographical 
errors (which do not modify content and/or intent of the 
original document) were made.
Throughout the protocol
See Appendix 1 for protocol history, including all amendments. 
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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
PRODUCT QUALITY COMPLAINTS..........................................................................................4
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................5
TABLE OF CONTENTS.................................................................................................................6
LIST OF TABLES.........................................................................................................................10
LIST OF FIGURES .......................................................................................................................10
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..................................................11
STUDY SYNOPSIS ......................................................................................................................12
STUDY SCHEDULES ..................................................................................................................17
BACKGROUND INFORMATION .......................................................................................21
1.
1.1
Short Bowel Syndrome........................................................................................21
1.2
Teduglutide..........................................................................................................22
OBJECTIVES.........................................................................................................................24
2.
2.1
Rationale for the Study........................................................................................24
2.2
Study Objectives..................................................................................................24
STUDY DESIGN ...................................................................................................................25
3.
3.1
Study Design and Flow Chart..............................................................................25
3.1.1
Screening Period..................................................................................................25
3.1.2
Treatment Period .................................................................................................25
3.1.3
Follow-up Period.................................................................................................26
3.2
Study Duration.....................................................................................................26
3.3
Sites and Regions ................................................................................................26
STUDY POPULATION.........................................................................................................27
4.
4.1
Inclusion Criteria.................................................................................................27
4.2
Exclusion Criteria................................................................................................27
4.3
Reproductive Potential ........................................................................................28
4.4
Discontinuation of Subjects.................................................................................28
4.4.1
Reasons for Discontinuation................................................................................29
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit...............................29
PRIOR AND CONCOMITANT TREATMENT ...................................................................30
5.
5.1
Prior Medications and Procedures.......................................................................30
5.2
Concomitant Medications and Procedures ..........................................................30
5.3
Permitted Treatment ............................................................................................30
5.4
Prohibited Treatment...........................................................................................30
INVESTIGATIONAL PRODUCT ........................................................................................31
6.
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6.1
Identity of Investigational Product ......................................................................31
6.2
Administration of Investigational Product ..........................................................31
6.2.1
Interactive Response Technology for Investigational Product Management ......31
6.2.2
Allocation of Subjects to Treatment....................................................................31
6.2.3
Dosing..................................................................................................................31
6.2.4
Unblinding the Treatment Assignment ...............................................................32
6.2.5
Dose Selection Rationale.....................................................................................32
6.3
Labeling, Packaging, and Storage .......................................................................33
6.3.1
Labeling...............................................................................................................33
6.3.2
Storage and Handling ..........................................................................................34
6.4
Drug Accountability ............................................................................................34
6.5
Subject Compliance.............................................................................................36
STUDY PROCEDURES........................................................................................................37
7.
7.1
Study Schedule ....................................................................................................37
7.1.1
Screening .............................................................................................................37
7.1.2
Treatment Period .................................................................................................37
7.1.3
Follow-up Period.................................................................................................37
7.2
Study Evaluations and Procedures ......................................................................37
7.2.1
Demographics and Other Baseline Characteristics .............................................37
7.2.2
Efficacy Assessments ..........................................................................................38
7.2.3
Safety Assessments .............................................................................................39
7.2.4
Pharmacokinetic Assessments.............................................................................42
7.2.5
Health Economics and Outcomes Research ........................................................42
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................43
8.
8.1
Definition of Adverse Events, Period of Observation, Recording of 
Adverse Events....................................................................................................43
8.1.1
Severity Categorization .......................................................................................43
8.1.2
Relationship Categorization ................................................................................44
8.1.3
Outcome Categorization......................................................................................44
8.1.4
Symptoms of the Disease under Study................................................................45
8.1.5
Clinical Laboratory and Other Safety Evaluations..............................................45
8.1.6
Pregnancy ............................................................................................................45
8.1.7
Abuse, Misuse, Overdose, and Medication Error................................................45
8.2
Serious Adverse Event Procedures......................................................................46
8.2.1
Reference Safety Information..............................................................................46
8.2.2
Reporting Procedures ..........................................................................................46
8.2.3
Serious Adverse Event Definition .......................................................................47
8.2.4
Serious Adverse Event Collection Time Frame ..................................................47
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8.2.5
Serious Adverse Event Onset and Resolution Dates...........................................47
8.2.6
Fatal Outcome .....................................................................................................48
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and 
Site Reporting.................................................................................................48
8.3
Adverse Events of Special Interest......................................................................48
8.4
Dose Interruption Criteria....................................................................................49
DATA MANAGEMENT AND STATISTICAL METHODS ...............................................50
9.
9.1
Data Collection....................................................................................................50
9.2
Clinical Data Management..................................................................................50
9.3
Statistical Analysis Process .................................................................................50
9.4
Planned Interim Analysis, and Data Monitoring Committee ..............................50
9.5
Sample Size Calculation and Power Considerations...........................................51
9.6
Study Population .................................................................................................51
9.7
Efficacy Analyses................................................................................................52
9.7.1
Efficacy Endpoints ..............................................................................................52
9.7.1.1
Primary Efficacy Endpoint.....................................................................52
9.7.1.2
Secondary Efficacy Endpoints ...............................................................52
9.7.2
Method of Analysis-Efficacy Endpoints .............................................................52
9.8
Safety Analyses ...................................................................................................53
9.8.1
Safety Endpoints..................................................................................................53
9.8.2
Method of Analysis-Safety Endpoints.................................................................54
9.9
Health Economics and Outcomes Research Analyses ........................................54
9.10
Pharmacokinetics Analyses .................................................................................54
SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES ............................................55
10.
10.1
Sponsor’s Responsibilities...................................................................................55
10.1.1
Good Clinical Practice Compliance ....................................................................55
10.1.2
Indemnity/Liability and Insurance ......................................................................55
10.1.3
Public Posting of Study Information ...................................................................55
10.1.4
Submission of Summary of Clinical Study Report to Competent 
Authorities of Member States Concerned and Ethics Committees ................55
10.1.5
Study Suspension, Termination, and Completion ...............................................56
10.2
Investigator’s Responsibilities.............................................................................56
10.2.1
Good Clinical Practice Compliance ....................................................................56
10.2.2
Protocol Adherence and Investigator Agreement................................................56
10.2.3
Documentation and Retention of Records...........................................................57
10.2.3.1
Electronic Case Report Forms................................................................57
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................57
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10.2.3.3
Audit/Inspection.....................................................................................58
10.2.3.4
Financial Disclosure...............................................................................58
10.3
Ethical Considerations.........................................................................................58
10.3.1
Informed Consent ................................................................................................58
10.3.2
Institutional Review Board or Ethics Committee................................................59
10.4
Privacy and Confidentiality.................................................................................59
10.5
Study Results/Publication Policy ........................................................................60
REFERENCES .......................................................................................................................62
11.
APPENDICES ........................................................................................................................64
12.
Appendix 1 Protocol History...................................................................................................65
Appendix 2 Guidelines for Nutritional Support Management During the Study ...................70
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LIST OF TABLES
Table 1:
Study Schedule: Visits -1 to 12 .....................................................................17
Table 2:
Study Schedule: Visits 13-28 ........................................................................19
Table 3:
Prohibited Treatment.....................................................................................30
Table 4:
List of Laboratory Tests ................................................................................40
Table 5:
Approximate Volume of Blood to be Drawn from Each Subject .................41
LIST OF FIGURES
Figure 1:
Study Schematic ............................................................................................25
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation
Definition
AE
adverse event
AUCss
area under the concentration-time curve at steady-state 
Cmax,ss
maximum plasma concentration at steady state
CRO
contract research organization
eCRF
electronic case report form
DMC
data monitoring committee
EDC
electronic data capture
EMA
European Medicines Agency
EN
enteral nutrition
EOS
end of study
EOT
end of treatment
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
gastrointestinal 
GLP
glucagon-like peptide
HIPAA
Health Insurance Portability and Accountability Act
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use
ICMJE
International Committee of Medicinal Journal Editors
I/O
oral fluid intake and urine output
IP
Investigational product
IRB
Institutional Review Board
ITT
intent-to-treat
MedDRA
Medical Dictionary for Regulatory Activities
PK
pharmacokinetics
PN
parenteral nutrition
SAE
serious adverse event
SAP
statistical analysis plan
SBS
short bowel syndrome
SC
subcutaneous
SD
standard deviation
SOC
standard of care
ULN
upper limit of normal 
US
United States
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STUDY SYNOPSIS
Protocol number: SHP633-301
Drug: Teduglutide
Title of the study: A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic Study of 
Teduglutide in Infants 4 to 12 Months of Age with Short Bowel Syndrome Who are Dependent on Parenteral 
Support
Number of subjects (total and for each treatment arm):
At least 10 subjects will be randomized: at least 5 subjects in a teduglutide treatment arm and at least 5 subjects in 
a standard of care (SOC) comparator arm
Investigator(s): Multicenter study
Site(s) and Region(s): 
This study is planned to be conducted in approximately 5 to 10 sites globally.
Study period (planned):
2017-2020
Clinical phase:
3
Objectives:
The objectives of this clinical study are to evaluate the safety, efficacy/pharmacodynamics and pharmacokinetics 
(PK) of teduglutide treatment in infants with short bowel syndrome (SBS) dependent on parenteral support.
Investigational product, dose, and mode of administration:
Teduglutide 0.05 mg/kg by subcutaneous (SC) injection once daily into 1 of the 4 quadrants of the abdomen or 
either thigh or arm.
Methodology:
This is a randomized, multicenter, open-label study, consisting of a 2 to 4 week screening period, a 24-week 
treatment period, and a 4-week follow-up period. 
* At EOS all subjects regardless of treatment arm may enroll in an extension study that will capture long-term 
safety data and provide the opportunity for additional teduglutide treatment. The follow-up period for subjects in 
the teduglutide treatment arm may be interrupted and the subjects may proceed immediately to the EOS if at least 
one “escape” criteria is met.
Extension 
study* 
1
24
1
3
5
7
9
12
16
20
28
2 to 4
Weeks
Screening
Teduglutide 0.05 mg/kg SC once daily for 24 weeks
Site Visit 
Telephone Visit
Standard of care for 24 weeks
Baseline: treatment 
randomization
0
24
3
5
7
9
12
16
20
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Study eligibility will be confirmed during the screening period (minimum: 2 weeks; maximum 4 weeks). At the 
baseline visit (Week 0), subjects will be randomized 1:1 to the teduglutide or SOC treatment arm. Randomization 
will be stratified according to the presence of a small bowel ostomy (eg, end jejunostomy or ileostomy). During 
the 24-week treatment period, subjects in the SOC treatment arm will receive standard medical therapy for SBS; 
while those in the teduglutide arm will receive 0.05 mg/kg SC once daily in addition to standard medical therapy. 
Subjects in both arms will follow the same visit schedule and assessments. Subjects will be monitored weekly 
with phone or clinic visits. Clinic visits will occur at Weeks 1, 3, 5, 7, 9, 12, 16, 20, 24, and 28. At all site visits 
and telephone contacts, safety will be monitored and nutritional support will be reviewed and adjusted as needed. 
To maintain consistency across centers, guidance and training will be provided to help sites follow the nutritional 
support adjustment guidelines (developed with SBS expert input and provided in the protocol) related to decisions 
for parenteral nutrition (PN) reduction and advances in enteral feeds based on weight gain, urine and stool output, 
and clinical stability. Deviations from the guidelines are not considered a protocol deviation.
Sparse PK sampling, in the teduglutide treatment arm only, will occur at baseline (predose and 1 hour 
±10 minutes and 4 hours ±10 minutes postdose) and at Week 7 or 12 (2 hours±10 minutes postdose).
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up period until the end 
of study (Week 28/EOS) during which time subjects will receive standard medical therapy, but no investigational 
product will be administered. At EOS all subjects regardless of treatment arm may enroll in an extension study 
that will capture long-term safety data and provide the opportunity for additional teduglutide treatment. The 
follow-up period for subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed 
immediately to the EOS if at least one of the following “escape” criteria is met:
1.
Increasing PN requirements following discontinuation of teduglutide.
2.
Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal tolerated enteral 
nutrition (EN) following teduglutide discontinuation.
3.
Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and electrolyte intake 
following teduglutide discontinuation.
4.
Severe diarrhea related to teduglutide discontinuation.
Inclusion and Exclusion Criteria:
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1.
Informed consent by the parent or legal guardian. 
2.
Male or female infant 4 to 12 months corrected gestational age at screening.
3.
Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and baseline.
4.
Short bowel syndrome with dependence on parenteral support to provide at least 50% of fluid or caloric 
needs.
5.
Stable PN requirements for at least 1 month prior to screening, defined as a ≤10% change in the 
weight-normalized parenteral total fluid and caloric intake, despite attempts to wean PN, 
notwithstanding transient instability for events such as sepsis or interruption of central venous access.
6.
This criteria was deleted.
7.
Parent or legal guardian understands and is willing and able to fully adhere to study requirements as 
defined in this protocol.
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Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1.
Previous treatment with teduglutide.
2.
Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus inclusion disease, 
etc.
3.
Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility, that is the primary contributing factor to feeding intolerance and 
inability to reduce parenteral support, prior to screening. Dysmotility is defined as severe if it is expected 
to limit the advancement of enteral feeding.
4.
Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral aversion in the 
absence of a feeding tube.
5.
Intestinal obstruction or clinically significant intestinal stenosis.
6.
Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or major intestinal 
resection or anastomosis, within 3 months prior to screening or planned during the study period.
7.
Unstable cardiac disease.
8.
Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
9.
Biliary obstruction, stenosis, or malformation. 
10. Clinically significant pancreatic disease. 
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b.
Platelet count <100×10^3/µl due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d.
Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 2-week period
13. More than 3 serious complications of intestinal failure (eg, catheter-associated bloodstream infections, 
interruption of nutrition due to feeding intolerance, catheter-associated thrombosis, severe fluid or 
electrolyte disturbances) within 1 month prior to or during screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile polyposis or 
Beckwith-Wiedemann syndrome, or first degree relative with early onset of gastrointestinal cancer 
(including hepatobiliary and pancreatic cancers). 
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 (GLP-2); 
insulin-like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs of these hormones; or 
glutamine. 
16. Participation in a clinical study using an experimental drug within 3 months or 5.5 half-lives of the 
experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, closely-related 
compounds, or any of the stated ingredients.
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts the subject at any 
undue risk, prevents completion of the study, or interferes with analysis of the study results.
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Maximum Duration of Subject Involvement in the Study:
The study consists of a 2 to 4 week screening period, a 24-week treatment period, and a 4-week follow-up period. 
The maximum duration of participation for each subject is 32 weeks.
Study completion is defined as the last subject, last visit. This is the visit date at which the last subject on the 
study has his or her last follow-up visit on the study (whether during the 24-week treatment period or the 4-week 
follow-up period).
Endpoints:
Efficacy
Efficacy endpoints consist of the following:
Primary

Reduction in weight-normalized PN fluid volume by at least 20% from baseline at Week 24/EOT
Secondary

Reduction in weight-normalized parenteral calories by at least 20% from baseline to Week 24/EOT

Achievement of enteral autonomy by week 24

Time to achieve enteral autonomy

Change in weight-normalized parenteral fluid volume from baseline to each visit

Change in weight-normalized parenteral calories from baseline to each visit

Change in weight-normalized enteral fluid volume from baseline to each visit

Change in weight-normalized enteral caloric intake from baseline to each visit

Increase in weight-normalized enteral fluid intake by at least 20% from baseline to Week 24/EOT

Increase in weight-normalized enteral caloric intake by at least 20% from baseline to Week 24/EOT
Pharmacokinetics
The pharmacokinetic endpoint is plasma teduglutide concentration at nominal time point.
Safety
Safety endpoints consist of the following:

Adverse events (AEs)

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output

Stool (including mixed) output  

Antibodies to teduglutide 
Health Economics and Outcomes Research
Health economics and outcomes research (HEOR) endpoints include the following:

Cumulative number of hospitalization days during the study
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Statistical Methods:
Efficacy
Analyses of weekly PN support will be based on 2 data sources: the subject diary data (also referred to as actual 
data) and the investigator prescribed data. 
The number and percentage of subjects who achieve at least a 20% reduction from baseline in weight-normalized 
average daily PN volume at Week 24/EOT and the number and percentage of subjects who achieve at least a 20% 
reduction from baseline in weight-normalized parenteral calories at Week 24/EOT will be summarized by 
treatment arm.
During the treatment period, a subject will be considered to have achieved enteral autonomy (completely weaned 
off PN) at a given visit if the investigator prescribes no PN at that visit and for the remainder of the treatment 
period, and there is no use of PN recorded in the subject diary during the week prior to that visit and for the 
remainder of the treatment period. During the follow-up period, a subject will be considered to have achieved 
enteral autonomy at a given visit if the investigator prescribes no PN at that visit and for the remainder of the 
follow-up period and there is no use of PN recorded in the subject diary during the week prior to that visit and for 
the remainder of the follow-up period. The number and percentage of subjects who achieve enteral autonomy at 
each scheduled visit, as well as at EOT, will be summarized by treatment arm. Descriptive statistics will be used 
to summarize time to achievement of enteral autonomy by treatment arm.
The absolute and percent change in weight-normalized weekly PN volume, parenteral calories, enteral fluid 
volume, and enteral caloric intake, from baseline to each scheduled visit, as well as at EOT, will be summarized 
by treatment arm using descriptive statistics.
The number and percentage of subjects who demonstrate an increase in weight-normalized enteral fluid intake by 
at least 20% from baseline to Week 24/EOT and the number and percentage of subjects who demonstrate an 
increase in weight-normalized enteral caloric intake by at least 20% from baseline to week 24/EOT will be 
summarized by treatment arm.
Pharmacokinetics
Plasma concentrations will be summarized using descriptive statistics (number, mean, standard deviation, 
geometric mean, coefficient of variation, minimum, median, and maximum) at nominal time points. 
Pharmacokinetic parameters will be estimated using a population PK modeling approach as appropriate and 
reported separately.
Safety
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Treatment-emergent AEs will be summarized by system organ class and preferred term using descriptive statistics 
(eg, number and percentage of subjects). Adverse events will be summarized by severity and relationship to 
treatment. In addition, serious adverse events  will also be tabulated by overall and treatment-related events. AEs 
leading to treatment discontinuation and death will also be summarized.
For laboratory tests; vital signs; urine and stool output; weight, length, and head circumference Z-scores; and 
descriptive statistics (eg, n, mean, standard deviation, median, minimum and maximum values, and the number 
and percentage of subjects in specified categories) will be used to summarize the absolute values and change from 
baseline at each visit.
The number and percentage of subjects classified as having antibodies to teduglutide will be used to summarize 
the presence of antibodies. 
Health Economics and Outcomes Research
The HEOR endpoints will be summarized descriptively. 
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STUDY SCHEDULES
Table 1:
Study Schedule: Visits -1 to 12
Procedures
Screening
Baseline 
(Week 0)
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
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit type
Site
Site
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Tel
Site
Study day
-14
0
7
14
21
28
35
42
49
56
63
70
77
84
±window (days)
-2 weeks
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Informed consent
X
Eligibility
X
X
Randomization
X
Demographics 
X
SBS history
X
Medical and surgical history
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications and 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, vital signs, 
weight
X
X
X
X
X
X
X
X
Length and head circumference
X
X
X
X
UGI/SBFT
X
Safety labs and urinalysisb, c
X
Xb
X
(X)
X
(X)
X
(X)
X
(X)
X
(X)
(X)
X
PK samplinga
X
 
[X]d
[X]d
Antibodies to teduglutidea,e
X
Xe
Native GLP-2f
X
Provide intake and output 
diariesg
X
X
X
X
X
X
X
X
Review diaries and nutritional 
support
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional support as 
neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense IPa, i
X
X
X
X
X
X
X
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Table 1:
Study Schedule: Visits -1 to 12
Procedures
Screening
Baseline 
(Week 0)
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
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit type
Site
Site
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Tel
Site
Study day
-14
0
7
14
21
28
35
42
49
56
63
70
77
84
±window (days)
-2 weeks
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Adjust IP dosej
X
EN=enteral nutrition; GLP-2=glucagon-like peptide 2; INR=international normalized ratio; IP=investigational product; PK=pharmacokinetics; PN=parenteral nutrition; PT=prothrombin time; 
UGI/SBFT=upper GI series with small bowel follow-through 
a Applicable to the teduglutide treatment arm only. 
b At baseline, safety labs (Table 4) and PK can be separated by 1 day if blood volumes are limiting. Safety labs at telephone visits will be collected at the discretion of the investigator. For all subjects in 
the teduglutide treatment arm, PT and INR will be tested at baseline, and repeated if clinically indicated.
c Urinalysis will consist of urine sodium and specific gravity. Urine collection should be attempted, but inability to obtain urinalysis is not a protocol deviation.
d Subjects will have blood samples taken for teduglutide PK analysis predose and 1 hour ±10 minutes and 4 hours ±10 minutes postdose at baseline (Visit 0). Subjects also will have blood samples taken 
for teduglutide PK analysis 2 hours ±10 minutes postdose at Week 7 (Visit 7) or Week 12 (Visit 12) of the treatment period.
e Samples for antibody analysis will be drawn at the baseline and Week 12 visits. Blood samples while subjects are receiving teduglutide should be drawn at least 14 hours after the previous dose.
f Blood samples for native GLP-2 should be collected postprandial. Native GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at investigator 
discretion based on weekly/monthly total volume. 
g Intake diaries will collect actual PN volume and hours per day and EN volume and calories. Intake diaries should be completed daily throughout the study. Urine and stool output should be recorded in 
the output diary over a 48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PN prescription. 
h Parenteral support adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment provided in Appendix 2.
i The initial dose will be calculated based on body weight measured at baseline (Visit 0).
j  The dose will be adjusted as needed, based on body weight measured at Week 12 visit.
Note: (X) denotes optional assessments; [X] denotes possible PK sampling time point (Refer to footnote “e”.)
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Table 2:
Study Schedule: Visits 13-28
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 
(EOT/ET)
Week 
25
Week 
26
Week 
27
Week 
28 
(EOS)a
Visit number
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit type
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Study day
91
98
105
112
119
126
133
140
147
154
161
168
175
182
189
196
±window (days)
±3
±3
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications 
and procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, vital 
signs, weight
X
X
X
X
Length and head 
circumference
X
X
X
X
Safety labs and 
urinalysisb,c
(X)
(X)
(X)
X
(X)
(X)
(X)
X
(X)
(X)
(X)
X
(X)
(X)
(X)
X
Antibodies to 
teduglutided,e
X
Native GLP-2f
X
Provide intake and output 
diaries
X
X
X
Review diaries and 
nutritional supportg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional support 
as neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess follow-up period 
escape criteriad
Xi
Xi
Xi
X
Dispense IPd
X
X
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Table 2:
Study Schedule: Visits 13-28
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 
(EOT/ET)
Week 
25
Week 
26
Week 
27
Week 
28 
(EOS)a
Visit number
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit type
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Study day
91
98
105
112
119
126
133
140
147
154
161
168
175
182
189
196
±window (days)
±3
±3
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
EN=enteral nutrition; EOS=end of study; EOT=end of treatment; ET=early termination; GLP-2=glucagon-like peptide 2; INR=international normalized ratio; IP=investigational product; PN=parenteral 
nutrition; PT=prothrombin time; UGI/SBFT=upper GI series with small bowel follow-through
a At EOS subjects may enroll in an extension study, if subjects require treatment before the end of the 4-week follow-up they may enter the extension study immediately. 
bSafety labs at telephone visits will be collected at the discretion of the investigator. For all subjects in the teduglutide treatment arm, PT and INR are tested if clinically indicated.
c Urinalysis will consist of urine sodium and specific gravity. 
d Applicable to the teduglutide treatment arm only. 
e Samples for antibody analysis will be drawn at the EOS (Week 28) visit.
f Blood samples for native GLP-2 should be collected postprandial. Blood samples drawn while subjects are receiving teduglutide should be drawn at least 14 hours after the previous dose. Native 
GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at investigator discretion based on weekly/monthly total volume. 
g Intake diaries will collect actual PN volume and hours per day and EN volume and calories. Intake diaries should be completed daily throughout the study. Urine and stool output should be recorded in 
the output diary over a 48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PN prescription. 
h Parenteral support adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment provided in Appendix 2.
Note: (X) denotes optional assessments.
i If a subject treated with teduglutide meets the escape criteria, the assessments scheduled for the EOS visit should be conducted.
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BACKGROUND INFORMATION
1.
1.1
Short Bowel Syndrome
Short bowel syndrome (SBS) is a rare disorder resulting from congenital abnormalities or severe 
intestinal diseases that result in major surgical resections of the small intestine (O'Keefe et al., 
2006). Unlike the adult population, the majority of cases of SBS in pediatric subjects are due to 
congenital anomalies or catastrophic events that occur during infancy such as necrotizing 
enterocolitis, gastroschisis, intestinal atresia, midgut volvulus, or long-segment Hirschsprung 
disease (Beattie et al., 2010; Goulet and Ruemmele, 2006). A Canadian population-based study 
in neonates estimates an overall incidence of SBS to be 24.5 cases per 100,000 live births (Wales 
et al., 2004). 
The small intestine is capable of remarkable adaptation, but excessive loss of absorptive surface 
area or specialized functions can lead to dependence on parenteral nutrition (PN)1 fluids 
(O'Keefe et al., 2006). Although PN is life-sustaining in intestinal failure, it is associated with 
serious complications, including liver disease, life-threatening catheter-related blood stream 
infections, and central venous thrombosis (Beattie et al., 2010; Goulet and Ruemmele, 2006). 
Dependence on PN is also associated with reduced quality of life in both patients and caregivers 
and has an extremely high cost of care (Huisman-de Waal et al., 2007). About 30% of infants 
with SBS become independent of PN requirements within 12 months of the initial insult, and an 
additional 10% wean off PN within 24 months. After this time, linear intestinal growth slows. It 
is estimated that 42% to 86% of pediatric patients with SBS are able to become independent of 
PN within 1 to 3 years (Gonzalez-Hernandez et al., 2017; Khan et al., 2015; Squires et al., 2012). 
Nevertheless, despite optimal medical management, some children remain dependent on PN for 
many years (Squires et al., 2012). Infants who have less than 10% of expected small intestinal 
length for their gestational age have a low likelihood of ever achieving enteral autonomy (ie, 
independence from parenteral support). Providing the maximum tolerated amount of enteral 
nutrition (EN) has been the primary strategy to promote enteral adaptation (Spencer et al., 2005). 
Accelerating the adaptive process and achieving enteral autonomy is an urgent goal for all 
patients with SBS who are dependent on PN (Khan et al., 2015; Squires et al., 2012). The 
adaptive process is in part controlled by glucagon-like peptide 2 (GLP-2), a 33 amino acid 
peptide hormone secreted from L-type enteroendocrine cells in the terminal ileum and colon in 
response to luminal nutrients and bile acids (Martin et al., 2006). The post-prandial plasma 
concentration of GLP-2 in infants with SBS correlates with length of the remaining small 
intestine (Sigalet et al., 2004). Infants who lack terminal ileum may have impaired adaptation 
due to inadequate production of GLP-2.
                                                
1 For the purpose of the study the terms parenteral support (PS) and parenteral nutrition (PN) are used 
interchangeably.
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1.2
Teduglutide
Teduglutide is a novel, recombinant analog of naturally occurring human GLP-2 that regulates 
the functional and structural integrity of the cells lining the gastrointestinal (GI) tract. 
Teduglutide is a 33-amino acid peptide that differs from native GLP-2 in the substitution of 
glycine for alanine at the second position at the N-terminus. As a result, teduglutide demonstrates 
resistance to degradation by dipeptidyl peptidase 4 (DPP-4) and therefore maintains a longer 
elimination half-life (t1/2), approximately 2 hours in healthy adult subjects, 1.3 hours in adult 
SBS subjects, and 0.22 hours in pediatric SBS subjects, compared to the native peptide, which 
has a t1/2 of approximately 7 minutes. Teduglutide has been shown in animal studies and previous 
human clinical trials to increase villus height and crypt depth in the intestinal epithelium, thereby 
increasing the absorptive surface area of the intestines (Tappenden et al., 2013; Thymann et al., 
2014). 
A Phase 3 study, TED-C13-003, has been completed in pediatric SBS subjects. In this study, 
teduglutide was administered to 3 cohorts of pediatric subjects from ages 1-17 years. 
Thirty-seven pediatric subjects received teduglutide at doses of 0.0125, 0.025, or 0.05 mg/kg/day 
for 12 weeks. Five additional pediatric subjects were enrolled in an observational standard of 
care (SOC) cohort. There were clear dose-dependent effects of teduglutide seen at the 0.025 and 
0.05 mg/kg/day doses compared to SOC and the 0.0125 mg/kg/day dose. In the 0.025 mg/kg/day 
cohort there was a reduction in PN volume at Week 12 of 37%, including complete 
independence from PN support in 1 subject, and a reduction of 3.94 hours per day infusion time. 
In the 0.05 mg/kg/day cohort there was a reduction in PN volume at Week 12 of 39%, including 
complete independence from PN support in 3 subjects, and a reduction of 4.18 hours per day 
infusion time. Teduglutide was generally safe and well tolerated by pediatric subjects in all 
dosing cohorts. There were no deaths during the study and no treatment-emergent serious 
adverse events (SAEs) related to teduglutide were reported. No discontinuations from study were 
due to adverse events (AEs). Additional studies in pediatric patients with SBS are ongoing.
TED-C14-006 is a recently completed study of pediatric subjects through 17 years which 
included 2 treatment arms: a teduglutide treatment arm and a SOC treatment arm. Subjects in 
both arms participated in a 2-week minimum screening period, a 24-week treatment period, and a 
4-week follow-up period. During the screening period, subjects chose into which arm to enroll. 
During the 24-week treatment period, subjects in the SOC treatment arm received standard 
medical therapy for SBS; while those in the teduglutide treatment arm received daily 
subcutaneous (SC) injections of teduglutide (study drug) in addition to standard medical therapy. 
The subjects enrolling in the teduglutide treatment arm were randomized 1:1 in a double-blinded 
manner into 2 parallel dose groups: 0.025 mg/kg/day or 0.05 mg/kg/day of teduglutide 
administered subcutaneously for 24 weeks. Compared to the SOC, treatment of pediatric subjects 
with SBS with teduglutide resulted in clinically meaningful reductions in PN/IV volume, 
calories, days per week, and hours per day. A total 10% of subjects who received teduglutide 
achieved enteral autonomy within 24 weeks despite prior dependence on PN/IV for several 
years. Teduglutide treatment also resulted in increases in EN volume and caloric intake as well 
as plasma citrulline. Although the differences in efficacy between the 0.025 and 0.05 mg/kg dose 
groups were small, a consistently greater effect was seen in the 0.05 mg/kg dose in all efficacy 
parameters. 
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The pharmacokinetic (PK) properties were well characterized in this population and were 
consistent with the prior 12 week pediatric study. Teduglutide was generally well tolerated by 
pediatric subjects with SBS. The safety profile was favorable and consistent with the prior 
pediatric study, the underlying disease, and previous experience with teduglutide in adult 
subjects with SBS.
Teduglutide (0.05 mg/kg/day) is currently approved for the treatment of adult patients with SBS 
in >30 countries. On 29 Jun 2016, the European Commission granted an extension of the Market 
Authorization for teduglutide for the treatment of patients aged 1 year and above with SBS. 
Always refer to the latest version of the investigator’s brochure for the overall risk/benefit 
assessment and the most accurate and current information regarding the drug metabolism, 
pharmacokinetics, efficacy and safety of teduglutide (SHP633).
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OBJECTIVES
2.
2.1
Rationale for the Study 
There is no approved pharmacological therapy to improve intestinal adaptation in infants with 
SBS who are dependent on parenteral support. This study will evaluate whether teduglutide is 
safe and effective in this patient population. 
2.2
Study Objectives
The objectives of this study are to evaluate the safety, efficacy/pharmacodynamics and 
pharmacokinetics (PK) of teduglutide treatment in infants with SBS dependent on parenteral 
support.
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STUDY DESIGN
3.
3.1
Study Design and Flow Chart
This is a randomized, multicenter, open-label study, consisting of a 2 to 4-week screening period, 
a 24-week treatment period and a 4-week follow-up period. A schematic representation of the 
study design is presented in Figure 1.
Figure 1:
Study Schematic
*At EOS all subjects regardless of treatment arm may enroll in an extension study that will capture long-term safety data and 
provide the opportunity for additional teduglutide treatment. The follow-up period for subjects in the teduglutide treatment arm 
may be interrupted and the subjects may proceed immediately to the EOS if at least one “escape” criteria is met.
3.1.1
Screening Period 
Study eligibility will be confirmed during the screening period (minimum: 2 weeks; maximum: 
4 weeks). The schedule of evaluations to be conducted during the Screening Period can be found 
in Table 1.
3.1.2
Treatment Period
At the baseline visit (Week 0), subjects will randomized 1:1 to the teduglutide or SOC treatment 
arm. Randomization will be stratified according to the presence of a small bowel ostomy (eg, end 
jejunostomy or ileostomy). During the 24-week treatment period, subjects in the SOC treatment 
arm will receive standard medical therapy for SBS, while those in the teduglutide arm will 
receive 0.05 mg/kg by SC injection once daily in addition to standard medical therapy. 
Subjects in both arms will follow the same visit schedule and assessments. Subjects will be 
monitored weekly with phone or clinic visits. 
Extension 
study* 
1
24
1
3
5
7
9
12
16
20
28
2 to 4
Weeks
Screening
Teduglutide 0.05 mg/kg SC once daily for 24 weeks
Site Visit 
Telephone Visit
Standard of care for 24 weeks
Baseline: treatment 
randomization
0
24
3
5
7
9
12
16
20
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Clinic visits will occur at Weeks 1, 3, 5, 7, 9, 12, 16, 20, 24, and 28. At all site visits and 
telephone contacts, safety will be monitored and nutritional support will be reviewed and 
adjusted as needed. To maintain consistency across centers, guidance and training will be 
provided to help sites follow the nutritional support adjustment guidelines (developed with SBS 
expert input and provided in the protocol) related to decisions for PN reduction and advances in 
enteral feeds based on weight gain, urine and stool output, and clinical stability (Appendix 2). 
Deviations from the guidelines are not considered a protocol deviation.
Sparse PK sampling, in the teduglutide treatment arm only, will occur at baseline (predose and 
1 hour ±10 minutes and 4 hours ±10 minutes postdose) and at Week 7 or 12 (2 hours±10 minutes 
postdose).
The schedule of evaluations for the Treatment Period can be found in Table 1 (Visits -1 to 12) 
and Table 2 (Visits 13 to 28). 
3.1.3
Follow-up Period
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up 
period until the end of study (Week 28/EOS) during which time subjects will receive standard 
medical therapy, but no investigational product (IP) will be administered. At EOS, all subjects
regardless of treatment arm may enroll in an extension study that will capture long-term safety 
data and provide the opportunity for additional teduglutide treatment. The follow-up period for 
subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed 
immediately to the EOS visit if at least one of the following “escape” criteria is met:
1. Increasing PN requirements following discontinuation of teduglutide.
2. Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation. 
4. Severe diarrhea related to teduglutide discontinuation.
The schedule of evaluations for the Follow-up Period can be found in Table 2 (Visits 13 to 28).
3.2
Study Duration
The study consists of a 2 to 4-week screening period, a 24-week treatment period and a 4-week 
follow-up period. The maximum duration of participation for each subject is 32 weeks.
Study completion is defined as the last subject, last visit. This is the visit date at which the last 
subject on the study has his or her last follow-up visit on the study (whether during the 24-week 
treatment period or the 4-week follow-up period).
3.3
Sites and Regions
This study is planned to be conducted at approximately 5 to 10 sites globally.
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STUDY POPULATION
4.
At least 10 subjects will be randomized: at least 5 subjects in a teduglutide treatment arm and at 
least 5 subjects in an SOC comparator arm.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1. Informed consent by the parent or legal guardian. 
2. Male or female infant 4 to 12 months corrected gestational age at screening.
3. Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and 
baseline.
4. Short bowel syndrome with dependence on parenteral support to provide at least 50% of 
fluid or caloric needs.
5. Stable PN requirements for at least 1 month prior to screening, defined as a ≤10% change 
in the weight-normalized parenteral total fluid and caloric intake, despite attempts to 
wean PN, notwithstanding transient instability for events such as sepsis or interruption of 
central venous access.
6. This criteria was deleted.
7. Parent or legal guardian understands and is willing and able to fully adhere to study 
requirements as defined in this protocol.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1. Previous treatment with teduglutide.
2. Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus 
inclusion disease, etc.
3. Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, 
active gastroschisis-related dysmotility, that is the primary contributing factor to feeding 
intolerance and inability to reduce parenteral support, prior to screening. Dysmotility is 
defined as severe if it is expected to limit the advancement of enteral feeding.
4. Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral 
aversion in the absence of a feeding tube.
5. Intestinal obstruction or clinically significant intestinal stenosis.
6. Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or 
major intestinal resection or anastomosis, within 3 months prior to screening or planned 
during the study period.
7. Unstable cardiac disease.
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8. Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
9. Biliary obstruction, stenosis, or malformation. 
10. Clinically significant pancreatic disease. 
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following 
parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b. Platelet count <100×10^3/µL due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d. Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 
2 week period.
13. More than 3 serious complications of intestinal failure (eg, catheter-associated
bloodstream infections, interruption of nutrition due to feeding intolerance, 
catheter-associated thrombosis, severe fluid or electrolyte disturbances) within 1 month 
prior to or during screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile 
polyposis or Beckwith-Wiedemann syndrome, or first degree relative with early onset of 
gastrointestinal cancer (including hepatobiliary and pancreatic cancers). 
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 
(GLP-2); insulin-like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs 
of these hormones; or glutamine. 
16. Participation in a clinical study using an experimental drug within 3 months or 
5.5 half-lives of the experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, 
closely-related compounds, or any of the stated ingredients. 
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts 
the subject at any undue risk, prevents completion of the study, or interferes with analysis 
of the study results.
4.3
Reproductive Potential 
Not applicable; this study will enroll infants.
4.4
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator should 
discuss withdrawal of a subject from investigational product with the medical monitor as soon as 
possible.
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If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 24/EOT/early termination are to be performed as completely as possible. Whenever 
possible, all discontinued subjects should also undergo the protocol-specified 4-week Follow-up 
Period. Comments (spontaneous or elicited) or complaints pertaining to IP discontinuation made 
by the subject must be recorded in the source documents. The reason for discontinuation, the 
date and the total amount of investigational product administered must be recorded in the 
electronic case report form (eCRF) and source documents.
Subjects who discontinue will not be replaced. 
4.4.1
Reasons for Discontinuation
The reason(s) for permanent discontinuation of treatment and/or withdrawal from the study must 
be determined by the investigator, and recorded in the subject’s medical record and in the eCRF. 
If a subject is withdrawn for more than 1 reason, each reason should be documented in the source 
document, and the most clinically relevant reason should be entered in the eCRF.
Reasons for discontinuation include, but are not limited to:

Adverse event

Death

Lost to follow-up

Physician decision

Protocol deviation

Study terminated by sponsor

Withdrawal by parent/guardian

Lack of efficacy

Other
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact the parent(s)/guardian(s) of any 
subject lost to follow-up at any time point prior to the last scheduled contact (office visit or 
telephone contact). At least 1 of these documented attempts must include a written 
communication sent to the subject’s last known address via courier or mail (with an 
acknowledgement of receipt request) asking that they return to the site for final safety 
evaluations and return any unused investigational product.
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PRIOR AND CONCOMITANT TREATMENT
5.
5.1
Prior Medications and Procedures
Prior treatment includes all treatment and procedures (including but not limited to prescription 
treatments, herbal treatments, vitamins, non-pharmacological treatment, as appropriate) received 
within 14 days prior to the screening visit (Visit -1) (or pharmacokinetic equivalent of 5 half 
lives, whichever is longer, must be recorded on the appropriate eCRF page.
5.2
Concomitant Medications and Procedures
The administration of all medications including concomitant medications (including prescription 
and nonprescription medications, dietary and nutritional supplements, and vitamins) and PN 
must be recorded from the first dose of investigational product and for the duration of the study 
in the appropriate sections of the eCRF. Any diagnostic, surgical or other therapeutic treatments 
received by a subject during the course of the study will also be recorded on the eCRF.
The mechanism of action of teduglutide may increase enteral absorption of oral drugs (eg, drugs 
used for management of SBS such as motility medication, opioids, psychotropics, 
metronidazole), so consideration should be given to modifying concomitant enteral medication 
regimens. Titration of concomitant enteral medications should be considered when drugs, 
especially those with a narrow therapeutic index (eg, warfarin, digoxin, psychotropics) are given.
5.3
Permitted Treatment
Standard medical therapy for SBS should be continued.
5.4
Prohibited Treatment
The following medications are prohibited during teduglutide treatment and within the provided 
timeframe prior to the pretreatment visit (Table 3):
Table 3:
Prohibited Treatment
Prior Therapy
Time Restriction Prior to 
the Pretreatment Visit
Teduglutide
Any
GLP-2, human growth hormone, or analogs of these hormones
6 months
Octreotide, GLP-1 analogs, and enteral glutamine
30 days
GLP=glucagon-like peptide
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INVESTIGATIONAL PRODUCT
6.
6.1
Identity of Investigational Product
The SOC treatment arm will receive standard medical therapy for SBS; while those in the 
teduglutide arm will receive 0.05 mg/kg SC once daily in addition to standard medical therapy.
The investigational product is teduglutide, which will be provided in sterile, single-use 3 mL 
vials containing 1.25 mg teduglutide as a white lyophilized powder to be reconstituted before use 
with 0.5 mL sterile water for injection. In addition to the active ingredient (teduglutide), each 
vial of teduglutide contains L-histidine, mannitol, monobasic sodium phosphate monohydrate, 
and dibasic sodium phosphate as excipients. Additional information is provided in the current 
investigator’s brochure.
6.2
Administration of Investigational Product
6.2.1
Interactive Response Technology for Investigational Product Management
All investigative study sites will be initially provided with sufficient investigational product to 
randomly assign a subject into the study (for either of the proposed treatment groups). 
Randomization will occur through an interactive response system. Random assignment of a 
subject will trigger replacement supplies for that investigative study site.
6.2.2
Allocation of Subjects to Treatment
Subjects will be randomized 1:1 to the teduglutide or SOC treatment arm. Randomization will be 
stratified according to the presence of a small bowel ostomy (eg, end jejunostomy or ileostomy). 
The actual treatment given to individual subjects is determined by a randomization schedule.
Subject numbers are assigned to all subjects as they consent to take part in the study. Within each 
site (numbered uniquely within a protocol), the subject number is assigned to subjects according 
to the sequence of presentation for study participation. 
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined.
6.2.3
Dosing
The initial dose will be calculated based on body weight measured at baseline (Visit 0), and 
adjusted as needed, based on body weight measured at Week 12. No other adjustments to dose 
will be made during the teduglutide treatment period, unless discussed with the sponsor’s 
medical monitor. 
Following reconstitution, teduglutide will be administered by SC injection once daily (QD) into 
1 of the 4 quadrants of the abdomen (in subjects without a stoma) or into either the thigh or arm. 
For subjects with a stoma, the quadrant of the abdomen containing the stoma should not be used. 
Teduglutide should be used as soon as possible after reconstitution, but no more than 3 hours 
later.
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The subject should be dosed at approximately the same time each day. Consecutive doses should 
be separated by at least 12 hours. Each day, the injection site should be alternated. 
Any subject who achieves complete independence from PN support at any time during the 
treatment period will continue to receive teduglutide treatment.
The first SC injection in teduglutide-naïve subjects should be administered under the supervision 
of the investigator or designee and the subject observed for hypersensitivity reactions for at least 
4 hours during their initial dosing visit. The site of administration (arm, thigh, and abdomen) of 
the first teduglutide dose must be specified and recorded in the eCRF. 
Detailed instructions for reconstitution and injection of the investigational product can be found 
in the Instructions for Use. 
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up 
period until the end of study (Week 28/EOS) during which time subjects will receive standard 
medical therapy, but no investigational product will be administered. At EOS all subjects 
regardless of treatment arm may enroll in an extension study that will capture long-term safety 
data and provide the opportunity for additional teduglutide treatment. The follow-up period for 
subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed 
immediately to the EOS if at least one of the following “escape” criteria is met:
1. Increasing PN requirements following teduglutide discontinuation.
2. Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation. 
4. Severe diarrhea related to teduglutide discontinuation.
6.2.4
Unblinding the Treatment Assignment
Not applicable for this open-label study.
6.2.5
Dose Selection Rationale
Teduglutide is approved for adult and pediatric use in the EU at a dose of 0.05 mg/kg SC once 
daily. A completed 12-week dose finding study (TED-C13-003) demonstrated that teduglutide 
dosing at 0.025 and 0.05 mg/kg/day was associated with a favorable benefit-risk profile most 
meaningful at the 0.05 mg/kg/day dose (Carter et al., 2017). 
Population pharmacokinetic modeling and simulations were conducted to determine the optimal 
dose to be used in pediatric subjects using data from 8 adult clinical studies including adult Phase 
1 studies and Phases 2/3 studies as well as TED-C13-003 and suggested the same adult dose 
(0.05mg/kg) in pediatric subjects (aged between 1.67-14.7 years) (Marier et al., 2017).
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To support dosing in the current age group, further PK simulation was conducted based on the 
population PK model previously established and a virtual population of 1000 pediatric patients 
created based on Centers for Disease Control (CDC) growth charts in the target age group (4 to 
12 months) and taking into consideration body weights of pediatric patients with SBS enrolled in 
study TED-C13-003 and TED-C14-006 (approximately 15% lower than healthy subjects in the 
same age group). The model was customized by including a maturation function on clearance 
(CL/F) as a function of estimated glomerular filtration rate. Monte Carlo simulations for all age 
groups were performed according to the SC dosing regimens of 0.0125, 0.025 and 0.05 mg/kg 
every 24 hours. Rich concentration-time profiles were simulated with the customized population 
PK model to derive the exposure metrics area under the concentration curve at steady state 
(AUCss) and maximum concentration at steady state (Cmax,ss). Exposure parameters in infant 
patients were compared to those derived in pediatric (1-17 years) and adult (≥18 years) patients 
with SBS using a Bayesian approach. Based on the clinical observations, Cmax is considered to be 
associated with clinical responses. Following 0.05 mg/kg daily SC administration, the median 
Cmax,ss of teduglutide in neonate patients (24.9 ng/mL) was within 20% of that observed in the 
2 to 4 and 4 to 6 years age groups (26.9 and 29.4 ng/mL, respectively); and approximately 
~28% lower than that in adult patients with SBS. The median Cmax,ss of teduglutide in infant 
patients 4 to 12 months (41.9 ng/mL) following 0.05 mg/kg once daily was within 8% of that 
previously observed in adult patients with SBS (39.0 ng/mL, refer to the attached Simulation 
Report). In addition, individual simulated Cmax,ss values of teduglutide in infant patients 4 to 
12 months (25.6 to 65.1 ng/mL) were contained within the range of Cmax,ss previously observed 
in pediatric patients 1 to 17 years (20.7 to 77.4 ng/mL). The clinical package in conjunction with 
Cmax was considered to support teduglutide dose selection since AUCss was previously shown not 
to correlate with efficacy. Individual simulated AUCss values of teduglutide in infant patients 
4 to 12 months (66.9 to 160 ng.h/mL) following 0.05 mg/kg once daily were contained within 
the range of AUCss values previously observed in pediatric patients 1 to 17 years (63.5 to 
421 ng.h/mL). Based on the totality of clinical data, 0.05 mg/kg once daily is expected to provide 
comparable Cmax concentrations in infants as compared to pediatric patients with SBS and was 
recommended as an evaluation dosing regimen in Study SHP633-301. 
6.3
Labeling, Packaging, and Storage
6.3.1
Labeling
The investigational product will be packaged, labeled, and shipped to the study site by the 
sponsor or designee. Kits containing 7 vials of investigational product will be provided for this 
study. The vials will be labeled in accordance with applicable regulatory requirements. 
Ancillary kits, containing supplies needed for the reconstitution and administration of the 
investigational product will also be provided and labeled in accordance with the applicable 
regulatory requirements. 
All investigational product used in this study will be manufactured, tested, labeled, and released 
according to current legal requirements and Good Manufacturing Practice.
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6.3.2
Storage and Handling
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.
Investigational product must be kept in a locked area with access restricted to specific study 
personnel. Investigational product will be stored refrigerated at a temperature between 2-8°C 
(35.6-46.4°F) until dispensed to a subject. Once dispensed to a subject, the IP can be stored 
refrigerated or up to a controlled room temperature (acceptable range of 2-25°C, or 35.6-77°F). 
Parent/legal guardian will be instructed to keep the subject’s IP and sterile water diluent at 
controlled room temperature. If there are concerns that the controlled room temperature cannot 
be maintained, the IP may be refrigerated. The IP is for single use only, and should be used 
within 3 hours following reconstitution.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (ie, certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
Investigational products are distributed by the pharmacy or nominated member of the study 
team. The pharmacist/nominated team member will enter the unique subject identifier on the 
investigational product bottle/carton labels, as they are distributed.
6.4
Drug Accountability
Investigational product will not be dispatched to the study site until the sponsor or 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 investigational product 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. Kits will be shipped to the site once the subject 
is screened.
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Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for dispensing investigational product. Where 
permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is adequately 
trained in the protocol and who works under the direct supervision of the investigator. This 
delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee will dispense the investigational product only to subjects 
included in this study following the procedures set out in the study protocol. Investigational 
product kits will be dispensed at each of the applicable study visits at which the subject is 
required to be at the clinic. Each investigational product kit is sufficient for a treatment period of 
1 week and enough kits will be supplied to cover the period until the next planned study visit. 
Additional study kits will be provided as necessary.
Each subject will be given the investigational product according to the protocol. The investigator 
is to keep a current record of the inventory and dispensing of all clinical supplies. All dispensed 
medication will be documented on the eCRFs and/or other investigational product record. The 
investigator is responsible for assuring the retrieval of all study supplies from subjects.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.
At the end of the study, or as instructed by the sponsor, all unused stock, subject returned 
investigational product, and empty/used investigational product packaging are to be sent to the
sponsor or designee. The investigator is responsible for assuring the retrieval of all study 
supplies from subjects.
Returned investigational product must be counted and verified by clinical site personnel and the 
sponsor (or study monitor). Shipment return forms, when used, must be signed prior to shipment 
from the site. Contact the sponsor for authorization to return any investigational product prior to 
shipment. Shipment of all returned investigational product must comply with local, state, and 
national laws. 
Please see the Pharmacy Manual for additional information.
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6.5
Subject Compliance
The parent(s)/guardian(s) of subjects must be instructed to bring unused investigational product 
and empty/used investigational product packaging to every visit. Drug accountability must be 
assessed and recorded at the container/packaging level for unused investigational product that is 
contained within the original tamper-evident sealed container (eg, bottles, trays, vials) or at the 
individual count level for opened containers/packaging. 
Subject compliance will be checked by site personnel at every visit by reviewing the subject 
diaries and asking the subject or the subject’s parent or legally-authorized representative if they 
have administered the investigational product according to instructions. If any doses have been 
missed, the reason for missed dose should be documented in the subject’s source documentation 
including, as applicable, the eCRF.
The investigator is responsible for contacting the sponsor or designee when the subject’s daily 
investigational product dosing regimen is interrupted. Attempts should be made to contact the 
sponsor or designee prior to dose interruption. Reasons for dosage interruption may include but 
are not limited to hospitalization and AEs, a lapse in investigational product delivery, etc.
Subjects who have received 80% of the planned doses administered will be assessed as being 
compliant with the study protocol.
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STUDY PROCEDURES
7.
7.1
Study Schedule
Detailed study procedures and assessments to be performed for subjects throughout the study are 
outlined in the study schedules (Table 1 and Table 2) and must be referred to in conjunction with 
the instructions provided in this section. 
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 24/EOT are to be performed as completely as possible. Whenever possible, all 
discontinued subjects should also undergo the protocol-specified 4-week Follow-up Period. 
7.1.1
Screening
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent from the 
parent(s)/guardian(s) of the subject. The screening visit assessments and procedures, beginning 
with informed consent, will be performed as outlined in Table 1. Rescreening will not be 
allowed.
7.1.2
Treatment Period
The randomized Treatment Period will comprise Weeks 1 to 24, during which all assessments 
will be performed as outlined in Table 1 and Table 2.
7.1.3
Follow-up Period
The Follow-up Period will comprise Weeks 25 to 28, during which all assessments will be 
performed as outlined in Table 2.
7.2
Study Evaluations and Procedures
7.2.1
Demographics and Other Baseline Characteristics
Demographics and Medical History
Demographic and/or other baseline variables obtained at the screening and/or baseline visits are 
listed below. Abnormal findings of clinical significance (if any) will be recorded as past medical 
history.

Demography (including age, gestational age, sex, and race)

Medical history (including surgical history)

SBS history, including remnant anatomy
Upper Gastrointestinal Series with Small Bowel Follow-through
An upper GI contrast series with small bowel follow-through will be performed on all subjects 
during the screening period if one has not been done since the subject's last GI surgery. 
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It is acceptable to only enroll subjects who have already had an upper GI series with small bowel 
follow-through performed since the subject’s most recent surgery. 
7.2.2
Efficacy Assessments
Subject Diaries
All available diary data will be reviewed by the investigator or their designee at each clinic and 
telephone visit to assess clinical status and opportunity for PN reduction and advance in feeds. 
Parenteral support adjustments should be made after review of the intake and output diaries and 
the safety lab data according to the guidance for nutrition support adjustment provided in 
Appendix 2.
Intake Diary
Intake diaries will be used to collect and evaluate each subject’s nutritional support. The 
parent/legally authorized representative/study site staff will complete the appropriate fields of the 
PN and EN sections of the intake diary daily throughout the study.
The following data will be captured in the intake diaries:

Parenteral support volume and infusion duration

Enteral nutrition (formula) including volume and calories
Site personnel will determine the actual PN and EN daily calories based on diary entries.
Output Diary
Urine and stool output should be recorded in the output diary over a 48-hour period of nutritional 
stability before every clinic visit; in addition, output should be recorded for subjects within 
1 week of implementing a change in the PN prescription.
Urine data:

Measure and record the weight of all urine-only diapers. Urine volume will be calculated 
using the following formula: 1 g (scale weight) = 1 mL or 1 cc

At the discretion of the investigator, the parent or legal guardian/study site staff may be 
asked to collect the first void after the daily PN infusion to measure specific gravity
Stool data (includes diapers with mixed urine and stool):

Record the weight of diapers containing stool (including diapers with mixed urine and 
stool) as stool output and score the stool consistency (see Output diary). Stool volume 
will be calculated using the formula: 1 g (scale weight)=1 mL or 1 cc
All ostomy output volume should be recorded. 
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Native GLP-2
Blood samples for native GLP-2 should be collected postprandial. Blood samples while subjects 
are receiving teduglutide should be drawn at least 14 hours after the previous dose. Native 
GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject 
weight or at investigator discretion based on weekly/monthly total volume. 
7.2.3
Safety Assessments
Laboratory Evaluations
Safety laboratory tests to be performed at site visits consist of clinical chemistry, hematology, 
and urinalysis and will be performed as outlined in the study plan (Table 1 and Table 2). 
Scheduled laboratory testing will be processed by a central lab. All laboratory assays will be 
performed according to the central laboratory’s normal procedures. Reference ranges are to be 
supplied by the laboratory. The investigator should assess out-of-range clinical laboratory values 
for clinical significance, indicating if the value(s) is/are not clinically significant or clinically 
significant. Abnormal clinical laboratory values, which are unexpected or not explained by the 
subject’s clinical condition, may, at the discretion of the investigator or sponsor, be repeated as 
soon as possible until confirmed, explained, or resolved.
During the Treatment Period, subjects will also have safety labs within approximately 5 to7 days 
after a PN adjustment. Safety labs performed after PN adjustment and between site visits will 
consist of clinical chemistry and urinalysis and may be processed by the central laboratory or a 
local laboratory. Local lab results are not required to be entered in the eCRFs; however, if the 
local lab results indicate any new clinically significant changes, they must be reported as an 
adverse event (see Section 8). Urine specimen collection should be attempted as part of the 
safety labs, but lack of urinalysis will not constitute a protocol deviation.
At baseline, blood samples for safety labs and PK can be separated by 1 day if blood volumes are 
limiting. 
Safety labs at telephone visits will be collected at the discretion of the investigator. 
For all subjects in the teduglutide treatment arm, prothrombin time (PT) and international 
normalized ratio (INR), tested at baseline, will be repeated if clinically indicated.
New clinically significant labs should be reported as AEs.
Close Monitoring Criteria Related To Liver Test Abnormalities:  
The investigator should contact the medical monitor within 24 hours of their awareness if the 
subject develops any of the following changes in laboratory parameters:

ALT or AST >5x ULN and >2x baseline value

Total or direct bilirubin that is >2x baseline value or an absolute increase of  ≥3 mg/dL 
(51.3 µmol/L)
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If such changes are observed, the labs should be repeated along with an INR, and an inquiry 
should be made as to the presence of clinical symptoms consistent with new liver injury. The 
subject should be followed closely to determine the trajectory of the laboratory abnormalities and 
appropriate evaluations should be made, such as abdominal ultrasound with Doppler imaging to 
exclude vascular causes and biliary obstruction, consideration of sepsis, liver hypoperfusion, 
acute viral hepatitis (such as hepatitis A, EBV, or HSV), exposure to hepatotoxic medications, 
mitochondrial hepatopathy, or metabolic liver disease (such as hereditary fructose intolerance or 
arginosuccinate synthetase deficiency). Further evaluations can be performed at the discretion of 
the investigator in consultation with the Shire medical monitor.
The following clinical laboratory assessments will be performed according to the study 
schedules:
Table 4:
List of Laboratory Tests
Biochemistry:

Albumin 

Alkaline phosphatase 

Alanine aminotransferase 

Amylase

Aspartate aminotransferase 

Bicarbonate

Bilirubin (total and indirect)

Blood urea nitrogen 

Calcium (total)

Chloride

Cholesterol

C-reactive protein 

Creatinine

Estimated Glomerular Filtration Rate 
(Schwartz formula)

Gamma-glutamyl transferase 

Glucose

Lipase

Magnesium

Phosphorus

Potassium 

Sodium 

Triglycerides
Hematologya:

Hematocrit 

Hemoglobin 

Platelet count

Red blood cell count 

Red blood cell morphology, if needed

White blood cell count with differential
Coagulationb:

Prothrombin time

International normalized ratio
Urinalysis: 

Specific gravity  

Urine Sodium
a Hematology is not collected at Week 1 or at telephone visits.
b For all subjects in the teduglutide treatment arm, PT and INR will be tested at baseline and repeated only if clinically indicated.
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Antibodies to Teduglutide 
Blood samples will be drawn to test for antibodies to teduglutide. Samples will be taken before 
teduglutide administration at the screening visit (Visit -1) and at least 14 hours after the previous 
dose at Week 12 (Visit 12); samples may be drawn from a central line or peripheral access. One 
additional sample will be collected at the EOS 4 weeks after the EOT (ie, Week 28 or EOS). 
Volume of Blood
Efforts will be made to minimize the amount of blood drawn from all pediatric subjects 
participating in this study. The volumes of blood to be drawn from each subject will vary 
depending on clinical status. Approximate volumes of blood to be drawn from each subject are 
shown in Table 5.
Table 5:
Approximate Volume of Blood to be Drawn from Each Subject 
Assessment
Sample 
Volume (mL)
No. 
Samples 
Total 
Volume (mL)
Notes
Subjects Receiving Teduglutide Treatment
Biochemistry 
0.6
12
7.2
Hematology
0.6
11
6.6
Coagulation 
Parameters
0.6
1
0.6
PT and INR tested at baseline 
only, repeat while on study 
only if clinically indicated.
Antibodies
1.5
5
7.5
Pharmacokinetics
1.5
4
6.0
Baseline: 3 timepoints
Week 7: 1 timepoint OR
Week 12: 1 timepoint
Native GLP-2
1.5
3
4.5
Total mL:
6.3
36
32.4
Subjects Receiving Standard of Care
Biochemistry 
0.6
12
7.2
Hematology
0.6
11
6.6
Native GLP-2
1.5
3
4.5
Total mL:
2.7
26
18.3
GLP=glucagon-like peptide; INR=international normalized ratio; PT=prothrombin time
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment. When more than 1 blood assessment is to be done at the time 
point/period, if they require the same type of tube, the assessments should be combined. Blood 
volume estimates do not include safety labs performed after PN adjustments.
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Physical Examinations, Vital Signs, Weight, Length, and Head Circumference
Physical examinations will be performed according to the study schedules (Table 1 and Table 2). 
Any new clinically significant findings noted during physical examinations should be recorded 
on the appropriate AE page of the eCRF.
Vital signs will be measured according to the study schedules. Measurements will include 
systolic and diastolic blood pressure (mmHg), pulse (beats per minute), and body temperature 
(°C/°F). Blood pressure should be determined by the appropriate size cuff (using the same 
method, the same leg, and in the supine position throughout the study, when possible). Blood 
pressure measurements should be attempted as part of the vital signs, but lack of blood pressure 
results will not constitute a protocol deviation. New clinically significant vital sign abnormalities 
should be recorded on the appropriate AE page of the eCRF.
Body weight will also be recorded in the eCRF; subjects should be weighed on the same scale 
at each study visit. Length and head circumference will be measured at selected visits. A height 
z-score, weight Z-score, and weight/length ratio will be calculated by the sponsor using the 
site-provided height and weight data collected at each site visit.
7.2.4
Pharmacokinetic Assessments
Subjects will have blood samples taken for teduglutide PK analysis predose, and 1 hour
±10 minutes and 4 hours ±10 minutes postdose at baseline (Visit 0). Subjects also will have 
blood samples taken for teduglutide PK analysis 2 hours ±10 minutes postdose at Week 7 
(Visit 7) or Week 12 (Visit 12) of the treatment period. Blood for PK sampling should be 
collected via peripheral IV or venipuncture, not from a central line. The site of teduglutide 
administration prior to PK blood draws (arm, thigh, abdomen) must be specified. 
7.2.5
Health Economics and Outcomes Research
Hospitalizations
Each hospitalization that occurs during the study will be recorded, including date of admission, 
date of discharge, reasons for hospitalization, discharge diagnosis, and discharge status. 
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ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.3. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, or 
a symptom is more severe or prolonged than expected given the diagnosis, then symptom(s) 
should be listed individually. All AEs should be captured on the appropriate AE pages in the 
eCRF and in source documents. In addition to untoward AEs, unexpected benefits outside the 
investigational product indication should also be captured on the AE eCRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
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8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of 
the investigational product is compelling and/or follows a known or 
suspected response pattern to that product, and the event cannot be 
explained by the subject’s medical condition, other therapies, or 
accident.
Not Related
The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident and no 
plausible temporal or biologic relationship exists between the 
investigational product and the event.
AEs that are related to IP that are not resolved at EOS will be followed until the event resolves or 
stabilizes, as judged by the investigator.
Laboratory values, vital signs, and clinical findings at the scheduled physical examinations must 
be reported as AEs if the investigator considers the finding to be a clinically significant change 
from the baseline.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the eCRF. Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved with Sequelae 

Recovering/Resolving

Unknown
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8.1.4
Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE. It is assumed that some of the infants participating in this study may be 
hospitalized for planned surgery(ies) that will occur during their participation in the study. Such 
pre-planned, elective surgeries, do not need to be reported as SAEs for this protocol. 
8.1.5
Clinical Laboratory and Other Safety Evaluations
An untoward change in the value of a clinical laboratory parameter, vital sign measure, or ECG
assessment can represent an AE if the change is clinically relevant or if, during administration of 
investigational product, a shift of a parameter is observed from a value in the normative range to 
a value that is outside the normal range and considered clinically significant, or a further waning 
of an already clinically significant value. Clinical significance is defined as any abnormal finding 
that results in further clinical investigation(s), treatment(s), or the diagnosis of new or 
progression of established condition. When evaluating such changes, the extent of deviation from 
the reference range, the duration until return to the reference range, either while continuing 
administration or after the end of administration with the investigational product, and the range 
of variation of the respective parameter within its reference range, should also be considered.
If, at the end of the treatment phase, there are abnormal clinical laboratory (such as hematology 
panel or clinical chemistry panel), vital sign, or ECG values which were not present at the 
beginning of the pretreatment evaluation observed closest to the start of study treatment, further 
investigations should be performed until the values return to within the reference range or until a 
plausible explanation (eg, concomitant disease or expected disease evolution) is found for the 
abnormal values.
The investigator should assess, based on the above criteria and the clinical condition of a subject, 
whether a change in a clinical laboratory value, vital sign, or ECG parameter is clinically 
significant and represents an AE.
8.1.6
Pregnancy
Not applicable.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for 
a non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner 
that may be detrimental to the individual and/or society.
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
Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol).

Overdose – Administration of a dose greater than the allocated dose of the study 
medication or at a frequency greater than the dosing interval specified by the protocol.

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product. For studies, medication errors are reportable to the sponsor 
only as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error. 
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally-authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator brochure which the sponsor 
has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Drug Safety Department and the Shire Medical Monitor within 24 hours of the first awareness of 
the event. Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, 
misuse, overdose, or medication errors (see Section 8.1.7) unless they result in an SAE.
All Adverse Events of Special Interest, as defined in Section 8.3, must be reported by the 
investigator to the Shire Global Drug Safety Department and the Shire Medical Monitor within 
24 hours of the first awareness of the event even if the event does not fulfill seriousness criterion.
The investigator must complete, sign, and date the Shire Clinical Study Adverse Event Form for 
SAEs and Non-serious AEs as Required by Protocol, and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested). Fax or e-mail the completed form to the Shire Global Drug Safety 
Department. A copy of the completed Shire Clinical Study Adverse Event Form for Serious 
Adverse Events (SAEs) and Non-serious AEs as Required by Protocol (and any applicable 
follow-up reports) must also be sent to the Shire medical monitor or designee using the details 
specified in the emergency contact information section of the protocol.
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8.2.3
Serious Adverse Event Definition
A SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose: 

Results in death

Is life-threatening. Note: The term 'life-threatening' in the definition of "serious" refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for pre
existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse. 
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to investigational product) are collected from the time the 
subject signs the informed consent until the defined follow-up period stated in Section 7.1.3, and 
must be reported to the Shire Global Drug Safety Department and the Shire Medical Monitor 
within 24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Drug Safety Department within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
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In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death. 
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting 
The Sponsor and/or Clinical Contract Research Organization (CRO) is responsible for notifying 
the relevant regulatory authorities, and US central Institutional Review Boards (IRBs)/EU central 
ethics committees (ECs), of related, unexpected SAEs.
In addition, the Clinical CRO is responsible for notifying active sites of all related, unexpected 
SAEs occurring during all interventional studies across the SHP633 program.
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
8.3
Adverse Events of Special Interest
An AE of special interest is an AE (serious or nonserious) of scientific and medical concern 
specific to the sponsor’s product or program and for which ongoing monitoring and immediate 
notification by the investigator to the sponsor is required.
The AEs of special interest that require expedited regulatory reporting include the following:

Growth of pre-existing polyps of the colon

Benign neoplasia of the GI tract including the hepatobiliary system

Tumor-promoting ability (eg, benign and/or malignant neoplasia of any kind, not limited 
to those of the GI or hepatobiliary system)
For AEs of special interest, the sponsor must be informed within 24 hours of first awareness as 
per the SAE notification instructions described in Section 8.2.2 even if the event does not fulfill 
the seriousness criteria.
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8.4
Dose Interruption Criteria
The investigator is responsible for contacting the sponsor/designee when the subject’s 
teduglutide dosing regimen is interrupted. The length of dose interruption, and whether 
teduglutide administration resumes or is permanently discontinued, depends on the clinical 
situation.
Investigational product must be interrupted if any of the following events occur:

An adverse event of special interest (see Section 8.3) 

Intestinal obstruction

Biliary obstruction

Pancreatic duct obstruction

Heart failure with severe fluid overload determined by the sponsor or investigator to 
be related to IP.
Investigational product must be permanently discontinued if any of the following events occur: 

Severe hypersensitivity, such as anaphylaxis, determined by the investigator to be 
related to IP. 

Any malignancy 
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DATA MANAGEMENT AND STATISTICAL METHODS
9.
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the eCRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered on the eCRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. Once a subject is randomized, it is expected that site 
personnel will complete the eCRF entry within approximately 3 business days of the subject’s 
visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the data management plan. Quality 
control and data validation procedures are applied to ensure the validity and accuracy of the 
clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Statistical Analysis Process
The study will be analyzed by the sponsor or designee. All statistical analyses will be performed 
using SAS® (SAS Institute, Cary, NC, US) version 9.3 or higher.
The statistical analysis plan (SAP) will provide the definitions and statistical methods  for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed.
9.4
Planned Interim Analysis, and Data Monitoring Committee 
No interim analyses is planned for this the study. 
A data monitoring committee (DMC) will be involved in the management of this study. The 
DMC members will review the data approximately every 3 months according to the DMC 
Charter. The DMC review will include all cumulative safety data (ie, AEs, laboratory 
assessments, physical examinations, etc.) from study assessments through each cutoff period. 
Further details regarding the DMC can be found in the DMC charter, which will be available 
prior to the administration of investigational product. 
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The DMC for this study will be conducted in accordance with the FDA Guidance for Clinical 
Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees 
(March 2006).
The DMC will be an external, independent board comprised of physicians with relevant training. 
The DMC will be restricted to individuals free of significant conflicts of interest, including, but 
not limited to, financial, scientific, or regulatory in nature. The DMC will be governed by a 
Charter agreed to by members of the Board and the sponsor. Members of the Board may not be 
study investigators or be employed at the same institution as a study investigator, individuals 
employed by the sponsor, independent contractors hired by the sponsor, or members of 
regulatory agencies. The DMC may make recommendations to the sponsor regarding study 
aspects including stopping, modifying or continuing the study; however, the sponsor will have 
the final responsibility to determine whether the study should be modified or temporarily or 
permanently stopped. If the DMC recommends termination of this pediatric study, the 
recommendations will be communicated to the relevant regulatory agencies within 7 calendar 
days.
9.5
Sample Size Calculation and Power Considerations
The sample size is determined based on enrollment feasibility for this rare condition and the age 
of the study population. 
9.6
Study Population
Intent to treat (ITT) population: All subjects randomized in the study.
Safety analysis population: The safety analysis set will contain all subjects who meet the 
following criteria:

Teduglutide treatment arm: subjects who receive at least 1 dose of teduglutide and 
have undergone at least 1 post-baseline safety assessment; analyses will be performed 
according to dose group as appropriate. 

Standard of care treatment arm: subjects who have undergone at least 1 post-baseline
safety assessment.
Per-protocol population: All subjects in the ITT population without any major protocol deviation 
that affects interpretation of efficacy results.
Pharmacokinetic analysis population: All subjects who received at least 1 dose of teduglutide 
and have at least 1 evaluable postdose PK concentration value. 
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9.7
Efficacy Analyses
9.7.1
Efficacy Endpoints
Efficacy endpoints consist of the following:
9.7.1.1
Primary Efficacy Endpoint 

Reduction in weight-normalized PN fluid volume by at least 20% from baseline at 
Week 24/EOT
9.7.1.2
Secondary Efficacy Endpoints

Reduction in weight-normalized parenteral calories by at least 20% from baseline to 
Week 24/EOT

Achievement of enteral autonomy by Week 24

Time to achieve enteral autonomy

Change in weight-normalized parenteral fluid volume from baseline to each visit

Change in weight-normalized parenteral calories from baseline to each visit

Change in weight-normalized enteral fluid volume from baseline to each visit

Change in weight-normalized enteral caloric intake from baseline to each visit

Increase in weight-normalized enteral fluid intake by at least 20% from baseline to week 
24/EOT

Increase in weight-normalized enteral caloric intake by at least 20% from baseline to 
week 24/EOT
9.7.2
Method of Analysis-Efficacy Endpoints
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 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.
Analyses of weekly PN support will be based on 2 data sources: the subject diary data (also 
referred to as actual data) and the investigator prescribed data. 
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The number and percentage of subjects who achieve at least a 20% reduction from baseline in 
weight-normalized average daily PN volume at Week 24/EOT and the number and percentage of 
subjects who achieve at least a 20% reduction from baseline in weight-normalized parenteral 
calories at Week 24/EOT will be summarized by treatment arm.
During the treatment period, a subject will be considered to have achieved enteral autonomy
(completely weaned off PN) at a given visit if the investigator prescribes no PN at that visit and 
for the remainder of the treatment period, and there is no use of PN recorded in the subject diary 
during the week prior to that visit and for the remainder of the treatment period. During the 
follow-up period, a subject will be considered to have achieved enteral autonomy at a given visit 
if the investigator prescribes no PN at that visit and for the remainder of the follow-up period and 
there is no use of PN recorded in the subject diary during the week prior to that visit and for the 
remainder of the follow-up period. The number and percentage of subjects who achieve enteral 
autonomy at each scheduled visit, as well as at EOT, will be summarized by treatment arm.
Descriptive statistics will be used to summarize time to achievement of enteral autonomy by 
treatment arm.
The absolute and percent change in weight-normalized weekly PN volume, parenteral calories, 
enteral fluid volume, and enteral caloric intake, from baseline to each scheduled visit, as well as 
at EOT, will be summarized by treatment arm using descriptive statistics.
The number and percentage of subjects who demonstrate an increase in weight-normalized 
enteral fluid intake by at least 20% from baseline to Week 24/EOT and the number and 
percentage of subjects who demonstrate an increase in weight-normalized enteral caloric intake 
by at least 20% from baseline to week 24/EOT will be summarized by treatment arm.
9.8
Safety Analyses
9.8.1
Safety Endpoints
Safety endpoints consist of the following:

Adverse events

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for 
gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output

Stool (including mixed) output

Antibodies to teduglutide
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9.8.2
Method of Analysis-Safety Endpoints
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Treatment-emergent AEs will be summarized by system organ class and preferred 
term using descriptive statistics (eg, number and percentage of subjects). Adverse events will be 
summarized by severity and relationship to treatment. In addition, SAEs will also be tabulated by 
overall and treatment-related events. AEs leading to treatment discontinuation and death will 
also be summarized.
For laboratory tests; vital signs; urine and stool output; weight, length, and head circumference 
Z-scores, and descriptive statistics (eg, n, mean, standard deviation, median, minimum and 
maximum values, and the number and percentage of subjects in specified categories) will be 
used to summarize the absolute values and change from baseline at each visit.
The number and percentage of subjects classified as having antibodies to teduglutide will be used 
to summarize the presence of antibodies. 
9.9
Health Economics and Outcomes Research Analyses
Health economics and outcomes research endpoints consist of the following:

Cumulative number of hospitalization days during the study
Health economics and outcomes research endpoints will be summarized using descriptive 
statistics (number, mean and standard deviation) at nominal time points. 
9.10
Pharmacokinetics Analyses
Plasma concentrations will be summarized using descriptive statistics (number, mean, standard 
deviation, geometric mean, coefficient of variation, minimum, median, and maximum ) at 
nominal time points. 
Pharmacokinetic parameters will be estimated using a population PK modeling approach as 
appropriate and reported separately.
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SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES
10.
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements. 
The name and address of each third-party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996), EU 
Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study. An insurance certificate is supplied as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. 
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This requirement will be fulfilled within 6 months of the end of the study completion date for 
pediatric studies and within 1 year for non-pediatric studies as per guidance. The sponsor will 
provide the ECs with a copy of the same summary.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly. The sponsor will make an end-of-study declaration to the relevant competent 
authority as required by Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub investigators are provided to the study
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator will be appointed to review the final clinical study report 
for multicenter studies. Agreement with the final clinical study report is documented by the 
signed and dated signature of the principal investigator (single-site study) or coordinating 
principal investigator (multicenter study), in compliance with Directive 2001/83/EC as amended 
by Directive 2003/63/EC and ICH Guidance E3 (1995).
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
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If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Electronic Case Report Forms
Electronic case report forms are supplied by the sponsor or designee and should be handled in 
accordance with instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Electronic case report forms 
must be completed by the investigator or designee as stated in the site delegation log. All data 
will have separate source documentation; no data will be recorded directly onto the eCRF.
All data sent to the sponsor must be endorsed by the investigator. 
The study monitor will verify the contents against the source data per the monitoring plan. If the 
data are unclear or contradictory, queries are sent for corrections or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject diaries, and original clinical laboratory reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF entries 
against the source documents. The consent form includes a statement by which the 
parent/guardian agrees to the monitor/auditor from the sponsor or its representatives, national or 
local regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical 
file, appointment books, original laboratory reports, X-rays etc). Non-study site personnel will 
not disclose any personal information or personal medical information.
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These records must be made available within reasonable times for inspection and 
duplication, if required, by a properly authorized representative of any regulatory agency 
(eg, the US FDA, EMA, UK Medicines and Healthcare products Regulatory Agency) or an 
auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the European Medicines Agency (EMA), the 
Medicines and Healthcare products Regulatory Agency, other regulatory authorities, the sponsor 
or its representatives, and the IRB/EC for each site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 
1 year after, whereby the outcome of the study could be influenced by the value of the 
compensation for conducting the study, or other payments the investigator received from the 
sponsor. The following information is collected: any significant payments from the sponsor 
or subsidiaries such as a grant to fund ongoing research, compensation in the form of 
equipment, retainer for ongoing consultation or honoraria; any proprietary interest in 
investigational product; any significant equity interest in the sponsor or subsidiaries as defined in 
21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent, where applicable, 
from the parent(s)/guardian(s) of all study subjects prior to any study-related procedures 
including screening assessments. All consent documentation must be in accordance with 
applicable regulations and GCP. Each subject’s legally authorized representative is requested to 
sign and date the subject informed consent form or a certified translation if applicable, after the 
subject’s parent or guardian has received and read (or been read) the written subject information 
and received an explanation of what the study involves, including but not limited to: the 
objectives, potential benefits and risk, inconveniences, and the subject’s rights and 
responsibilities. A copy of the informed consent documentation (ie, a complete set of subject 
information sheets and fully executed signature pages) must be given to the subject’s legally 
authorized representative, as applicable. This document may require translation into the local 
language. Signed consent forms must remain in each subject’s study file and must be available 
for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form  that was 
reviewed by the IRB/EC and received their favorable opinion/approval. 
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A copy of the IRB/EC’s written favorable opinion/approval of these documents must be 
provided to the sponsor prior to the start of the study unless it is agreed to and documented 
(abiding by regulatory guidelines and national provisions) prior to study start that another party 
(ie, sponsor or coordinating principal investigator) is responsible for this action. Additionally, if 
the IRB/EC requires modification of the sample subject information and consent document 
provided by the sponsor, the documentation supporting this requirement must be provided to the 
sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the sponsor/designee has received 
written IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB/EC informed of any serious and 
significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996. A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the sponsor/designee.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. 
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These records and data may, in addition, be reviewed by others including the following: 
independent auditors who validate the data on behalf of the sponsor; third parties with whom the 
sponsor may develop, register, or market teduglutide; national or local regulatory authorities; and 
the IRB(s)/EC(s) which gave approval for the study to proceed. The sponsor and/or its 
representatives accessing the records and data will take all reasonable precautions in accordance 
with applicable laws, regulations, and guidelines to maintain the confidentiality of subjects’ 
identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2 to 4 and certain other studies as determined by Shire. The purpose of 
the publication steering committee is to act as a non-commercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, royalty 
free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
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Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.
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REFERENCES
11.
Beattie, L. M., Barclay, A. R. & Wilson, D. C. 2010. Short bowel syndrome and intestinal failure 
in infants and children. Paediatrics and Child Health, 20, 485-491.
Carter, Cohran, Cole, Corkins, Dimmitt, Duggan, Hill, Horslen, Lim, Mercer, Merritt, Nichol, 
Sigurdsson, Teitelbaum, Thompson, Vanderpool, Vaughan, Li, Youssef, Venick & 
Kocoshis 2017. Outcomes from a 12-Week, Open-Label, Multicenter Clinical Trial of 
Teduglutide in Pediatric Short Bowel Syndrome. Journal of Pediatrics, The, 181, 102-
111.e5.
Gonzalez-Hernandez, Prajapati, Ogola, Channabasappa, Drews & Piper 2017. Predicting time to 
full enteral nutrition in children after significant bowel resection. Journal of Pediatric 
Surgery, 52, 764-767.
Goulet, O. & Ruemmele, F. 2006. Causes and Management of Intestinal Failure in Children. 
Gastroenterology, 130, S16-S28.
Huisman-de Waal, G., Schoonhoven, L., Jansen, J., Wanten, G. & van Achterberg, T. 2007. The 
impact of home parenteral nutrition on daily life-A review. Clinical Nutrition, 26, 275-
288.
Khan, F. A., Squires, R. H., Litman, H. J., Balint, J., Carter, B. A., Fisher, J. G., Horslen, S. P., 
Jaksic, T., Kocoshis, S., Martinez, J. A., Mercer, D., Rhee, S., Rudolph, J. A., Soden, J., 
Sudan, D., Superina, R. A., Teitelbaum, D. H., Venick, R., Wales, P. W. & Duggan, C. 
2015. Predictors of Enteral Autonomy in Children with Intestinal Failure: A Multicenter 
Cohort Study. J Pediatr, 167, 29-34.e1.
Marier, J., Kassir, N., Martin, P. & Wang, Y. 2017. Population pharmacokinetic modeling of 
teduglutide to support dosing in pediatric patients with short bowel syndrome. Clinical 
Pharmacology & Therapeutics, 101, S91.
Martin, G.-R., Beck, P.-L. & Sigalet, D.-L. 2006. Gut hormones, and short bowel syndrome: the 
enigmatic role of glucagon-like peptide-2 in the regulation of intestinal adaptation. World 
Journal of Gastroenterology, 12, 4117-29.
O'Keefe, S. J., Buchman, A. L., Fishbein, T. M., Jeejeebhoy, K. N., Jeppesen, P. B. & Shaffer, J. 
2006. Short bowel syndrome and intestinal failure: consensus definitions and overview. 
Clin Gastroenterol Hepatol, 4, 6-10.
Sigalet, D. L., Martin, G., Meddings, J., Hartman, B. & Holst, J. J. 2004. GLP-2 levels in infants 
with intestinal dysfunction. Pediatr Res, 56, 371-6.
Spencer, A. U., Neaga, A., West, B., Safran, J., Brown, P., Btaiche, I., Kuzma-O'Reilly, B. & 
Teitelbaum, D. H. 2005. Pediatric Short Bowel Syndrome: Redefining Predictors of 
Success. Annals of Surgery, 242, 403-412.
Squires, R. H., Duggan, C., Teitelbaum, D. H., Wales, P. W., Balint, J., Venick, R., Rhee, S., 
Sudan, D., Mercer, D., Martinez, J. A., Carter, B. A., Soden, J., Horslen, S., Rudolph, J. 
A., Kocoshis, S., Superina, R., Lawlor, S., Haller, T., Kurs-Lasky, M. & Belle, S. H. 
2012. Natural history of pediatric intestinal failure: initial report from the Pediatric 
Intestinal Failure Consortium. J Pediatr, 161, 723-8.e2.
Tappenden, K. A., Edelman, J. & Joelsson, B. 2013. Teduglutide enhances structural adaptation 
of the small intestinal mucosa in patients with short bowel syndrome. J Clin 
Gastroenterol, 47, 602-7.
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Thymann, T., Stoll, B., Mecklenburg, L., Burrin, D. G., Vegge, A., Qvist, N., Eriksen, T., 
Jeppesen, P. B. & Sangild, P. T. 2014. Acute effects of the glucagon-like peptide 2 
analogue, teduglutide, on intestinal adaptation in short bowel syndrome. J Pediatr 
Gastroenterol Nutr, 58, 694-702.
Wales, P. W., de Silva, N., Kim, J., Lecce, L., To, T. & Moore, A. 2004. Neonatal short bowel 
syndrome: population-based estimates of incidence and mortality rates. J Pediatr Surg,
39, 690-5.
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APPENDICES
12.
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Appendix 1
Protocol History
Document
Date
Global/Country/Site Specific
Original Protocol
03 Oct 2017
Global
Amendment 1
18 Jan 2018
Global
Amendment 2
04 Dec 2018
Global
Amendment 3
24 May 2019
Global
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change
Section(s) Affected by Change
Updated emergency contact information to reflect the change 
of the Contract Research Organization’s name.
Emergency Contact 
Information
Clarified the duration of the screening period and total time 
on study. 
Provided a clear definition of study completion.
Synopsis, Section 3.1, 
Section 3.2
Updated the study schematic to reflect the study design 
changes.
Revised the telephone and clinic visit schedule to assure 
laboratory measurement could be collected without 
exceeding weekly/monthly total blood volume restrictions. 
Synopsis, Table 1,
Section 3.1.2
Moved the PK sampling from Week 6 to Week 7 so that the 
samples could be collected without exceeding 
weekly/monthly total blood volume restrictions.
Synopsis, Table 1, 
Section 3.1.2, Section 7.2.4, 
Table 5
Clarified that blood for pharmacokinetic samples of postdose 
may be taken within ± 10 minutes of the time pre-specified.
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change
Section(s) Affected by Change
Clarified that end jejunostomy or ileostomy are examples  of 
small bowel ostomy rather than the stratification factors.
Synopsis, Section 3.1.2, 
Section 6.2.2
Clarified that all subjects regardless of treatment arm are 
eligible for the extension study.
Synopsis, Section 3.1.3
Clarified that if a subject treated with teduglutide meets the 
escape criteria, the assessments scheduled for the EOS visit 
should be conducted.
Synopsis, Table 2, 
Section 3.1.3, Section 6.2.3
Clarified that subjects must be 4 to 12 months corrected 
gestational age at screening.
Synopsis, Section 4.1
Changed dose adjustments to Week 12 rather than at every 
clinic visit to reduce site burden.
Synopsis, Table 1, 
Section 6.2.3
Clarified the definition of enteral autonomy.
Synopsis, Section 9.7.2
Updated the pharmacokinetic endpoint and analysis to reflect 
that only descriptive statistics will be calculated on plasma 
teduglutide concentration values. Pharmacokinetic 
parameters will be estimated using a population PK 
modeling approach as appropriate and reported separately.
Synopsis, Section 9.10
Removed assessment of the 5-level EuroQol five dimensions 
questionnaire to reduce caregiver burden.
Synopsis, Table 1, 
Section 7.2.5, Section 9.9
Clarified that native GLP-2 samples drawn while subjects are 
receiving teduglutide should be drawn at least 14 hours after 
the previous dose.
Table 2, Section 7.2.2
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change
Section(s) Affected by Change
Inserted a footnote to clarify that parenteral support and 
parenteral nutrition are used interchangeably.
Section 1.1
Removed the 5 mg vial of teduglutide as this size vial will 
not be supplied for this study.
Section 6.1
Clarified the procedures for assessing subject compliance. 
Section 6.5
Specified that it is acceptable to only enroll subjects who 
have already had an upper GI series with small bowel follow 
through performed since the subject’s most recent surgery. 
Section 7.2.1
Corrected the volume of blood to be collected for native 
GLP-2.
Table 5
Removed references to subject assent as assent is not 
possible in a study of infants. 
Section 7.1.1, Section 10.3.1
Clarified the definitions of the analysis sets.
Section 9.6
Clarified that an adjustment to enteral nutrition as 
appropriate is part of the PN/IV adjustment algorithm.
Figure A-1
Minor editorial changes and corrections to typographical 
errors (which do not modify content and/or intent of the 
original document) were made.
Throughout protocol.
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2
Amendment Date
04 Dec 2018
Global
Description of Change
Section(s) Affected by Change
The fax number currently used to send the Shire Medical 
Monitor a copy of the Shire Clinical Study Adverse Event 
Form for Serious Adverse Events (SAEs) and Non-serious 
AEs as Required by Protocol is now retired; a copy of the 
form must be sent by email only.
Updated emergency contact information to reflect the change 
of Shire medical monitor to 
, IQVIA back 
up medical support to 
, and IQVIA 
phone number for medical emergencies.
Emergency Contact Information
A single email address (
) is now used to 
report a Product Quality Complaint, independently from 
where it has originated. 
Product Quality Complaints
Added the new secondary efficacy endpoint “Time to achieve 
enteral autonomy” and statistical methodology to be used.
Synopsis, Section 9.7.1.2, 
Section 9.7.2
Updated  the information on the clinical studies with 
teduglutide in pediatric subjects to include the results of 
TED-C14-006.
Section 1.2
Clarified that teduglutide is the investigational product for 
this study.
Section 6.1
Updated the dose selection rationale with results from a 
simulation work using the previous population 
pharmacokinetic model. Based on the totality of clinical data, 
0.05 mg/kg once daily is expected to provide comparable 
Cmax concentrations in infants as compared to pediatric 
patients with SBS and was recommended as an evaluation 
Section 6.2.5
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2
Amendment Date
04 Dec 2018
Global
Description of Change
Section(s) Affected by Change
dosing regimen in Study SHP633-301.
Clarified that rescreening of subjects in the study will not be 
allowed. (Administrative amendment dated 03 Oct 2018)
Section 7.1.1
Clarifications were made to the definition of adverse events.
Section 8.1, Section 8.1.5, 
Section 8.2.4
Added heart failure with severe fluid overload, determined by 
the sponsor or investigator to be related to the investigational 
product, to the list of events leading to interruption of 
investigational product administration. This addition is in 
alignment with the warnings and special precautions listed in 
the investigator brochure.
Section 8.4
As recommended by the FDA, specified that if the DMC 
recommends termination of this pediatric study, the 
recommendations will be communicated to the relevant 
regulatory agencies within 7 calendar days.
Section 9.4
Minor editorial changes and corrections to typographical 
errors (which do not modify content and/or intent of the 
original document) were made.
Throughout the protocol
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Appendix 2
Guidelines for Nutritional Support Management During the Study
The nutritional support adjustment guidelines are designed to standardize management of 
parenteral and enteral nutritional support in this study. Adjustments to nutritional support should 
be considered at every scheduled clinic visit. Adjustments at phone visits may also be performed, 
but nutritional assessments at phone visits serve primarily to confirm that nutritional adjustments 
at prior clinic visits were tolerated.
All attempts should be made to follow the guidelines, but departure from the guidelines will not 
constitute a protocol deviation.
Clinical judgment is required within the algorithm. Each decision point requires integrating 
multiple sources of information into a yes/no decision. When individual data points are 
conflicting, the investigator must use their best judgment in the assessment.
If intestinal adaptation is occurring, reductions in parenteral support volume and calories are 
expected to be in decrements of 5 to 10% relative to baseline values. Parenteral support 
components are at the discretion of the investigator, but care should be taken to balance 
carbohydrate, fat, and protein. Likewise, if intestinal adaptation is occurring, enteral nutrition 
volume and calories should be increased in increments of approximately 10% relative to baseline 
values.
Assessment of the severity of malabsorption may require estimation of stool output for children 
who have mixed stool and urine output.
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.
During the 48-hour output measurement period prior to the subject’s scheduled visit, no further 
changes to the prescribed nutritional support should be made.
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Figure A-1:
Parenteral Nutrition/Intravenous Adjustment Algorithm for All Subjects  
BUN=blood urea nitrogen; Cr=creatinine; PN=parenteral nutrition; UNa=urine sodium; UOP=urine output; USpGr=Urine specific gravity; VS=vital signs; vol=volume
Adequately hydrated?
•
Normal exam and VS
•
Weight stable
•
UOP > 1 ml/kg/h
•
USpGr < 1.020
•
UNa > 20 meq/L
•
Stable, normal BUN/Cr
yes
no
Adequate weight gain 
and linear growth?
↑ PN kcal or no change
↓PN vol and kcal
↑ PN vol +/- kcal
yes
no
Assess severity of malabsorption and adjust EN as appropriate
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PROTOCOL: SHP633-301
TITLE:
A Randomized, Open-label, 24-Week Safety, Efficacy, and 
Pharmacokinetic Study of Teduglutide in Infants 4 to 12 Months of Age 
with Short Bowel Syndrome Who are Dependent on Parenteral Support
NUMBER
SHP633-301
PHASE
3 
DRUG:
Teduglutide
INDICATION:
Short bowel syndrome
EUDRACT NO.:
2017-003606-40
SPONSOR: 
Shire Human Genetic Therapies, Inc.
300 Shire Way
Lexington, MA 02421 USA
PROTOCOL 
HISTORY:
Original Protocol: 03 Oct 2017
Amendment 1: 18 Jan 2018
Amendment 1.1: 07 Aug 2018 (France-specific) 
Amendment 2.1: 04 Dec 2018 (France-specific)
Amendment 3.1: 24 May 2019 (France-specific)
Confidentiality Statement
This document contains confidential and proprietary information of Shire and is disclosed 
pursuant to confidentiality and non-disclosure obligations. This information should be used 
solely for the purposes for which it was provided and should not be copied, shared with, or 
disclosed to any third party without the express written consent of Shire.
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SHP633-301 Protocol Amendment 3.1 (France-specific) 
Teduglutide 
24 May 2019 
PROTOCOL SIGNATURE PAGE 
Sponsor's (Shire) Approval 
Signature: 
=e 
l
D_a_ti:-
-j· 
I
, MD PhD
------1 
--
Investigator's Acknowledgement 
I have read this protocol for Shire Study SHP633-301. 
Title: A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic Study of 
Teduglutide in Infants 4 to 12 Months of Age with Shmi Bowel Syndrome Who are Dependent 
on Parenteral Suppmi 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to paiiicipate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) guidelines on Good Clinical Practice (GCP) and with the 
applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
te1mination of my paiiicipation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Address: 
(please hand print or type) 
Signature: 
Date: 
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EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Adverse Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as 
Required by Protocol within 24 hours to the Shire Global Drug Safety Department. Applicable 
fax numbers and e-mail address can be found on the form (sent under separate cover). A copy of 
this form must also be sent to the Shire Medical Monitor by e-mail at 
.
For protocol- or safety-related issues, the investigator must contact IQVIA Medical Support:
Primary Contact
Backup Contact 
, MD
, MD, PhD
Mobile:  
Mobile: 
Phone: 
(medical emergencies)
Phone: 
 (medical emergencies)
Email:  
Email: 
In addition, the investigator may also contact Shire:
, MD 
Mobile Phone: 
Email: 
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PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please use the E-mail address below to report the Product Quality Complaint:
Telephone numbers (provided for reference, if needed): 
Shire (USA)
 
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SUMMARY OF CHANGES FROM PREVIOUS VERSION
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
3.1
Amendment Date
24 May 2019
France-specific
Description of Change and Rationale
Section(s) Affected by Change
Deleted Inclusion Criteria #6, Lack of terminal ileum and ileocecal valve, 
due to difficulties in enrollment. 
Synopsis, Section 4.1
Minor editorial changes and corrections to typographical errors (which do 
not modify content and/or intent of the original document) were made.
Throughout the protocol
See Appendix 1 for protocol history, including all amendments. 
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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
PRODUCT QUALITY COMPLAINTS..........................................................................................4
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................5
TABLE OF CONTENTS.................................................................................................................6
LIST OF TABLES.........................................................................................................................10
LIST OF FIGURES .......................................................................................................................10
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..................................................11
STUDY SYNOPSIS ......................................................................................................................12
STUDY SCHEDULES ..................................................................................................................17
BACKGROUND INFORMATION .......................................................................................21
1.
1.1
Short Bowel Syndrome ............................................................................................21
1.2
Teduglutide...............................................................................................................22
OBJECTIVES.........................................................................................................................24
2.
2.1
Rationale for the Study.............................................................................................24
2.2
Study Objectives ......................................................................................................24
STUDY DESIGN ...................................................................................................................25
3.
3.1
Study Design and Flow Chart ..................................................................................25
3.1.1
Screening Period ........................................................................................25
3.1.2
Treatment Period........................................................................................25
3.1.3
Follow-up Period .......................................................................................26
3.2
Study Duration .........................................................................................................26
3.3
Sites and Regions .....................................................................................................26
STUDY POPULATION.........................................................................................................27
4.
4.1
Inclusion Criteria......................................................................................................27
4.2
Exclusion Criteria.....................................................................................................27
4.3
Reproductive Potential .............................................................................................29
4.4
Discontinuation of Subjects .....................................................................................29
4.4.1
Reasons for Discontinuation......................................................................29
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit .....................30
PRIOR AND CONCOMITANT TREATMENT ...................................................................31
5.
5.1
Prior Medications and Procedures............................................................................31
5.2
Concomitant Medications and Procedures...............................................................31
5.3
Permitted Treatment.................................................................................................31
5.4
Prohibited Treatment................................................................................................31
INVESTIGATIONAL PRODUCT ........................................................................................32
6.
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6.1
Identity of Investigational Product...........................................................................32
6.2
Administration of Investigational Product ...............................................................32
6.2.1
Interactive Response Technology for Investigational Product 
Management...............................................................................................32
6.2.2
Allocation of Subjects to Treatment ..........................................................32
6.2.3
Dosing........................................................................................................32
6.2.4
Unblinding the Treatment Assignment......................................................33
6.2.5
Dose Selection Rationale ...........................................................................33
6.3
Labeling, Packaging, and Storage ............................................................................34
6.3.1
Labeling .....................................................................................................34
6.3.2
Storage and Handling.................................................................................35
6.4
Drug Accountability.................................................................................................35
6.5
Subject Compliance..................................................................................................37
STUDY PROCEDURES........................................................................................................38
7.
7.1
Study Schedule.........................................................................................................38
7.1.1
Screening....................................................................................................38
7.1.2
Treatment Period........................................................................................38
7.1.3
Follow-up Period .......................................................................................38
7.2
Study Evaluations and Procedures ...........................................................................38
7.2.1
Demographics and Other Baseline Characteristics....................................38
7.2.2
Efficacy Assessments.................................................................................39
7.2.3
Safety Assessments....................................................................................40
7.2.4
Pharmacokinetic Assessments ...................................................................43
7.2.5
Health Economics and Outcomes Research ..............................................43
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................44
8.
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................44
8.1.1
Severity Categorization..............................................................................44
8.1.2
Relationship Categorization.......................................................................45
8.1.3
Outcome Categorization ............................................................................45
8.1.4
Symptoms of the Disease under Study ......................................................46
8.1.5
Clinical Laboratory and Other Safety Evaluations ....................................46
8.1.6
Pregnancy...................................................................................................46
8.1.7
Abuse, Misuse, Overdose, and Medication Error ......................................46
8.2
Serious Adverse Event Procedures ..........................................................................47
8.2.1
Reference Safety Information ....................................................................47
8.2.2
Reporting Procedures.................................................................................47
8.2.3
Serious Adverse Event Definition .............................................................48
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8.2.4
Serious Adverse Event Collection Time Frame.........................................48
8.2.5
Serious Adverse Event Onset and Resolution Dates .................................48
8.2.6
Fatal Outcome............................................................................................49
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, 
and Site Reporting......................................................................................49
8.3
Adverse Events of Special Interest...........................................................................49
8.4
Dose Interruption Criteria ........................................................................................50
DATA MANAGEMENT AND STATISTICAL METHODS ...............................................51
9.
9.1
Data Collection.........................................................................................................51
9.2
Clinical Data Management.......................................................................................51
9.3
Statistical Analysis Process......................................................................................51
9.4
Planned Interim Analysis, and Data Monitoring Committee ...................................51
9.5
Sample Size Calculation and Power Considerations................................................52
9.6
Study Population ......................................................................................................52
9.7
Efficacy Analyses.....................................................................................................53
9.7.1
Efficacy Endpoints.....................................................................................53
9.7.1.1
Primary Efficacy Endpoint.....................................................................53
9.7.1.2
Secondary Efficacy Endpoints ...............................................................53
9.7.2
Method of Analysis-Efficacy Endpoints....................................................53
9.8
Safety Analyses ........................................................................................................54
9.8.1
Safety Endpoints ........................................................................................54
9.8.2
Method of Analysis-Safety Endpoints.......................................................55
9.9
Health Economics and Outcomes Research Analyses .............................................55
9.10
Pharmacokinetics Analyses......................................................................................55
SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES ............................................56
10.
10.1
Sponsor’s Responsibilities .......................................................................................56
10.1.1
Good Clinical Practice Compliance...........................................................56
10.1.2
Indemnity/Liability and Insurance.............................................................56
10.1.3
Public Posting of Study Information..........................................................56
10.1.4
Submission of Summary of Clinical Study Report to Competent 
Authorities of Member States Concerned and Ethics Committees............56
10.1.5
Study Suspension, Termination, and Completion......................................57
10.2
Investigator’s Responsibilities .................................................................................57
10.2.1
Good Clinical Practice Compliance...........................................................57
10.2.2
Protocol Adherence and Investigator Agreement ......................................57
10.2.3
Documentation and Retention of Records .................................................58
10.2.3.1
Electronic Case Report Forms................................................................58
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10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................58
10.2.3.3
Audit/Inspection .....................................................................................59
10.2.3.4
Financial Disclosure...............................................................................59
10.3
Ethical Considerations..............................................................................................59
10.3.1
Informed Consent.......................................................................................59
10.3.2
Institutional Review Board or Ethics Committee ......................................60
10.4
Privacy and Confidentiality......................................................................................60
10.5
Study Results/Publication Policy .............................................................................61
REFERENCES .......................................................................................................................63
11.
APPENDICES ........................................................................................................................65
12.
Appendix 1
Protocol History.........................................................................................66
Appendix 2
Guidelines for Nutritional Support Management During the Study ..........70
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LIST OF TABLES
Table 1:
Study Schedule: Visits -1 to 12 .....................................................................17
Table 2:
Study Schedule: Visits 13-28 ........................................................................19
Table 3:
Prohibited Treatment.....................................................................................31
Table 4:
List of Laboratory Tests ................................................................................41
Table 5:
Approximate Volume of Blood to be Drawn from Each Subject .................42
LIST OF FIGURES
Figure 1:
Study Schematic ............................................................................................25
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation
Definition
AE
adverse event
AUCss
area under the concentration-time curve at steady-state 
Cmax,ss
maximum plasma concentration at steady state
CRO
contract research organization
eCRF
electronic case report form
DMC
data monitoring committee
EDC
electronic data capture
EMA
European Medicines Agency
EN
enteral nutrition
EOS
end of study
EOT
end of treatment
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
gastrointestinal 
GLP
glucagon-like peptide
HIPAA
Health Insurance Portability and Accountability Act
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use
ICMJE
International Committee of Medicinal Journal Editors
I/O
oral fluid intake and urine output
IP
Investigational product
IRB
Institutional Review Board
ITT
intent-to-treat
MedDRA
Medical Dictionary for Regulatory Activities
PK
pharmacokinetics
PN
parenteral nutrition
SAE
serious adverse event
SAP
statistical analysis plan
SBS
short bowel syndrome
SC
subcutaneous
SD
standard deviation
SOC
standard of care
ULN
upper limit of normal 
US
United States
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STUDY SYNOPSIS
Protocol number: SHP633-301
Drug: Teduglutide
Title of the study: A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic Study of 
Teduglutide in Infants 4 to 12 Months of Age with Short Bowel Syndrome Who are Dependent on Parenteral 
Support
Number of subjects (total and for each treatment arm):
At least 10 subjects will be randomized: at least 5 subjects in a teduglutide treatment arm and at least 5 subjects in 
a standard of care (SOC) comparator arm
Investigator(s): Multicenter study
Site(s) and Region(s): 
This study is planned to be conducted in approximately 5 to 10 sites globally.
Study period (planned):
2017-2020
Clinical phase:
3
Objectives:
The objectives of this clinical study are to evaluate the safety, efficacy/pharmacodynamics and pharmacokinetics 
(PK) of teduglutide treatment in infants with short bowel syndrome (SBS) dependent on parenteral support.
Investigational product, dose, and mode of administration:
Teduglutide 0.05 mg/kg by subcutaneous (SC) injection once daily into 1 of the 4 quadrants of the abdomen or 
either thigh or arm.
Methodology:
This is a randomized, multicenter, open-label study, consisting of a 2 to 4 week screening period, a 24-week 
treatment period, and a 4-week follow-up period. 
* At EOS all subjects regardless of treatment arm may enroll in an extension study that will capture long-term 
safety data and provide the opportunity for additional teduglutide treatment. The follow-up period for subjects in 
the teduglutide treatment arm may be interrupted and the subjects may proceed immediately to the EOS if at least 
one “escape” criteria is met.
Extension 
study* 
1
24
1
3
5
7
9
12
16
20
28
2 to 4
Weeks
Screening
Teduglutide 0.05 mg/kg SC once daily for 24 weeks
Site Visit 
Telephone Visit
Standard of care for 24 weeks
Baseline: treatment 
randomization
0
24
3
5
7
9
12
16
20
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Study eligibility will be confirmed during the screening period (minimum: 2 weeks; maximum 4 weeks). At the 
baseline visit (Week 0), subjects will be randomized 1:1 to the teduglutide or SOC treatment arm. Randomization 
will be stratified according to the presence of a small bowel ostomy (eg, end jejunostomy or ileostomy). During 
the 24-week treatment period, subjects in the SOC treatment arm will receive standard medical therapy for SBS; 
while those in the teduglutide arm will receive 0.05 mg/kg SC once daily in addition to standard medical therapy. 
Subjects in both arms will follow the same visit schedule and assessments. Subjects will be monitored weekly 
with phone or clinic visits. Clinic visits will occur at Weeks 1, 3, 5, 7, 9, 12, 16, 20, 24, and 28. At all site visits 
and telephone contacts, safety will be monitored and nutritional support will be reviewed and adjusted as needed. 
To maintain consistency across centers, guidance and training will be provided to help sites follow the nutritional 
support adjustment guidelines (developed with SBS expert input and provided in the protocol) related to decisions 
for parenteral nutrition (PN) reduction and advances in enteral feeds based on weight gain, urine and stool output, 
and clinical stability. Deviations from the guidelines are not considered a protocol deviation.
Sparse PK sampling, in the teduglutide treatment arm only, will occur at baseline (predose and 1 hour 
±10 minutes and 4 hours ±10 minutes postdose) and at Week 7 or 12 (2 hours±10 minutes postdose).
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up period until the end 
of study (Week 28/EOS) during which time subjects will receive standard medical therapy, but no investigational 
product will be administered. At EOS all subjects regardless of treatment arm may enroll in an extension study 
that will capture long-term safety data and provide the opportunity for additional teduglutide treatment. The 
follow-up period for subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed 
immediately to the EOS if at least one of the following “escape” criteria is met:
1.
Increasing PN requirements following discontinuation of teduglutide.
2.
Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal tolerated enteral 
nutrition (EN) following teduglutide discontinuation.
3.
Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and electrolyte intake 
following teduglutide discontinuation.
4.
Severe diarrhea related to teduglutide discontinuation.
Inclusion and Exclusion Criteria:
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1.
Informed consent by the parent or legal guardian. 
2.
Male or female infant 4 to 12 months corrected gestational age at screening.
3.
Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and baseline.
4.
Short bowel syndrome with dependence on parenteral support to provide at least 50% of fluid or caloric 
needs.
5.
Stable PN requirements for at least 1 month prior to screening, defined as a ≤10% change in the 
weight-normalized parenteral total fluid and caloric intake, despite attempts to wean PN, 
notwithstanding transient instability for events such as sepsis or interruption of central venous access.
6.
This criteria was deleted.
7.
Parent or legal guardian understands and is willing and able to fully adhere to study requirements as 
defined in this protocol.
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Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1.
Previous treatment with teduglutide.
2.
Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus inclusion disease, 
etc.
3.
Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility, that is the primary contributing factor to feeding intolerance and 
inability to reduce parenteral support, prior to screening. Dysmotility is defined as severe if it is expected 
to limit the advancement of enteral feeding.
4.
Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral aversion in the 
absence of a feeding tube.
5.
Intestinal obstruction or clinically significant intestinal stenosis.
6.
Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or major intestinal 
resection or anastomosis, within 3 months prior to screening or planned during the study period.
7.
Unstable cardiac disease.
8.
Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
9.
Biliary obstruction, stenosis, or malformation. 
10. Clinically significant pancreatic disease. 
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b.
Platelet count <100×10^3/µl due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d.
Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 2-week period
13. More than 3 serious complications of intestinal failure (eg, catheter-associated bloodstream infections, 
interruption of nutrition due to feeding intolerance, catheter-associated thrombosis, severe fluid or 
electrolyte disturbances) within 1 month prior to or during screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile polyposis or 
Beckwith-Wiedemann syndrome, or first degree relative with early onset of gastrointestinal cancer 
(including hepatobiliary and pancreatic cancers). 
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 (GLP-2); 
insulin-like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs of these hormones; or 
glutamine. 
16. Participation in a clinical study using an experimental drug within 3 months or 5.5 half-lives of the 
experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, closely-related 
compounds, or any of the stated ingredients.
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts the subject at any 
undue risk, prevents completion of the study, or interferes with analysis of the study results.
19. Hypersensitivity to trace residues of tetracycline.
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20. Signs of active severe or unstable, clinically significant hepatic impairment shown by any of the below 
laboratory test results at screening:
a. Total bilirubin ≥2 x upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥5 x ULN
c. Alanine aminotransferase (ALT) ≥5 x ULN
For subjects with Gilbert’s disease:
d. Indirect (unconjugated) bilirubin ≥2 x ULN
Maximum Duration of Subject Involvement in the Study:
The study consists of a 2 to 4 week screening period, a 24-week treatment period, and a 4-week follow-up period. 
The maximum duration of participation for each subject is 32 weeks.
Study completion is defined as the last subject, last visit. This is the visit date at which the last subject on the 
study has his or her last follow-up visit on the study (whether during the 24-week treatment period or the 4-week 
follow-up period).
Endpoints:
Efficacy
Efficacy endpoints consist of the following:
Primary

Reduction in weight-normalized PN fluid volume by at least 20% from baseline at Week 24/EOT
Secondary

Reduction in weight-normalized parenteral calories by at least 20% from baseline to Week 24/EOT

Achievement of enteral autonomy by Week 24

Time to achieve enteral autonomy

Change in weight-normalized parenteral fluid volume from baseline to each visit

Change in weight-normalized parenteral calories from baseline to each visit

Change in weight-normalized enteral fluid volume from baseline to each visit

Change in weight-normalized enteral caloric intake from baseline to each visit

Increase in weight-normalized enteral fluid intake by at least 20% from baseline to Week 24/EOT

Increase in weight-normalized enteral caloric intake by at least 20% from baseline to Week 24/EOT
Pharmacokinetics
The pharmacokinetic endpoint is plasma teduglutide concentration at nominal time point.
Safety
Safety endpoints consist of the following:

Adverse events (AEs)

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output

Stool (including mixed) output  

Antibodies to teduglutide 
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Health Economics and Outcomes Research
Health economics and outcomes research (HEOR) endpoints include the following:

Cumulative number of hospitalization days during the study
Statistical Methods:
Efficacy
Analyses of weekly PN support will be based on 2 data sources: the subject diary data (also referred to as actual 
data) and the investigator prescribed data. 
The number and percentage of subjects who achieve at least a 20% reduction from baseline in weight-normalized 
average daily PN volume at Week 24/EOT and the number and percentage of subjects who achieve at least a 20% 
reduction from baseline in weight-normalized parenteral calories at Week 24/EOT will be summarized by 
treatment arm.
During the treatment period, a subject will be considered to have achieved enteral autonomy (completely weaned 
off PN) at a given visit if the investigator prescribes no PN at that visit and for the remainder of the treatment 
period, and there is no use of PN recorded in the subject diary during the week prior to that visit and for the 
remainder of the treatment period. During the follow-up period, a subject will be considered to have achieved 
enteral autonomy at a given visit if the investigator prescribes no PN at that visit and for the remainder of the 
follow-up period and there is no use of PN recorded in the subject diary during the week prior to that visit and for 
the remainder of the follow-up period. The number and percentage of subjects who achieve enteral autonomy at 
each scheduled visit, as well as at EOT, will be summarized by treatment arm. Descriptive statistics will be used 
to summarize time to achievement of enteral autonomy by treatment arm.
The absolute and percent change in weight-normalized weekly PN volume, parenteral calories, enteral fluid 
volume, and enteral caloric intake, from baseline to each scheduled visit, as well as at EOT, will be summarized 
by treatment arm using descriptive statistics.
The number and percentage of subjects who demonstrate an increase in weight-normalized enteral fluid intake by 
at least 20% from baseline to Week 24/EOT and the number and percentage of subjects who demonstrate an 
increase in weight-normalized enteral caloric intake by at least 20% from baseline to week 24/EOT will be 
summarized by treatment arm.
Pharmacokinetics
Plasma concentrations will be summarized using descriptive statistics (number, mean, standard deviation, 
geometric mean, coefficient of variation, minimum, median, and maximum) at nominal time points. 
Pharmacokinetic parameters will be estimated using a population PK modeling approach as appropriate and 
reported separately.
Safety
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Treatment-emergent AEs will be summarized by system organ class and preferred term using descriptive statistics 
(eg, number and percentage of subjects). Adverse events will be summarized by severity and relationship to 
treatment. In addition, serious adverse events  will also be tabulated by overall and treatment-related events. AEs 
leading to treatment discontinuation and death will also be summarized.
For laboratory tests; vital signs; urine and stool output; weight, length, and head circumference Z-scores; and 
descriptive statistics (eg, n, mean, standard deviation, median, minimum and maximum values, and the number 
and percentage of subjects in specified categories) will be used to summarize the absolute values and change from 
baseline at each visit.
The number and percentage of subjects classified as having antibodies to teduglutide will be used to summarize 
the presence of antibodies. 
Health Economics and Outcomes Research
The HEOR endpoints will be summarized descriptively. 
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STUDY SCHEDULES
Table 1:
Study Schedule: Visits -1 to 12
Procedures
Screening
Baseline 
(Week 0)
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
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit type
Site
Site
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Tel
Site
Study day
-14
0
7
14
21
28
35
42
49
56
63
70
77
84
±window (days)
-2 weeks
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Informed consent
X
Eligibility
X
X
Randomization
X
Demographics 
X
SBS history
X
Medical and surgical history
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications and 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, vital signs, 
weight
X
X
X
X
X
X
X
X
Length and head circumference
X
X
X
X
UGI/SBFT
X
Safety labs and urinalysisb, c
X
Xb
X
(X)
X
(X)
X
(X)
X
(X)
X
(X)
(X)
X
PK samplinga
X
 
[X]d
[X]d
Antibodies to teduglutidea,e
X
Xe
Native GLP-2f
X
Provide intake and output 
diariesg
X
X
X
X
X
X
X
X
Review diaries and nutritional 
support
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional support as 
neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
Dispense IPa, i
X
X
X
X
X
X
X
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Table 1:
Study Schedule: Visits -1 to 12
Procedures
Screening
Baseline 
(Week 0)
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
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit type
Site
Site
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Tel
Site
Study day
-14
0
7
14
21
28
35
42
49
56
63
70
77
84
±window (days)
-2 weeks
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Adjust IP dosej
X
EN=enteral nutrition; GLP-2=glucagon-like peptide 2; INR=international normalized ratio; IP=investigational product; PK=pharmacokinetics; PN=parenteral nutrition; PT=prothrombin time; 
UGI/SBFT=upper GI series with small bowel follow-through 
a Applicable to the teduglutide treatment arm only. 
b At baseline, safety labs (Table 4) and PK can be separated by 1 day if blood volumes are limiting. Safety labs at telephone visits will be collected at the discretion of the investigator. For all subjects in 
the teduglutide treatment arm, PT and INR will be tested at baseline, and repeated if clinically indicated.
c Urinalysis will consist of urine sodium and specific gravity. Urine collection should be attempted, but inability to obtain urinalysis is not a protocol deviation.
d Subjects will have blood samples taken for teduglutide PK analysis predose and 1 hour ±10 minutes and 4 hours ±10 minutes postdose at baseline (Visit 0). Subjects also will have blood samples taken 
for teduglutide PK analysis 2 hours ±10 minutes postdose at Week 7 (Visit 7) or Week 12 (Visit 12) of the treatment period.
e Samples for antibody analysis will be drawn at the baseline and Week 12 visits. Blood samples while subjects are receiving teduglutide should be drawn at least 14 hours after the previous dose.
f Blood samples for native GLP-2 should be collected postprandial. Native GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at investigator 
discretion based on weekly/monthly total volume. 
g Intake diaries will collect actual PN volume and hours per day and EN volume and calories. Intake diaries should be completed daily throughout the study. Urine and stool output should be recorded in 
the output diary over a 48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PN prescription. 
h Parenteral support adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment provided in Appendix 2.
i The initial dose will be calculated based on body weight measured at baseline (Visit 0).
j  The dose will be adjusted as needed, based on body weight measured at Week 12 visit.
Note: (X) denotes optional assessments; [X] denotes possible PK sampling time point (Refer to footnote “e”.)
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Table 2:
Study Schedule: Visits 13-28
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 
(EOT/ET)
Week 
25
Week 
26
Week 
27
Week 
28 
(EOS)a
Visit number
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit type
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Study day
91
98
105
112
119
126
133
140
147
154
161
168
175
182
189
196
±window (days)
±3
±3
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications 
and procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, vital 
signs, weight
X
X
X
X
Length and head 
circumference
X
X
X
X
Safety labs and 
urinalysisb,c
(X)
(X)
(X)
X
(X)
(X)
(X)
X
(X)
(X)
(X)
X
(X)
(X)
(X)
X
Antibodies to 
teduglutided,e
X
Native GLP-2f
X
Provide intake and output 
diaries
X
X
X
Review diaries and 
nutritional supportg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional support 
as neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess follow-up period 
escape criteriad
Xi
Xi
Xi
X
Dispense IPd
X
X
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Table 2:
Study Schedule: Visits 13-28
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 
(EOT/ET)
Week 
25
Week 
26
Week 
27
Week 
28 
(EOS)a
Visit number
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit type
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Study day
91
98
105
112
119
126
133
140
147
154
161
168
175
182
189
196
±window (days)
±3
±3
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
EN=enteral nutrition; EOS=end of study; EOT=end of treatment; ET=early termination; GLP-2=glucagon-like peptide 2; INR=international normalized ratio; IP=investigational product; PN=parenteral 
nutrition; PT=prothrombin time; UGI/SBFT=upper GI series with small bowel follow-through
a At EOS subjects may enroll in an extension study, if subjects require treatment before the end of the 4-week follow-up they may enter the extension study immediately. 
b Safety labs at telephone visits will be collected at the discretion of the investigator. For all subjects in the teduglutide treatment arm, PT and INR are tested if clinically indicated.
c Urinalysis will consist of urine sodium and specific gravity. 
d Applicable to the teduglutide treatment arm only. 
e Samples for antibody analysis will be drawn at the EOS (Week 28) visit.
f Blood samples for native GLP-2 should be collected postprandial. Blood samples drawn while subjects are receiving teduglutide should be drawn at least 14 hours after the previous dose. Native GLP-
2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at investigator discretion based on weekly/monthly total volume. 
g Intake diaries will collect actual PN volume and hours per day and EN volume and calories. Intake diaries should be completed daily throughout the study. Urine and stool output should be recorded in 
the output diary over a 48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PN prescription. 
h Parenteral support adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment provided in Appendix 2.
Note: (X) denotes optional assessments.
i If a subject treated with teduglutide meets the escape criteria, the assessments scheduled for the EOS visit should be conducted.
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BACKGROUND INFORMATION
1.
1.1
Short Bowel Syndrome
Short bowel syndrome (SBS) is a rare disorder resulting from congenital abnormalities or severe 
intestinal diseases that result in major surgical resections of the small intestine (O'Keefe et al., 
2006). Unlike the adult population, the majority of cases of SBS in pediatric subjects are due to 
congenital anomalies or catastrophic events that occur during infancy such as necrotizing 
enterocolitis, gastroschisis, intestinal atresia, midgut volvulus, or long-segment Hirschsprung 
disease (Beattie et al., 2010; Goulet and Ruemmele, 2006). A Canadian population-based study 
in neonates estimates an overall incidence of SBS to be 24.5 cases per 100,000 live births (Wales 
et al., 2004). 
The small intestine is capable of remarkable adaptation, but excessive loss of absorptive surface 
area or specialized functions can lead to dependence on parenteral nutrition (PN)1 fluids 
(O'Keefe et al., 2006). Although PN is life-sustaining in intestinal failure, it is associated with 
serious complications, including liver disease, life-threatening catheter-related blood stream 
infections, and central venous thrombosis (Beattie et al., 2010; Goulet and Ruemmele, 2006). 
Dependence on PN is also associated with reduced quality of life in both patients and caregivers 
and has an extremely high cost of care (Huisman-de Waal et al., 2007). About 30% of infants 
with SBS become independent of PN requirements within 12 months of the initial insult, and an 
additional 10% wean off PN within 24 months. After this time, linear intestinal growth slows. It 
is estimated that 42% to 86% of pediatric patients with SBS are able to become independent of 
PN within 1 to 3 years (Gonzalez-Hernandez et al., 2017; Khan et al., 2015; Squires et al., 2012). 
Nevertheless, despite optimal medical management, some children remain dependent on PN for 
many years (Squires et al., 2012). Infants who have less than 10% of expected small intestinal 
length for their gestational age have a low likelihood of ever achieving enteral autonomy (ie, 
independence from parenteral support). Providing the maximum tolerated amount of enteral 
nutrition (EN) has been the primary strategy to promote enteral adaptation (Spencer et al., 2005). 
Accelerating the adaptive process and achieving enteral autonomy is an urgent goal for all 
patients with SBS who are dependent on PN (Khan et al., 2015; Squires et al., 2012). The 
adaptive process is in part controlled by glucagon-like peptide 2 (GLP-2), a 33 amino acid 
peptide hormone secreted from L-type enteroendocrine cells in the terminal ileum and colon in 
response to luminal nutrients and bile acids (Martin et al., 2006). The post-prandial plasma 
concentration of GLP-2 in infants with SBS correlates with length of the remaining small 
intestine (Sigalet et al., 2004). Infants who lack terminal ileum may have impaired adaptation 
due to inadequate production of GLP-2.
                                                
1 For the purpose of the study the terms parenteral support (PS) and parenteral nutrition (PN) are used 
interchangeably.
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1.2
Teduglutide
Teduglutide is a novel, recombinant analog of naturally occurring human GLP-2 that regulates 
the functional and structural integrity of the cells lining the gastrointestinal (GI) tract. 
Teduglutide is a 33-amino acid peptide that differs from native GLP-2 in the substitution of 
glycine for alanine at the second position at the N-terminus. As a result, teduglutide demonstrates 
resistance to degradation by dipeptidyl peptidase 4 (DPP-4) and therefore maintains a longer 
elimination half-life (t1/2), approximately 2 hours in healthy adult subjects, 1.3 hours in adult 
SBS subjects, and 0.22 hours in pediatric SBS subjects, compared to the native peptide, which 
has a t1/2 of approximately 7 minutes. Teduglutide has been shown in animal studies and previous 
human clinical trials to increase villus height and crypt depth in the intestinal epithelium, thereby 
increasing the absorptive surface area of the intestines (Tappenden et al., 2013; Thymann et al., 
2014). 
A Phase 3 study, TED-C13-003, has been completed in pediatric SBS subjects. In this study, 
teduglutide was administered to 3 cohorts of pediatric subjects from ages 1-17 years. 
Thirty-seven pediatric subjects received teduglutide at doses of 0.0125, 0.025, or 0.05 mg/kg/day 
for 12 weeks. Five additional pediatric subjects were enrolled in an observational standard of 
care (SOC) cohort. There were clear dose-dependent effects of teduglutide seen at the 0.025 and 
0.05 mg/kg/day doses compared to SOC and the 0.0125 mg/kg/day dose. In the 0.025 mg/kg/day 
cohort there was a reduction in PN volume at Week 12 of 37%, including complete 
independence from PN support in 1 subject, and a reduction of 3.94 hours per day infusion time. 
In the 0.05 mg/kg/day cohort there was a reduction in PN volume at Week 12 of 39%, including 
complete independence from PN support in 3 subjects, and a reduction of 4.18 hours per day 
infusion time. Teduglutide was generally safe and well tolerated by pediatric subjects in all 
dosing cohorts. There were no deaths during the study and no treatment-emergent serious 
adverse events (SAEs) related to teduglutide were reported. No discontinuations from study were 
due to adverse events (AEs). Additional studies in pediatric patients with SBS are ongoing.
TED-C14-006 is a recently completed study of pediatric subjects through 17 years which 
included 2 treatment arms: a teduglutide treatment arm and a SOC treatment arm. Subjects 
in both arms participated in a 2-week minimum screening period, a 24-week treatment 
period, and a 4-week follow-up period. During the screening period, subjects chose into 
which arm to enroll. During the 24-week treatment period, subjects in the SOC treatment 
arm received standard medical therapy for SBS; while those in the teduglutide treatment 
arm received daily subcutaneous (SC) injections of teduglutide (study drug) in addition to 
standard medical therapy. The subjects enrolling in the teduglutide treatment arm were 
randomized 1:1 in a double-blinded manner into 2 parallel dose groups: 0.025 mg/kg/day or 
0.05 mg/kg/day of teduglutide administered subcutaneously for 24 weeks. Compared to the 
SOC, treatment of pediatric subjects with SBS with teduglutide resulted in clinically 
meaningful reductions in PN/IV volume, calories, days per week, and hours per day. A total 
10% of subjects who received teduglutide achieved enteral autonomy within 24 weeks 
despite prior dependence on PN/IV for several years. Teduglutide treatment also resulted in 
increases in EN volume and caloric intake as well as plasma citrulline. 
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Although the differences in efficacy between the 0.025 and 0.05 mg/kg dose groups were small, 
a consistently greater effect was seen in the 0.05 mg/kg dose in all efficacy parameters. The 
pharmacokinetic (PK) properties were well characterized in this population and were consistent 
with the prior 12 week pediatric study. Teduglutide was generally well tolerated by pediatric 
subjects with SBS. The safety profile was favorable and consistent with the prior pediatric study, 
the underlying disease, and previous experience with teduglutide in adult subjects with SBS.
Teduglutide (0.05 mg/kg/day) is currently approved for the treatment of adult patients with SBS 
in >30 countries. On 29 Jun 2016, the European Commission granted an extension of the Market 
Authorization for teduglutide for the treatment of patients aged 1 year and above with SBS. 
Always refer to the latest version of the investigator’s brochure for the overall risk/benefit 
assessment and the most accurate and current information regarding the drug metabolism, 
pharmacokinetics, efficacy and safety of teduglutide (SHP633).
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OBJECTIVES
2.
2.1
Rationale for the Study 
There is no approved pharmacological therapy to improve intestinal adaptation in infants with 
SBS who are dependent on parenteral support. This study will evaluate whether teduglutide is 
safe and effective in this patient population. 
2.2
Study Objectives
The objectives of this study are to evaluate the safety, efficacy/pharmacodynamics and 
pharmacokinetics (PK) of teduglutide treatment in infants with SBS dependent on parenteral 
support.
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STUDY DESIGN
3.
3.1
Study Design and Flow Chart
This is a randomized, multicenter, open-label study, consisting of a 2 to 4-week screening period, 
a 24-week treatment period and a 4-week follow-up period. A schematic representation of the 
study design is presented in Figure 1.
Figure 1:
Study Schematic
*At EOS all subjects regardless of treatment arm may enroll in an extension study that will capture long-term safety data and 
provide the opportunity for additional teduglutide treatment. The follow-up period for subjects in the teduglutide treatment arm 
may be interrupted and the subjects may proceed immediately to the EOS if at least one “escape” criteria is met.
3.1.1
Screening Period 
Study eligibility will be confirmed during the screening period (minimum: 2 weeks; maximum: 
4 weeks). The schedule of evaluations to be conducted during the Screening Period can be found 
in Table 1.
3.1.2
Treatment Period
At the baseline visit (Week 0), subjects will randomized 1:1 to the teduglutide or SOC treatment 
arm. Randomization will be stratified according to the presence of a small bowel ostomy (eg, end 
jejunostomy or ileostomy). During the 24-week treatment period, subjects in the SOC treatment 
arm will receive standard medical therapy for SBS, while those in the teduglutide arm will 
receive 0.05 mg/kg by SC injection once daily in addition to standard medical therapy. 
Subjects in both arms will follow the same visit schedule and assessments. Subjects will be 
monitored weekly with phone or clinic visits. Clinic visits will occur at Weeks 1, 3, 5, 7, 9, 12, 
16, 20, 24, and 28. 
Extension 
study* 
1
24
1
3
5
7
9
12
16
20
28
2 to 4
Weeks
Screening
Teduglutide 0.05 mg/kg SC once daily for 24 weeks
Site Visit 
Telephone Visit
Standard of care for 24 weeks
Baseline: treatment 
randomization
0
24
3
5
7
9
12
16
20
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At all site visits and telephone contacts, safety will be monitored and nutritional support will be 
reviewed and adjusted as needed. To maintain consistency across centers, guidance and training 
will be provided to help sites follow the nutritional support adjustment guidelines (developed 
with SBS expert input and provided in the protocol) related to decisions for PN reduction and 
advances in enteral feeds based on weight gain, urine and stool output, and clinical stability 
(Appendix 2). Deviations from the guidelines are not considered a protocol deviation.
Sparse PK sampling, in the teduglutide treatment arm only, will occur at baseline (predose and 
1 hour ±10 minutes and 4 hours ±10 minutes postdose) and at Week 7 or 12 (2 hours±10 minutes 
postdose).
The schedule of evaluations for the Treatment Period can be found in Table 1 (Visits -1 to 12) 
and Table 2 (Visits 13 to 28). 
3.1.3
Follow-up Period
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up 
period until the end of study (Week 28/EOS) during which time subjects will receive standard 
medical therapy, but no investigational product (IP) will be administered. At EOS, all subjects 
regardless of treatment arm may enroll in an extension study that will capture long-term safety 
data and provide the opportunity for additional teduglutide treatment. The follow-up period for 
subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed 
immediately to the EOS visit if at least one of the following “escape” criteria is met:
1. Increasing PN requirements following discontinuation of teduglutide.
2. Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation. 
4. Severe diarrhea related to teduglutide discontinuation.
The schedule of evaluations for the Follow-up Period can be found in Table 2 (Visits 13 to 28).
3.2
Study Duration
The study consists of a 2 to 4-week screening period, a 24-week treatment period and a 4-week 
follow-up period. The maximum duration of participation for each subject is 32 weeks.
Study completion is defined as the last subject, last visit. This is the visit date at which the last 
subject on the study has his or her last follow-up visit on the study (whether during the 24-week 
treatment period or the 4-week follow-up period).
3.3
Sites and Regions
This study is planned to be conducted at approximately 5 to 10 sites globally.
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STUDY POPULATION
4.
At least 10 subjects will be randomized: at least 5 subjects in a teduglutide treatment arm and at 
least 5 subjects in an SOC comparator arm.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1. Informed consent by the parent or legal guardian. 
2. Male or female infant 4 to 12 months corrected gestational age at screening.
3. Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and baseline.
4. Short bowel syndrome with dependence on parenteral support to provide at least 50% of fluid 
or caloric needs.
5. Stable PN requirements for at least 1 month prior to screening, defined as a ≤10% change in 
the weight-normalized parenteral total fluid and caloric intake, despite attempts to wean PN, 
notwithstanding transient instability for events such as sepsis or interruption of central 
venous access.
6. This criteria was deleted.
7. Parent or legal guardian understands and is willing and able to fully adhere to study 
requirements as defined in this protocol.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1. Previous treatment with teduglutide.
2. Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus 
inclusion disease, etc.
3. Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility, that is the primary contributing factor to feeding intolerance 
and inability to reduce parenteral support, prior to screening. Dysmotility is defined as severe 
if it is expected to limit the advancement of enteral feeding.
4. Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral 
aversion in the absence of a feeding tube.
5. Intestinal obstruction or clinically significant intestinal stenosis.
6. Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or major 
intestinal resection or anastomosis, within 3 months prior to screening or planned during the 
study period.
7. Unstable cardiac disease.
8. Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
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9. Biliary obstruction, stenosis, or malformation. 
10. Clinically significant pancreatic disease. 
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following 
parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b. Platelet count <100×10^3/µL due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d. Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 2 week 
period.
13. More than 3 serious complications of intestinal failure (eg, catheter-associated bloodstream 
infections, interruption of nutrition due to feeding intolerance, catheter-associated 
thrombosis, severe fluid or electrolyte disturbances) within 1 month prior to or during 
screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile polyposis or 
Beckwith-Wiedemann syndrome, or first degree relative with early onset of gastrointestinal 
cancer (including hepatobiliary and pancreatic cancers). 
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 
(GLP-2); insulin-like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs of 
these hormones; or glutamine. 
16. Participation in a clinical study using an experimental drug within 3 months or 5.5 half-lives 
of the experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, 
closely-related compounds, or any of the stated ingredients. 
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts the 
subject at any undue risk, prevents completion of the study, or interferes with analysis of the 
study results.
19. Hypersensitivity to trace residues of tetracycline.
20. Signs of active severe or unstable, clinically significant hepatic impairment shown by any of 
the below laboratory test results at screening:
a.Total bilirubin ≥2 x upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥5 x ULN
c.
Alanine aminotransferase (ALT) ≥5 x ULN
For subjects with Gilbert’s disease:
d. Indirect (unconjugated) bilirubin ≥2 x ULN
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4.3
Reproductive Potential 
Not applicable; this study will enroll infants.
4.4
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator should 
discuss withdrawal of a subject from investigational product with the medical monitor as soon as 
possible.
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 24/EOT/early termination are to be performed as completely as possible. Whenever 
possible, all discontinued subjects should also undergo the protocol-specified 4-week Follow-up 
Period. Comments (spontaneous or elicited) or complaints pertaining to IP discontinuation made 
by the subject must be recorded in the source documents. The reason for discontinuation, the 
date and the total amount of investigational product administered must be recorded in the 
electronic case report form (eCRF) and source documents.
Subjects who discontinue will not be replaced. 
4.4.1
Reasons for Discontinuation
The reason(s) for permanent discontinuation of treatment and/or withdrawal from the study must 
be determined by the investigator, and recorded in the subject’s medical record and in the eCRF. 
If a subject is withdrawn for more than 1 reason, each reason should be documented in the source 
document, and the most clinically relevant reason should be entered in the eCRF.
Reasons for discontinuation include, but are not limited to:

Adverse event

Death

Lost to follow-up

Physician decision

Protocol deviation

Study terminated by sponsor

Withdrawal by parent/guardian

Lack of efficacy

Other
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4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact the parent(s)/guardian(s) of any 
subject lost to follow-up at any time point prior to the last scheduled contact (office visit or 
telephone contact). At least 1 of these documented attempts must include a written 
communication sent to the subject’s last known address via courier or mail (with an 
acknowledgement of receipt request) asking that they return to the site for final safety 
evaluations and return any unused investigational product.
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PRIOR AND CONCOMITANT TREATMENT
5.
5.1
Prior Medications and Procedures
Prior treatment includes all treatment and procedures (including but not limited to prescription 
treatments, herbal treatments, vitamins, non-pharmacological treatment, as appropriate) received 
within 14 days prior to the screening visit (Visit -1) (or pharmacokinetic equivalent of 5 half 
lives, whichever is longer, must be recorded on the appropriate eCRF page.
5.2
Concomitant Medications and Procedures
The administration of all medications including concomitant medications (including prescription 
and nonprescription medications, dietary and nutritional supplements, and vitamins) and PN 
must be recorded from the first dose of investigational product and for the duration of the study 
in the appropriate sections of the eCRF. Any diagnostic, surgical or other therapeutic treatments 
received by a subject during the course of the study will also be recorded on the eCRF.
The mechanism of action of teduglutide may increase enteral absorption of oral drugs (eg, drugs 
used for management of SBS such as motility medication, opioids, psychotropics, 
metronidazole), so consideration should be given to modifying concomitant enteral medication 
regimens. Titration of concomitant enteral medications should be considered when drugs, 
especially those with a narrow therapeutic index (eg, warfarin, digoxin, psychotropics) are given.
5.3
Permitted Treatment
Standard medical therapy for SBS should be continued.
5.4
Prohibited Treatment
The following medications are prohibited during teduglutide treatment and within the provided 
timeframe prior to the pretreatment visit (Table 3):
Table 3:
Prohibited Treatment
Prior Therapy
Time Restriction Prior to 
the Pretreatment Visit
Teduglutide
Any
GLP-2, human growth hormone, or analogs of these hormones
6 months
Octreotide, GLP-1 analogs, and enteral glutamine
30 days
GLP=glucagon-like peptide
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INVESTIGATIONAL PRODUCT
6.
6.1
Identity of Investigational Product
The SOC treatment arm will receive standard medical therapy for SBS; while those in the 
teduglutide arm will receive 0.05 mg/kg SC once daily in addition to standard medical therapy.
The investigational product is teduglutide, which will be provided in sterile, single-use 3 mL 
vials containing 1.25 mg teduglutide as a white lyophilized powder to be reconstituted before use 
with 0.5 mL sterile water for injection. In addition to the active ingredient (teduglutide), each 
vial of teduglutide contains L-histidine, mannitol, monobasic sodium phosphate monohydrate, 
and dibasic sodium phosphate as excipients. Additional information is provided in the current 
investigator’s brochure.
6.2
Administration of Investigational Product
6.2.1
Interactive Response Technology for Investigational Product Management
All investigative study sites will be initially provided with sufficient investigational product to 
randomly assign a subject into the study (for either of the proposed treatment groups). 
Randomization will occur through an interactive response system. Random assignment of a 
subject will trigger replacement supplies for that investigative study site.
6.2.2
Allocation of Subjects to Treatment
Subjects will be randomized 1:1 to the teduglutide or SOC treatment arm. Randomization will be 
stratified according to the presence of a small bowel ostomy (eg, end jejunostomy or ileostomy). 
The actual treatment given to individual subjects is determined by a randomization schedule.
Subject numbers are assigned to all subjects as they consent to take part in the study. Within each 
site (numbered uniquely within a protocol), the subject number is assigned to subjects according 
to the sequence of presentation for study participation. 
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined.
6.2.3
Dosing
The initial dose will be calculated based on body weight measured at baseline (Visit 0), and 
adjusted as needed, based on body weight measured at Week 12. No other adjustments to dose 
will be made during the teduglutide treatment period, unless discussed with the sponsor’s 
medical monitor. 
Following reconstitution, teduglutide will be administered by SC injection once daily (QD) into 
1 of the 4 quadrants of the abdomen (in subjects without a stoma) or into either the thigh or arm. 
For subjects with a stoma, the quadrant of the abdomen containing the stoma should not be used. 
Teduglutide should be used as soon as possible after reconstitution, but no more than 3 hours 
later.
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The subject should be dosed at approximately the same time each day. Consecutive doses should 
be separated by at least 12 hours. Each day, the injection site should be alternated. 
Any subject who achieves complete independence from PN support at any time during the 
treatment period will continue to receive teduglutide treatment.
The first SC injection in teduglutide-naïve subjects should be administered under the supervision 
of the investigator or designee and the subject observed for hypersensitivity reactions for at least 
4 hours during their initial dosing visit. The site of administration (arm, thigh, and abdomen) of 
the first teduglutide dose must be specified and recorded in the eCRF. 
Detailed instructions for reconstitution and injection of the investigational product can be found 
in the Instructions for Use. 
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up 
period until the end of study (Week 28/EOS) during which time subjects will receive standard 
medical therapy, but no investigational product will be administered. At EOS all subjects 
regardless of treatment arm may enroll in an extension study that will capture long-term safety 
data and provide the opportunity for additional teduglutide treatment. The follow-up period for 
subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed 
immediately to the EOS if at least one of the following “escape” criteria is met:
1. Increasing PN requirements following teduglutide discontinuation.
2. Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation. 
4. Severe diarrhea related to teduglutide discontinuation.
6.2.4
Unblinding the Treatment Assignment
Not applicable for this open-label study.
6.2.5
Dose Selection Rationale
Teduglutide is approved for adult and pediatric use in the EU at a dose of 0.05 mg/kg SC once 
daily. A completed 12-week dose finding study (TED-C13-003) demonstrated that teduglutide 
dosing at 0.025 and 0.05 mg/kg/day was associated with a favorable benefit-risk profile most 
meaningful at the 0.05 mg/kg/day dose (Carter et al., 2017). 
Population pharmacokinetic modeling and simulations were conducted to determine the optimal 
dose to be used in pediatric subjects using data from 8 adult clinical studies including adult Phase 
1 studies and Phases 2/3 studies as well as TED-C13-003 and suggested the same adult dose 
(0.05mg/kg) in pediatric subjects (aged between 1.67-14.7 years) (Marier et al., 2017).
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To support dosing in the current age group, further PK simulation was conducted based on the 
population PK model previously established and a virtual population of 1000 pediatric patients 
created based on Centers for Disease Control (CDC) growth charts in the target age group (4 to 
12 months) and taking into consideration body weights of pediatric patients with SBS enrolled in 
study TED-C13-003 and TED-C14-006 (approximately 15% lower than healthy subjects in the 
same age group). The model was customized by including a maturation function on clearance 
(CL/F) as a function of estimated glomerular filtration rate. Monte Carlo simulations for all age 
groups were performed according to the SC dosing regimens of 0.0125, 0.025 and 0.05 mg/kg 
every 24 hours. Rich concentration-time profiles were simulated with the customized population 
PK model to derive the exposure metrics area under the concentration curve at steady state 
(AUCss) and maximum concentration at steady state (Cmax,ss). Exposure parameters in infant 
patients were compared to those derived in pediatric (1-17 years) and adult (≥18 years) patients 
with SBS using a Bayesian approach. Based on the clinical observations, Cmax is considered to be 
associated with clinical responses. Following 0.05 mg/kg daily SC administration, the median 
Cmax,ss of teduglutide in neonate patients (24.9 ng/mL) was within 20% of that observed in the 
2 to 4 and 4 to 6 years age groups (26.9 and 29.4 ng/mL, respectively); and approximately 
~28% lower than that in adult patients with SBS. The median Cmax,ss of teduglutide in infant 
patients 4 to 12 months (41.9 ng/mL) following 0.05 mg/kg once daily was within 8% of that 
previously observed in adult patients with SBS (39.0 ng/mL, refer to the attached Simulation 
Report). In addition, individual simulated Cmax,ss values of teduglutide in infant patients 4 to 
12 months (25.6 to 65.1 ng/mL) were contained within the range of Cmax,ss previously observed 
in pediatric patients 1 to 17 years (20.7 to 77.4 ng/mL). The clinical package in conjunction with 
Cmax was considered to support teduglutide dose selection since AUCss was previously shown not 
to correlate with efficacy. Individual simulated AUCss values of teduglutide in infant patients 
4 to 12 months (66.9 to 160 ng.h/mL) following 0.05 mg/kg once daily were contained within 
the range of AUCss values previously observed in pediatric patients 1 to 17 years (63.5 to 
421 ng.h/mL). Based on the totality of clinical data, 0.05 mg/kg once daily is expected to provide 
comparable Cmax concentrations in infants as compared to pediatric patients with SBS and was 
recommended as an evaluation dosing regimen in Study SHP633-301.
6.3
Labeling, Packaging, and Storage
6.3.1
Labeling
The investigational product will be packaged, labeled, and shipped to the study site by the 
sponsor or designee. Kits containing 7 vials of investigational product will be provided for this 
study. The vials will be labeled in accordance with applicable regulatory requirements. 
Ancillary kits, containing supplies needed for the reconstitution and administration of the 
investigational product will also be provided and labeled in accordance with the applicable 
regulatory requirements. 
All investigational product used in this study will be manufactured, tested, labeled, and released 
according to current legal requirements and Good Manufacturing Practice.
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6.3.2
Storage and Handling
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.
Investigational product must be kept in a locked area with access restricted to specific study 
personnel. Investigational product will be stored refrigerated at a temperature between 2-8°C 
(35.6-46.4°F) until dispensed to a subject. Once dispensed to a subject, the IP can be stored 
refrigerated or up to a controlled room temperature (acceptable range of 2-25°C, or 35.6-77°F). 
Parent/legal guardian will be instructed to keep the subject’s IP and sterile water diluent at 
controlled room temperature. If there are concerns that the controlled room temperature cannot 
be maintained, the IP may be refrigerated. The IP is for single use only, and should be used 
within 3 hours following reconstitution.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (ie, certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
Investigational products are distributed by the pharmacy or nominated member of the study 
team. The pharmacist/nominated team member will enter the unique subject identifier on the 
investigational product bottle/carton labels, as they are distributed.
6.4
Drug Accountability
Investigational product will not be dispatched to the study site until the sponsor or 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 investigational product 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. Kits will be shipped to the site once the subject 
is screened.
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Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for dispensing investigational product. Where 
permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is adequately 
trained in the protocol and who works under the direct supervision of the investigator. This 
delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee will dispense the investigational product only to subjects 
included in this study following the procedures set out in the study protocol. Investigational 
product kits will be dispensed at each of the applicable study visits at which the subject is 
required to be at the clinic. Each investigational product kit is sufficient for a treatment period of 
1 week and enough kits will be supplied to cover the period until the next planned study visit. 
Additional study kits will be provided as necessary.
Each subject will be given the investigational product according to the protocol. The investigator 
is to keep a current record of the inventory and dispensing of all clinical supplies. All dispensed 
medication will be documented on the eCRFs and/or other investigational product record. The 
investigator is responsible for assuring the retrieval of all study supplies from subjects.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.
At the end of the study, or as instructed by the sponsor, all unused stock, subject returned 
investigational product, and empty/used investigational product packaging are to be sent to the 
sponsor or designee. The investigator is responsible for assuring the retrieval of all study 
supplies from subjects.
Returned investigational product must be counted and verified by clinical site personnel and the 
sponsor (or study monitor). Shipment return forms, when used, must be signed prior to shipment 
from the site. Contact the sponsor for authorization to return any investigational product prior to 
shipment. Shipment of all returned investigational product must comply with local, state, and 
national laws. 
Please see the Pharmacy Manual for additional information.
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6.5
Subject Compliance
The parent(s)/guardian(s) of subjects must be instructed to bring unused investigational product 
and empty/used investigational product packaging to every visit. Drug accountability must be 
assessed and recorded at the container/packaging level for unused investigational product that is 
contained within the original tamper-evident sealed container (eg, bottles, trays, vials) or at the 
individual count level for opened containers/packaging. 
Subject compliance will be checked by site personnel at every visit by reviewing the subject 
diaries and asking the subject or the subject’s parent or legally-authorized representative if they 
have administered the investigational product according to instructions. If any doses have been 
missed, the reason for missed dose should be documented in the subject’s source documentation 
including, as applicable, the eCRF.
The investigator is responsible for contacting the sponsor or designee when the subject’s daily 
investigational product dosing regimen is interrupted. Attempts should be made to contact the 
sponsor or designee prior to dose interruption. Reasons for dosage interruption may include but 
are not limited to hospitalization and AEs, a lapse in investigational product delivery, etc.
Subjects who have received 80% of the planned doses administered will be assessed as being 
compliant with the study protocol.
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STUDY PROCEDURES
7.
7.1
Study Schedule
Detailed study procedures and assessments to be performed for subjects throughout the study are 
outlined in the study schedules (Table 1 and Table 2) and must be referred to in conjunction with 
the instructions provided in this section. 
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 24/EOT are to be performed as completely as possible. Whenever possible, all 
discontinued subjects should also undergo the protocol-specified 4-week Follow-up Period. 
7.1.1
Screening
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent from the 
parent(s)/guardian(s) of the subject. The screening visit assessments and procedures, beginning 
with informed consent, will be performed as outlined in Table 1. Rescreening will not be 
allowed.
7.1.2
Treatment Period
The randomized Treatment Period will comprise Weeks 1 to 24, during which all assessments 
will be performed as outlined in Table 1 and Table 2.
7.1.3
Follow-up Period
The Follow-up Period will comprise Weeks 25 to 28, during which all assessments will be 
performed as outlined in Table 2.
7.2
Study Evaluations and Procedures
7.2.1
Demographics and Other Baseline Characteristics
Demographics and Medical History
Demographic and/or other baseline variables obtained at the screening and/or baseline visits are 
listed below. Abnormal findings of clinical significance (if any) will be recorded as past medical 
history.

Demography (including age, gestational age, sex, and race)

Medical history (including surgical history)

SBS history, including remnant anatomy
Upper Gastrointestinal Series with Small Bowel Follow-through
An upper GI contrast series with small bowel follow-through will be performed on all subjects 
during the screening period if one has not been done since the subject's last GI surgery. 
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It is acceptable to only enroll subjects who have already had an upper GI series with small bowel 
follow-through performed since the subject’s most recent surgery. 
7.2.2
Efficacy Assessments
Subject Diaries
All available diary data will be reviewed by the investigator or their designee at each clinic and 
telephone visit to assess clinical status and opportunity for PN reduction and advance in feeds. 
Parenteral support adjustments should be made after review of the intake and output diaries and 
the safety lab data according to the guidance for nutrition support adjustment provided in 
Appendix 2.
Intake Diary
Intake diaries will be used to collect and evaluate each subject’s nutritional support. The 
parent/legally authorized representative/study site staff will complete the appropriate fields of the 
PN and EN sections of the intake diary daily throughout the study.
The following data will be captured in the intake diaries:

Parenteral support volume and infusion duration

Enteral nutrition (formula) including volume and calories
Site personnel will determine the actual PN and EN daily calories based on diary entries.
Output Diary
Urine and stool output should be recorded in the output diary over a 48-hour period of nutritional 
stability before every clinic visit; in addition, output should be recorded for subjects within 
1 week of implementing a change in the PN prescription.
Urine data:

Measure and record the weight of all urine-only diapers. Urine volume will be calculated 
using the following formula: 1 g (scale weight) = 1 mL or 1 cc

At the discretion of the investigator, the parent or legal guardian/study site staff may be 
asked to collect the first void after the daily PN infusion to measure specific gravity
Stool data (includes diapers with mixed urine and stool):

Record the weight of diapers containing stool (including diapers with mixed urine and 
stool) as stool output and score the stool consistency (see Output diary). Stool volume 
will be calculated using the formula: 1 g (scale weight)=1 mL or 1 cc
All ostomy output volume should be recorded. 
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Native GLP-2
Blood samples for native GLP-2 should be collected postprandial. Blood samples while subjects 
are receiving teduglutide should be drawn at least 14 hours after the previous dose. Native 
GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject 
weight or at investigator discretion based on weekly/monthly total volume. 
7.2.3
Safety Assessments
Laboratory Evaluations
Safety laboratory tests to be performed at site visits consist of clinical chemistry, hematology, 
and urinalysis and will be performed as outlined in the study plan (Table 1 and Table 2). 
Scheduled laboratory testing will be processed by a central lab. All laboratory assays will be 
performed according to the central laboratory’s normal procedures. Reference ranges are to be 
supplied by the laboratory. The investigator should assess out-of-range clinical laboratory values 
for clinical significance, indicating if the value(s) is/are not clinically significant or clinically 
significant. Abnormal clinical laboratory values, which are unexpected or not explained by the 
subject’s clinical condition, may, at the discretion of the investigator or sponsor, be repeated as 
soon as possible until confirmed, explained, or resolved.
During the Treatment Period, subjects will also have safety labs within approximately 5 to7 days 
after a PN adjustment. Safety labs performed after PN adjustment and between site visits will 
consist of clinical chemistry and urinalysis and may be processed by the central laboratory or a 
local laboratory. Local lab results are not required to be entered in the eCRFs; however, if the 
local lab results indicate any new clinically significant changes, they must be reported as an 
adverse event (see Section 8). Urine specimen collection should be attempted as part of the 
safety labs, but lack of urinalysis will not constitute a protocol deviation.
At baseline, blood samples for safety labs and PK can be separated by 1 day if blood volumes are 
limiting. 
Safety labs at telephone visits will be collected at the discretion of the investigator. 
For all subjects in the teduglutide treatment arm, prothrombin time (PT) and international 
normalized ratio (INR), tested at baseline, will be repeated if clinically indicated.
New clinically significant labs should be reported as AEs.
Close Monitoring Criteria Related To Liver Test Abnormalities:  
The investigator should contact the medical monitor within 24 hours of their awareness if the 
subject develops any of the following changes in laboratory parameters:

ALT or AST >5x ULN and >2x baseline value

Total or direct bilirubin that is >2x baseline value or an absolute increase of ≥3 mg/dL 
(51.3 µmol/L)
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If such changes are observed, the labs should be repeated along with an INR, and an inquiry 
should be made as to the presence of clinical symptoms consistent with new liver injury. The 
subject should be followed closely to determine the trajectory of the laboratory abnormalities and 
appropriate evaluations should be made, such as abdominal ultrasound with Doppler imaging to 
exclude vascular causes and biliary obstruction, consideration of sepsis, liver hypoperfusion, 
acute viral hepatitis (such as hepatitis A, EBV, or HSV), exposure to hepatotoxic medications, 
mitochondrial hepatopathy, or metabolic liver disease (such as hereditary fructose intolerance or 
arginosuccinate synthetase deficiency). Further evaluations can be performed at the discretion of 
the investigator in consultation with the Shire medical monitor.
The following clinical laboratory assessments will be performed according to the study 
schedules:
Table 4:
List of Laboratory Tests
Biochemistry:

Albumin 

Alkaline phosphatase 

Alanine aminotransferase 

Amylase

Aspartate aminotransferase 

Bicarbonate

Bilirubin (total and indirect)

Blood urea nitrogen 

Calcium (total)

Chloride

Cholesterol

C-reactive protein 

Creatinine

Estimated Glomerular Filtration Rate 
(Schwartz formula)

Gamma-glutamyl transferase 

Glucose

Lipase

Magnesium

Phosphorus

Potassium 

Sodium 

Triglycerides
Hematologya:

Hematocrit 

Hemoglobin 

Platelet count

Red blood cell count 

Red blood cell morphology, if needed

White blood cell count with differential
Coagulationb:

Prothrombin time

International normalized ratio
Urinalysis: 

Specific gravity  

Urine Sodium
a Hematology is not collected at Week 1 or at telephone visits.
b For all subjects in the teduglutide treatment arm, PT and INR will be tested at baseline and repeated only if clinically indicated.
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Antibodies to Teduglutide 
Blood samples will be drawn to test for antibodies to teduglutide. Samples will be taken before 
teduglutide administration at the screening visit (Visit -1) and at least 14 hours after the previous 
dose at Week 12 (Visit 12); samples may be drawn from a central line or peripheral access. One 
additional sample will be collected at the EOS 4 weeks after the EOT (ie, Week 28 or EOS). 
Volume of Blood
Efforts will be made to minimize the amount of blood drawn from all pediatric subjects 
participating in this study. The volumes of blood to be drawn from each subject will vary 
depending on clinical status. Approximate volumes of blood to be drawn from each subject are 
shown in Table 5.
Table 5:
Approximate Volume of Blood to be Drawn from Each Subject 
Assessment
Sample 
Volume (mL)
No. 
Samples 
Total 
Volume (mL)
Notes
Subjects Receiving Teduglutide Treatment
Biochemistry 
0.6
12
7.2
Hematology
0.6
11
6.6
Coagulation 
Parameters
0.6
1
0.6
PT and INR tested at baseline 
only, repeat while on study 
only if clinically indicated.
Antibodies
1.5
5
7.5
Pharmacokinetics
1.5
4
6.0
Baseline: 3 timepoints
Week 7: 1 timepoint OR
Week 12: 1 timepoint
Native GLP-2
1.5
3
4.5
Total mL:
6.3
36
32.4
Subjects Receiving Standard of Care
Biochemistry 
0.6
12
7.2
Hematology
0.6
11
6.6
Native GLP-2
1.5
3
4.5
Total mL:
2.7
26
18.3
GLP=glucagon-like peptide; INR=international normalized ratio; PT=prothrombin time
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment. When more than 1 blood assessment is to be done at the time 
point/period, if they require the same type of tube, the assessments should be combined. Blood 
volume estimates do not include safety labs performed after PN adjustments.
Consistent with standard medical practice, efforts to minimize pain and discomfort during 
procedures such as peripheral venipuncture should be implemented as applicable. This may 
include oral sucrose solutions, a pacifier, distraction techniques, and the use of topical anesthetic 
such as EMLA. 
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Physical Examinations, Vital Signs, Weight, Length, and Head Circumference
Physical examinations will be performed according to the study schedules (Table 1 and Table 2). 
Any new clinically significant findings noted during physical examinations should be recorded 
on the appropriate AE page of the eCRF.
Vital signs will be measured according to the study schedules. Measurements will include 
systolic and diastolic blood pressure (mmHg), pulse (beats per minute), and body temperature 
(°C/°F). Blood pressure should be determined by the appropriate size cuff (using the same 
method, the same leg, and in the supine position throughout the study, when possible). Blood 
pressure measurements should be attempted as part of the vital signs, but lack of blood pressure 
results will not constitute a protocol deviation. New clinically significant vital sign abnormalities 
should be recorded on the appropriate AE page of the eCRF.
Body weight will also be recorded in the eCRF; subjects should be weighed on the same scale 
at each study visit. Length and head circumference will be measured at selected visits. A height 
z-score, weight Z-score, and weight/length ratio will be calculated by the sponsor using the 
site-provided height and weight data collected at each site visit.
7.2.4
Pharmacokinetic Assessments
Subjects will have blood samples taken for teduglutide PK analysis predose, and 1 hour 
±10 minutes and 4 hours ±10 minutes postdose at baseline (Visit 0). Subjects also will have 
blood samples taken for teduglutide PK analysis 2 hours ±10 minutes postdose at Week 7 
(Visit 7) or Week 12 (Visit 12) of the treatment period. Blood for PK sampling should be 
collected via peripheral IV or venipuncture, not from a central line. The site of teduglutide 
administration prior to PK blood draws (arm, thigh, abdomen) must be specified. 
7.2.5
Health Economics and Outcomes Research
Hospitalizations
Each hospitalization that occurs during the study will be recorded, including date of admission, 
date of discharge, reasons for hospitalization, discharge diagnosis, and discharge status. 
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ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.3. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, or 
a symptom is more severe or prolonged than expected given the diagnosis, then symptom(s)
should be listed individually. All AEs should be captured on the appropriate AE pages in the 
eCRF and in source documents. In addition to untoward AEs, unexpected benefits outside the 
investigational product indication should also be captured on the AE eCRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
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8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of 
the investigational product is compelling and/or follows a known or 
suspected response pattern to that product, and the event cannot be 
explained by the subject’s medical condition, other therapies, or 
accident.
Not Related
The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident and no 
plausible temporal or biologic relationship exists between the 
investigational product and the event.
AEs that are related to IP that are not resolved at EOS will be followed until the event resolves or 
stabilizes, as judged by the investigator.
Laboratory values, vital signs, and clinical findings at the scheduled physical examinations must 
be reported as AEs if the investigator considers the finding to be a clinically significant change 
from the baseline.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the eCRF. Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved with Sequelae 

Recovering/Resolving

Unknown
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8.1.4
Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE. It is assumed that some of the infants participating in this study may be 
hospitalized for planned surgery(ies) that will occur during their participation in the study. Such 
pre-planned, elective surgeries, do not need to be reported as SAEs for this protocol. 
8.1.5
Clinical Laboratory and Other Safety Evaluations
An untoward change in the value of a clinical laboratory parameter, vital sign measure, or ECG 
assessment can represent an AE if the change is clinically relevant or if, during administration of 
investigational product, a shift of a parameter is observed from a value in the normative range to 
a value that is outside the normal range and considered clinically significant, or a further waning 
of an already clinically significant value. Clinical significance is defined as any abnormal finding 
that results in further clinical investigation(s), treatment(s), or the diagnosis of new or 
progression of established condition. When evaluating such changes, the extent of deviation from 
the reference range, the duration until return to the reference range, either while continuing 
administration or after the end of administration with the investigational product, and the range 
of variation of the respective parameter within its reference range, should also be considered.
If, at the end of the treatment phase, there are abnormal clinical laboratory (such as hematology 
panel or clinical chemistry panel),  vital sign, or ECG values which were not present at the 
beginning of the pretreatment evaluation observed closest to the start of study treatment, further 
investigations should be performed until the values return to within the reference range or until a 
plausible explanation (eg, concomitant disease or expected disease evolution) is found for the 
abnormal values.
The investigator should assess, based on the above criteria and the clinical condition of a subject, 
whether a change in a clinical laboratory value, vital sign, or ECG parameter is clinically 
significant and represents an AE.
8.1.6
Pregnancy
Not applicable.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for 
a non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner 
that may be detrimental to the individual and/or society.
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
Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol).

Overdose – Administration of a dose greater than the allocated dose of the study 
medication or at a frequency greater than the dosing interval specified by the protocol.

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product. For studies, medication errors are reportable to the sponsor 
only as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error. 
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally-authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator brochure which the sponsor 
has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Drug Safety Department and the Shire Medical Monitor within 24 hours of the first awareness of 
the event. Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, 
misuse, overdose, or medication errors (see Section 8.1.7) unless they result in an SAE.
All Adverse Events of Special Interest, as defined in Section 8.3, must be reported by the 
investigator to the Shire Global Drug Safety Department and the Shire Medical Monitor within 
24 hours of the first awareness of the event even if the event does not fulfill seriousness criterion.
The investigator must complete, sign, and date the Shire Clinical Study Adverse Event Form for 
SAEs and Non-serious AEs as Required by Protocol, and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested). Fax or e-mail the completed form to the Shire Global Drug Safety 
Department. A copy of the completed Shire Clinical Study Adverse Event Form for Serious 
Adverse Events (SAEs) and Non-serious AEs as Required by Protocol (and any applicable 
follow-up reports) must also be sent to the Shire medical monitor or designee using the details 
specified in the emergency contact information section of the protocol.
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8.2.3
Serious Adverse Event Definition
A SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose: 

Results in death

Is life-threatening. Note: The term 'life-threatening' in the definition of "serious" refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for pre 
existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse. 
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to investigational product) are collected from the time the 
subject signs the informed consent until the defined follow-up period stated in Section 7.1.3, and 
must be reported to the Shire Global Drug Safety Department and the Shire Medical Monitor 
within 24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Drug Safety Department within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
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In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death. 
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting 
The Sponsor and/or Clinical Contract Research Organization (CRO) is responsible for notifying 
the relevant regulatory authorities, and US central Institutional Review Boards (IRBs)/EU central 
ethics committees (ECs), of related, unexpected SAEs.
In addition, the Clinical CRO is responsible for notifying active sites of all related, unexpected 
SAEs occurring during all interventional studies across the SHP633 program.
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
8.3
Adverse Events of Special Interest
An AE of special interest is an AE (serious or nonserious) of scientific and medical concern 
specific to the sponsor’s product or program and for which ongoing monitoring and immediate 
notification by the investigator to the sponsor is required.
The AEs of special interest that require expedited regulatory reporting include the following:

Growth of pre-existing polyps of the colon

Benign neoplasia of the GI tract including the hepatobiliary system

Tumor-promoting ability (eg, benign and/or malignant neoplasia of any kind, not limited 
to those of the GI or hepatobiliary system)
For AEs of special interest, the sponsor must be informed within 24 hours of first awareness as 
per the SAE notification instructions described in Section 8.2.2 even if the event does not fulfill 
the seriousness criteria.
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8.4
Dose Interruption Criteria
The investigator is responsible for contacting the sponsor/designee when the subject’s 
teduglutide dosing regimen is interrupted. The length of dose interruption, and whether 
teduglutide administration resumes or is permanently discontinued, depends on the clinical 
situation.
Investigational product must be interrupted if any of the following events occur:

An adverse event of special interest (see Section 8.3) 

Intestinal obstruction

Biliary obstruction

Pancreatic duct obstruction

Heart failure with severe fluid overload determined by the sponsor or investigator to 
be related to IP.
Investigational product must be permanently discontinued if any of the following events occur: 

Severe hypersensitivity, such as anaphylaxis, determined by the investigator to be 
related to IP. 

Any malignancy 
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DATA MANAGEMENT AND STATISTICAL METHODS
9.
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the eCRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered on the eCRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. Once a subject is randomized, it is expected that site 
personnel will complete the eCRF entry within approximately 3 business days of the subject’s 
visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the data management plan. Quality 
control and data validation procedures are applied to ensure the validity and accuracy of the 
clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Statistical Analysis Process
The study will be analyzed by the sponsor or designee. All statistical analyses will be performed 
using SAS® (SAS Institute, Cary, NC, US) version 9.3 or higher.
The statistical analysis plan (SAP) will provide the definitions and statistical methods  for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed.
9.4
Planned Interim Analysis, and Data Monitoring Committee 
No interim analyses is planned for this the study. 
A data monitoring committee (DMC) will be involved in the management of this study. The 
DMC members will review the data approximately every 3 months according to the DMC 
Charter. The DMC review will include all cumulative safety data (ie, AEs, laboratory 
assessments, physical examinations, etc.) from study assessments through each cutoff period. 
Further details regarding the DMC can be found in the DMC charter, which will be available 
prior to the administration of investigational product. 
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The DMC for this study will be conducted in accordance with the FDA Guidance for Clinical 
Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees 
(March 2006).
The DMC will be an external, independent board comprised of physicians with relevant training. 
The DMC will be restricted to individuals free of significant conflicts of interest, including, but 
not limited to, financial, scientific, or regulatory in nature. The DMC will be governed by a 
Charter agreed to by members of the Board and the sponsor. Members of the Board may not be 
study investigators or be employed at the same institution as a study investigator, individuals 
employed by the sponsor, independent contractors hired by the sponsor, or members of 
regulatory agencies. The DMC may make recommendations to the sponsor regarding study 
aspects including stopping, modifying or continuing the study; however, the sponsor will have 
the final responsibility to determine whether the study should be modified or temporarily or 
permanently stopped. If the DMC recommends termination of this pediatric study, the 
recommendations will be communicated to the relevant regulatory agencies within 7 calendar 
days.
9.5
Sample Size Calculation and Power Considerations
The sample size is determined based on enrollment feasibility for this rare condition and the age 
of the study population. 
9.6
Study Population
Intent to treat (ITT) population: All subjects randomized in the study.
Safety analysis population: The safety analysis set will contain all subjects who meet the 
following criteria:

Teduglutide treatment arm: subjects who receive at least 1 dose of teduglutide and 
have undergone at least 1 post-baseline safety assessment; analyses will be performed 
according to dose group as appropriate. 

Standard of care treatment arm: subjects who have undergone at least 1 post-baseline 
safety assessment.
Per-protocol population: All subjects in the ITT population without any major protocol deviation 
that affects interpretation of efficacy results.
Pharmacokinetic analysis population: All subjects who received at least 1 dose of teduglutide 
and have at least 1 evaluable postdose PK concentration value. 
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9.7
Efficacy Analyses
9.7.1
Efficacy Endpoints
Efficacy endpoints consist of the following:
9.7.1.1
Primary Efficacy Endpoint 

Reduction in weight-normalized PN fluid volume by at least 20% from baseline at 
Week 24/EOT
9.7.1.2
Secondary Efficacy Endpoints

Reduction in weight-normalized parenteral calories by at least 20% from baseline to 
Week 24/EOT

Achievement of enteral autonomy by Week 24

Time to achieve enteral autonomy

Change in weight-normalized parenteral fluid volume from baseline to each visit

Change in weight-normalized parenteral calories from baseline to each visit

Change in weight-normalized enteral fluid volume from baseline to each visit

Change in weight-normalized enteral caloric intake from baseline to each visit

Increase in weight-normalized enteral fluid intake by at least 20% from baseline to week 
24/EOT

Increase in weight-normalized enteral caloric intake by at least 20% from baseline to 
week 24/EOT
9.7.2
Method of Analysis-Efficacy Endpoints
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 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.
Analyses of weekly PN support will be based on 2 data sources: the subject diary data (also 
referred to as actual data) and the investigator prescribed data. 
The number and percentage of subjects who achieve at least a 20% reduction from baseline in 
weight-normalized average daily PN volume at Week 24/EOT and the number and percentage of 
subjects who achieve at least a 20% reduction from baseline in weight-normalized parenteral 
calories at Week 24/EOT will be summarized by treatment arm.
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During the treatment period, a subject will be considered to have achieved enteral autonomy 
(completely weaned off PN) at a given visit if the investigator prescribes no PN at that visit and 
for the remainder of the treatment period, and there is no use of PN recorded in the subject diary 
during the week prior to that visit and for the remainder of the treatment period. During the 
follow-up period, a subject will be considered to have achieved enteral autonomy at a given visit 
if the investigator prescribes no PN at that visit and for the remainder of the follow-up period and 
there is no use of PN recorded in the subject diary during the week prior to that visit and for the 
remainder of the follow-up period. The number and percentage of subjects who achieve enteral 
autonomy at each scheduled visit, as well as at EOT, will be summarized by treatment arm.
Descriptive statistics will be used to summarize time to achievement of enteral autonomy by 
treatment arm.
The absolute and percent change in weight-normalized weekly PN volume, parenteral calories, 
enteral fluid volume, and enteral caloric intake, from baseline to each scheduled visit, as well as 
at EOT, will be summarized by treatment arm using descriptive statistics.
The number and percentage of subjects who demonstrate an increase in weight-normalized 
enteral fluid intake by at least 20% from baseline to Week 24/EOT and the number and 
percentage of subjects who demonstrate an increase in weight-normalized enteral caloric intake 
by at least 20% from baseline to week 24/EOT will be summarized by treatment arm.
9.8
Safety Analyses
9.8.1
Safety Endpoints
Safety endpoints consist of the following:

Adverse events

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for 
gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output

Stool (including mixed) output

Antibodies to teduglutide
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9.8.2
Method of Analysis-Safety Endpoints
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Treatment-emergent AEs will be summarized by system organ class and preferred 
term using descriptive statistics (eg, number and percentage of subjects). Adverse events will be 
summarized by severity and relationship to treatment. In addition, SAEs will also be tabulated by 
overall and treatment-related events. AEs leading to treatment discontinuation and death will 
also be summarized.
For laboratory tests; vital signs; urine and stool output; weight, length, and head circumference 
Z-scores, and descriptive statistics (eg, n, mean, standard deviation, median, minimum and 
maximum values, and the number and percentage of subjects in specified categories) will be 
used to summarize the absolute values and change from baseline at each visit.
The number and percentage of subjects classified as having antibodies to teduglutide will be used 
to summarize the presence of antibodies. 
9.9
Health Economics and Outcomes Research Analyses
Health economics and outcomes research endpoints consist of the following:

Cumulative number of hospitalization days during the study
Health economics and outcomes research endpoints will be summarized using descriptive 
statistics (number, mean and standard deviation) at nominal time points. 
9.10
Pharmacokinetics Analyses
Plasma concentrations will be summarized using descriptive statistics (number, mean, standard 
deviation, geometric mean, coefficient of variation, minimum, median, and maximum ) at 
nominal time points. 
Pharmacokinetic parameters will be estimated using a population PK modeling approach as 
appropriate and reported separately.
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SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES
10.
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements. 
The name and address of each third-party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996), EU 
Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study. An insurance certificate is supplied as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. 
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This requirement will be fulfilled within 6 months of the end of the study completion date for 
pediatric studies and within 1 year for non-pediatric studies as per guidance. The sponsor will 
provide the ECs with a copy of the same summary.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly. The sponsor will make an end-of-study declaration to the relevant competent 
authority as required by Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator will be appointed to review the final clinical study report 
for multicenter studies. Agreement with the final clinical study report is documented by the 
signed and dated signature of the principal investigator (single-site study) or coordinating 
principal investigator (multicenter study), in compliance with Directive 2001/83/EC as amended 
by Directive 2003/63/EC and ICH Guidance E3 (1995).
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
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If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Electronic Case Report Forms
Electronic case report forms are supplied by the sponsor or designee and should be handled in 
accordance with instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Electronic case report forms 
must be completed by the investigator or designee as stated in the site delegation log. All data 
will have separate source documentation; no data will be recorded directly onto the eCRF.
All data sent to the sponsor must be endorsed by the investigator. 
The study monitor will verify the contents against the source data per the monitoring plan. If the 
data are unclear or contradictory, queries are sent for corrections or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject diaries, and original clinical laboratory reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF entries 
against the source documents. The consent form includes a statement by which the 
parent/guardian agrees to the monitor/auditor from the sponsor or its representatives, national or 
local regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical 
file, appointment books, original laboratory reports, X-rays etc). Non-study site personnel will 
not disclose any personal information or personal medical information.
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
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Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the European Medicines Agency (EMA), the 
Medicines and Healthcare products Regulatory Agency, other regulatory authorities, the sponsor 
or its representatives, and the IRB/EC for each site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent, where applicable, 
from the parent(s)/guardian(s) of all study subjects prior to any study-related procedures 
including screening assessments. All consent documentation must be in accordance with 
applicable regulations and GCP. Each subject’s legally authorized representative is requested to 
sign and date the subject informed consent form or a certified translation if applicable, after the 
subject’s parent or guardian has received and read (or been read) the written subject information 
and received an explanation of what the study involves, including but not limited to: the 
objectives, potential benefits and risk, inconveniences, and the subject’s rights and 
responsibilities. A copy of the informed consent documentation (ie, a complete set of subject 
information sheets and fully executed signature pages) must be given to the subject’s legally 
authorized representative, as applicable. This document may require translation into the local 
language. Signed consent forms must remain in each subject’s study file and must be available 
for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form  that was 
reviewed by the IRB/EC and received their favorable opinion/approval. A copy of the IRB/EC’s 
written favorable opinion/approval of these documents must be provided to the sponsor prior to 
the start of the study unless it is agreed to and documented (abiding by regulatory guidelines and 
national provisions) prior to study start that another party (ie, sponsor or coordinating principal 
investigator) is responsible for this action. Additionally, if the IRB/EC requires modification of 
the sample subject information and consent document provided by the sponsor, the 
documentation supporting this requirement must be provided to the sponsor.
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10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the sponsor/designee has received 
written IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB/EC informed of any serious and 
significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996. A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the sponsor/designee.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market teduglutide; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
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Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2 to 4 and certain other studies as determined by Shire. The purpose of 
the publication steering committee is to act as a non-commercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, royalty 
free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
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If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.
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REFERENCES
11.
Beattie, L. M., Barclay, A. R. & Wilson, D. C. 2010. Short bowel syndrome and intestinal failure 
in infants and children. Paediatrics and Child Health, 20, 485-491.
Carter, Cohran, Cole, Corkins, Dimmitt, Duggan, Hill, Horslen, Lim, Mercer, Merritt, Nichol, 
Sigurdsson, Teitelbaum, Thompson, Vanderpool, Vaughan, Li, Youssef, Venick & 
Kocoshis 2017. Outcomes from a 12-Week, Open-Label, Multicenter Clinical Trial of 
Teduglutide in Pediatric Short Bowel Syndrome. Journal of Pediatrics, The, 181, 102-
111.e5.
Gonzalez-Hernandez, Prajapati, Ogola, Channabasappa, Drews & Piper 2017. Predicting time to 
full enteral nutrition in children after significant bowel resection. Journal of Pediatric 
Surgery, 52, 764-767.
Goulet, O. & Ruemmele, F. 2006. Causes and Management of Intestinal Failure in Children. 
Gastroenterology, 130, S16-S28.
Huisman-de Waal, G., Schoonhoven, L., Jansen, J., Wanten, G. & van Achterberg, T. 2007. The 
impact of home parenteral nutrition on daily life-A review. Clinical Nutrition, 26, 275-
288.
Khan, F. A., Squires, R. H., Litman, H. J., Balint, J., Carter, B. A., Fisher, J. G., Horslen, S. P., 
Jaksic, T., Kocoshis, S., Martinez, J. A., Mercer, D., Rhee, S., Rudolph, J. A., Soden, J., 
Sudan, D., Superina, R. A., Teitelbaum, D. H., Venick, R., Wales, P. W. & Duggan, C. 
2015. Predictors of Enteral Autonomy in Children with Intestinal Failure: A Multicenter 
Cohort Study. J Pediatr, 167, 29-34.e1.
Marier, J., Kassir, N., Martin, P. & Wang, Y. 2017. Population pharmacokinetic modeling of 
teduglutide to support dosing in pediatric patients with short bowel syndrome. Clinical 
Pharmacology & Therapeutics, 101, S91.
Martin, G.-R., Beck, P.-L. & Sigalet, D.-L. 2006. Gut hormones, and short bowel syndrome: the 
enigmatic role of glucagon-like peptide-2 in the regulation of intestinal adaptation. World 
Journal of Gastroenterology, 12, 4117-29.
O'Keefe, S. J., Buchman, A. L., Fishbein, T. M., Jeejeebhoy, K. N., Jeppesen, P. B. & Shaffer, J. 
2006. Short bowel syndrome and intestinal failure: consensus definitions and overview. 
Clin Gastroenterol Hepatol, 4, 6-10.
Sigalet, D. L., Martin, G., Meddings, J., Hartman, B. & Holst, J. J. 2004. GLP-2 levels in infants 
with intestinal dysfunction. Pediatr Res, 56, 371-6.
Spencer, A. U., Neaga, A., West, B., Safran, J., Brown, P., Btaiche, I., Kuzma-O'Reilly, B. & 
Teitelbaum, D. H. 2005. Pediatric Short Bowel Syndrome: Redefining Predictors of 
Success. Annals of Surgery, 242, 403-412.
Squires, R. H., Duggan, C., Teitelbaum, D. H., Wales, P. W., Balint, J., Venick, R., Rhee, S., 
Sudan, D., Mercer, D., Martinez, J. A., Carter, B. A., Soden, J., Horslen, S., Rudolph, J. 
A., Kocoshis, S., Superina, R., Lawlor, S., Haller, T., Kurs-Lasky, M. & Belle, S. H. 
2012. Natural history of pediatric intestinal failure: initial report from the Pediatric 
Intestinal Failure Consortium. J Pediatr, 161, 723-8.e2.
Tappenden, K. A., Edelman, J. & Joelsson, B. 2013. Teduglutide enhances structural adaptation 
of the small intestinal mucosa in patients with short bowel syndrome. J Clin 
Gastroenterol, 47, 602-7.
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Thymann, T., Stoll, B., Mecklenburg, L., Burrin, D. G., Vegge, A., Qvist, N., Eriksen, T., 
Jeppesen, P. B. & Sangild, P. T. 2014. Acute effects of the glucagon-like peptide 2 
analogue, teduglutide, on intestinal adaptation in short bowel syndrome. J Pediatr 
Gastroenterol Nutr, 58, 694-702.
Wales, P. W., de Silva, N., Kim, J., Lecce, L., To, T. & Moore, A. 2004. Neonatal short bowel 
syndrome: population-based estimates of incidence and mortality rates. J Pediatr Surg,
39, 690-5.
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APPENDICES
12.
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Appendix 1
Protocol History
Document
Date
Global/Country/Site Specific
Original Protocol
03 Oct 2017
Global
Amendment 1
18 Jan 2018
Global
Amendment 1.1
07 Aug 2018
France-specific
Amendment 2.1
04 Dec 2018
France-specific
Amendment 3.1
24 May 2019
France-specific
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change and Rationale
Section(s) Affected by Change
Updated emergency contact information to reflect the change of the 
Contract Research Organization’s name.
Emergency Contact Information
Clarified the duration of the screening period and total time on study. 
Provided a clear definition of study completion.
Synopsis, Section 3.1, Section 3.2
Updated the study schematic to reflect the study design changes.
Revised the telephone and clinic visit schedule to assure laboratory 
measurement could be collected without exceeding weekly/monthly 
total blood volume restrictions. 
Synopsis, Table 1, Section 3.1.2
Moved the PK sampling from Week 6 to Week 7 so that the samples 
could be collected without exceeding weekly/monthly total blood 
volume restrictions.
Synopsis, Table 1, Section 3.1.2, 
Section 7.2.4, Table 5
Clarified that blood for pharmacokinetic samples of postdose may be 
taken within ± 10 minutes of the time pre-specified.
Clarified that end jejunostomy or ileostomy are examples  of small 
bowel ostomy rather than the stratification factors.
Synopsis, Section 3.1.2, Section 6.2.2
Clarified that all subjects regardless of treatment arm are eligible for the 
extension study.
Synopsis, Section 3.1.3
Clarified that if a subject treated with teduglutide meets the escape 
criteria, the assessments scheduled for the EOS visit should be 
conducted.
Synopsis, Table 2, Section 3.1.3, 
Section 6.2.3
Clarified that subjects must be 4 to 12 months corrected gestational age 
at screening.
Synopsis, Section 4.1
Changed dose adjustments to Week 12 rather than at every clinic visit 
to reduce site burden.
Synopsis, Table 1, Section 6.2.3
Clarified the definition of enteral autonomy.
Synopsis, Section 9.7.2
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change and Rationale
Section(s) Affected by Change
Updated the pharmacokinetic endpoint and analysis to reflect that only 
descriptive statistics will be calculated on plasma teduglutide 
concentration values. Pharmacokinetic parameters will be estimated 
using a population PK modeling approach as appropriate and reported 
separately.
Synopsis, Section 9.10
Removed assessment of the 5-level EuroQol five dimensions 
questionnaire to reduce caregiver burden.
Synopsis, Table 1, Section 7.2.5, 
Section 9.9
Clarified that native GLP-2 samples drawn while subjects are receiving 
teduglutide should be drawn at least 14 hours after the previous dose.
Table 2, Section 7.2.2
Inserted a footnote to clarify that parenteral support and parenteral 
nutrition are used interchangeably.
Section 1.1
Removed the 5 mg vial of teduglutide as this size vial will not be 
supplied for this study.
Section 6.1
Clarified the procedures for assessing subject compliance. 
Section 6.5
Specified that it is acceptable to only enroll subjects who have already 
had an upper GI series with small bowel follow through performed 
since the subject’s most recent surgery. 
Section 7.2.1
Corrected the volume of blood to be collected for native GLP-2.
Table 5
Removed references to subject assent as assent is not possible in a study 
of infants. 
Section 7.1.1, Section 10.3.1
Clarified the definitions of the analysis sets.
Section 9.6
Clarified that an adjustment to enteral nutrition as appropriate is part of 
the PN/IV adjustment algorithm.
Figure A-1
Minor editorial changes and corrections to typographical errors (which 
do not modify content and/or intent of the original document) were 
made.
Throughout protocol.
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1.1
Amendment Date
07 Aug 2018
France-specific
Description of Change and Rationale
Section(s) Affected by Change
The Shire contact was updated to 
.
Emergency Contact Information
Added an exclusion criterion for Gilbert’s disease and liver failure 
based on the values of the transaminases and of total bilirubin as 
requested by Agence Nationale de Sécurité du Medicament et des 
Produits de Santé (ANSM).
Synopsis, Section 4.2
Added an exclusion criterion for hypersensitivity to trace residues of 
tetracycline to be consistent with the European Summary of Product 
Characteristics of teduglutide as requested by ANSM.
Synopsis, Section 4.2
Added text to specify that efforts to minimize pain and discomfort 
during procedures such as peripheral venipuncture will be implemented.
Section 7.2.3
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2.1
Amendment Date
04 Dec 2018
France-specific
Description of Change and Rationale
Section(s) Affected by Change
The fax number currently used to send the Shire Medical Monitor a 
copy of the Shire Clinical Study Adverse Event Form for Serious 
Adverse Events (SAEs) and Non-serious AEs as Required by Protocol 
is now retired; a copy of the form must be sent by email only.
Updated emergency contact information to reflect the change of Shire 
medical monitor to 
, IQVIA back up medical support 
to 
, and IQVIA phone number for medical 
emergencies.
Emergency Contact Information
A single email address (
) is now used to report a 
Product Quality Complaint, independently from where it has originated. 
Product Quality Complaints
Added the new secondary efficacy endpoint “Time to achieve enteral 
autonomy” and statistical methodology to be used.
Synopsis, Section 9.7.1.2, Section 
9.7.2
Updated  the information on the clinical studies with teduglutide in 
pediatric subjects to include the results of TED-C14-006.
Section 1.2
Clarified that teduglutide is the investigational product for this study.
Section 6.1
Updated the dose selection rationale with results from a simulation 
work using the previous population pharmacokinetic model. Based on 
the totality of clinical data, 0.05 mg/kg once daily is  expected to 
provide comparable Cmax concentrations in infants as compared to 
pediatric patients with SBS and was recommended as an evaluation 
dosing regimen in Study SHP633-301.
Section 6.2.5
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2.1
Amendment Date
04 Dec 2018
France-specific
Description of Change and Rationale
Section(s) Affected by Change
Clarified that rescreening of subjects in the study will not be allowed. 
(Administrative amendment dated 03 Oct 2018)
Section 7.1.1
Clarifications were made to the definition of adverse events.
Section 8.1, Section 8.1.5, Section 
8.2.4
Added heart failure with severe fluid overload, determined by the 
sponsor or investigator to be related to the investigational product, to 
the list of events leading to interruption of investigational product 
administration. This addition is in alignment with the warnings and 
special precautions listed in the investigator brochure.
Section 8.4
As recommended by the FDA, specified that if the DMC recommends 
termination of this pediatric study, the recommendations will be 
communicated to the relevant regulatory agencies within 7 calendar 
days.
Section 9.4
Minor editorial changes and corrections to typographical errors (which 
do not modify content and/or intent of the original document) were 
made.
Throughout the protocol
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Appendix 2
Guidelines for Nutritional Support Management During the Study
The nutritional support adjustment guidelines are designed to standardize management of 
parenteral and enteral nutritional support in this study. Adjustments to nutritional support should 
be considered at every scheduled clinic visit. Adjustments at phone visits may also be performed, 
but nutritional assessments at phone visits serve primarily to confirm that nutritional adjustments 
at prior clinic visits were tolerated.
All attempts should be made to follow the guidelines, but departure from the guidelines will not 
constitute a protocol deviation.
Clinical judgment is required within the algorithm. Each decision point requires integrating 
multiple sources of information into a yes/no decision. When individual data points are 
conflicting, the investigator must use their best judgment in the assessment.
If intestinal adaptation is occurring, reductions in parenteral support volume and calories are 
expected to be in decrements of 5 to 10% relative to baseline values. Parenteral support 
components are at the discretion of the investigator, but care should be taken to balance 
carbohydrate, fat, and protein. Likewise, if intestinal adaptation is occurring, enteral nutrition 
volume and calories should be increased in increments of approximately 10% relative to baseline 
values.
Assessment of the severity of malabsorption may require estimation of stool output for children 
who have mixed stool and urine output.
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.
During the 48-hour output measurement period prior to the subject’s scheduled visit, no further 
changes to the prescribed nutritional support should be made.
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Figure A-1:
Parenteral Nutrition/Intravenous Adjustment Algorithm for All Subjects  
BUN=blood urea nitrogen; Cr=creatinine; PN=parenteral nutrition; UNa=urine sodium; UOP=urine output; USpGr=Urine specific gravity; VS=vital signs; vol=volume
Adequately hydrated?
•
Normal exam and VS
•
Weight stable
•
UOP > 1 ml/kg/h
•
USpGr < 1.020
•
UNa > 20 meq/L
•
Stable, normal BUN/Cr
yes
no
Adequate weight gain 
and linear growth?
↑ PN kcal or no change
↓PN vol and kcal
↑ PN vol +/- kcal
yes
no
Assess severity of malabsorption and adjust EN as appropriate
For non-commercial use only


cShire 
I 
Protocol Administrative Amendment 
MEMORANDUM 
To: 
SHP633-301 Trial Master File (TMF), SHP633-301 Study Sites 
From: 
, MD 
Date: 
6 Sep 2019 
Subject: Protocol Administrative Amendment: Change in Section 9.4 to include and Interim Analysis 
EUDRACT NO: 2017-003606-40 
Protocol Title: 
Protocol Version: 
A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic Study of Teduglutide 
in Infants 4 to 12 Months of Age with Short Bowel Syndrome Who are Dependent on Parenteral 
Support 
Protocol Amendment 3 dated 24May2019 
The following Administrative Amendment is for Protocol SHP633-301, Protocol Amendment 3 dated 24May2019. 
Administrative Change : Section 9.4 may be updated to include an Interim Analysis. 
These changes are considered administrative in nature and do not compromise the scope, design, or integrity of the study 
or subject safety in any way. The revisions will be incorporated into any subsequent amendment to the protocol. 
Copies of this letter shall be distributed to the Principal Investigators of the study and should be forwarded to the site 
Ethics Committees as necessary. 
If you have further questions, please do not hesitate to contact your CRA or Shire directly. 
I have reviewed the above Memorandum and am in agreement with the specified administrative clarifications. 
--
Thank you, -
Date 
cc: SHP633-301 TMF Main Study File 
For non-commercial use only


PROTOCOL: SHP633-301
TITLE:
A Randomized, Open-label, 24-Week Safety, Efficacy, and 
Pharmacokinetic Study of Teduglutide in Infants 4 to 12 Months of Age 
with Short Bowel Syndrome Who are Dependent on Parenteral Support
NUMBER
SHP633-301
PHASE
3 
DRUG:
Teduglutide
INDICATION:
Short bowel syndrome
EUDRACT NO.:
2017-003606-40
SPONSOR: 
Shire Human Genetic Therapies, Inc.
300 Shire Way
Lexington, MA 02421 USA
PROTOCOL 
HISTORY:
Original Protocol: 03 Oct 2017
Amendment 1: 18 Jan 2018
Amendment 2: 04 Dec 2018
Amendment 3: 24 May 2019
Amendment 4: 17 Dec 2019
Confidentiality Statement
This document contains confidential and proprietary information of Shire and is disclosed 
pursuant to confidentiality and non-disclosure obligations. This information should be used 
solely for the purposes for which it was provided and should not be copied, shared with, or 
disclosed to any third party without the express written consent of Shire.
For non-commercial use only


Shitt 
SHP63J.JOI ProtOC'OI \mt'ndment-' 
Tectuclu1id«" 
.- Dec 2019 
PROTOCOL 'IGNATlJRE PA<a: 
(Shire:) Appro\al 
Sign•tur<: 
 :\1D f•hD 
Dale:
. Glnhal Clinical Science 
Im cc,tigator 'c, \d .. nowle<lgcmcnt 
I hnvc 
thb protocol for Shire Study <\11P6J3 10 I 
Title: !\ Ran<l<Hni1cd. Ot en-label. 24-Weck Safct). l•Oic:ic.). and Phnrmucnkincuc 
of 
I \:duglu11dc 111 lnlhnt 
lo 12 Months of Age \\Ith hort Uo,,cl .. )ntlromc \\ho are Dependent 
on Parenteral suppcin 
lhn\cfull)di u edtheobjecthe<s 
\ rd th content ofthhprolocol"ilhche 
r' rcpr\.-scntnth 
I undc tnmJ 1hn1 the infi nnaticn in th-.-:; p t 
othl.!r thun to tho c direct I) 1m ol ed iu ti ... (; 
"ithoul '' rittcn nuthori1.ation from the 
... ,., .... , 
inform.111on \;ontnin ·d herdn lo a subject in 
I .1gre'-' 10 ctim.lu 1 this tud) accordtng t thi proto ol nnd to com pl) '' ith 
rcquiremenb. 
"uhjc1,;t to cthicnl anJ sakt) con-.1Jeration and guideline . and lo conJuc;t thc '-lUd) m 
ucwrdam;c \\ i1h ln1t·mn1ionul (.ounciJ for I lnrmoni .. ution ul I 1.•ch111c.:al Rc<.1t11r'-'111cnts tor 
Phurrnuccu11cal., for I lurnnn Lise (ICH) guideline<; nn 1ond Clsrrn:al P1:11.th.I! (CiCP) and \\ith the 
applicuhlc rcgul11to1 > rcquirumt!nlS. 
I unckrstam.l th.11 
lll <.;nmply wiLh the rct1uhc1m:nts pf the pr11111wl may lcud lo the 
tcnn11101ion ol'm) p.1n1cirat1on ru. an 
for 1hi' '\lUd) 
I under 1unJ thut the ... pun'{'r ma) decide to 'u"r'-'nd or rrcmaiurc:l) tcnt1inatc the ... tud) at an) 
time for "hate\ er rca on: 
J aec:isioo " ill be ommunac tell to me: in \Hi tine. om erseh. 
-
. 
hould I dcddc to '' nhl.lru\\ fmm nec:LJl110 of thl' tud) I \\ill ommunic tc m) intcnti •n 
immcdimcl) in \\riling to the .. ponsoc 
In\ cstigntor Nnmc anlf 
tplca.sc hand pnnt or l) pc) 
Uutl': 
For non-commercial use only


Shire
CONFIDENTIAL
Page 3
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Adverse Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as 
Required by Protocol within 24 hours to the Shire Global Drug Safety Department. Applicable 
fax numbers and e-mail address can be found on the form (sent under separate cover). A copy of 
this form must also be sent to the Shire Medical Monitor by e-mail at 
.
For protocol- or safety-related issues, the investigator must contact IQVIA Medical Support:
Primary Contact
Backup Contact 
, MD
, MD, PhD
Mobile:  
Mobile: 
Phone: 
 (medical emergencies)
Phone: 
 (medical emergencies)
Email: 
Email: 
In addition, the investigator may also contact Shire:
, MD
Mobile Phone: 
Email: 
For non-commercial use only


Shire
CONFIDENTIAL
Page 4
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please use the E-mail address below to report the Product Quality Complaint:
Telephone numbers (provided for reference, if needed): 
Shire (USA)
 
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Shire
CONFIDENTIAL
Page 5
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
SUMMARY OF CHANGES FROM PREVIOUS VERSION
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
4
Amendment Date
17 Dec 2019
Global
Description of Change and Rationale
Section(s) Affected by Change
Clarified that subjects may enroll in an extension study at end of study 
(EOS) if that study is open to enrollment at the time of the SHP633-301 
EOS.
Synopsis, Table 2, Section 3.1, 
Section 3.1.3, Section 6.2.3
Clarified when and how parenteral nutrition prescriptions are to be 
recorded.
Table 1, Table 2, Section 7.2.2
Clarified that at baseline safety labs and PK samples will be separated by 
1 day. 
Synopsis; Table 1, Table 5, 
Section 7.2.4
PT/INR measurements should be performed at screening for all subjects 
instead of baseline for teduglutide-treated subjects.
Table 1, Section 7.2.3, Table 4, 
Table 5
Specified that C-reactive will not be collected at screening for all subjects 
and will not be collected at any visit for subjects who weigh <7 kg.
Table 1, Table 4, Table 5
Removed the optional PK measurement at Week 12. Postbaseline PK 
samples should be performed at Week 7.  
Table 1, Section 3.1.2, Table 5
Specified that the predose PK sample will not be collected from subjects 
who weigh <7 kg.
Table 1, Section 7.2.3, Table 5
Clarified that hematology laboratories are not collected at Week 1.  
Specified that hematology will not be collected at screening for subjects 
who weigh <7 kg.
Table 1, Section 7.2.3, Table 4,
Table 5
Simplified the language describing the population PK modeling and 
simulations in previous studies.
Section 6.2.5
Updated to allow 1 rescreening attempt to aide in enrollment.
Section 7.1.1
Clarified information to be collected for the pharmacokinetic assessments.
Section 7.2.4
Interim analysis will be conducted for regulatory submissions, as needed. 
Analyses will be descriptive in nature. No formal comparisons are 
planned, and no hypotheses will be formally tested.  Due to the open-label 
nature of this study, personnel involved in conducting the interim analyses 
will have access to treatment assignments.
Section 9.4
Minor editorial changes and corrections to typographical errors (which do 
not modify content and/or intent of the original document) were made.
Throughout the protocol
See Appendix 1 for protocol history, including all amendments. 
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CONFIDENTIAL
Page 6
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
PRODUCT QUALITY COMPLAINTS..........................................................................................4
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................5
TABLE OF CONTENTS.................................................................................................................6
LIST OF TABLES.........................................................................................................................10
LIST OF FIGURES .......................................................................................................................10
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..................................................11
STUDY SYNOPSIS ......................................................................................................................12
STUDY SCHEDULES ..................................................................................................................17
BACKGROUND INFORMATION .......................................................................................21
1.
1.1
Short Bowel Syndrome ............................................................................................21
1.2
Teduglutide...............................................................................................................22
OBJECTIVES.........................................................................................................................24
2.
2.1
Rationale for the Study.............................................................................................24
2.2
Study Objectives ......................................................................................................24
STUDY DESIGN ...................................................................................................................25
3.
3.1
Study Design and Flow Chart ..................................................................................25
3.1.1
Screening Period ....................................................................................................25
3.1.2
Treatment Period....................................................................................................25
3.1.3
Follow-up Period ...................................................................................................26
3.2
Study Duration .........................................................................................................26
3.3
Sites and Regions .....................................................................................................27
STUDY POPULATION.........................................................................................................28
4.
4.1
Inclusion Criteria......................................................................................................28
4.2
Exclusion Criteria.....................................................................................................28
4.3
Reproductive Potential .............................................................................................29
4.4
Discontinuation of Subjects .....................................................................................29
4.4.1
Reasons for Discontinuation..................................................................................30
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit .................................30
PRIOR AND CONCOMITANT TREATMENT ...................................................................31
5.
5.1
Prior Medications and Procedures............................................................................31
5.2
Concomitant Medications and Procedures...............................................................31
5.3
Permitted Treatment.................................................................................................31
5.4
Prohibited Treatment................................................................................................31
INVESTIGATIONAL PRODUCT ........................................................................................32
6.
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SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
6.1
Identity of Investigational Product...........................................................................32
6.2
Administration of Investigational Product ...............................................................32
6.2.1
Interactive Response Technology for Investigational Product Management ........32
6.2.2
Allocation of Subjects to Treatment ......................................................................32
6.2.3
Dosing....................................................................................................................32
6.2.4
Unblinding the Treatment Assignment..................................................................33
6.2.5
Dose Selection Rationale .......................................................................................33
6.3
Labeling, Packaging, and Storage ............................................................................34
6.3.1
Labeling .................................................................................................................34
6.3.2
Storage and Handling.............................................................................................35
6.4
Drug Accountability.................................................................................................35
6.5
Subject Compliance..................................................................................................37
STUDY PROCEDURES........................................................................................................38
7.
7.1
Study Schedule.........................................................................................................38
7.1.1
Screening................................................................................................................38
7.1.2
Treatment Period....................................................................................................38
7.1.3
Follow-up Period ...................................................................................................38
7.2
Study Evaluations and Procedures ...........................................................................38
7.2.1
Demographics and Other Baseline Characteristics................................................38
7.2.2
Efficacy Assessments.............................................................................................39
7.2.3
Safety Assessments................................................................................................40
7.2.4
Pharmacokinetic Assessments ...............................................................................44
7.2.5
Health Economics and Outcomes Research ..........................................................44
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................45
8.
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................45
8.1.1
Severity Categorization..........................................................................................45
8.1.2
Relationship Categorization...................................................................................46
8.1.3
Outcome Categorization ........................................................................................46
8.1.4
Symptoms of the Disease under Study ..................................................................47
8.1.5
Clinical Laboratory and Other Safety Evaluations ................................................47
8.1.6
Pregnancy...............................................................................................................47
8.1.7
Abuse, Misuse, Overdose, and Medication Error ..................................................47
8.2
Serious Adverse Event Procedures ..........................................................................48
8.2.1
Reference Safety Information ................................................................................48
8.2.2
Reporting Procedures.............................................................................................48
8.2.3
Serious Adverse Event Definition .........................................................................49
8.2.4
Serious Adverse Event Collection Time Frame.....................................................49
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SHP633-301 Protocol Amendment 4
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17 Dec 2019
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................49
8.2.6
Fatal Outcome........................................................................................................50
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................50
8.3
Adverse Events of Special Interest...........................................................................50
8.4
Dose Interruption Criteria ........................................................................................51
DATA MANAGEMENT AND STATISTICAL METHODS...............................................52
9.
9.1
Data Collection.........................................................................................................52
9.2
Clinical Data Management.......................................................................................52
9.3
Statistical Analysis Process......................................................................................52
9.4
Planned Interim Analysis, and Data Monitoring Committee ...................................52
9.5
Sample Size Calculation and Power Considerations................................................53
9.6
Study Population ......................................................................................................53
9.7
Efficacy Analyses.....................................................................................................54
9.7.1
Efficacy Endpoints.................................................................................................54
9.7.1.1
Primary Efficacy Endpoint.....................................................................54
9.7.1.2
Secondary Efficacy Endpoints ...............................................................54
9.7.2
Method of Analysis-Efficacy Endpoints................................................................54
9.8
Safety Analyses ........................................................................................................55
9.8.1
Safety Endpoints ....................................................................................................55
9.8.2
Method of Analysis-Safety Endpoints...................................................................56
9.9
Health Economics and Outcomes Research Analyses .............................................56
9.10
Pharmacokinetics Analyses......................................................................................56
SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES ............................................57
10.
10.1
Sponsor’s Responsibilities .......................................................................................57
10.1.1 Good Clinical Practice Compliance.......................................................................57
10.1.2 Indemnity/Liability and Insurance.........................................................................57
10.1.3 Public Posting of Study Information......................................................................57
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................57
10.1.5 Study Suspension, Termination, and Completion..................................................58
10.2
Investigator’s Responsibilities .................................................................................58
10.2.1 Good Clinical Practice Compliance.......................................................................58
10.2.2 Protocol Adherence and Investigator Agreement ..................................................58
10.2.3 Documentation and Retention of Records .............................................................59
10.2.3.1
Electronic Case Report Forms................................................................59
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................59
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SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
10.2.3.3
Audit/Inspection .....................................................................................60
10.2.3.4
Financial Disclosure...............................................................................60
10.3
Ethical Considerations..............................................................................................60
10.3.1 Informed Consent...................................................................................................60
10.3.2 Institutional Review Board or Ethics Committee ..................................................61
10.4
Privacy and Confidentiality......................................................................................61
10.5
Study Results/Publication Policy .............................................................................62
REFERENCES .......................................................................................................................64
11.
APPENDICES ........................................................................................................................66
12.
Appendix 1
Protocol History .....................................................................................67
Appendix 2
Guidelines for Nutritional Support Management During the Study ......70
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Shire
CONFIDENTIAL
Page 10
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
LIST OF TABLES
Table 1:
Study Schedule: Visits -1 to 12 .....................................................................17
Table 2:
Study Schedule: Visits 13-28 ........................................................................19
Table 3:
Prohibited Treatment.....................................................................................31
Table 4:
List of Laboratory Tests ................................................................................42
Table 5:
Approximate Volume of Blood to be Drawn from Each Subject .................43
LIST OF FIGURES
Figure 1:
Study Schematic ............................................................................................25
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Page 11
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation
Definition
AE
adverse event
AUCss
area under the concentration-time curve at steady-state 
Cmax,ss
maximum plasma concentration at steady state
CRO
contract research organization
eCRF
electronic case report form
DMC
data monitoring committee
EDC
electronic data capture
EMA
European Medicines Agency
EN
enteral nutrition
EOS
end of study
EOT
end of treatment
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
gastrointestinal 
GLP
glucagon-like peptide
HIPAA
Health Insurance Portability and Accountability Act
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use
ICMJE
International Committee of Medicinal Journal Editors
I/O
oral fluid intake and urine output
IP
Investigational product
IRB
Institutional Review Board
ITT
intent-to-treat
MedDRA
Medical Dictionary for Regulatory Activities
PK
pharmacokinetics
PN
parenteral nutrition
SAE
serious adverse event
SAP
statistical analysis plan
SBS
short bowel syndrome
SC
subcutaneous
SD
standard deviation
SOC
standard of care
ULN
upper limit of normal 
US
United States
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CONFIDENTIAL
Page 12
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
STUDY SYNOPSIS
Protocol number: SHP633-301
Drug: Teduglutide
Title of the study: A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic Study of 
Teduglutide in Infants 4 to 12 Months of Age with Short Bowel Syndrome Who are Dependent on Parenteral 
Support
Number of subjects (total and for each treatment arm):
At least 10 subjects will be randomized: at least 5 subjects in a teduglutide treatment arm and at least 5 subjects in 
a standard of care (SOC) comparator arm
Investigator(s): Multicenter study
Site(s) and Region(s): 
This study is planned to be conducted in approximately 5 to 10 sites globally.
Study period (planned):
2017-2020
Clinical phase:
3
Objectives:
The objectives of this clinical study are to evaluate the safety, efficacy/pharmacodynamics and pharmacokinetics 
(PK) of teduglutide treatment in infants with short bowel syndrome (SBS) dependent on parenteral support.
Investigational product, dose, and mode of administration:
Teduglutide 0.05 mg/kg by subcutaneous (SC) injection once daily into 1 of the 4 quadrants of the abdomen or 
either thigh or arm.
Methodology:
This is a randomized, multicenter, open-label study, consisting of a 2 to 4 week screening period, a 24-week 
treatment period, and a 4-week follow-up period. 
* At EOS all subjects regardless of treatment arm may enroll in an extension study if that study is open to 
enrollment at the time of the SHP633-301 EOS that will capture long-term safety data and provide the 
opportunity for additional teduglutide treatment. The follow-up period for subjects in the teduglutide treatment 
arm may be interrupted and the subjects may proceed immediately to the EOS if at least one “escape” criteria is 
met.
Extension 
study* 
1
24
1
3
5
7
9
12
16
20
28
2 to 4
Weeks
Screening
Teduglutide 0.05 mg/kg SC once daily for 24 weeks
Site Visit 
Telephone Visit
Standard of care for 24 weeks
Baseline: treatment 
randomization
0
24
3
5
7
9
12
16
20
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CONFIDENTIAL
Page 13
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
Study eligibility will be confirmed during the screening period (minimum: 2 weeks; maximum 4 weeks). At the 
baseline visit (Week 0), subjects will be randomized 1:1 to the teduglutide or SOC treatment arm. Randomization 
will be stratified according to the presence of a small bowel ostomy (eg, end jejunostomy or ileostomy). During 
the 24-week treatment period, subjects in the SOC treatment arm will receive standard medical therapy for SBS; 
while those in the teduglutide arm will receive 0.05 mg/kg SC once daily in addition to standard medical therapy. 
Subjects in both arms will follow the same visit schedule and assessments. Subjects will be monitored weekly 
with phone or clinic visits. Clinic visits will occur at Weeks 1, 3, 5, 7, 9, 12, 16, 20, 24, and 28. At all site visits 
and telephone contacts, safety will be monitored and nutritional support will be reviewed and adjusted as needed. 
To maintain consistency across centers, guidance and training will be provided to help sites follow the nutritional 
support adjustment guidelines (developed with SBS expert input and provided in the protocol) related to decisions 
for parenteral nutrition (PN) reduction and advances in enteral feeds based on weight gain, urine and stool output, 
and clinical stability. Deviations from the guidelines are not considered a protocol deviation.
Sparse PK sampling, in the teduglutide treatment arm only, will occur at baseline (predose and 1 hour 
±10 minutes and 4 hours ±10 minutes postdose) and at Week 7 (2 hours±10 minutes postdose). At baseline, safety 
labs and PK will be separated by 1 day.
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up period until the end 
of study (Week 28/EOS) during which time subjects will receive standard medical therapy, but no investigational 
product will be administered. At EOS all subjects regardless of treatment arm may enroll in an extension study if 
that study is open to enrollment at the time of the SHP633-301 EOS that will capture long-term safety data and 
provide the opportunity for additional teduglutide treatment. The follow-up period for subjects in the teduglutide 
treatment arm may be interrupted and the subjects may proceed immediately to the EOS if at least one of the 
following “escape” criteria is met:
1.
Increasing PN requirements following discontinuation of teduglutide.
2.
Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal tolerated enteral 
nutrition (EN) following teduglutide discontinuation.
3.
Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and electrolyte intake 
following teduglutide discontinuation.
4.
Severe diarrhea related to teduglutide discontinuation.
Inclusion and Exclusion Criteria:
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1.
Informed consent by the parent or legal guardian. 
2.
Male or female infant 4 to 12 months corrected gestational age at screening.
3.
Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and baseline.
4.
Short bowel syndrome with dependence on parenteral support to provide at least 50% of fluid or caloric 
needs.
5.
Stable PN requirements for at least 1 month prior to screening, defined as a ≤10% change in the 
weight-normalized parenteral total fluid and caloric intake, despite attempts to wean PN, 
notwithstanding transient instability for events such as sepsis or interruption of central venous access.
6.
This criteria was deleted.
7.
Parent or legal guardian understands and is willing and able to fully adhere to study requirements as 
defined in this protocol.
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Page 14
SHP633-301 Protocol Amendment 4
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Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1.
Previous treatment with teduglutide.
2.
Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus inclusion disease, 
etc.
3.
Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility, that is the primary contributing factor to feeding intolerance and 
inability to reduce parenteral support, prior to screening. Dysmotility is defined as severe if it is expected 
to limit the advancement of enteral feeding.
4.
Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral aversion in the 
absence of a feeding tube.
5.
Intestinal obstruction or clinically significant intestinal stenosis.
6.
Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or major intestinal 
resection or anastomosis, within 3 months prior to screening or planned during the study period.
7.
Unstable cardiac disease.
8.
Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
9.
Biliary obstruction, stenosis, or malformation. 
10. Clinically significant pancreatic disease. 
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b.
Platelet count <100×10^3/µl due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d.
Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 2-week period
13. More than 3 serious complications of intestinal failure (eg, catheter-associated bloodstream infections, 
interruption of nutrition due to feeding intolerance, catheter-associated thrombosis, severe fluid or 
electrolyte disturbances) within 1 month prior to or during screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile polyposis or 
Beckwith-Wiedemann syndrome, or first degree relative with early onset of gastrointestinal cancer 
(including hepatobiliary and pancreatic cancers). 
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 (GLP-2); 
insulin-like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs of these hormones; or 
glutamine. 
16. Participation in a clinical study using an experimental drug within 3 months or 5.5 half-lives of the 
experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, closely-related 
compounds, or any of the stated ingredients.
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts the subject at any 
undue risk, prevents completion of the study, or interferes with analysis of the study results.
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Maximum Duration of Subject Involvement in the Study:
The study consists of a 2 to 4 week screening period, a 24-week treatment period, and a 4-week follow-up period. 
The maximum duration of participation for each subject is 32 weeks.
Study completion is defined as the last subject, last visit. This is the visit date at which the last subject on the 
study has his or her last follow-up visit on the study (whether during the 24-week treatment period or the 4-week 
follow-up period).
Endpoints:
Efficacy
Efficacy endpoints consist of the following:
Primary

Reduction in weight-normalized PN fluid volume by at least 20% from baseline at Week 24/EOT
Secondary

Reduction in weight-normalized parenteral calories by at least 20% from baseline to Week 24/EOT

Achievement of enteral autonomy by week 24

Time to achieve enteral autonomy

Change in weight-normalized parenteral fluid volume from baseline to each visit

Change in weight-normalized parenteral calories from baseline to each visit

Change in weight-normalized enteral fluid volume from baseline to each visit

Change in weight-normalized enteral caloric intake from baseline to each visit

Increase in weight-normalized enteral fluid intake by at least 20% from baseline to Week 24/EOT

Increase in weight-normalized enteral caloric intake by at least 20% from baseline to Week 24/EOT
Pharmacokinetics
The pharmacokinetic endpoint is plasma teduglutide concentration at nominal time points.
Safety
Safety endpoints consist of the following:

Adverse events (AEs)

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output

Stool (including mixed) output  

Antibodies to teduglutide 
Health Economics and Outcomes Research
Health economics and outcomes research (HEOR) endpoints include the following:

Cumulative number of hospitalization days during the study
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Statistical Methods:
Efficacy
Analyses of weekly PN support will be based on 2 data sources: the subject diary data (also referred to as actual 
data) and the investigator prescribed data. 
The number and percentage of subjects who achieve at least a 20% reduction from baseline in weight-normalized 
average daily PN volume at Week 24/EOT and the number and percentage of subjects who achieve at least a 
20% reduction from baseline in weight-normalized parenteral calories at Week 24/EOT will be summarized by 
treatment arm.
During the treatment period, a subject will be considered to have achieved enteral autonomy (completely weaned 
off PN) at a given visit if the investigator prescribes no PN at that visit and for the remainder of the treatment 
period, and there is no use of PN recorded in the subject diary during the week prior to that visit and for the 
remainder of the treatment period. During the follow-up period, a subject will be considered to have achieved 
enteral autonomy at a given visit if the investigator prescribes no PN at that visit and for the remainder of the 
follow-up period and there is no use of PN recorded in the subject diary during the week prior to that visit and for 
the remainder of the follow-up period. The number and percentage of subjects who achieve enteral autonomy at 
each scheduled visit, as well as at EOT, will be summarized by treatment arm. Descriptive statistics will be used 
to summarize time to achievement of enteral autonomy by treatment arm.
The absolute and percent change in weight-normalized weekly PN volume, parenteral calories, enteral fluid 
volume, and enteral caloric intake, from baseline to each scheduled visit, as well as at EOT, will be summarized 
by treatment arm using descriptive statistics.
The number and percentage of subjects who demonstrate an increase in weight-normalized enteral fluid intake by 
at least 20% from baseline to Week 24/EOT and the number and percentage of subjects who demonstrate an 
increase in weight-normalized enteral caloric intake by at least 20% from baseline to week 24/EOT will be 
summarized by treatment arm.
Pharmacokinetics
Plasma concentrations will be summarized using descriptive statistics (number, mean, standard deviation, 
geometric mean, coefficient of variation, minimum, median, and maximum) at nominal time points. 
Pharmacokinetic parameters will be estimated using a population PK modeling approach as appropriate and will 
be reported separately.
Safety
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Treatment-emergent AEs will be summarized by system organ class and preferred term using descriptive statistics 
(eg, number and percentage of subjects). Adverse events will be summarized by severity and relationship to 
treatment. In addition, serious adverse events  will also be tabulated by overall and treatment-related events. AEs 
leading to treatment discontinuation and death will also be summarized.
For laboratory tests; vital signs; urine and stool output; weight, length, and head circumference Z-scores; and 
descriptive statistics (eg, n, mean, standard deviation, median, minimum and maximum values, and the number 
and percentage of subjects in specified categories) will be used to summarize the absolute values and change from 
baseline at each visit.
The number and percentage of subjects classified as having antibodies to teduglutide will be used to summarize 
the presence of antibodies. 
Health Economics and Outcomes Research
The HEOR endpoints will be summarized descriptively. 
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STUDY SCHEDULES
Table 1:
Study Schedule: Visits -1 to 12
Procedures
Screening
Baseline 
(Week 0)
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
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit type
Site
Site
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Tel
Site
Study day
-14
0
7
14
21
28
35
42
49
56
63
70
77
84
±window (days)
-2 weeks
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Informed consent
X
Eligibility
X
X
Randomization
X
Demographics 
X
SBS history
X
Medical and surgical history
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications and 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, vital signs, 
weight
X
X
X
X
X
X
X
X
Length and head circumference
X
X
X
X
UGI/SBFT
X
Safety labs and urinalysisb, c
X
Xb
X
(X)
X
(X)
X
(X)
X
(X)
X
(X)
(X)
X
PK samplinga
X
[X]d
Antibodies to teduglutidea,e
X
Xe
Native GLP-2f
X
Provide intake and output 
diariesg
X
X
X
X
X
X
X
X
Review diaries and nutritional 
support
X
X
X
X
X
X
X
X
X
X
X
X
X
Record PN prescription and 
adjust nutritional support as 
neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
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Table 1:
Study Schedule: Visits -1 to 12
Procedures
Screening
Baseline 
(Week 0)
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
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit type
Site
Site
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Tel
Site
Study day
-14
0
7
14
21
28
35
42
49
56
63
70
77
84
±window (days)
-2 weeks
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Dispense IPa, i
X
X
X
X
X
X
X
Adjust IP dosej
X
EN=enteral nutrition; GLP-2=glucagon-like peptide 2; INR=international normalized ratio; IP=investigational product; PK=pharmacokinetics; PN=parenteral nutrition;
PT=prothrombin time; UGI/SBFT=upper GI series with small bowel follow-through 
a Applicable to the teduglutide treatment arm only. 
b At baseline, safety labs (Table 4) and PK will be separated by 1 day. Safety labs at telephone visits will be collected at the discretion of the investigator. For all subjects in the 
teduglutide treatment arm, PT and INR will be tested at screening, and repeated if clinically indicated. Hematology is not collected at Week 1 or at telephone visits.  Hematology 
will not be collected at screening for subjects who weigh <7 kg. C-reactive will not be collected at screening for all subjects and will not be collected at any visit for subjects who 
weigh <7 kg.
c Urinalysis will consist of urine sodium and specific gravity. Urine collection should be attempted, but inability to obtain urinalysis is not a protocol deviation.
d Subjects will have blood samples taken for teduglutide PK analysis predose and 1 hour ±10 minutes and 4 hours ±10 minutes postdose at baseline (Visit 0). The predose sample 
will not be collected from subjects who weigh <7 kg. Subjects also will have blood samples taken for teduglutide PK analysis 2 hours ±10 minutes postdose at Week 7 (Visit 7) of 
the treatment period.
e Samples for antibody analysis will be drawn at the baseline and Week 12 visits. Blood samples while subjects are receiving teduglutide should be drawn at least 14 hours after the 
previous dose.
f Blood samples for native GLP-2 should be collected postprandial. Native GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at 
investigator discretion based on weekly/monthly total volume. 
g Intake diaries will collect actual PN volume and hours per day and EN volume and calories. Intake diaries should be completed daily throughout the study. Urine and stool output 
should be recorded in the output diary over a 48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PN prescription. 
h Parenteral support adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment 
provided in Appendix 2.
i The initial dose will be calculated based on body weight measured at baseline (Visit 0).
j The dose will be adjusted as needed, based on body weight measured at Week 12 visit.
Note: (X) denotes optional assessments.
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Table 2:
Study Schedule: Visits 13-28
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 
(EOT/ET)
Week 
25
Week 
26
Week 
27
Week 
28 
(EOS)a
Visit number
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit type
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Study day
91
98
105
112
119
126
133
140
147
154
161
168
175
182
189
196
±window (days)
±3
±3
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications 
and procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, vital 
signs, weight
X
X
X
X
Length and head 
circumference
X
X
X
X
Safety labs and 
urinalysisb,c
(X)
(X)
(X)
X
(X)
(X)
(X)
X
(X)
(X)
(X)
X
(X)
(X)
(X)
X
Antibodies to 
teduglutided,e
X
Native GLP-2f
X
Provide intake and output 
diaries
X
X
X
Review diaries and 
nutritional supportg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Record PN prescription 
and adjust nutritional 
support as neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess follow-up period 
escape criteriad
Xi
Xi
Xi
X
Dispense IPd
X
X
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Table 2:
Study Schedule: Visits 13-28
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 
(EOT/ET)
Week 
25
Week 
26
Week 
27
Week 
28 
(EOS)a
Visit number
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit type
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Study day
91
98
105
112
119
126
133
140
147
154
161
168
175
182
189
196
±window (days)
±3
±3
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
EN=enteral nutrition; EOS=end of study; EOT=end of treatment; ET=early termination; GLP-2=glucagon-like peptide 2; INR=international normalized ratio; IP=investigational 
product; PN=parenteral nutrition; PT=prothrombin time; UGI/SBFT=upper GI series with small bowel follow-through
a At EOS subjects may enroll in an extension study if that study is open to enrollment at the time of the SHP633-301 EOS; if subjects require treatment before the end of the 
4-week follow-up they may enter the extension study immediately. 
b Safety labs at telephone visits will be collected at the discretion of the investigator. For all subjects in the teduglutide treatment arm, PT and INR are tested if clinically indicated.
c Urinalysis will consist of urine sodium and specific gravity. 
d Applicable to the teduglutide treatment arm only. 
e Samples for antibody analysis will be drawn at the EOS (Week 28) visit.
f Blood samples for native GLP-2 should be collected postprandial. Blood samples drawn while subjects are receiving teduglutide should be drawn at least 14 hours after the 
previous dose. Native GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at investigator discretion based on weekly/monthly 
total volume. 
g Intake diaries will collect actual PN volume and hours per day and EN volume and calories. Intake diaries should be completed daily throughout the study. Urine and stool output 
should be recorded in the output diary over a 48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PN prescription. 
h Parenteral support adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment 
provided in Appendix 2.
i If a subject treated with teduglutide meets the escape criteria, the assessments scheduled for the EOS visit should be conducted.
Note: (X) denotes optional assessments.
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BACKGROUND INFORMATION
1.
1.1
Short Bowel Syndrome
Short bowel syndrome (SBS) is a rare disorder resulting from congenital abnormalities or severe 
intestinal diseases that result in major surgical resections of the small intestine (O'Keefe et al., 
2006). Unlike the adult population, the majority of cases of SBS in pediatric subjects are due to 
congenital anomalies or catastrophic events that occur during infancy such as necrotizing 
enterocolitis, gastroschisis, intestinal atresia, midgut volvulus, or long-segment Hirschsprung 
disease (Beattie et al., 2010; Goulet and Ruemmele, 2006). A Canadian population-based study 
in neonates estimates an overall incidence of SBS to be 24.5 cases per 100,000 live births (Wales 
et al., 2004). 
The small intestine is capable of remarkable adaptation, but excessive loss of absorptive surface 
area or specialized functions can lead to dependence on parenteral nutrition (PN)1 fluids 
(O'Keefe et al., 2006). Although PN is life-sustaining in intestinal failure, it is associated with 
serious complications, including liver disease, life-threatening catheter-related blood stream 
infections, and central venous thrombosis (Beattie et al., 2010; Goulet and Ruemmele, 2006). 
Dependence on PN is also associated with reduced quality of life in both patients and caregivers 
and has an extremely high cost of care (Huisman-de Waal et al., 2007). About 30% of infants 
with SBS become independent of PN requirements within 12 months of the initial insult, and an 
additional 10% wean off PN within 24 months. After this time, linear intestinal growth slows. It 
is estimated that 42% to 86% of pediatric patients with SBS are able to become independent of 
PN within 1 to 3 years (Gonzalez-Hernandez et al., 2017; Khan et al., 2015; Squires et al., 2012). 
Nevertheless, despite optimal medical management, some children remain dependent on PN for 
many years (Squires et al., 2012). Infants who have less than 10% of expected small intestinal 
length for their gestational age have a low likelihood of ever achieving enteral autonomy (ie, 
independence from parenteral support). Providing the maximum tolerated amount of enteral 
nutrition (EN) has been the primary strategy to promote enteral adaptation (Spencer et al., 2005). 
Accelerating the adaptive process and achieving enteral autonomy is an urgent goal for all 
patients with SBS who are dependent on PN (Khan et al., 2015; Squires et al., 2012). The 
adaptive process is in part controlled by glucagon-like peptide 2 (GLP-2), a 33 amino acid 
peptide hormone secreted from L-type enteroendocrine cells in the terminal ileum and colon in 
response to luminal nutrients and bile acids (Martin et al., 2006). The post-prandial plasma 
concentration of GLP-2 in infants with SBS correlates with length of the remaining small 
intestine (Sigalet et al., 2004). Infants who lack terminal ileum may have impaired adaptation 
due to inadequate production of GLP-2.
                                                
1 For the purpose of the study the terms parenteral support (PS) and parenteral nutrition (PN) are used 
interchangeably.
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1.2
Teduglutide
Teduglutide is a novel, recombinant analog of naturally occurring human GLP-2 that regulates 
the functional and structural integrity of the cells lining the gastrointestinal (GI) tract. 
Teduglutide is a 33-amino acid peptide that differs from native GLP-2 in the substitution of 
glycine for alanine at the second position at the N-terminus. As a result, teduglutide demonstrates 
resistance to degradation by dipeptidyl peptidase 4 (DPP-4) and therefore maintains a longer 
elimination half-life (t1/2), approximately 2 hours in healthy adult subjects, 1.3 hours in adult 
SBS subjects, and 0.22 hours in pediatric SBS subjects, compared to the native peptide, which 
has a t1/2 of approximately 7 minutes. Teduglutide has been shown in animal studies and 
previous human clinical trials to increase villus height and crypt depth in the intestinal 
epithelium, thereby increasing the absorptive surface area of the intestines (Tappenden et al., 
2013; Thymann et al., 2014). 
A Phase 3 study, TED-C13-003, has been completed in pediatric SBS subjects. In this study, 
teduglutide was administered to 3 cohorts of pediatric subjects from ages 1-17 years. 
Thirty-seven pediatric subjects received teduglutide at doses of 0.0125, 0.025, or 0.05 mg/kg/day 
for 12 weeks. Five additional pediatric subjects were enrolled in an observational standard of 
care (SOC) cohort. There were clear dose-dependent effects of teduglutide seen at the 0.025 and 
0.05 mg/kg/day doses compared to SOC and the 0.0125 mg/kg/day dose. In the 0.025 mg/kg/day 
cohort there was a reduction in PN volume at Week 12 of 37%, including complete 
independence from PN support in 1 subject, and a reduction of 3.94 hours per day infusion time. 
In the 0.05 mg/kg/day cohort there was a reduction in PN volume at Week 12 of 39%, including 
complete independence from PN support in 3 subjects, and a reduction of 4.18 hours per day 
infusion time. Teduglutide was generally safe and well tolerated by pediatric subjects in 
all dosing cohorts. There were no deaths during the study and no treatment-emergent 
serious adverse events (SAEs) related to teduglutide were reported. No discontinuations from 
study were due to adverse events (AEs). Additional studies in pediatric patients with SBS are
ongoing.
TED-C14-006 is a recently completed study of pediatric subjects through 17 years which 
included 2 treatment arms: a teduglutide treatment arm and a SOC treatment arm. Subjects in 
both arms participated in a 2-week minimum screening period, a 24-week treatment period, and a
4-week follow-up period. During the screening period, subjects chose into which arm to enroll. 
During the 24-week treatment period, subjects in the SOC treatment arm received standard 
medical therapy for SBS; while those in the teduglutide treatment arm received daily
subcutaneous (SC) injections of teduglutide (study drug) in addition to standard medical therapy. 
The subjects enrolling in the teduglutide treatment arm were randomized 1:1 in a double-blinded 
manner into 2 parallel dose groups: 0.025 mg/kg/day or 0.05 mg/kg/day of teduglutide 
administered subcutaneously for 24 weeks. Compared to the SOC, treatment of pediatric subjects
with SBS with teduglutide resulted in clinically meaningful reductions in PN volume, calories, 
days per week, and hours per day. A total 10% of subjects who received teduglutide achieved 
enteral autonomy within 24 weeks despite prior dependence on PN for several years. Teduglutide 
treatment also resulted in increases in EN volume and caloric intake as well as plasma citrulline. 
Although the differences in efficacy between the 0.025 and 0.05 mg/kg dose groups were small, 
a consistently greater effect was seen in the 0.05 mg/kg dose in all efficacy parameters. 
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The pharmacokinetic (PK) properties were well characterized in this population and were 
consistent with the prior 12 week pediatric study. Teduglutide was generally well tolerated by 
pediatric subjects with SBS. The safety profile was favorable and consistent with the prior 
pediatric study, the underlying disease, and previous experience with teduglutide in adult 
subjects with SBS.
Teduglutide (0.05 mg/kg/day) is currently approved for the treatment of adult patients with SBS 
in >30 countries. On 29 Jun 2016, the European Commission granted an extension of the Market 
Authorization for teduglutide for the treatment of patients aged 1 year and above with SBS. 
Always refer to the latest version of the investigator’s brochure for the overall risk/benefit 
assessment and the most accurate and current information regarding the drug metabolism, 
pharmacokinetics, efficacy and safety of teduglutide (SHP633).
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OBJECTIVES
2.
2.1
Rationale for the Study 
There is no approved pharmacological therapy to improve intestinal adaptation in infants with 
SBS who are dependent on parenteral support. This study will evaluate whether teduglutide is 
safe and effective in this patient population. 
2.2
Study Objectives
The objectives of this study are to evaluate the safety, efficacy/pharmacodynamics and 
pharmacokinetics (PK) of teduglutide treatment in infants with SBS dependent on parenteral 
support.
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STUDY DESIGN
3.
3.1
Study Design and Flow Chart
This is a randomized, multicenter, open-label study, consisting of a 2 to 4-week screening period, 
a 24-week treatment period and a 4-week follow-up period. A schematic representation of the 
study design is presented in Figure 1.
Figure 1:
Study Schematic
*At EOS all subjects regardless of treatment arm may enroll in an extension study if that study is open to enrollment at the time 
of the SHP633-301 EOS that will capture long-term safety data and provide the opportunity for additional teduglutide treatment. 
The follow-up period for subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed immediately 
to the EOS if at least one “escape” criteria is met.
3.1.1
Screening Period 
Study eligibility will be confirmed during the screening period (minimum: 2 weeks; maximum: 
4 weeks). The schedule of evaluations to be conducted during the Screening Period can be found 
in Table 1.
3.1.2
Treatment Period
At the baseline visit (Week 0), subjects will randomized 1:1 to the teduglutide or SOC treatment 
arm. Randomization will be stratified according to the presence of a small bowel ostomy (eg, end 
jejunostomy or ileostomy). During the 24-week treatment period, subjects in the SOC treatment 
arm will receive standard medical therapy for SBS, while those in the teduglutide arm will 
receive 0.05 mg/kg by SC injection once daily in addition to standard medical therapy. 
Extension 
study* 
1
24
1
3
5
7
9
12
16
20
28
2 to 4
Weeks
Screening
Teduglutide 0.05 mg/kg SC once daily for 24 weeks
Site Visit 
Telephone Visit
Standard of care for 24 weeks
Baseline: treatment 
randomization
0
24
3
5
7
9
12
16
20
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Subjects in both arms will follow the same visit schedule and assessments. Subjects will be 
monitored weekly with phone or clinic visits.
Clinic visits will occur at Weeks 1, 3, 5, 7, 9, 12, 16, 20, 24, and 28. At all site visits and 
telephone contacts, safety will be monitored and nutritional support will be reviewed and 
adjusted as needed. To maintain consistency across centers, guidance and training will be 
provided to help sites follow the nutritional support adjustment guidelines (developed with SBS 
expert input and provided in the protocol) related to decisions for PN reduction and advances in 
enteral feeds based on weight gain, urine and stool output, and clinical stability (Appendix 2). 
Deviations from the guidelines are not considered a protocol deviation.
Sparse PK sampling, in the teduglutide treatment arm only, will occur at baseline (predose and 
1 hour±10 minutes and 4 hours±10 minutes postdose) and at Week 7 (2 hours±10 minutes 
postdose).
The schedule of evaluations for the Treatment Period can be found in Table 1 (Visits -1 to 12) 
and Table 2 (Visits 13 to 28). 
3.1.3
Follow-up Period
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up 
period until the end of study (Week 28/EOS) during which time subjects will receive standard 
medical therapy, but no investigational product (IP) will be administered. At EOS, all subjects 
regardless of treatment arm may enroll in an extension study if that study is open to enrollment at 
the time of the SHP633-301 EOS that will capture long-term safety data and provide the 
opportunity for additional teduglutide treatment. The follow-up period for subjects in the 
teduglutide treatment arm may be interrupted and the subjects may proceed immediately to the 
EOS visit if at least one of the following “escape” criteria is met:
1. Increasing PN requirements following discontinuation of teduglutide.
2. Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation. 
4. Severe diarrhea related to teduglutide discontinuation.
The schedule of evaluations for the Follow-up Period can be found in Table 2 (Visits 13 to 28).
3.2
Study Duration
The study consists of a 2 to 4-week screening period, a 24-week treatment period and a 4-week 
follow-up period. The maximum duration of participation for each subject is 32 weeks.
Study completion is defined as the last subject, last visit. This is the visit date at which the last 
subject on the study has his or her last follow-up visit on the study (whether during the 24-week 
treatment period or the 4-week follow-up period).
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3.3
Sites and Regions
This study is planned to be conducted at approximately 5 to 10 sites globally.
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STUDY POPULATION
4.
At least 10 subjects will be randomized: at least 5 subjects in a teduglutide treatment arm and at 
least 5 subjects in an SOC comparator arm.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1. Informed consent by the parent or legal guardian. 
2. Male or female infant 4 to 12 months corrected gestational age at screening.
3. Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and 
baseline.
4. Short bowel syndrome with dependence on parenteral support to provide at least 50% of 
fluid or caloric needs.
5. Stable PN requirements for at least 1 month prior to screening, defined as a ≤10% change 
in the weight-normalized parenteral total fluid and caloric intake, despite attempts to 
wean PN, notwithstanding transient instability for events such as sepsis or interruption of 
central venous access.
6. This criteria was deleted.
7. Parent or legal guardian understands and is willing and able to fully adhere to study 
requirements as defined in this protocol.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1. Previous treatment with teduglutide.
2. Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus 
inclusion disease, etc.
3. Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, 
active gastroschisis-related dysmotility, that is the primary contributing factor to feeding 
intolerance and inability to reduce parenteral support, prior to screening. Dysmotility is 
defined as severe if it is expected to limit the advancement of enteral feeding.
4. Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral 
aversion in the absence of a feeding tube.
5. Intestinal obstruction or clinically significant intestinal stenosis.
6. Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or 
major intestinal resection or anastomosis, within 3 months prior to screening or planned 
during the study period.
7. Unstable cardiac disease.
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8. Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
9. Biliary obstruction, stenosis, or malformation. 
10. Clinically significant pancreatic disease. 
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following 
parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b. Platelet count <100×10^3/µL due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d. Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 
2 week period.
13. More than 3 serious complications of intestinal failure (eg, catheter-associated 
bloodstream infections, interruption of nutrition due to feeding intolerance, 
catheter-associated thrombosis, severe fluid or electrolyte disturbances) within 1 month 
prior to or during screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile 
polyposis or Beckwith-Wiedemann syndrome, or first degree relative with early onset of 
gastrointestinal cancer (including hepatobiliary and pancreatic cancers). 
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 
(GLP-2); insulin-like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs 
of these hormones; or glutamine. 
16. Participation in a clinical study using an experimental drug within 3 months or 
5.5 half-lives of the experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, 
closely-related compounds, or any of the stated ingredients. 
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts 
the subject at any undue risk, prevents completion of the study, or interferes with analysis 
of the study results.
4.3
Reproductive Potential 
Not applicable; this study will enroll infants.
4.4
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator should 
discuss withdrawal of a subject from investigational product with the medical monitor as soon as 
possible.
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If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 24/EOT/early termination are to be performed as completely as possible. Whenever 
possible, all discontinued subjects should also undergo the protocol-specified 4-week Follow-up 
Period. Comments (spontaneous or elicited) or complaints pertaining to IP discontinuation made 
by the subject must be recorded in the source documents. The reason for discontinuation, the 
date and the total amount of investigational product administered must be recorded in the 
electronic case report form (eCRF) and source documents.
Subjects who discontinue will not be replaced. 
4.4.1
Reasons for Discontinuation
The reason(s) for permanent discontinuation of treatment and/or withdrawal from the study must 
be determined by the investigator, and recorded in the subject’s medical record and in the eCRF. 
If a subject is withdrawn for more than 1 reason, each reason should be documented in the source 
document, and the most clinically relevant reason should be entered in the eCRF.
Reasons for discontinuation include, but are not limited to:

Adverse event

Death

Lost to follow-up

Physician decision

Protocol deviation

Study terminated by sponsor

Withdrawal by parent/guardian

Lack of efficacy

Other
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact the parent(s)/guardian(s) of any 
subject lost to follow-up at any time point prior to the last scheduled contact (office visit or 
telephone contact). At least 1 of these documented attempts must include a written 
communication sent to the subject’s last known address via courier or mail (with an 
acknowledgement of receipt request) asking that they return to the site for final safety 
evaluations and return any unused investigational product.
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PRIOR AND CONCOMITANT TREATMENT
5.
5.1
Prior Medications and Procedures
Prior treatment includes all treatment and procedures (including but not limited to prescription 
treatments, herbal treatments, vitamins, non-pharmacological treatment, as appropriate) received 
within 14 days prior to the screening visit (Visit -1) (or pharmacokinetic equivalent of 5 half 
lives, whichever is longer, must be recorded on the appropriate eCRF page.
5.2
Concomitant Medications and Procedures
The administration of all medications including concomitant medications (including prescription 
and nonprescription medications, dietary and nutritional supplements, and vitamins) and PN 
must be recorded from the first dose of investigational product and for the duration of the study 
in the appropriate sections of the eCRF. Any diagnostic, surgical or other therapeutic treatments 
received by a subject during the course of the study will also be recorded on the eCRF.
The mechanism of action of teduglutide may increase enteral absorption of oral drugs (eg, drugs 
used for management of SBS such as motility medication, opioids, psychotropics, 
metronidazole), so consideration should be given to modifying concomitant enteral medication 
regimens. Titration of concomitant enteral medications should be considered when drugs, 
especially those with a narrow therapeutic index (eg, warfarin, digoxin, psychotropics) are given.
5.3
Permitted Treatment
Standard medical therapy for SBS should be continued.
5.4
Prohibited Treatment
The following medications are prohibited during teduglutide treatment and within the provided 
timeframe prior to the pretreatment visit (Table 3):
Table 3:
Prohibited Treatment
Prior Therapy
Time Restriction Prior to 
the Pretreatment Visit
Teduglutide
Any
GLP-2, human growth hormone, or analogs of these hormones
6 months
Octreotide, GLP-1 analogs, and enteral glutamine
30 days
GLP=glucagon-like peptide
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INVESTIGATIONAL PRODUCT
6.
6.1
Identity of Investigational Product
The SOC treatment arm will receive standard medical therapy for SBS; while those in the 
teduglutide arm will receive 0.05 mg/kg SC once daily in addition to standard medical therapy.
The investigational product is teduglutide, which will be provided in sterile, single-use 3 mL 
vials containing 1.25 mg teduglutide as a white lyophilized powder to be reconstituted before use 
with 0.5 mL sterile water for injection. In addition to the active ingredient (teduglutide), each 
vial of teduglutide contains L-histidine, mannitol, monobasic sodium phosphate monohydrate, 
and dibasic sodium phosphate as excipients. Additional information is provided in the current 
investigator’s brochure.
6.2
Administration of Investigational Product
6.2.1
Interactive Response Technology for Investigational Product Management
All investigative study sites will be initially provided with sufficient investigational product to 
randomly assign a subject into the study (for either of the proposed treatment groups). 
Randomization will occur through an interactive response system. Random assignment of a 
subject will trigger replacement supplies for that investigative study site.
6.2.2
Allocation of Subjects to Treatment
Subjects will be randomized 1:1 to the teduglutide or SOC treatment arm. Randomization will be 
stratified according to the presence of a small bowel ostomy (eg, end jejunostomy or ileostomy). 
The actual treatment given to individual subjects is determined by a randomization schedule.
Subject numbers are assigned to all subjects as they consent to take part in the study. Within each 
site (numbered uniquely within a protocol), the subject number is assigned to subjects according 
to the sequence of presentation for study participation. 
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined.
6.2.3
Dosing
The initial dose will be calculated based on body weight measured at baseline (Visit 0), and 
adjusted as needed, based on body weight measured at Week 12. No other adjustments to dose 
will be made during the teduglutide treatment period, unless discussed with the sponsor’s 
medical monitor. 
Following reconstitution, teduglutide will be administered by SC injection once daily (QD) into 
1 of the 4 quadrants of the abdomen (in subjects without a stoma) or into either the thigh or arm. 
For subjects with a stoma, the quadrant of the abdomen containing the stoma should not be used. 
Teduglutide should be used as soon as possible after reconstitution, but no more than 3 hours 
later.
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The subject should be dosed at approximately the same time each day. Consecutive doses should 
be separated by at least 12 hours. Each day, the injection site should be alternated. 
Any subject who achieves complete independence from PN support at any time during the 
treatment period will continue to receive teduglutide treatment.
The first SC injection in teduglutide-naïve subjects should be administered under the supervision 
of the investigator or designee and the subject observed for hypersensitivity reactions for at least 
4 hours during their initial dosing visit. The site of administration (arm, thigh, and abdomen) of 
the first teduglutide dose must be specified and recorded in the eCRF. 
Detailed instructions for reconstitution and injection of the investigational product can be found 
in the Instructions for Use. 
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up 
period until the end of study (Week 28/EOS) during which time subjects will receive standard 
medical therapy, but no investigational product will be administered. At EOS all subjects 
regardless of treatment arm may enroll in an extension study if that study is open to enrollment at 
the time of the SHP633-301 EOS that will capture long-term safety data and provide the 
opportunity for additional teduglutide treatment. The follow-up period for subjects in the 
teduglutide treatment arm may be interrupted and the subjects may proceed immediately to the 
EOS if at least one of the following “escape” criteria is met:
1. Increasing PN requirements following teduglutide discontinuation.
2. Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation. 
4. Severe diarrhea related to teduglutide discontinuation.
6.2.4
Unblinding the Treatment Assignment
Not applicable for this open-label study.
6.2.5
Dose Selection Rationale
Teduglutide is approved for adult and pediatric use in the EU at a dose of 0.05 mg/kg SC once 
daily. A completed 12-week dose finding study (TED-C13-003) demonstrated that teduglutide 
dosing at 0.025 and 0.05 mg/kg/day was associated with a favorable benefit-risk profile most 
meaningful at the 0.05 mg/kg/day dose (Carter et al., 2017). 
Population pharmacokinetic modeling and simulations were conducted  using data from 8 adult
clinical studies including adult Phase 1 studies and Phases 2/3 studies as well as 
study TED-C13-003 and suggested that the same adult dose (0.05mg/kg) be used in pediatric 
subjects (aged between 1.67-14.7 years) (Marier et al., 2017).
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To support dosing in the current age group, further PK simulation was conducted based on the 
population PK model previously established and a virtual population of 1000 pediatric patients 
created based on Centers for Disease Control (CDC) growth charts in the target age group (4 to 
12 months) and taking into consideration body weights of pediatric patients with SBS enrolled in 
study TED-C13-003 and TED-C14-006 (approximately 15% lower than healthy subjects in the 
same age group). The model was customized by including a maturation function on clearance 
(CL/F) as a function of estimated glomerular filtration rate. Monte Carlo simulations for all age 
groups were performed according to the SC dosing regimens of 0.0125, 0.025 and 0.05 mg/kg 
every 24 hours. Rich concentration-time profiles were simulated with the customized population 
PK model to derive the exposure metrics area under the concentration curve at steady state 
(AUCss) and maximum concentration at steady state (Cmax,ss). Exposure parameters in infant 
patients were compared to those derived in pediatric (1-17 years) and adult (≥18 years) patients 
with SBS using a Bayesian approach. Based on the clinical observations, Cmax is considered to be 
associated with clinical responses. Following 0.05 mg/kg daily SC administration, the median 
Cmax,ss of teduglutide in neonate patients (24.9 ng/mL) was within 20% of that observed in the 
2 to 4 and 4 to 6 years age groups (26.9 and 29.4 ng/mL, respectively); and approximately 
~28% lower than that in adult patients with SBS. The median Cmax,ss of teduglutide in infant 
patients 4 to 12 months (41.9 ng/mL) following 0.05 mg/kg once daily was within 8% of that 
previously observed in adult patients with SBS (39.0 ng/mL, refer to the attached Simulation 
Report). In addition, individual simulated Cmax,ss values of teduglutide in infant patients 4 to 
12 months (25.6 to 65.1 ng/mL) were contained within the range of Cmax,ss previously observed 
in pediatric patients 1 to 17 years (20.7 to 77.4 ng/mL). The clinical package in conjunction with 
Cmax was considered to support teduglutide dose selection since AUCss was previously shown not 
to correlate with efficacy. Individual simulated AUCss values of teduglutide in infant patients 
4 to 12 months (66.9 to 160 ng.h/mL) following 0.05 mg/kg once daily were contained within 
the range of AUCss values previously observed in pediatric patients 1 to 17 years (63.5 to 
421 ng.h/mL). Based on the totality of clinical data, 0.05 mg/kg once daily is expected to provide 
comparable Cmax concentrations in infants as compared to pediatric patients with SBS and was 
recommended as an evaluation dosing regimen in Study SHP633-301. 
6.3
Labeling, Packaging, and Storage
6.3.1
Labeling
The investigational product will be packaged, labeled, and shipped to the study site by the 
sponsor or designee. Kits containing 7 vials of investigational product will be provided for this 
study. The vials will be labeled in accordance with applicable regulatory requirements. 
Ancillary kits, containing supplies needed for the reconstitution and administration of the 
investigational product will also be provided and labeled in accordance with the applicable 
regulatory requirements. 
All investigational product used in this study will be manufactured, tested, labeled, and released 
according to current legal requirements and Good Manufacturing Practice.
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6.3.2
Storage and Handling
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.
Investigational product must be kept in a locked area with access restricted to specific study 
personnel. Investigational product will be stored refrigerated at a temperature between 2-8°C 
(35.6-46.4°F) until dispensed to a subject. Once dispensed to a subject, the IP can be stored 
refrigerated or up to a controlled room temperature (acceptable range of 2-25°C, or 35.6-77°F). 
Parent/legal guardian will be instructed to keep the subject’s IP and sterile water diluent at 
controlled room temperature. If there are concerns that the controlled room temperature cannot 
be maintained, the IP may be refrigerated. The IP is for single use only, and should be used 
within 3 hours following reconstitution.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (ie, certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
Investigational products are distributed by the pharmacy or nominated member of the study 
team. The pharmacist/nominated team member will enter the unique subject identifier on the 
investigational product bottle/carton labels, as they are distributed.
6.4
Drug Accountability
Investigational product will not be dispatched to the study site until the sponsor or 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 investigational product 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. Kits will be shipped to the site once the subject 
is screened.
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Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for dispensing investigational product. Where 
permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is adequately 
trained in the protocol and who works under the direct supervision of the investigator. This 
delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee will dispense the investigational product only to subjects 
included in this study following the procedures set out in the study protocol. Investigational 
product kits will be dispensed at each of the applicable study visits at which the subject is 
required to be at the clinic. Each investigational product kit is sufficient for a treatment period of 
1 week and enough kits will be supplied to cover the period until the next planned study visit. 
Additional study kits will be provided as necessary.
Each subject will be given the investigational product according to the protocol. The investigator 
is to keep a current record of the inventory and dispensing of all clinical supplies. All dispensed 
medication will be documented on the eCRFs and/or other investigational product record. The 
investigator is responsible for assuring the retrieval of all study supplies from subjects.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.
At the end of the study, or as instructed by the sponsor, all unused stock, subject returned 
investigational product, and empty/used investigational product packaging are to be sent to the 
sponsor or designee. The investigator is responsible for assuring the retrieval of all study 
supplies from subjects.
Returned investigational product must be counted and verified by clinical site personnel and the 
sponsor (or study monitor). Shipment return forms, when used, must be signed prior to shipment 
from the site. Contact the sponsor for authorization to return any investigational product prior to 
shipment. Shipment of all returned investigational product must comply with local, state, and 
national laws. 
Please see the Pharmacy Manual for additional information.
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6.5
Subject Compliance
The parent(s)/guardian(s) of subjects must be instructed to bring unused investigational product 
and empty/used investigational product packaging to every visit. Drug accountability must be 
assessed and recorded at the container/packaging level for unused investigational product that is 
contained within the original tamper-evident sealed container (eg, bottles, trays, vials) or at the 
individual count level for opened containers/packaging. 
Subject compliance will be checked by site personnel at every visit by reviewing the subject 
diaries and asking the subject or the subject’s parent or legally-authorized representative if they 
have administered the investigational product according to instructions. If any doses have been 
missed, the reason for missed dose should be documented in the subject’s source documentation 
including, as applicable, the eCRF.
The investigator is responsible for contacting the sponsor or designee when the subject’s daily 
investigational product dosing regimen is interrupted. Attempts should be made to contact the 
sponsor or designee prior to dose interruption. Reasons for dosage interruption may include but 
are not limited to hospitalization and AEs, a lapse in investigational product delivery, etc.
Subjects who have received 80% of the planned doses administered will be assessed as being 
compliant with the study protocol.
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STUDY PROCEDURES
7.
7.1
Study Schedule
Detailed study procedures and assessments to be performed for subjects throughout the study are 
outlined in the study schedules (Table 1 and Table 2) and must be referred to in conjunction with 
the instructions provided in this section. 
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 24/EOT are to be performed as completely as possible. Whenever possible, all 
discontinued subjects should also undergo the protocol-specified 4-week Follow-up Period. 
7.1.1
Screening
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent from the 
parent(s)/guardian(s) of the subject. The screening visit assessments and procedures, beginning 
with informed consent, will be performed as outlined in Table 1. 
Subjects will be designated as a screen failure if they fail to meet all inclusion criteria and/or 
meet any of the exclusion criteria. Screen failures will not be administered investigational 
product.
At the discretion of the investigator, subjects who fail screening may be rescreened one time with 
prior sponsor approval. In the event of rescreening, the subject should be reconsented, a new 
subject number assigned, and all screening procedures (except UGI/SBFT if performed within 
2 months prior to rescreening) should be repeated.
7.1.2
Treatment Period
The randomized Treatment Period will comprise Weeks 1 to 24, during which all assessments 
will be performed as outlined in Table 1 and Table 2.
7.1.3
Follow-up Period
The Follow-up Period will comprise Weeks 25 to 28, during which all assessments will be 
performed as outlined in Table 2.
7.2
Study Evaluations and Procedures
7.2.1
Demographics and Other Baseline Characteristics
Demographics and Medical History
Demographic and/or other baseline variables obtained at the screening and/or baseline visits are 
listed below. Abnormal findings of clinical significance (if any) will be recorded as past medical 
history.

Demography (including age, gestational age, sex, and race)
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
Medical history (including surgical history)

SBS history, including remnant anatomy
Upper Gastrointestinal Series with Small Bowel Follow-through
An upper GI contrast series with small bowel follow-through will be performed on all subjects 
during the screening period if one has not been done since the subject's last GI surgery. 
It is acceptable to only enroll subjects who have already had an upper GI series with small bowel 
follow-through performed since the subject’s most recent surgery. 
7.2.2
Efficacy Assessments
Subject Diaries
All available diary data will be reviewed by the investigator or their designee at each clinic and 
telephone visit to assess clinical status and opportunity for PN reduction and advance in feeds. 
Parenteral support adjustments should be made after review of the intake and output diaries and 
the safety lab data according to the guidance for nutrition support adjustment provided in 
Appendix 2.
Intake Diary
Intake diaries will be used to collect and evaluate each subject’s nutritional support. The 
parent/legally authorized representative/study site staff will complete the appropriate fields of the 
PN and EN sections of the intake diary daily throughout the study.
The following data will be captured in the intake diaries:

Parenteral support volume and infusion duration

Enteral nutrition (formula) including volume and calories
Site personnel will determine the actual PN and EN daily calories based on diary entries.
Output Diary
Urine and stool output should be recorded in the output diary over a 48-hour period of nutritional 
stability before every clinic visit; in addition, output should be recorded for subjects within 
1 week of implementing a change in the PN prescription.
Urine data:

Measure and record the weight of all urine-only diapers. Urine volume will be calculated 
using the following formula: 1 g (scale weight)=1 mL or 1 cc

At the discretion of the investigator, the parent or legal guardian/study site staff may be 
asked to collect the first void after the daily PN infusion to measure specific gravity
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Stool data (includes diapers with mixed urine and stool):

Record the weight of diapers containing stool (including diapers with mixed urine and 
stool) as stool output and score the stool consistency (see Output diary). Stool volume 
will be calculated using the formula: 1 g (scale weight)=1 mL or 1 cc
All ostomy output volume should be recorded. 
Prescribed Parenteral Nutrition
The prescribed PN weekly total volume and days per week will be recorded. Changes in PN 
prescription that reflect changes in the subject's intestinal absorption are recorded.  
Temporary adjustments to PN that last less than 72 hours should be recorded as concomitant 
medications, not a PN adjustments.  Examples include fluid resuscitation during treatment 
of sepsis or acute gastroenteritis, and modification of PS due to interruption of entral venous 
access.  
Parenteral nutrition prescriptions that last more than 72 hours should be recorded as PN 
adjustments.  Examples include recurrent replacement of fluid losses, titration of PN due to 
changes in intestinal absorptive function, and discontinuation of PN due to achievement of 
enteral autonomy.
Native GLP-2
Blood samples for native GLP-2 should be collected postprandial. Blood samples while subjects 
are receiving teduglutide should be drawn at least 14 hours after the previous dose. Native 
GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject 
weight or at investigator discretion based on weekly/monthly total volume. 
7.2.3
Safety Assessments
Laboratory Evaluations
Safety laboratory tests to be performed at site visits consist of clinical chemistry, hematology, 
and urinalysis and will be performed as outlined in the study plan (Table 1 and Table 2). 
Scheduled laboratory testing will be processed by a central lab. All laboratory assays will be 
performed according to the central laboratory’s normal procedures. Reference ranges are to be 
supplied by the laboratory. The investigator should assess out-of-range clinical laboratory values 
for clinical significance, indicating if the value(s) is/are not clinically significant or clinically 
significant. Abnormal clinical laboratory values, which are unexpected or not explained by the 
subject’s clinical condition, may, at the discretion of the investigator or sponsor, be repeated as 
soon as possible until confirmed, explained, or resolved.
During the Treatment Period, subjects will also have safety labs within approximately 5 to7 days 
after a PN adjustment. Safety labs performed after PN adjustment and between site visits 
will consist of clinical chemistry and urinalysis and may be processed by the central 
laboratory or a local laboratory. 
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Local lab results are not required to be entered in the eCRFs; however, if the local lab results 
indicate any new clinically significant changes, they must be reported as an adverse event (see 
Section 8). Urine specimen collection should be attempted as part of the safety labs, but lack of 
urinalysis will not constitute a protocol deviation.
At baseline, blood samples for safety labs and PK will be separated by 1 day. The predose 
sample will not be collected from subjects who weigh <7 kg.
Safety labs at telephone visits will be collected at the discretion of the investigator. 
Hematology will not be collected at Week 1 or at telephone visits. Hematology will not be 
collected at screening for subjects <7 kg.
For all subjects, prothrombin time (PT) and international normalized ratio (INR), tested at 
screening, will be repeated if clinically indicated.
New clinically significant labs should be reported as AEs.
Close Monitoring Criteria Related To Liver Test Abnormalities:  
The investigator should contact the medical monitor within 24 hours of their awareness if the 
subject develops any of the following changes in laboratory parameters:

ALT or AST >5x ULN and >2x baseline value

Total or direct bilirubin that is >2x baseline value or an absolute increase of ≥3 mg/dL 
(51.3 µmol/L)
If such changes are observed, the labs should be repeated along with an INR, and an inquiry 
should be made as to the presence of clinical symptoms consistent with new liver injury. The 
subject should be followed closely to determine the trajectory of the laboratory abnormalities and 
appropriate evaluations should be made, such as abdominal ultrasound with Doppler imaging to 
exclude vascular causes and biliary obstruction, consideration of sepsis, liver hypoperfusion, 
acute viral hepatitis (such as hepatitis A, EBV, or HSV), exposure to hepatotoxic medications, 
mitochondrial hepatopathy, or metabolic liver disease (such as hereditary fructose intolerance or 
arginosuccinate synthetase deficiency). Further evaluations can be performed at the discretion of 
the investigator in consultation with the Shire medical monitor.
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The following clinical laboratory assessments will be performed according to the study 
schedules:
Table 4:
List of Laboratory Tests
Biochemistry:

Albumin 

Alkaline phosphatase 

Alanine aminotransferase 

Amylase

Aspartate aminotransferase 

Bicarbonate

Bilirubin (total and indirect)

Blood urea nitrogen 

Calcium (total)

Chloride

Cholesterol

C-reactive proteinc

Creatinine

Estimated Glomerular Filtration Rate 
(Schwartz formula)

Gamma-glutamyl transferase 

Glucose

Lipase

Magnesium

Phosphorus

Potassium 

Sodium 

Triglycerides
Hematologya:

Hematocrit 

Hemoglobin 

Platelet count

Red blood cell count 

Red blood cell morphology, if needed

White blood cell count with differential
Coagulationb:

Prothrombin time

International normalized ratio
Urinalysis: 

Specific gravity  

Urine Sodium
a Hematology will not be collected at Week 1 or at telephone visits.  Hematology will not be collected at screening for subjects 
<7 kg.
b For all subjects, PT and INR will be tested at screening and repeated only if clinically indicated.
c C-reactive protein will not be collected at screening for all subjects and will not be collected at any visit for subjects <7 kg.
Antibodies to Teduglutide 
Blood samples will be drawn to test for antibodies to teduglutide. Samples will be taken before 
teduglutide administration at the screening visit (Visit -1) and at least 14 hours after the previous 
dose at Week 12 (Visit 12); samples may be drawn from a central line or peripheral access. One 
additional sample will be collected at the EOS 4 weeks after the EOT (ie, Week 28 or EOS). 
Volume of Blood
Efforts will be made to minimize the amount of blood drawn from all pediatric subjects 
participating in this study. The volumes of blood to be drawn from each subject will vary 
depending on clinical status. Approximate volumes of blood to be drawn from each subject are 
shown in Table 5.
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Table 5:
Approximate Volume of Blood to be Drawn from Each Subject 
Assessment
Sample Volume 
(mL)
No. Samples for 
Subjects > 7kg
Total Volume 
(mL)
Subjects Receiving Teduglutide Treatment
Biochemistry (not including CRP)
1.1
12
13.2
CRPa
1.1
11
12.1
Hematologyb
1.2
11
13.2
Coagulation Parametersc
1.4
1
1.4
Antibodies
2.0
3
6.0
Pharmacokineticsd
2.0
4
8.0
Native GLP-2e
1.5
2
3
Total mL:
56.9
Subjects Receiving Standard of Care
Biochemistry (not including CRP)
1.1
12
13.2
CRPa
1.1
11
12.1
Hematologyb
1.2
11
13.2
Coagulation Parametersc
1.4
1
1.4
Native GLP-2 e
1.5
2
3.0
Total mL:
42.9
CRP=C-reactive protein; GLP=glucagon-like peptide; INR=international normalized ratio; PT=prothrombin time
a C-reactive will not be collected at screening for all subjects and will not be collected at any visit for subjects <7 kg.
b Hematology will not be collected at Week 1 or at telephone visits.  Hematology will not be collected at screening for subjects 
<7 kg.
c PT and INR tested at screening only, repeat while on study only if clinically indicated.
dAt baseline, safety labs and PK will be separated by 1 day.  Baseline: 3 timepoints; The predose sample will not be collected 
from subjects who weigh <7 kg. Week 7: 1 timepoint.
e Native GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at investigator 
discretion based on weekly/monthly total volume.
Note: The amount of blood to be drawn for each assessment is an estimate. Blood volume 
estimates do not include safety labs performed after PN adjustments.  
Physical Examinations, Vital Signs, Weight, Length, and Head Circumference
Physical examinations will be performed according to the study schedules (Table 1 and Table 2). 
Any new clinically significant findings noted during physical examinations should be recorded 
on the appropriate AE page of the eCRF.
Vital signs will be measured according to the study schedules. Measurements will 
include systolic and diastolic blood pressure (mmHg), pulse (beats per minute), and 
body temperature (°C/°F). Blood pressure should be determined by the appropriate size 
cuff (using the same method, the same leg, and in the supine position throughout the 
study, when possible). 
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Blood pressure measurements should be attempted as part of the vital signs, but lack of blood 
pressure results will not constitute a protocol deviation. New clinically significant vital sign 
abnormalities should be recorded on the appropriate AE page of the eCRF.
Body weight will also be recorded in the eCRF; subjects should be weighed on the same scale 
at each study visit. Length and head circumference will be measured at selected visits. A height 
z-score, weight Z-score, and weight/length ratio will be calculated by the sponsor using the 
site-provided height and weight data collected at each site visit.
7.2.4
Pharmacokinetic Assessments
Subjects will have blood samples taken for teduglutide PK analysis predose, and 
1 hour±10 minutes and 4 hours ±10 minutes postdose at baseline (Visit 0). At baseline, safety 
labs and PK will be separated by 1 day.  Subjects also will have blood samples taken for 
teduglutide PK analysis 2 hours ±10 minutes postdose at Week 7 (Visit 7) of the treatment 
period. Blood for PK sampling should be collected via peripheral IV or venipuncture, not from a 
central line. The site of teduglutide administration prior to PK blood draws (arm, thigh, 
abdomen) must be specified as well as the exact date and time of the sample. 
7.2.5
Health Economics and Outcomes Research
Hospitalizations
Each hospitalization that occurs during the study will be recorded, including date of admission, 
date of discharge, reasons for hospitalization, discharge diagnosis, and discharge status. 
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ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.3. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, or 
a symptom is more severe or prolonged than expected given the diagnosis, then symptom(s) 
should be listed individually. All AEs should be captured on the appropriate AE pages in the 
eCRF and in source documents. In addition to untoward AEs, unexpected benefits outside the 
investigational product indication should also be captured on the AE eCRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
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Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence
of the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of 
the investigational product is compelling and/or follows a known or 
suspected response pattern to that product, and the event cannot be 
explained by the subject’s medical condition, other therapies, or 
accident.
Not Related
The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident and no 
plausible temporal or biologic relationship exists between the 
investigational product and the event.
AEs that are related to IP that are not resolved at EOS will be followed until the event resolves or 
stabilizes, as judged by the investigator.
Laboratory values, vital signs, and clinical findings at the scheduled physical examinations must 
be reported as AEs if the investigator considers the finding to be a clinically significant change 
from the baseline.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the eCRF. Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved with Sequelae 

Recovering/Resolving

Unknown
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8.1.4
Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE. It is assumed that some of the infants participating in this study may be 
hospitalized for planned surgery(ies) that will occur during their participation in the study. Such 
pre-planned, elective surgeries, do not need to be reported as SAEs for this protocol. 
8.1.5
Clinical Laboratory and Other Safety Evaluations
An untoward change in the value of a clinical laboratory parameter, vital sign measure, or ECG 
assessment can represent an AE if the change is clinically relevant or if, during administration of 
investigational product, a shift of a parameter is observed from a value in the normative range to
a value that is outside the normal range and considered clinically significant, or a further waning 
of an already clinically significant value. Clinical significance is defined as any abnormal finding 
that results in further clinical investigation(s), treatment(s), or the diagnosis of new or 
progression of established condition. When evaluating such changes, the extent of deviation from 
the reference range, the duration until return to the reference range, either while continuing 
administration or after the end of administration with the investigational product, and the range 
of variation of the respective parameter within its reference range, should also be considered.
If, at the end of the treatment phase, there are abnormal clinical laboratory (such as hematology 
panel or clinical chemistry panel),  vital sign, or ECG values which were not present at the 
beginning of the pretreatment evaluation observed closest to the start of study treatment, further 
investigations should be performed until the values return to within the reference range or until a 
plausible explanation (eg, concomitant disease or expected disease evolution) is found for the 
abnormal values.
The investigator should assess, based on the above criteria and the clinical condition of a subject, 
whether a change in a clinical laboratory value, vital sign, or ECG parameter is clinically 
significant and represents an AE.
8.1.6
Pregnancy
Not applicable.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for 
a non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner 
that may be detrimental to the individual and/or society.
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
Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol).

Overdose – Administration of a dose greater than the allocated dose of the study 
medication or at a frequency greater than the dosing interval specified by the protocol.

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product. For studies, medication errors are reportable to the sponsor 
only as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error. 
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally-authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator brochure which the sponsor 
has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Drug Safety Department and the Shire Medical Monitor within 24 hours of the first awareness of 
the event. Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, 
misuse, overdose, or medication errors (see Section 8.1.7) unless they result in an SAE.
All Adverse Events of Special Interest, as defined in Section 8.3, must be reported by the 
investigator to the Shire Global Drug Safety Department and the Shire Medical Monitor within 
24 hours of the first awareness of the event even if the event does not fulfill seriousness criterion.
The investigator must complete, sign, and date the Shire Clinical Study Adverse Event Form for 
SAEs and Non-serious AEs as Required by Protocol, and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested). Fax or e-mail the completed form to the Shire Global Drug Safety 
Department. A copy of the completed Shire Clinical Study Adverse Event Form for Serious 
Adverse Events (SAEs) and Non-serious AEs as Required by Protocol (and any applicable 
follow-up reports) must also be sent to the Shire medical monitor or designee using the details 
specified in the emergency contact information section of the protocol.
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8.2.3
Serious Adverse Event Definition
A SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose: 

Results in death

Is life-threatening. Note: The term 'life-threatening' in the definition of "serious" refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for pre 
existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse. 
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to investigational product) are collected from the time the 
subject signs the informed consent until the defined follow-up period stated in Section 7.1.3, and 
must be reported to the Shire Global Drug Safety Department and the Shire Medical Monitor 
within 24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Drug Safety Department within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
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In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death. 
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting 
The Sponsor and/or Clinical Contract Research Organization (CRO) is responsible for notifying 
the relevant regulatory authorities, and US central Institutional Review Boards (IRBs)/EU central 
ethics committees (ECs), of related, unexpected SAEs.
In addition, the Clinical CRO is responsible for notifying active sites of all related, unexpected 
SAEs occurring during all interventional studies across the SHP633 program.
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
8.3
Adverse Events of Special Interest
An AE of special interest is an AE (serious or nonserious) of scientific and medical concern 
specific to the sponsor’s product or program and for which ongoing monitoring and immediate 
notification by the investigator to the sponsor is required.
The AEs of special interest that require expedited regulatory reporting include the following:

Growth of pre-existing polyps of the colon

Benign neoplasia of the GI tract including the hepatobiliary system

Tumor-promoting ability (eg, benign and/or malignant neoplasia of any kind, not limited 
to those of the GI or hepatobiliary system)
For AEs of special interest, the sponsor must be informed within 24 hours of first awareness as 
per the SAE notification instructions described in Section 8.2.2 even if the event does not fulfill 
the seriousness criteria.
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8.4
Dose Interruption Criteria
The investigator is responsible for contacting the sponsor/designee when the subject’s 
teduglutide dosing regimen is interrupted. The length of dose interruption, and whether 
teduglutide administration resumes or is permanently discontinued, depends on the clinical 
situation.
Investigational product must be interrupted if any of the following events occur:

An adverse event of special interest (see Section 8.3) 

Intestinal obstruction

Biliary obstruction

Pancreatic duct obstruction

Heart failure with severe fluid overload determined by the sponsor or investigator to 
be related to IP.
Investigational product must be permanently discontinued if any of the following events occur: 

Severe hypersensitivity, such as anaphylaxis, determined by the investigator to be 
related to IP. 

Any malignancy 
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DATA MANAGEMENT AND STATISTICAL METHODS
9.
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the eCRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered on the eCRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. Once a subject is randomized, it is expected that site 
personnel will complete the eCRF entry within approximately 3 business days of the subject’s 
visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the data management plan. Quality 
control and data validation procedures are applied to ensure the validity and accuracy of the 
clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Statistical Analysis Process
The study will be analyzed by the sponsor or designee. All statistical analyses will be performed 
using SAS® (SAS Institute, Cary, NC, US) version 9.3 or higher.
The statistical analysis plan (SAP) will provide the definitions and statistical methods  for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed.
9.4
Planned Interim Analysis, and Data Monitoring Committee 
Interim analysis will be conducted for regulatory submissions, as needed. Analyses will be 
descriptive in nature. No formal comparisons are planned, and no hypotheses will be formally 
tested.  Due to the open-label nature of this study, personnel involved in conducting the interim 
analyses will have access to treatment assignments. 
A data monitoring committee (DMC) will be involved in the management of this study. The 
DMC members will review the data approximately every 3 months according to the DMC 
Charter. The DMC review will include all cumulative safety data (ie, AEs, laboratory 
assessments, physical examinations, etc.) from study assessments through each cutoff period. 
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Further details regarding the DMC can be found in the DMC charter, which will be available 
prior to the administration of investigational product. 
The DMC for this study will be conducted in accordance with the FDA Guidance for Clinical 
Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees 
(March 2006).
The DMC will be an external, independent board comprised of physicians with relevant training. 
The DMC will be restricted to individuals free of significant conflicts of interest, including, but 
not limited to, financial, scientific, or regulatory in nature. The DMC will be governed by a 
Charter agreed to by members of the Board and the sponsor. Members of the Board may not be 
study investigators or be employed at the same institution as a study investigator, individuals 
employed by the sponsor, independent contractors hired by the sponsor, or members of 
regulatory agencies. The DMC may make recommendations to the sponsor regarding study 
aspects including stopping, modifying or continuing the study; however, the sponsor will have 
the final responsibility to determine whether the study should be modified or temporarily or 
permanently stopped. If the DMC recommends termination of this pediatric study, the 
recommendations will be communicated to the relevant regulatory agencies within 7 calendar 
days.
9.5
Sample Size Calculation and Power Considerations
The sample size is determined based on enrollment feasibility for this rare condition and the age 
of the study population. 
9.6
Study Population
Intent to treat (ITT) population: All subjects randomized in the study.
Safety analysis population: The safety analysis set will contain all subjects who meet the 
following criteria:

Teduglutide treatment arm: subjects who receive at least 1 dose of teduglutide and 
have undergone at least 1 post-baseline safety assessment; analyses will be performed 
according to dose group as appropriate.  

Standard of care treatment arm: subjects who have undergone at least 1 post-baseline 
safety assessment.
Per-protocol population: All subjects in the ITT population without any major protocol deviation 
that affects interpretation of efficacy results.
Pharmacokinetic analysis population: All subjects who received at least 1 dose of teduglutide 
and have at least 1 evaluable postdose PK concentration value.  
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9.7
Efficacy Analyses
9.7.1
Efficacy Endpoints
Efficacy endpoints consist of the following:
9.7.1.1
Primary Efficacy Endpoint 

Reduction in weight-normalized PN fluid volume by at least 20% from baseline at 
Week 24/EOT
9.7.1.2
Secondary Efficacy Endpoints

Reduction in weight-normalized parenteral calories by at least 20% from baseline to 
Week 24/EOT

Achievement of enteral autonomy by Week 24

Time to achieve enteral autonomy

Change in weight-normalized parenteral fluid volume from baseline to each visit

Change in weight-normalized parenteral calories from baseline to each visit

Change in weight-normalized enteral fluid volume from baseline to each visit

Change in weight-normalized enteral caloric intake from baseline to each visit

Increase in weight-normalized enteral fluid intake by at least 20% from baseline to week 
24/EOT

Increase in weight-normalized enteral caloric intake by at least 20% from baseline to 
week 24/EOT
9.7.2
Method of Analysis-Efficacy Endpoints
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 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.
Analyses of weekly PN support will be based on 2 data sources: the subject diary data (also 
referred to as actual data) and the investigator prescribed data. 
The number and percentage of subjects who achieve at least a 20% reduction from baseline in 
weight-normalized average daily PN volume at Week 24/EOT and the number and percentage of 
subjects who achieve at least a 20% reduction from baseline in weight-normalized parenteral 
calories at Week 24/EOT will be summarized by treatment arm.
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During the treatment period, a subject will be considered to have achieved enteral autonomy 
(completely weaned off PN) at a given visit if the investigator prescribes no PN at that visit and 
for the remainder of the treatment period, and there is no use of PN recorded in the subject diary 
during the week prior to that visit and for the remainder of the treatment period. During the 
follow-up period, a subject will be considered to have achieved enteral autonomy at a given visit 
if the investigator prescribes no PN at that visit and for the remainder of the follow-up period and 
there is no use of PN recorded in the subject diary during the week prior to that visit and for the 
remainder of the follow-up period. The number and percentage of subjects who achieve enteral 
autonomy at each scheduled visit, as well as at EOT, will be summarized by treatment arm. 
Descriptive statistics will be used to summarize time to achievement of enteral autonomy by 
treatment arm.
The absolute and percent change in weight-normalized weekly PN volume, parenteral calories, 
enteral fluid volume, and enteral caloric intake, from baseline to each scheduled visit, as well as 
at EOT, will be summarized by treatment arm using descriptive statistics.
The number and percentage of subjects who demonstrate an increase in weight-normalized 
enteral fluid intake by at least 20% from baseline to Week 24/EOT and the number and 
percentage of subjects who demonstrate an increase in weight-normalized enteral caloric intake 
by at least 20% from baseline to week 24/EOT will be summarized by treatment arm.
9.8
Safety Analyses
9.8.1
Safety Endpoints
Safety endpoints consist of the following:

Adverse events

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for 
gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output

Stool (including mixed) output

Antibodies to teduglutide
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9.8.2
Method of Analysis-Safety Endpoints
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Treatment-emergent AEs will be summarized by system organ class and preferred 
term using descriptive statistics (eg, number and percentage of subjects). Adverse events will be 
summarized by severity and relationship to treatment. In addition, SAEs will also be tabulated by 
overall and treatment-related events. AEs leading to treatment discontinuation and death will 
also be summarized.
For laboratory tests; vital signs; urine and stool output; weight, length, and head circumference 
Z-scores, and descriptive statistics (eg, n, mean, standard deviation, median, minimum and 
maximum values, and the number and percentage of subjects in specified categories) will be 
used to summarize the absolute values and change from baseline at each visit.
The number and percentage of subjects classified as having antibodies to teduglutide will be used 
to summarize the presence of antibodies. 
9.9
Health Economics and Outcomes Research Analyses
Health economics and outcomes research endpoints consist of the following:

Cumulative number of hospitalization days during the study
Health economics and outcomes research endpoints will be summarized using descriptive 
statistics (number, mean and standard deviation) at nominal time points. 
9.10
Pharmacokinetics Analyses
Plasma concentrations will be summarized using descriptive statistics (number, mean, standard 
deviation, geometric mean, coefficient of variation, minimum, median, and maximum ) at 
nominal time points. 
Pharmacokinetic parameters will be estimated using a population PK modeling approach as 
appropriate and will be reported separately.
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SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES
10.
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements. 
The name and address of each third-party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996), EU 
Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study. An insurance certificate is supplied as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. 
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This requirement will be fulfilled within 6 months of the end of the study completion date for 
pediatric studies and within 1 year for non-pediatric studies as per guidance. The sponsor will 
provide the ECs with a copy of the same summary.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly. The sponsor will make an end-of-study declaration to the relevant competent 
authority as required by Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator will be appointed to review the final clinical study report 
for multicenter studies. Agreement with the final clinical study report is documented by the 
signed and dated signature of the principal investigator (single-site study) or coordinating 
principal investigator (multicenter study), in compliance with Directive 2001/83/EC as amended 
by Directive 2003/63/EC and ICH Guidance E3 (1995).
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
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If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Electronic Case Report Forms
Electronic case report forms are supplied by the sponsor or designee and should be handled in 
accordance with instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Electronic case report forms 
must be completed by the investigator or designee as stated in the site delegation log. All data 
will have separate source documentation; no data will be recorded directly onto the eCRF.
All data sent to the sponsor must be endorsed by the investigator. 
The study monitor will verify the contents against the source data per the monitoring plan. If the 
data are unclear or contradictory, queries are sent for corrections or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject diaries, and original clinical laboratory reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF entries 
against the source documents. The consent form includes a statement by which the 
parent/guardian agrees to the monitor/auditor from the sponsor or its representatives, national or 
local regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical 
file, appointment books, original laboratory reports, X-rays etc). Non-study site personnel will 
not disclose any personal information or personal medical information.
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These records must be made available within reasonable times for inspection and 
duplication, if required, by a properly authorized representative of any regulatory agency 
(eg, the US FDA, EMA, UK Medicines and Healthcare products Regulatory Agency) or an 
auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the European Medicines Agency (EMA), the 
Medicines and Healthcare products Regulatory Agency, other regulatory authorities, the sponsor 
or its representatives, and the IRB/EC for each site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 
1 year after, whereby the outcome of the study could be influenced by the value of the 
compensation for conducting the study, or other payments the investigator received from the 
sponsor. The following information is collected: any significant payments from the sponsor 
or subsidiaries such as a grant to fund ongoing research, compensation in the form of 
equipment, retainer for ongoing consultation or honoraria; any proprietary interest in 
investigational product; any significant equity interest in the sponsor or subsidiaries as defined in 
21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent, where applicable, 
from the parent(s)/guardian(s) of all study subjects prior to any study-related procedures 
including screening assessments. All consent documentation must be in accordance with 
applicable regulations and GCP. Each subject’s legally authorized representative is requested to 
sign and date the subject informed consent form or a certified translation if applicable, after the 
subject’s parent or guardian has received and read (or been read) the written subject information 
and received an explanation of what the study involves, including but not limited to: the 
objectives, potential benefits and risk, inconveniences, and the subject’s rights and 
responsibilities. A copy of the informed consent documentation (ie, a complete set of subject 
information sheets and fully executed signature pages) must be given to the subject’s legally 
authorized representative, as applicable. This document may require translation into the local 
language. Signed consent forms must remain in each subject’s study file and must be available 
for verification at any time.
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The principal investigator provides the sponsor with a copy of the consent form  that was 
reviewed by the IRB/EC and received their favorable opinion/approval. A copy of the IRB/EC’s
written favorable opinion/approval of these documents must be provided to the sponsor prior to 
the start of the study unless it is agreed to and documented (abiding by regulatory guidelines and 
national provisions) prior to study start that another party (ie, sponsor or coordinating principal 
investigator) is responsible for this action. Additionally, if the IRB/EC requires modification of 
the sample subject information and consent document provided by the sponsor, the 
documentation supporting this requirement must be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the sponsor/designee has received 
written IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB/EC informed of any serious and 
significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996. A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the sponsor/designee.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. 
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These records and data may, in addition, be reviewed by others including the following: 
independent auditors who validate the data on behalf of the sponsor; third parties with whom the 
sponsor may develop, register, or market teduglutide; national or local regulatory authorities; and 
the IRB(s)/EC(s) which gave approval for the study to proceed. The sponsor and/or its 
representatives accessing the records and data will take all reasonable precautions in accordance 
with applicable laws, regulations, and guidelines to maintain the confidentiality of subjects’ 
identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2 to 4 and certain other studies as determined by Shire. The purpose of 
the publication steering committee is to act as a non-commercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, royalty 
free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
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Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.
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REFERENCES
11.
Beattie, L. M., Barclay, A. R. & Wilson, D. C. 2010. Short bowel syndrome and intestinal failure 
in infants and children. Paediatrics and Child Health, 20, 485-491.
Carter, Cohran, Cole, Corkins, Dimmitt, Duggan, Hill, Horslen, Lim, Mercer, Merritt, Nichol, 
Sigurdsson, Teitelbaum, Thompson, Vanderpool, Vaughan, Li, Youssef, Venick & 
Kocoshis 2017. Outcomes from a 12-Week, Open-Label, Multicenter Clinical Trial of 
Teduglutide in Pediatric Short Bowel Syndrome. Journal of Pediatrics, The, 181, 102-
111.e5.
Gonzalez-Hernandez, Prajapati, Ogola, Channabasappa, Drews & Piper 2017. Predicting time to 
full enteral nutrition in children after significant bowel resection. Journal of Pediatric 
Surgery, 52, 764-767.
Goulet, O. & Ruemmele, F. 2006. Causes and Management of Intestinal Failure in Children. 
Gastroenterology, 130, S16-S28.
Huisman-de Waal, G., Schoonhoven, L., Jansen, J., Wanten, G. & van Achterberg, T. 2007. The 
impact of home parenteral nutrition on daily life-A review. Clinical Nutrition, 26, 275-
288.
Khan, F. A., Squires, R. H., Litman, H. J., Balint, J., Carter, B. A., Fisher, J. G., Horslen, S. P., 
Jaksic, T., Kocoshis, S., Martinez, J. A., Mercer, D., Rhee, S., Rudolph, J. A., Soden, J., 
Sudan, D., Superina, R. A., Teitelbaum, D. H., Venick, R., Wales, P. W. & Duggan, C. 
2015. Predictors of Enteral Autonomy in Children with Intestinal Failure: A Multicenter 
Cohort Study. J Pediatr, 167, 29-34.e1.
Marier, J., Kassir, N., Martin, P. & Wang, Y. 2017. Population pharmacokinetic modeling of 
teduglutide to support dosing in pediatric patients with short bowel syndrome. Clinical 
Pharmacology & Therapeutics, 101, S91.
Martin, G.-R., Beck, P.-L. & Sigalet, D.-L. 2006. Gut hormones, and short bowel syndrome: the 
enigmatic role of glucagon-like peptide-2 in the regulation of intestinal adaptation. World 
Journal of Gastroenterology, 12, 4117-29.
O'Keefe, S. J., Buchman, A. L., Fishbein, T. M., Jeejeebhoy, K. N., Jeppesen, P. B. & Shaffer, J. 
2006. Short bowel syndrome and intestinal failure: consensus definitions and overview. 
Clin Gastroenterol Hepatol, 4, 6-10.
Sigalet, D. L., Martin, G., Meddings, J., Hartman, B. & Holst, J. J. 2004. GLP-2 levels in infants 
with intestinal dysfunction. Pediatr Res, 56, 371-6.
Spencer, A. U., Neaga, A., West, B., Safran, J., Brown, P., Btaiche, I., Kuzma-O'Reilly, B. & 
Teitelbaum, D. H. 2005. Pediatric Short Bowel Syndrome: Redefining Predictors of 
Success. Annals of Surgery, 242, 403-412.
Squires, R. H., Duggan, C., Teitelbaum, D. H., Wales, P. W., Balint, J., Venick, R., Rhee, S., 
Sudan, D., Mercer, D., Martinez, J. A., Carter, B. A., Soden, J., Horslen, S., Rudolph, J. 
A., Kocoshis, S., Superina, R., Lawlor, S., Haller, T., Kurs-Lasky, M. & Belle, S. H. 
2012. Natural history of pediatric intestinal failure: initial report from the Pediatric 
Intestinal Failure Consortium. J Pediatr, 161, 723-8.e2.
Tappenden, K. A., Edelman, J. & Joelsson, B. 2013. Teduglutide enhances structural adaptation 
of the small intestinal mucosa in patients with short bowel syndrome. J Clin 
Gastroenterol, 47, 602-7.
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Thymann, T., Stoll, B., Mecklenburg, L., Burrin, D. G., Vegge, A., Qvist, N., Eriksen, T., 
Jeppesen, P. B. & Sangild, P. T. 2014. Acute effects of the glucagon-like peptide 2 
analogue, teduglutide, on intestinal adaptation in short bowel syndrome. J Pediatr 
Gastroenterol Nutr, 58, 694-702.
Wales, P. W., de Silva, N., Kim, J., Lecce, L., To, T. & Moore, A. 2004. Neonatal short bowel 
syndrome: population-based estimates of incidence and mortality rates. J Pediatr Surg,
39, 690-5.
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APPENDICES
12.
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Appendix 1
Protocol History
Document
Date
Global/Country/Site Specific
Original Protocol
03 Oct 2017
Global
Amendment 1
18 Jan 2018
Global
Amendment 2
04 Dec 2018
Global
Amendment 3
24 May 2019
Global
Amendment 4
17 Dec 2019
Global
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change
Section(s) Affected by Change
Updated emergency contact information to reflect the change of the 
Contract Research Organization’s name.
Emergency Contact Information
Clarified the duration of the screening period and total time on study. 
Provided a clear definition of study completion.
Synopsis, Section 3.1.1, 
Section 3.2
Updated the study schematic to reflect the study design changes.
Revised the telephone and clinic visit schedule to assure laboratory 
measurement could be collected without exceeding weekly/monthly total 
blood volume restrictions. 
Synopsis, Table 1,
Section 3.1.2
Moved the PK sampling from Week 6 to Week 7 so that the samples could 
be collected without exceeding weekly/monthly total blood volume 
restrictions.
Synopsis, Table 1, 
Section 3.1.2, Section 7.2.4, Table 5
Clarified that blood for pharmacokinetic samples of postdose may be taken 
within ±10 minutes of the time pre-specified.
Clarified that end jejunostomy or ileostomy are examples  of small bowel 
ostomy rather than the stratification factors.
Synopsis, Section 3.1.2, Section 6.2.2
Clarified that all subjects regardless of treatment arm are eligible for the 
extension study.
Synopsis, Section 3.1.3
Clarified that if a subject treated with teduglutide meets the escape criteria, 
the assessments scheduled for the EOS visit should be conducted.
Synopsis, Table 2, 
Section 3.1.3, Section 6.2.3
Clarified that subjects must be 4 to 12 months corrected gestational age at 
screening.
Synopsis, Section 4.1
Changed dose adjustments to Week 12 rather than at every clinic visit to 
reduce site burden.
Synopsis, Table 1, 
Section 6.2.3
Clarified the definition of enteral autonomy.
Synopsis, Section 9.7.2
Updated the pharmacokinetic endpoint and analysis to reflect that only 
descriptive statistics will be calculated on plasma teduglutide concentration 
values. Pharmacokinetic parameters will be estimated using a population 
PK modeling approach as appropriate and reported separately.
Synopsis, Section 9.10
Removed assessment of the 5-level EuroQol five dimensions questionnaire 
to reduce caregiver burden.
Synopsis, Table 1, 
Section 7.2.5, Section 9.9
For non-commercial use only


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CONFIDENTIAL
Page 68
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change
Section(s) Affected by Change
Clarified that native GLP-2 samples drawn while subjects are receiving 
teduglutide should be drawn at least 14 hours after the previous dose.
Table 2, Section 7.2.2
Inserted a footnote to clarify that parenteral support and parenteral 
nutrition are used interchangeably.
Section 1.1
Removed the 5 mg vial of teduglutide as this size vial will not be supplied 
for this study.
Section 6.1
Clarified the procedures for assessing subject compliance. 
Section 6.5
Specified that it is acceptable to only enroll subjects who have already had 
an upper GI series with small bowel follow through performed since the 
subject’s most recent surgery. 
Section 7.2.1
Corrected the volume of blood to be collected for native GLP-2.
Table 5
Removed references to subject assent as assent is not possible in a study of 
infants. 
Section 7.1.1, Section 10.3.1
Clarified the definitions of the analysis sets.
Section 9.6
Clarified that an adjustment to enteral nutrition as appropriate is part of the PN 
adjustment algorithm.
Figure A-1
Minor editorial changes and corrections to typographical errors (which do 
not modify content and/or intent of the original document) were made.
Throughout protocol.
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2
Amendment Date
04 Dec 2018
Global
Description of Change
Section(s) Affected by Change
The fax number currently used to send the Shire Medical Monitor a copy of 
the Shire Clinical Study Adverse Event Form for Serious Adverse Events 
(SAEs) and Non-serious AEs as Required by Protocol is now retired; a 
copy of the form must be sent by email only.
Updated emergency contact information to reflect the change of Shire 
medical monitor to 
, IQVIA back up medical support to 
, and IQVIA phone number for medical emergencies.
Emergency Contact Information
A single email address (
) is now used to report a Product 
Quality Complaint, independently from where it has originated.  
Product Quality Complaints
Added the new secondary efficacy endpoint “Time to achieve enteral 
autonomy” and statistical methodology to be used.
Synopsis, Section 9.7.1.2, 
Section 9.7.2
Updated  the information on the clinical studies with teduglutide in 
pediatric subjects to include the results of TED-C14-006.
Section 1.2
Clarified that teduglutide is the investigational product for this study.
Section 6.1
For non-commercial use only


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CONFIDENTIAL
Page 69
SHP633-301 Protocol Amendment 4
Teduglutide
17 Dec 2019
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2
Amendment Date
04 Dec 2018
Global
Description of Change
Section(s) Affected by Change
Updated the dose selection rationale with results from a simulation work 
using the previous population pharmacokinetic model. Based on the totality 
of clinical data, 0.05 mg/kg once daily is expected to provide comparable 
Cmax concentrations in infants as compared to pediatric patients with SBS 
and was recommended as an evaluation dosing regimen in Study SHP633-
301.
Section 6.2.5
Clarified that rescreening of subjects in the study will not be allowed. 
(Administrative amendment dated 03 Oct 2018)
Section 7.1.1
Clarifications were made to the definition of adverse events.
Section 8.1, Section 8.1.5, 
Section 8.2.4
Added heart failure with severe fluid overload, determined by the sponsor 
or investigator to be related to the investigational product, to the list of 
events leading to interruption of investigational product administration. 
This addition is in alignment with the warnings and special precautions 
listed in the investigator brochure.
Section 8.4
As recommended by the FDA, specified that if the DMC recommends 
termination of this pediatric study, the recommendations will be 
communicated to the relevant regulatory agencies within 7 calendar days.
Section 9.4
Minor editorial changes and corrections to typographical errors (which do 
not modify content and/or intent of the original document) were made.
Throughout the protocol
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
3
Amendment Date
24 May 2019
Global
Description of Change and Rationale
Section(s) Affected by Change
Deleted Inclusion Criteria #6, Lack of terminal ileum and ileocecal valve, 
due to difficulties in enrollment. 
Synopsis, Section 4.1
Minor editorial changes and corrections to typographical errors (which do 
not modify content and/or intent of the original document) were made.
Throughout the protocol
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Page 70
SHP633-301 Protocol Amendment 4
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17 Dec 2019
Appendix 2
Guidelines for Nutritional Support Management During the Study
The nutritional support adjustment guidelines are designed to standardize management of 
parenteral and enteral nutritional support in this study. Adjustments to nutritional support should 
be considered at every scheduled clinic visit. Adjustments at phone visits may also be performed, 
but nutritional assessments at phone visits serve primarily to confirm that nutritional adjustments 
at prior clinic visits were tolerated.
All attempts should be made to follow the guidelines, but departure from the guidelines will not 
constitute a protocol deviation.
Clinical judgment is required within the algorithm. Each decision point requires integrating 
multiple sources of information into a yes/no decision. When individual data points are 
conflicting, the investigator must use their best judgment in the assessment.
If intestinal adaptation is occurring, reductions in parenteral support volume and calories are 
expected to be in decrements of 5 to 10% relative to baseline values. Parenteral support 
components are at the discretion of the investigator, but care should be taken to balance 
carbohydrate, fat, and protein. Likewise, if intestinal adaptation is occurring, enteral nutrition 
volume and calories should be increased in increments of approximately 10% relative to baseline 
values.
Assessment of the severity of malabsorption may require estimation of stool output for children 
who have mixed stool and urine output.
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.
During the 48-hour output measurement period prior to the subject’s scheduled visit, no further 
changes to the prescribed nutritional support should be made.
For non-commercial use only


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Page 71
SHP633-301 Protocol Amendment 4
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17 Dec 2019
Figure A-1:
Parenteral Nutrition/Intravenous Adjustment Algorithm for All Subjects  
BUN=blood urea nitrogen; Cr=creatinine; PN=parenteral nutrition; UNa=urine sodium; UOP=urine output; USpGr=Urine specific gravity; VS=vital signs; vol=volume
Adequately hydrated?
•
Normal exam and VS
•
Weight stable
•
UOP > 1 ml/kg/h
•
USpGr < 1.020
•
UNa > 20 meq/L
•
Stable, normal BUN/Cr
yes
no
Adequate weight gain 
and linear growth?
↑ PN kcal or no change
↓PN vol and kcal
↑ PN vol +/- kcal
yes
no
Assess severity of malabsorption and adjust EN as appropriate
For non-commercial use only


PROTOCOL: SHP633-301
TITLE:
A Randomized, Open-label, 24-Week Safety, Efficacy, and 
Pharmacokinetic Study of Teduglutide in Infants 4 to 12 Months of Age 
with Short Bowel Syndrome Who are Dependent on Parenteral Support
NUMBER
SHP633-301
PHASE
3 
DRUG:
Teduglutide
INDICATION:
Short bowel syndrome
EUDRACT NO.:
2017-003606-40
SPONSOR: 
Shire Human Genetic Therapies, Inc.
300 Shire Way
Lexington, MA 02421 USA
PROTOCOL 
HISTORY:
Original Protocol: 03 Oct 2017
Amendment 1: 18 Jan 2018
Amendment 1.1: 07 Aug 2018 (France-specific) 
Amendment 2.1: 04 Dec 2018 (France-specific)
Amendment 3.1: 24 May 2019 (France-specific)
Amendment 4.1: 17 Dec 2019 (France-specific)
Confidentiality Statement
This document contains confidential and proprietary information of Shire and is disclosed 
pursuant to confidentiality and non-disclosure obligations. This information should be used 
solely for the purposes for which it was provided and should not be copied, shared with, or 
disclosed to any third party without the express written consent of Shire.
For non-commercial use only


CONFID£NTI I 
•tadmnd .C.I (Frwe specitk) 
PROTOCOL IG 
TURE P GE 
5po1uor• ( lllttj ppro,-al 
Date: 
 
In\ ei1tlK1ttor'!I Acknowledgement 
I hove n·11d 1111'1 protucol l'or Shire Study SI 11'611 Hll 
Title: 
RnnJumi1cd, Oren-label. 2-!-\\\:ck S11fc1y, l fl1l.1q. unu Phurmucokinctic S1udy of 
lcdu lutidc i11 lnfon1 4 10 12 Months of .'\ge v.i1h 
h11:1 Bm1.cl S)nllromc Who are Dependent 
on P renternl uppon 
I h \ c f Ull) di u scd the objecth'C(s) of lhi stud} nd the ontc:nts of thi protocol v. ith ilie 
pon or' n-pn: nt tl\C. 
I und rstnnd th t the information in Uir. protoo 1 i .. confidenti I nd 
ould not be disclosed. 
other than 10 tho 
invoked in 
or 1hc ientm /cth1 1 re' ie\\ of the stUd). 
n 
lt1 ,h 
iblclopro\idelbe 
infonnnlion COnUlincd herein to a subfl!ct in rder to 
tnin ahcir consent 10 p.irtkipare. 
I agree to 'lOndu t thi stud) according to this prolocot nd 10 com pl) \\ ith its 
ubjcct to ethical nnd 
fet} con-:demrian ond guideline 
nc.l to \;unduct the 
in 
nccordtmcc '' i1h ln1cm111ional Council 1or Hurmoni u1il1n of I cchnic:nl Rcl)uircmcnts for 
l'h11m1;Kt=Ulic11f.. 1l1r 1 luman Use (lCH) guideline 1111 (mud Clink·nl Prm:1icc ({1C P) and wilh the 
.1ppltcnhlc 
rcqurrcmems. 
I mulc1·'tlu11d thnt liiilurc to comply with lhc 1·cqulrcmcnt'I ol'thc proh,col mny lead to the 
ll'm1h1.11ion of tn) panicipation as an imestigator lor thrs stuJy 
I undcrstnnd 1h111 1hc 'ponsM ma) decide to .su,pcnJ or prcmnturel) tcm1ina1c the -.md) at an) 
11me Ii r \\ hnte\ er rea n; ... 
a decision "ill be c-ommunicatcd to me in 
Com erseb. 
h uld I decide to \\ithdro" from execution of1h 
tud} I \'-ill commum tc m) inremion 
im1ncdiatcl) in \\fitin to lh 'J>Onsor. 
lnvcsciptor Name and Address: 
{plate 
Of l)pc) 
Slanalure: 
For non-commercial use only


Shire
CONFIDENTIAL
Page 3
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Adverse Event Form for Serious Adverse Events (SAEs) and Non-serious AEs as 
Required by Protocol within 24 hours to the Shire Global Drug Safety Department. Applicable 
fax numbers and e-mail address can be found on the form (sent under separate cover). A copy of 
this form must also be sent to the Shire Medical Monitor by e-mail at 
.
For protocol- or safety-related issues, the investigator must contact IQVIA Medical Support:
Primary Contact
Backup Contact 
, MD
, MD, PhD
Mobile:  
Mobile: 
Phone: 
 (medical emergencies)
Phone: 
 (medical emergencies)
Email: 
Email: 
In addition, the investigator may also contact Shire:
, MD 
Mobile Phone: 
Email: 
For non-commercial use only


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CONFIDENTIAL
Page 4
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please use the E-mail address below to report the Product Quality Complaint:
Telephone numbers (provided for reference, if needed): 
Shire (USA)
 
For non-commercial use only


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Page 5
SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
SUMMARY OF CHANGES FROM PREVIOUS VERSION
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
4.1
Amendment Date
17 Dec 2019
Global
Description of Change and Rationale
Section(s) Affected by Change
Clarified that subjects may enroll in an extension study at end of study 
(EOS) if that study is open to enrollment at the time of the SHP633-301 
EOS.
Synopsis, Table 2, Section 3.1, 
Section 3.1.3, Section 6.2.3
Clarified when and how parenteral nutrition prescriptions are to be 
recorded.
Table 1, Table 2, Section 7.2.2
Clarified that at baseline safety labs and PK samples will be separated by 
1 day. 
Synopsis, Table 1, Table 5, 
Section 7.2.4
PT/INR measurements should be performed at screening for all subjects 
instead of baseline for teduglutide-treated subjects.
Table 1, Section 7.2.3, Table 4, 
Table 5
Specified that C-reactive will not be collected at screening for all subjects 
and will not be collected at any visit for subjects who weigh <7 kg.
Table 1, Table 4, Table 5
Removed the optional PK measurement at Week 12. Postbaseline PK 
samples should be performed at Week 7.  
Table 1, Section 3.1.2, Table 5
Specified that the predose PK sample will not be collected from subjects 
who weigh <7 kg.
Table 1, Section 7.2.3, Table 5
Clarified that hematology laboratories are not collected at Week 1.  
Specified that hematology will not be collected at screening for subjects 
who weigh <7 kg.
Table 1, Section 7.2.3, Table 4, 
Table 5
Simplified the language describing the population PK modeling and 
simulations in previous studies.
Section 6.2.5
Updated to allow 1 rescreening attempt to aide in enrollment.
Section 7.1.1
Clarified information to be collected for the pharmacokinetic assessments.
Section 7.2.4
Interim analysis will be conducted for regulatory submissions, as needed. 
Analyses will be descriptive in nature. No formal comparisons are 
planned, and no hypotheses will be formally tested.  Due to the open-label 
nature of this study, personnel involved in conducting the interim analyses 
will have access to treatment assignments.
Section 9.4
Minor editorial changes and corrections to typographical errors (which do 
not modify content and/or intent of the original document) were made.
Throughout the protocol
See Appendix 1 for protocol history, including all amendments. 
For non-commercial use only


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SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
PRODUCT QUALITY COMPLAINTS..........................................................................................4
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................5
TABLE OF CONTENTS.................................................................................................................6
LIST OF TABLES.........................................................................................................................10
LIST OF FIGURES .......................................................................................................................10
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..................................................11
STUDY SYNOPSIS ......................................................................................................................12
STUDY SCHEDULES..................................................................................................................17
1.
BACKGROUND INFORMATION.......................................................................................21
1.1
Short Bowel Syndrome ............................................................................................21
1.2
Teduglutide...............................................................................................................22
2.
OBJECTIVES.........................................................................................................................24
2.1
Rationale for the Study.............................................................................................24
2.2
Study Objectives ......................................................................................................24
3.
STUDY DESIGN ...................................................................................................................25
3.1
Study Design and Flow Chart ..................................................................................25
3.1.1
Screening Period....................................................................................................25
3.1.2
Treatment Period....................................................................................................25
3.1.3
Follow-up Period ...................................................................................................26
3.2
Study Duration .........................................................................................................26
3.3
Sites and Regions .....................................................................................................26
4.
STUDY POPULATION.........................................................................................................27
4.1
Inclusion Criteria......................................................................................................27
4.2
Exclusion Criteria.....................................................................................................27
4.3
Discontinuation of Subjects .....................................................................................29
4.3.1
Reasons for Discontinuation..................................................................................29
4.3.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................29
5.
PRIOR AND CONCOMITANT TREATMENT ...................................................................30
5.1
Prior Medications and Procedures............................................................................30
5.2
Concomitant Medications and Procedures...............................................................30
5.3
Permitted Treatment.................................................................................................30
5.4
Prohibited Treatment................................................................................................30
6.
INVESTIGATIONAL PRODUCT ........................................................................................31
6.1
Identity of Investigational Product...........................................................................31
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6.2
Administration of Investigational Product ...............................................................31
6.2.1
Interactive Response Technology for Investigational Product Management ........31
6.2.2
Allocation of Subjects to Treatment ......................................................................31
6.2.3
Dosing....................................................................................................................31
6.2.4
Unblinding the Treatment Assignment..................................................................32
6.2.5
Dose Selection Rationale.......................................................................................32
6.3
Labeling, Packaging, and Storage............................................................................33
6.3.1
Labeling .................................................................................................................33
6.3.2
Storage and Handling.............................................................................................34
6.4
Drug Accountability.................................................................................................34
6.5
Subject Compliance..................................................................................................36
7.
STUDY PROCEDURES........................................................................................................37
7.1
Study Schedule.........................................................................................................37
7.1.1
Screening................................................................................................................37
7.1.2
Treatment Period....................................................................................................37
7.1.3
Follow-up Period ...................................................................................................37
7.2
Study Evaluations and Procedures ...........................................................................37
7.2.1
Demographics and Other Baseline Characteristics................................................37
7.2.2
Efficacy Assessments.............................................................................................38
7.2.3
Safety Assessments................................................................................................39
7.2.4
Pharmacokinetic Assessments ...............................................................................43
7.2.5
Health Economics and Outcomes Research ..........................................................43
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................44
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................44
8.1.1
Severity Categorization..........................................................................................44
8.1.2
Relationship Categorization...................................................................................45
8.1.3
Outcome Categorization ........................................................................................45
8.1.4
Symptoms of the Disease under Study ..................................................................46
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................46
8.1.6
Pregnancy...............................................................................................................46
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................46
8.2
Serious Adverse Event Procedures ..........................................................................47
8.2.1
Reference Safety Information................................................................................47
8.2.2
Reporting Procedures.............................................................................................47
8.2.3
Serious Adverse Event Definition .........................................................................48
8.2.4
Serious Adverse Event Collection Time Frame.....................................................48
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................48
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8.2.6
Fatal Outcome........................................................................................................49
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................49
8.3
Adverse Events of Special Interest...........................................................................49
8.4
Dose Interruption Criteria ........................................................................................50
9.
DATA MANAGEMENT AND STATISTICAL METHODS...............................................51
9.1
Data Collection.........................................................................................................51
9.2
Clinical Data Management.......................................................................................51
9.3
Statistical Analysis Process......................................................................................51
9.4
Planned Interim Analysis, and Data Monitoring Committee...................................51
9.5
Sample Size Calculation and Power Considerations................................................52
9.6
Study Population ......................................................................................................52
9.7
Efficacy Analyses.....................................................................................................53
9.7.1
Efficacy Endpoints.................................................................................................53
9.7.1.1
Primary Efficacy Endpoint.....................................................................53
9.7.1.2
Secondary Efficacy Endpoints ...............................................................53
9.7.2
Method of Analysis-Efficacy Endpoints................................................................53
9.8
Safety Analyses........................................................................................................54
9.8.1
Safety Endpoints....................................................................................................54
9.8.2
Method of Analysis-Safety Endpoints...................................................................55
9.9
Health Economics and Outcomes Research Analyses .............................................55
9.10
Pharmacokinetics Analyses......................................................................................55
10. SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES ............................................56
10.1
Sponsor’s Responsibilities .......................................................................................56
10.1.1 Good Clinical Practice Compliance.......................................................................56
10.1.2 Indemnity/Liability and Insurance.........................................................................56
10.1.3 Public Posting of Study Information......................................................................56
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................56
10.1.5 Study Suspension, Termination, and Completion..................................................57
10.2
Investigator’s Responsibilities .................................................................................57
10.2.1 Good Clinical Practice Compliance.......................................................................57
10.2.2 Protocol Adherence and Investigator Agreement..................................................57
10.2.3 Documentation and Retention of Records.............................................................58
10.2.3.1
Electronic Case Report Forms................................................................58
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................58
10.2.3.3
Audit/Inspection.....................................................................................59
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10.2.3.4
Financial Disclosure...............................................................................59
10.3
Ethical Considerations..............................................................................................59
10.3.1 Informed Consent...................................................................................................59
10.3.2 Institutional Review Board or Ethics Committee..................................................60
10.4
Privacy and Confidentiality......................................................................................60
11. REFERENCES .......................................................................................................................63
12. APPENDICES ........................................................................................................................65
Appendix 1
Protocol History .....................................................................................66
Appendix 2
Guidelines for Nutritional Support Management During the Study ......70
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17 Dec 2019
LIST OF TABLES
Table 1:
Study Schedule: Visits -1 to 12 .....................................................................17
Table 2:
Study Schedule: Visits 13-28 ........................................................................19
Table 3:
Prohibited Treatment.....................................................................................30
Table 4:
List of Laboratory Tests ................................................................................41
Table 5:
Approximate Volume of Blood to be Drawn from Each Subject .................42
LIST OF FIGURES
Figure 1:
Study Schematic ............................................................................................25
For non-commercial use only


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Teduglutide
17 Dec 2019
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation
Definition
AE
adverse event
AUCss
area under the concentration-time curve at steady-state 
Cmax,ss
maximum plasma concentration at steady state
CRO
contract research organization
eCRF
electronic case report form
DMC
data monitoring committee
EDC
electronic data capture
EMA
European Medicines Agency
EN
enteral nutrition
EOS
end of study
EOT
end of treatment
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
gastrointestinal 
GLP
glucagon-like peptide
HIPAA
Health Insurance Portability and Accountability Act
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use
ICMJE
International Committee of Medicinal Journal Editors
I/O
oral fluid intake and urine output
IP
Investigational product
IRB
Institutional Review Board
ITT
intent-to-treat
MedDRA
Medical Dictionary for Regulatory Activities
PK
pharmacokinetics
PN
parenteral nutrition
SAE
serious adverse event
SAP
statistical analysis plan
SBS
short bowel syndrome
SC
subcutaneous
SD
standard deviation
SOC
standard of care
ULN
upper limit of normal 
US
United States
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SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
17 Dec 2019
STUDY SYNOPSIS
Protocol number: SHP633-301
Drug: Teduglutide
Title of the study: A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic Study of 
Teduglutide in Infants 4 to 12 Months of Age with Short Bowel Syndrome Who are Dependent on Parenteral 
Support
Number of subjects (total and for each treatment arm):
At least 10 subjects will be randomized: at least 5 subjects in a teduglutide treatment arm and at least 5 subjects in 
a standard of care (SOC) comparator arm
Investigator(s): Multicenter study
Site(s) and Region(s): 
This study is planned to be conducted in approximately 5 to 10 sites globally.
Study period (planned):
2017-2020
Clinical phase:
3
Objectives:
The objectives of this clinical study are to evaluate the safety, efficacy/pharmacodynamics and pharmacokinetics 
(PK) of teduglutide treatment in infants with short bowel syndrome (SBS) dependent on parenteral support.
Investigational product, dose, and mode of administration:
Teduglutide 0.05 mg/kg by subcutaneous (SC) injection once daily into 1 of the 4 quadrants of the abdomen or 
either thigh or arm.
Methodology:
This is a randomized, multicenter, open-label study, consisting of a 2 to 4 week screening period, a 24-week 
treatment period, and a 4-week follow-up period. 
* At EOS all subjects regardless of treatment arm may enroll in an extension study if that study is open to 
enrollment at the time of the SHP633-301 EOS that will capture long-term safety data and provide the 
opportunity for additional teduglutide treatment. The follow-up period for subjects in the teduglutide treatment 
arm may be interrupted and the subjects may proceed immediately to the EOS if at least one “escape” criteria is 
met.
Extension 
study* 
1
24
1
3
5
7
9
12
16
20
28
2 to 4
Weeks
Screening
Teduglutide 0.05 mg/kg SC once daily for 24 weeks
Site Visit 
Telephone Visit
Standard of care for 24 weeks
Baseline: treatment 
randomization
0
24
3
5
7
9
12
16
20
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Study eligibility will be confirmed during the screening period (minimum: 2 weeks; maximum 4 weeks). At the 
baseline visit (Week 0), subjects will be randomized 1:1 to the teduglutide or SOC treatment arm. Randomization 
will be stratified according to the presence of a small bowel ostomy (eg, end jejunostomy or ileostomy). During 
the 24-week treatment period, subjects in the SOC treatment arm will receive standard medical therapy for SBS; 
while those in the teduglutide arm will receive 0.05 mg/kg SC once daily in addition to standard medical therapy. 
Subjects in both arms will follow the same visit schedule and assessments. Subjects will be monitored weekly 
with phone or clinic visits. Clinic visits will occur at Weeks 1, 3, 5, 7, 9, 12, 16, 20, 24, and 28. At all site visits 
and telephone contacts, safety will be monitored and nutritional support will be reviewed and adjusted as needed. 
To maintain consistency across centers, guidance and training will be provided to help sites follow the nutritional 
support adjustment guidelines (developed with SBS expert input and provided in the protocol) related to decisions 
for parenteral nutrition (PN) reduction and advances in enteral feeds based on weight gain, urine and stool output, 
and clinical stability. Deviations from the guidelines are not considered a protocol deviation.
Sparse PK sampling, in the teduglutide treatment arm only, will occur at baseline (predose and 1 hour 
±10 minutes and 4 hours ±10 minutes postdose) and at Week 7 or 12 (2 hours±10 minutes postdose).  At baseline, 
safety labs and PK will be separated by 1 day.
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up period until the end 
of study (Week 28/EOS) during which time subjects will receive standard medical therapy, but no investigational 
product will be administered. At EOS all subjects regardless of treatment arm may enroll in an extension study if 
that study is open to enrollment at the time of the SHP633-301 EOS that will capture long-term safety data and 
provide the opportunity for additional teduglutide treatment. The follow-up period for subjects in the teduglutide 
treatment arm may be interrupted and the subjects may proceed immediately to the EOS if at least one of the 
following “escape” criteria is met:
1.
Increasing PN requirements following discontinuation of teduglutide.
2.
Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal tolerated enteral 
nutrition (EN) following teduglutide discontinuation.
3.
Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and electrolyte intake 
following teduglutide discontinuation.
4.
Severe diarrhea related to teduglutide discontinuation.
Inclusion and Exclusion Criteria:
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1.
Informed consent by the parent or legal guardian. 
2.
Male or female infant 4 to 12 months corrected gestational age at screening.
3.
Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and baseline.
4.
Short bowel syndrome with dependence on parenteral support to provide at least 50% of fluid or caloric 
needs.
5.
Stable PN requirements for at least 1 month prior to screening, defined as a ≤10% change in the 
weight-normalized parenteral total fluid and caloric intake, despite attempts to wean PN, 
notwithstanding transient instability for events such as sepsis or interruption of central venous access.
6.
This criteria was deleted.
7.
Parent or legal guardian understands and is willing and able to fully adhere to study requirements as 
defined in this protocol.
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Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1.
Previous treatment with teduglutide.
2.
Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus inclusion disease, 
etc.
3.
Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility, that is the primary contributing factor to feeding intolerance and 
inability to reduce parenteral support, prior to screening. Dysmotility is defined as severe if it is expected 
to limit the advancement of enteral feeding.
4.
Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral aversion in the 
absence of a feeding tube.
5.
Intestinal obstruction or clinically significant intestinal stenosis.
6.
Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or major intestinal 
resection or anastomosis, within 3 months prior to screening or planned during the study period.
7.
Unstable cardiac disease.
8.
Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
9.
Biliary obstruction, stenosis, or malformation. 
10. Clinically significant pancreatic disease. 
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b.
Platelet count <100×10^3/µl due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d.
Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 2-week period
13. More than 3 serious complications of intestinal failure (eg, catheter-associated bloodstream infections, 
interruption of nutrition due to feeding intolerance, catheter-associated thrombosis, severe fluid or 
electrolyte disturbances) within 1 month prior to or during screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile polyposis or 
Beckwith-Wiedemann syndrome, or first degree relative with early onset of gastrointestinal cancer 
(including hepatobiliary and pancreatic cancers). 
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 (GLP-2); 
insulin-like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs of these hormones; or 
glutamine. 
16. Participation in a clinical study using an experimental drug within 3 months or 5.5 half-lives of the 
experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, closely-related 
compounds, or any of the stated ingredients.
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts the subject at any 
undue risk, prevents completion of the study, or interferes with analysis of the study results.
19. Hypersensitivity to trace residues of tetracycline.
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Teduglutide
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20. Signs of active severe or unstable, clinically significant hepatic impairment shown by any of the below 
laboratory test results at screening:
a. Total bilirubin ≥2 x upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥5 x ULN
c. Alanine aminotransferase (ALT) ≥5 x ULN
For subjects with Gilbert’s disease:
d. Indirect (unconjugated) bilirubin ≥2 x ULN
Maximum Duration of Subject Involvement in the Study:
The study consists of a 2 to 4 week screening period, a 24-week treatment period, and a 4-week follow-up period. 
The maximum duration of participation for each subject is 32 weeks.
Study completion is defined as the last subject, last visit. This is the visit date at which the last subject on the 
study has his or her last follow-up visit on the study (whether during the 24-week treatment period or the 4-week 
follow-up period).
Endpoints:
Efficacy
Efficacy endpoints consist of the following:
Primary

Reduction in weight-normalized PN fluid volume by at least 20% from baseline at Week 24/EOT
Secondary

Reduction in weight-normalized parenteral calories by at least 20% from baseline to Week 24/EOT

Achievement of enteral autonomy by Week 24

Time to achieve enteral autonomy

Change in weight-normalized parenteral fluid volume from baseline to each visit

Change in weight-normalized parenteral calories from baseline to each visit

Change in weight-normalized enteral fluid volume from baseline to each visit

Change in weight-normalized enteral caloric intake from baseline to each visit

Increase in weight-normalized enteral fluid intake by at least 20% from baseline to Week 24/EOT

Increase in weight-normalized enteral caloric intake by at least 20% from baseline to Week 24/EOT
Pharmacokinetics
The pharmacokinetic endpoint is plasma teduglutide concentration at nominal time points.
Safety
Safety endpoints consist of the following:

Adverse events (AEs)

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output

Stool (including mixed) output  

Antibodies to teduglutide 
Health Economics and Outcomes Research
Health economics and outcomes research (HEOR) endpoints include the following:

Cumulative number of hospitalization days during the study
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Statistical Methods:
Efficacy
Analyses of weekly PN support will be based on 2 data sources: the subject diary data (also referred to as actual 
data) and the investigator prescribed data. 
The number and percentage of subjects who achieve at least a 20% reduction from baseline in weight-normalized 
average daily PN volume at Week 24/EOT and the number and percentage of subjects who achieve at least a 20% 
reduction from baseline in weight-normalized parenteral calories at Week 24/EOT will be summarized by 
treatment arm.
During the treatment period, a subject will be considered to have achieved enteral autonomy (completely weaned 
off PN) at a given visit if the investigator prescribes no PN at that visit and for the remainder of the treatment 
period, and there is no use of PN recorded in the subject diary during the week prior to that visit and for the 
remainder of the treatment period. During the follow-up period, a subject will be considered to have achieved 
enteral autonomy at a given visit if the investigator prescribes no PN at that visit and for the remainder of the 
follow-up period and there is no use of PN recorded in the subject diary during the week prior to that visit and for 
the remainder of the follow-up period. The number and percentage of subjects who achieve enteral autonomy at 
each scheduled visit, as well as at EOT, will be summarized by treatment arm. Descriptive statistics will be used 
to summarize time to achievement of enteral autonomy by treatment arm.
The absolute and percent change in weight-normalized weekly PN volume, parenteral calories, enteral fluid 
volume, and enteral caloric intake, from baseline to each scheduled visit, as well as at EOT, will be summarized 
by treatment arm using descriptive statistics.
The number and percentage of subjects who demonstrate an increase in weight-normalized enteral fluid intake by 
at least 20% from baseline to Week 24/EOT and the number and percentage of subjects who demonstrate an 
increase in weight-normalized enteral caloric intake by at least 20% from baseline to week 24/EOT will be 
summarized by treatment arm.
Pharmacokinetics
Plasma concentrations will be summarized using descriptive statistics (number, mean, standard deviation, 
geometric mean, coefficient of variation, minimum, median, and maximum) at nominal time points. 
Pharmacokinetic parameters will be estimated using a population PK modeling approach as appropriate and will 
be reported separately.
Safety
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Treatment-emergent AEs will be summarized by system organ class and preferred term using descriptive statistics 
(eg, number and percentage of subjects). Adverse events will be summarized by severity and relationship to 
treatment. In addition, serious adverse events  will also be tabulated by overall and treatment-related events. AEs 
leading to treatment discontinuation and death will also be summarized.
For laboratory tests; vital signs; urine and stool output; weight, length, and head circumference Z-scores; and 
descriptive statistics (eg, n, mean, standard deviation, median, minimum and maximum values, and the number 
and percentage of subjects in specified categories) will be used to summarize the absolute values and change from 
baseline at each visit.
The number and percentage of subjects classified as having antibodies to teduglutide will be used to summarize 
the presence of antibodies. 
Health Economics and Outcomes Research
The HEOR endpoints will be summarized descriptively. 
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SHP633-301 Protocol Amendment 4.1 (France-specific)
Teduglutide
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STUDY SCHEDULES
Table 1:
Study Schedule: Visits -1 to 12
Procedures
Screening
Baseline 
(Week 0)
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
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit type
Site
Site
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Tel
Site
Study day
-14
0
7
14
21
28
35
42
49
56
63
70
77
84
±window (days)
-2 weeks
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Informed consent
X
Eligibility
X
X
Randomization
X
Demographics 
X
SBS history
X
Medical and surgical history
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications and 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, vital signs, 
weight
X
X
X
X
X
X
X
X
Length and head circumference
X
X
X
X
UGI/SBFT
X
Safety labs and urinalysisb, c
X
Xb
X
(X)
X
(X)
X
(X)
X
(X)
X
(X)
(X)
X
PK samplinga
X
 
[X]d
Antibodies to teduglutidea,e
X
Xe
Native GLP-2f
X
Provide intake and output 
diariesg
X
X
X
X
X
X
X
X
Review diaries and nutritional 
support
X
X
X
X
X
X
X
X
X
X
X
X
X
Record PN prescription and 
adjust nutritional support as 
neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
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SHP633-301 Protocol Amendment 4.1 (France-specific)
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Table 1:
Study Schedule: Visits -1 to 12
Procedures
Screening
Baseline 
(Week 0)
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
0
1
2
3
4
5
6
7
8
9
10
11
12
Visit type
Site
Site
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Site
Tel
Tel
Site
Study day
-14
0
7
14
21
28
35
42
49
56
63
70
77
84
±window (days)
-2 weeks
±2
±2
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Dispense IPa, i
X
X
X
X
X
X
X
Adjust IP dosej
X
EN=enteral nutrition; GLP-2=glucagon-like peptide 2; INR=international normalized ratio; IP=investigational product; PK=pharmacokinetics; PN=parenteral nutrition;
PT=prothrombin time; UGI/SBFT=upper GI series with small bowel follow-through 
a Applicable to the teduglutide treatment arm only. 
b At baseline, safety labs (Table 4) and PK will be separated by 1 day. Safety labs at telephone visits will be collected at the discretion of the investigator. For all subjects in the 
teduglutide treatment arm, PT and INR will be tested at screening, and repeated if clinically indicated.  Hematology is not collected at Week 1 or at telephone visits.  Hematology 
will not be collected at screening for subjects who weigh <7 kg. C-reactive will not be collected at screening for all subjects and will not be collected at any visit for subjects who 
weigh <7 kg.
c Urinalysis will consist of urine sodium and specific gravity. Urine collection should be attempted, but inability to obtain urinalysis is not a protocol deviation.
d Subjects will have blood samples taken for teduglutide PK analysis predose and 1 hour ±10 minutes and 4 hours ±10 minutes postdose at baseline (Visit 0). The predose sample 
will not be collected from subjects who weigh <7 kg. Subjects also will have blood samples taken for teduglutide PK analysis 2 hours ±10 minutes postdose at Week 7 (Visit 7) of 
the treatment period.
e Samples for antibody analysis will be drawn at the baseline and Week 12 visits. Blood samples while subjects are receiving teduglutide should be drawn at least 14 hours after the 
previous dose.
f Blood samples for native GLP-2 should be collected postprandial. Native GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at 
investigator discretion based on weekly/monthly total volume. 
g Intake diaries will collect actual PN volume and hours per day and EN volume and calories. Intake diaries should be completed daily throughout the study. Urine and stool output 
should be recorded in the output diary over a 48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PN prescription. 
h Parenteral support adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment 
provided in Appendix 2.
i The initial dose will be calculated based on body weight measured at baseline (Visit 0).
j The dose will be adjusted as needed, based on body weight measured at Week 12 visit.
Note: (X) denotes optional assessments.
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Teduglutide
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Table 2:
Study Schedule: Visits 13-28
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 
(EOT/ET)
Week 
25
Week 
26
Week 
27
Week 
28 
(EOS)a
Visit number
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit type
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Study day
91
98
105
112
119
126
133
140
147
154
161
168
175
182
189
196
±window (days)
±3
±3
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications 
and procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hospitalizations
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination, vital 
signs, weight
X
X
X
X
Length and head 
circumference
X
X
X
X
Safety labs and 
urinalysisb,c
(X)
(X)
(X)
X
(X)
(X)
(X)
X
(X)
(X)
(X)
X
(X)
(X)
(X)
X
Antibodies to 
teduglutided,e
X
Native GLP-2f
X
Provide intake and output 
diaries
X
X
X
Review diaries and 
nutritional supportg
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Record PN prescription 
and adjust nutritional 
support as neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assess follow-up period 
escape criteriad
Xi
Xi
Xi
X
Dispense IPd
X
X
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Table 2:
Study Schedule: Visits 13-28
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 
(EOT/ET)
Week 
25
Week 
26
Week 
27
Week 
28 
(EOS)a
Visit number
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Visit type
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Tel
Tel
Tel
Site
Study day
91
98
105
112
119
126
133
140
147
154
161
168
175
182
189
196
±window (days)
±3
±3
±3
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
±4
EN=enteral nutrition; EOS=end of study; EOT=end of treatment; ET=early termination; GLP-2=glucagon-like peptide 2; INR=international normalized ratio; IP=investigational 
product; PN=parenteral nutrition; PT=prothrombin time; UGI/SBFT=upper GI series with small bowel follow-through
a At EOS subjects may enroll in an extension study if that study is open to enrollment at the time of the SHP633-301 EOS; if subjects require treatment before the end of the 
4-week follow-up they may enter the extension study immediately. 
b Safety labs at telephone visits will be collected at the discretion of the investigator. For all subjects in the teduglutide treatment arm, PT and INR are tested if clinically indicated.
c Urinalysis will consist of urine sodium and specific gravity. 
d Applicable to the teduglutide treatment arm only. 
e Samples for antibody analysis will be drawn at the EOS (Week 28) visit.
f Blood samples for native GLP-2 should be collected postprandial. Blood samples drawn while subjects are receiving teduglutide should be drawn at least 14 hours after the 
previous dose. Native GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at investigator discretion based on weekly/monthly 
total volume. 
g Intake diaries will collect actual PN volume and hours per day and EN volume and calories. Intake diaries should be completed daily throughout the study. Urine and stool output 
should be recorded in the output diary over a 48-hour period of nutritional stability before every clinic visit, and within 1 week of implementing a change in the PN prescription. 
h Parenteral support adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance for nutrition support adjustment 
provided in Appendix 2.
i If a subject treated with teduglutide meets the escape criteria, the assessments scheduled for the EOS visit should be conducted.
Note: (X) denotes optional assessments.
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Teduglutide
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1.
BACKGROUND INFORMATION
1.1
Short Bowel Syndrome
Short bowel syndrome (SBS) is a rare disorder resulting from congenital abnormalities or severe 
intestinal diseases that result in major surgical resections of the small intestine (O'Keefe et al., 
2006). Unlike the adult population, the majority of cases of SBS in pediatric subjects are due to 
congenital anomalies or catastrophic events that occur during infancy such as necrotizing 
enterocolitis, gastroschisis, intestinal atresia, midgut volvulus, or long-segment Hirschsprung 
disease (Beattie et al., 2010; Goulet and Ruemmele, 2006). A Canadian population-based study 
in neonates estimates an overall incidence of SBS to be 24.5 cases per 100,000 live births (Wales 
et al., 2004). 
The small intestine is capable of remarkable adaptation, but excessive loss of absorptive surface 
area or specialized functions can lead to dependence on parenteral nutrition (PN)1 fluids 
(O'Keefe et al., 2006). Although PN is life-sustaining in intestinal failure, it is associated with 
serious complications, including liver disease, life-threatening catheter-related blood stream 
infections, and central venous thrombosis (Beattie et al., 2010; Goulet and Ruemmele, 2006). 
Dependence on PN is also associated with reduced quality of life in both patients and caregivers 
and has an extremely high cost of care (Huisman-de Waal et al., 2007). About 30% of infants 
with SBS become independent of PN requirements within 12 months of the initial insult, and an 
additional 10% wean off PN within 24 months. After this time, linear intestinal growth slows. It 
is estimated that 42% to 86% of pediatric patients with SBS are able to become independent of 
PN within 1 to 3 years (Gonzalez-Hernandez et al., 2017; Khan et al., 2015; Squires et al., 2012). 
Nevertheless, despite optimal medical management, some children remain dependent on PN for 
many years (Squires et al., 2012). Infants who have less than 10% of expected small intestinal 
length for their gestational age have a low likelihood of ever achieving enteral autonomy (ie, 
independence from parenteral support). Providing the maximum tolerated amount of enteral 
nutrition (EN) has been the primary strategy to promote enteral adaptation (Spencer et al., 2005). 
Accelerating the adaptive process and achieving enteral autonomy is an urgent goal for all 
patients with SBS who are dependent on PN (Khan et al., 2015; Squires et al., 2012). The 
adaptive process is in part controlled by glucagon-like peptide 2 (GLP-2), a 33 amino acid 
peptide hormone secreted from L-type enteroendocrine cells in the terminal ileum and colon in 
response to luminal nutrients and bile acids (Martin et al., 2006). The post-prandial plasma 
concentration of GLP-2 in infants with SBS correlates with length of the remaining small 
intestine (Sigalet et al., 2004). Infants who lack terminal ileum may have impaired adaptation 
due to inadequate production of GLP-2.
                                                
1 For the purpose of the study the terms parenteral support (PS) and parenteral nutrition (PN) are used 
interchangeably.
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1.2
Teduglutide
Teduglutide is a novel, recombinant analog of naturally occurring human GLP-2 that regulates 
the functional and structural integrity of the cells lining the gastrointestinal (GI) tract. 
Teduglutide is a 33-amino acid peptide that differs from native GLP-2 in the substitution of 
glycine for alanine at the second position at the N-terminus. As a result, teduglutide demonstrates 
resistance to degradation by dipeptidyl peptidase 4 (DPP-4) and therefore maintains a longer 
elimination half-life (t1/2), approximately 2 hours in healthy adult subjects, 1.3 hours in adult 
SBS subjects, and 0.22 hours in pediatric SBS subjects, compared to the native peptide, which 
has a t1/2 of approximately 7 minutes. Teduglutide has been shown in animal studies and previous 
human clinical trials to increase villus height and crypt depth in the intestinal epithelium, thereby 
increasing the absorptive surface area of the intestines (Tappenden et al., 2013; Thymann et al., 
2014). 
A Phase 3 study, TED-C13-003, has been completed in pediatric SBS subjects. In this study, 
teduglutide was administered to 3 cohorts of pediatric subjects from ages 1-17 years. 
Thirty-seven pediatric subjects received teduglutide at doses of 0.0125, 0.025, or 0.05 mg/kg/day 
for 12 weeks. Five additional pediatric subjects were enrolled in an observational standard of 
care (SOC) cohort. There were clear dose-dependent effects of teduglutide seen at the 0.025 and 
0.05 mg/kg/day doses compared to SOC and the 0.0125 mg/kg/day dose. In the 0.025 mg/kg/day 
cohort there was a reduction in PN volume at Week 12 of 37%, including complete 
independence from PN support in 1 subject, and a reduction of 3.94 hours per day infusion time. 
In the 0.05 mg/kg/day cohort there was a reduction in PN volume at Week 12 of 39%, including 
complete independence from PN support in 3 subjects, and a reduction of 4.18 hours per day 
infusion time. Teduglutide was generally safe and well tolerated by pediatric subjects in all 
dosing cohorts. There were no deaths during the study and no treatment-emergent serious 
adverse events (SAEs) related to teduglutide were reported. No discontinuations from study were 
due to adverse events (AEs). Additional studies in pediatric patients with SBS are ongoing.
TED-C14-006 is a recently completed study of pediatric subjects through 17 years which 
included 2 treatment arms: a teduglutide treatment arm and a SOC treatment arm. Subjects in 
both arms participated in a 2-week minimum screening period, a 24-week treatment period, and a 
4-week follow-up period. During the screening period, subjects chose into which arm to enroll. 
During the 24-week treatment period, subjects in the SOC treatment arm received standard 
medical therapy for SBS; while those in the teduglutide treatment arm received daily 
subcutaneous (SC) injections of teduglutide (study drug) in addition to standard medical therapy. 
The subjects enrolling in the teduglutide treatment arm were randomized 1:1 in a double-blinded 
manner into 2 parallel dose groups: 0.025 mg/kg/day or 0.05 mg/kg/day of teduglutide 
administered subcutaneously for 24 weeks. Compared to the SOC, treatment of pediatric subjects 
with SBS with teduglutide resulted in clinically meaningful reductions in PN volume, calories, 
days per week, and hours per day. A total 10% of subjects who received teduglutide achieved 
enteral autonomy within 24 weeks despite prior dependence on PN for several years. Teduglutide 
treatment also resulted in increases in EN volume and caloric intake as well as plasma citrulline. 
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Although the differences in efficacy between the 0.025 and 0.05 mg/kg dose groups were small, 
a consistently greater effect was seen in the 0.05 mg/kg dose in all efficacy parameters. The 
pharmacokinetic (PK) properties were well characterized in this population and were consistent 
with the prior 12 week pediatric study. Teduglutide was generally well tolerated by pediatric 
subjects with SBS. The safety profile was favorable and consistent with the prior pediatric study, 
the underlying disease, and previous experience with teduglutide in adult subjects with SBS.
Teduglutide (0.05 mg/kg/day) is currently approved for the treatment of adult patients with SBS 
in >30 countries. On 29 Jun 2016, the European Commission granted an extension of the Market 
Authorization for teduglutide for the treatment of patients aged 1 year and above with SBS. 
Always refer to the latest version of the investigator’s brochure for the overall risk/benefit 
assessment and the most accurate and current information regarding the drug metabolism, 
pharmacokinetics, efficacy and safety of teduglutide (SHP633).
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2.
OBJECTIVES
2.1
Rationale for the Study 
There is no approved pharmacological therapy to improve intestinal adaptation in infants with 
SBS who are dependent on parenteral support. This study will evaluate whether teduglutide is 
safe and effective in this patient population. 
2.2
Study Objectives
The objectives of this study are to evaluate the safety, efficacy/pharmacodynamics and 
pharmacokinetics (PK) of teduglutide treatment in infants with SBS dependent on parenteral 
support.
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3.
STUDY DESIGN
3.1
Study Design and Flow Chart
This is a randomized, multicenter, open-label study, consisting of a 2 to 4-week screening period, 
a 24-week treatment period and a 4-week follow-up period. A schematic representation of the 
study design is presented in Figure 1.
Figure 1:
Study Schematic
*At EOS all subjects regardless of treatment arm may enroll in an extension study if that study is open to enrollment at the time 
of the SHP633-301 EOS that will capture long-term safety data and provide the opportunity for additional teduglutide treatment. 
The follow-up period for subjects in the teduglutide treatment arm may be interrupted and the subjects may proceed immediately 
to the EOS if at least one “escape” criteria is met.
3.1.1
Screening Period 
Study eligibility will be confirmed during the screening period (minimum: 2 weeks; maximum: 
4 weeks). The schedule of evaluations to be conducted during the Screening Period can be found 
in Table 1.
3.1.2
Treatment Period
At the baseline visit (Week 0), subjects will randomized 1:1 to the teduglutide or SOC treatment 
arm. Randomization will be stratified according to the presence of a small bowel ostomy (eg, end 
jejunostomy or ileostomy). During the 24-week treatment period, subjects in the SOC treatment 
arm will receive standard medical therapy for SBS, while those in the teduglutide arm will 
receive 0.05 mg/kg by SC injection once daily in addition to standard medical therapy. 
Subjects in both arms will follow the same visit schedule and assessments. Subjects will be 
monitored weekly with phone or clinic visits. Clinic visits will occur at Weeks 1, 3, 5, 7, 9, 12, 
16, 20, 24, and 28. 
Extension 
study* 
1
24
1
3
5
7
9
12
16
20
28
2 to 4
Weeks
Screening
Teduglutide 0.05 mg/kg SC once daily for 24 weeks
Site Visit 
Telephone Visit
Standard of care for 24 weeks
Baseline: treatment 
randomization
0
24
3
5
7
9
12
16
20
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At all site visits and telephone contacts, safety will be monitored and nutritional support will be 
reviewed and adjusted as needed. To maintain consistency across centers, guidance and training 
will be provided to help sites follow the nutritional support adjustment guidelines (developed 
with SBS expert input and provided in the protocol) related to decisions for PN reduction and 
advances in enteral feeds based on weight gain, urine and stool output, and clinical stability 
(Appendix 2). Deviations from the guidelines are not considered a protocol deviation.
Sparse PK sampling, in the teduglutide treatment arm only, will occur at baseline (predose and 
1 hour ±10 minutes and 4 hours ±10 minutes postdose) and at Week 7 (2 hours±10 minutes 
postdose).
The schedule of evaluations for the Treatment Period can be found in Table 1 (Visits -1 to 12) 
and Table 2 (Visits 13 to 28). 
3.1.3
Follow-up Period
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up 
period until the end of study (Week 28/EOS) during which time subjects will receive standard 
medical therapy, but no investigational product (IP) will be administered. At EOS, all subjects 
regardless of treatment arm may enroll in an extension study if that study is open to enrollment at 
the time of the SHP633-301 EOS that will capture long-term safety data and provide the 
opportunity for additional teduglutide treatment. The follow-up period for subjects in the 
teduglutide treatment arm may be interrupted and the subjects may proceed immediately to the 
EOS visit if at least one of the following “escape” criteria is met:
1. Increasing PN requirements following discontinuation of teduglutide.
2. Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation. 
4. Severe diarrhea related to teduglutide discontinuation.
The schedule of evaluations for the Follow-up Period can be found in Table 2 (Visits 13 to 28).
3.2
Study Duration
The study consists of a 2 to 4-week screening period, a 24-week treatment period and a 4-week 
follow-up period. The maximum duration of participation for each subject is 32 weeks.
Study completion is defined as the last subject, last visit. This is the visit date at which the last 
subject on the study has his or her last follow-up visit on the study (whether during the 24-week 
treatment period or the 4-week follow-up period).
3.3
Sites and Regions
This study is planned to be conducted at approximately 5 to 10 sites globally.
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4.
STUDY POPULATION
At least 10 subjects will be randomized: at least 5 subjects in a teduglutide treatment arm and at 
least 5 subjects in an SOC comparator arm.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1. Informed consent by the parent or legal guardian. 
2. Male or female infant 4 to 12 months corrected gestational age at screening.
3. Weight at least 5 kg and weight-for-length Z-score greater than -2 at screening and baseline.
4. Short bowel syndrome with dependence on parenteral support to provide at least 50% of fluid 
or caloric needs.
5. Stable PN requirements for at least 1 month prior to screening, defined as a ≤10% change in 
the weight-normalized parenteral total fluid and caloric intake, despite attempts to wean PN, 
notwithstanding transient instability for events such as sepsis or interruption of central 
venous access.
6. This criteria was deleted.
7. Parent or legal guardian understands and is willing and able to fully adhere to study 
requirements as defined in this protocol.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1. Previous treatment with teduglutide.
2. Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus 
inclusion disease, etc.
3. Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, active 
gastroschisis-related dysmotility, that is the primary contributing factor to feeding intolerance 
and inability to reduce parenteral support, prior to screening. Dysmotility is defined as severe 
if it is expected to limit the advancement of enteral feeding.
4. Inability to advance oral or enteral feeding due to lack of access to the gut, such as oral 
aversion in the absence of a feeding tube.
5. Intestinal obstruction or clinically significant intestinal stenosis.
6. Major gastrointestinal surgical intervention, such as serial transverse enteroplasty or major 
intestinal resection or anastomosis, within 3 months prior to screening or planned during the 
study period.
7. Unstable cardiac disease.
8. Renal dysfunction, defined as estimated glomerular filtration rate <50 mL/min/1.73 m2.
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9. Biliary obstruction, stenosis, or malformation. 
10. Clinically significant pancreatic disease. 
11. Severe hepatic dysfunction or portal hypertension, defined by at least 2 of the following 
parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b. Platelet count <100×10^3/µL due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d. Documented cirrhosis
12. Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 µmol/L) over a 2 week 
period.
13. More than 3 serious complications of intestinal failure (eg, catheter-associated bloodstream 
infections, interruption of nutrition due to feeding intolerance, catheter-associated 
thrombosis, severe fluid or electrolyte disturbances) within 1 month prior to or during 
screening.
14. A history of cancer or a known cancer predisposition syndrome, such as juvenile polyposis or 
Beckwith-Wiedemann syndrome, or first degree relative with early onset of gastrointestinal 
cancer (including hepatobiliary and pancreatic cancers). 
15. Concurrent treatment with glucagon-like peptide-1 (GLP-1); glucagon-like peptide-2 
(GLP-2); insulin-like growth factor-1 (IGF-1); growth hormone, somatostatin, or analogs of 
these hormones; or glutamine. 
16. Participation in a clinical study using an experimental drug within 3 months or 5.5 half-lives 
of the experimental drug, whichever is longer.
17. Known or suspected intolerance or hypersensitivity to the investigational product, 
closely-related compounds, or any of the stated ingredients. 
18. Any condition, disease, illness, or circumstance that, in the investigator’s opinion, puts the 
subject at any undue risk, prevents completion of the study, or interferes with analysis of the 
study results.
19. Hypersensitivity to trace residues of tetracycline.
20. Signs of active severe or unstable, clinically significant hepatic impairment shown by any of 
the below laboratory test results at screening:
a.Total bilirubin ≥2 x upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥5 x ULN
c.
Alanine aminotransferase (ALT) ≥5 x ULN
For subjects with Gilbert’s disease:
d. Indirect (unconjugated) bilirubin ≥2 x ULN
Reproductive Potential 
Not applicable; this study will enroll infants.
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4.3
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator should 
discuss withdrawal of a subject from investigational product with the medical monitor as soon as 
possible.
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 24/EOT/early termination are to be performed as completely as possible. Whenever 
possible, all discontinued subjects should also undergo the protocol-specified 4-week Follow-up 
Period. Comments (spontaneous or elicited) or complaints pertaining to IP discontinuation made 
by the subject must be recorded in the source documents. The reason for discontinuation, the 
date and the total amount of investigational product administered must be recorded in the 
electronic case report form (eCRF) and source documents.
Subjects who discontinue will not be replaced. 
4.3.1
Reasons for Discontinuation
The reason(s) for permanent discontinuation of treatment and/or withdrawal from the study must 
be determined by the investigator, and recorded in the subject’s medical record and in the eCRF. 
If a subject is withdrawn for more than 1 reason, each reason should be documented in the source 
document, and the most clinically relevant reason should be entered in the eCRF.
Reasons for discontinuation include, but are not limited to:

Adverse event

Death

Lost to follow-up

Physician decision

Protocol deviation

Study terminated by sponsor

Withdrawal by parent/guardian

Lack of efficacy

Other
4.3.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact the parent(s)/guardian(s) of any 
subject lost to follow-up at any time point prior to the last scheduled contact (office visit or 
telephone contact). At least 1 of these documented attempts must include a written 
communication sent to the subject’s last known address via courier or mail (with an 
acknowledgement of receipt request) asking that they return to the site for final safety 
evaluations and return any unused investigational product.
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5.
PRIOR AND CONCOMITANT TREATMENT
5.1
Prior Medications and Procedures
Prior treatment includes all treatment and procedures (including but not limited to prescription 
treatments, herbal treatments, vitamins, non-pharmacological treatment, as appropriate) received 
within 14 days prior to the screening visit (Visit -1) (or pharmacokinetic equivalent of 5 half 
lives, whichever is longer, must be recorded on the appropriate eCRF page.
5.2
Concomitant Medications and Procedures
The administration of all medications including concomitant medications (including prescription 
and nonprescription medications, dietary and nutritional supplements, and vitamins) and PN 
must be recorded from the first dose of investigational product and for the duration of the study 
in the appropriate sections of the eCRF. Any diagnostic, surgical or other therapeutic treatments 
received by a subject during the course of the study will also be recorded on the eCRF.
The mechanism of action of teduglutide may increase enteral absorption of oral drugs (eg, drugs 
used for management of SBS such as motility medication, opioids, psychotropics, 
metronidazole), so consideration should be given to modifying concomitant enteral medication 
regimens. Titration of concomitant enteral medications should be considered when drugs, 
especially those with a narrow therapeutic index (eg, warfarin, digoxin, psychotropics) are given.
5.3
Permitted Treatment
Standard medical therapy for SBS should be continued.
5.4
Prohibited Treatment
The following medications are prohibited during teduglutide treatment and within the provided 
timeframe prior to the pretreatment visit (Table 3):
Table 3:
Prohibited Treatment
Prior Therapy
Time Restriction Prior to 
the Pretreatment Visit
Teduglutide
Any
GLP-2, human growth hormone, or analogs of these hormones
6 months
Octreotide, GLP-1 analogs, and enteral glutamine
30 days
GLP=glucagon-like peptide
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6.
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The SOC treatment arm will receive standard medical therapy for SBS; while those in the 
teduglutide arm will receive 0.05 mg/kg SC once daily in addition to standard medical therapy.
The investigational product is teduglutide, which will be provided in sterile, single-use 3 mL 
vials containing 1.25 mg teduglutide as a white lyophilized powder to be reconstituted before use 
with 0.5 mL sterile water for injection. In addition to the active ingredient (teduglutide), each 
vial of teduglutide contains L-histidine, mannitol, monobasic sodium phosphate monohydrate, 
and dibasic sodium phosphate as excipients. Additional information is provided in the current 
investigator’s brochure.
6.2
Administration of Investigational Product
6.2.1
Interactive Response Technology for Investigational Product Management
All investigative study sites will be initially provided with sufficient investigational product to 
randomly assign a subject into the study (for either of the proposed treatment groups). 
Randomization will occur through an interactive response system. Random assignment of a 
subject will trigger replacement supplies for that investigative study site.
6.2.2
Allocation of Subjects to Treatment
Subjects will be randomized 1:1 to the teduglutide or SOC treatment arm. Randomization will be 
stratified according to the presence of a small bowel ostomy (eg, end jejunostomy or ileostomy). 
The actual treatment given to individual subjects is determined by a randomization schedule.
Subject numbers are assigned to all subjects as they consent to take part in the study. Within each 
site (numbered uniquely within a protocol), the subject number is assigned to subjects according 
to the sequence of presentation for study participation. 
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined.
6.2.3
Dosing
The initial dose will be calculated based on body weight measured at baseline (Visit 0), and 
adjusted as needed, based on body weight measured at Week 12. No other adjustments to dose 
will be made during the teduglutide treatment period, unless discussed with the sponsor’s 
medical monitor. 
Following reconstitution, teduglutide will be administered by SC injection once daily (QD) into 
1 of the 4 quadrants of the abdomen (in subjects without a stoma) or into either the thigh or arm. 
For subjects with a stoma, the quadrant of the abdomen containing the stoma should not be used. 
Teduglutide should be used as soon as possible after reconstitution, but no more than 3 hours 
later.
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The subject should be dosed at approximately the same time each day. Consecutive doses should 
be separated by at least 12 hours. Each day, the injection site should be alternated. 
Any subject who achieves complete independence from PN support at any time during the 
treatment period will continue to receive teduglutide treatment.
The first SC injection in teduglutide-naïve subjects should be administered under the supervision 
of the investigator or designee and the subject observed for hypersensitivity reactions for at least 
4 hours during their initial dosing visit. The site of administration (arm, thigh, and abdomen) of 
the first teduglutide dose must be specified and recorded in the eCRF. 
Detailed instructions for reconstitution and injection of the investigational product can be found 
in the Instructions for Use. 
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week follow-up 
period until the end of study (Week 28/EOS) during which time subjects will receive standard 
medical therapy, but no investigational product will be administered. At EOS all subjects 
regardless of treatment arm may enroll in an extension study if that study is open to enrollment at 
the time of the SHP633-301 EOS that will capture long-term safety data and provide the 
opportunity for additional teduglutide treatment. The follow-up period for subjects in the 
teduglutide treatment arm may be interrupted and the subjects may proceed immediately to the 
EOS if at least one of the following “escape” criteria is met:
1. Increasing PN requirements following teduglutide discontinuation.
2. Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal 
tolerated EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation. 
4. Severe diarrhea related to teduglutide discontinuation.
6.2.4
Unblinding the Treatment Assignment
Not applicable for this open-label study.
6.2.5
Dose Selection Rationale
Teduglutide is approved for adult and pediatric use in the EU at a dose of 0.05 mg/kg SC once 
daily. A completed 12-week dose finding study (TED-C13-003) demonstrated that teduglutide 
dosing at 0.025 and 0.05 mg/kg/day was associated with a favorable benefit-risk profile most 
meaningful at the 0.05 mg/kg/day dose (Carter et al., 2017). 
Population pharmacokinetic modeling and simulations were conducted using data from 8 adult 
clinical studies including adult Phase 1 studies and Phases 2/3 studies as well as study 
TED-C13-003 and suggested that the same adult dose (0.05mg/kg) be used in pediatric subjects 
(aged between 1.67-14.7 years) (Marier et al., 2017).
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To support dosing in the current age group, further PK simulation was conducted based on the 
population PK model previously established and a virtual population of 1000 pediatric patients 
created based on Centers for Disease Control (CDC) growth charts in the target age group (4 to 
12 months) and taking into consideration body weights of pediatric patients with SBS enrolled in 
study TED-C13-003 and TED-C14-006 (approximately 15% lower than healthy subjects in the 
same age group). The model was customized by including a maturation function on clearance 
(CL/F) as a function of estimated glomerular filtration rate. Monte Carlo simulations for all age 
groups were performed according to the SC dosing regimens of 0.0125, 0.025 and 0.05 mg/kg 
every 24 hours. Rich concentration-time profiles were simulated with the customized population 
PK model to derive the exposure metrics area under the concentration curve at steady state 
(AUCss) and maximum concentration at steady state (Cmax,ss). Exposure parameters in infant 
patients were compared to those derived in pediatric (1-17 years) and adult (≥18 years) patients 
with SBS using a Bayesian approach. Based on the clinical observations, Cmax is considered to be 
associated with clinical responses. Following 0.05 mg/kg daily SC administration, the median 
Cmax,ss of teduglutide in neonate patients (24.9 ng/mL) was within 20% of that observed in the 
2 to 4 and 4 to 6 years age groups (26.9 and 29.4 ng/mL, respectively); and approximately 
~28% lower than that in adult patients with SBS. The median Cmax,ss of teduglutide in infant 
patients 4 to 12 months (41.9 ng/mL) following 0.05 mg/kg once daily was within 8% of that 
previously observed in adult patients with SBS (39.0 ng/mL, refer to the attached Simulation 
Report). In addition, individual simulated Cmax,ss values of teduglutide in infant patients 4 to 
12 months (25.6 to 65.1 ng/mL) were contained within the range of Cmax,ss previously observed 
in pediatric patients 1 to 17 years (20.7 to 77.4 ng/mL). The clinical package in conjunction with 
Cmax was considered to support teduglutide dose selection since AUCss was previously shown not 
to correlate with efficacy. Individual simulated AUCss values of teduglutide in infant patients 
4 to 12 months (66.9 to 160 ng.h/mL) following 0.05 mg/kg once daily were contained within 
the range of AUCss values previously observed in pediatric patients 1 to 17 years (63.5 to 
421 ng.h/mL). Based on the totality of clinical data, 0.05 mg/kg once daily is expected to provide 
comparable Cmax concentrations in infants as compared to pediatric patients with SBS and was 
recommended as an evaluation dosing regimen in Study SHP633-301.
6.3
Labeling, Packaging, and Storage
6.3.1
Labeling
The investigational product will be packaged, labeled, and shipped to the study site by the 
sponsor or designee. Kits containing 7 vials of investigational product will be provided for this 
study. The vials will be labeled in accordance with applicable regulatory requirements. 
Ancillary kits, containing supplies needed for the reconstitution and administration of the 
investigational product will also be provided and labeled in accordance with the applicable 
regulatory requirements. 
All investigational product used in this study will be manufactured, tested, labeled, and released 
according to current legal requirements and Good Manufacturing Practice.
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6.3.2
Storage and Handling
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.
Investigational product must be kept in a locked area with access restricted to specific study 
personnel. Investigational product will be stored refrigerated at a temperature between 2-8°C 
(35.6-46.4°F) until dispensed to a subject. Once dispensed to a subject, the IP can be stored 
refrigerated or up to a controlled room temperature (acceptable range of 2-25°C, or 35.6-77°F). 
Parent/legal guardian will be instructed to keep the subject’s IP and sterile water diluent at 
controlled room temperature. If there are concerns that the controlled room temperature cannot 
be maintained, the IP may be refrigerated. The IP is for single use only, and should be used 
within 3 hours following reconstitution.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (ie, certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
Investigational products are distributed by the pharmacy or nominated member of the study 
team. The pharmacist/nominated team member will enter the unique subject identifier on the 
investigational product bottle/carton labels, as they are distributed.
6.4
Drug Accountability
Investigational product will not be dispatched to the study site until the sponsor or 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 investigational product 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. Kits will be shipped to the site once the subject 
is screened.
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Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for dispensing investigational product. Where 
permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is adequately 
trained in the protocol and who works under the direct supervision of the investigator. This 
delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee will dispense the investigational product only to subjects 
included in this study following the procedures set out in the study protocol. Investigational 
product kits will be dispensed at each of the applicable study visits at which the subject is 
required to be at the clinic. Each investigational product kit is sufficient for a treatment period of 
1 week and enough kits will be supplied to cover the period until the next planned study visit. 
Additional study kits will be provided as necessary.
Each subject will be given the investigational product according to the protocol. The investigator 
is to keep a current record of the inventory and dispensing of all clinical supplies. All dispensed 
medication will be documented on the eCRFs and/or other investigational product record. The 
investigator is responsible for assuring the retrieval of all study supplies from subjects.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.
At the end of the study, or as instructed by the sponsor, all unused stock, subject returned 
investigational product, and empty/used investigational product packaging are to be sent to the 
sponsor or designee. The investigator is responsible for assuring the retrieval of all study 
supplies from subjects.
Returned investigational product must be counted and verified by clinical site personnel and the 
sponsor (or study monitor). Shipment return forms, when used, must be signed prior to shipment 
from the site. Contact the sponsor for authorization to return any investigational product prior to 
shipment. Shipment of all returned investigational product must comply with local, state, and 
national laws. 
Please see the Pharmacy Manual for additional information.
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6.5
Subject Compliance
The parent(s)/guardian(s) of subjects must be instructed to bring unused investigational product 
and empty/used investigational product packaging to every visit. Drug accountability must be 
assessed and recorded at the container/packaging level for unused investigational product that is 
contained within the original tamper-evident sealed container (eg, bottles, trays, vials) or at the 
individual count level for opened containers/packaging. 
Subject compliance will be checked by site personnel at every visit by reviewing the subject 
diaries and asking the subject or the subject’s parent or legally-authorized representative if they 
have administered the investigational product according to instructions. If any doses have been 
missed, the reason for missed dose should be documented in the subject’s source documentation 
including, as applicable, the eCRF.
The investigator is responsible for contacting the sponsor or designee when the subject’s daily 
investigational product dosing regimen is interrupted. Attempts should be made to contact the 
sponsor or designee prior to dose interruption. Reasons for dosage interruption may include but 
are not limited to hospitalization and AEs, a lapse in investigational product delivery, etc.
Subjects who have received 80% of the planned doses administered will be assessed as being 
compliant with the study protocol.
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7.
STUDY PROCEDURES
7.1
Study Schedule
Detailed study procedures and assessments to be performed for subjects throughout the study are 
outlined in the study schedules (Table 1 and Table 2) and must be referred to in conjunction with 
the instructions provided in this section. 
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Week 24/EOT are to be performed as completely as possible. Whenever possible, all 
discontinued subjects should also undergo the protocol-specified 4-week Follow-up Period. 
7.1.1
Screening
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent from the 
parent(s)/guardian(s) of the subject. The screening visit assessments and procedures, beginning 
with informed consent, will be performed as outlined in Table 1. 
Subjects will be designated as a screen failure if they fail to meet all inclusion criteria and/or 
meet any of the exclusion criteria. Screen failures will not be administered investigational 
product.
At the discretion of the investigator, subjects who fail screening may be rescreened one time with 
prior sponsor approval. In the event of rescreening, the subject should be reconsented, a new 
subject number assigned, and all screening procedures (except UGI/SBFT if performed within 
2 months prior to rescreening) should be repeated.
7.1.2
Treatment Period
The randomized Treatment Period will comprise Weeks 1 to 24, during which all assessments 
will be performed as outlined in Table 1 and Table 2.
7.1.3
Follow-up Period
The Follow-up Period will comprise Weeks 25 to 28, during which all assessments will be 
performed as outlined in Table 2.
7.2
Study Evaluations and Procedures
7.2.1
Demographics and Other Baseline Characteristics
Demographics and Medical History
Demographic and/or other baseline variables obtained at the screening and/or baseline visits are 
listed below. Abnormal findings of clinical significance (if any) will be recorded as past medical 
history.

Demography (including age, gestational age, sex, and race)
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
Medical history (including surgical history)

SBS history, including remnant anatomy
Upper Gastrointestinal Series with Small Bowel Follow-through
An upper GI contrast series with small bowel follow-through will be performed on all subjects 
during the screening period if one has not been done since the subject's last GI surgery. 
It is acceptable to only enroll subjects who have already had an upper GI series with small bowel 
follow-through performed since the subject’s most recent surgery. 
7.2.2
Efficacy Assessments
Subject Diaries
All available diary data will be reviewed by the investigator or their designee at each clinic and 
telephone visit to assess clinical status and opportunity for PN reduction and advance in feeds. 
Parenteral support adjustments should be made after review of the intake and output diaries and 
the safety lab data according to the guidance for nutrition support adjustment provided in 
Appendix 2.
Intake Diary
Intake diaries will be used to collect and evaluate each subject’s nutritional support. The 
parent/legally authorized representative/study site staff will complete the appropriate fields of the 
PN and EN sections of the intake diary daily throughout the study.
The following data will be captured in the intake diaries:

Parenteral support volume and infusion duration

Enteral nutrition (formula) including volume and calories
Site personnel will determine the actual PN and EN daily calories based on diary entries.
Output Diary
Urine and stool output should be recorded in the output diary over a 48-hour period of nutritional 
stability before every clinic visit; in addition, output should be recorded for subjects within 
1 week of implementing a change in the PN prescription.
Urine data:

Measure and record the weight of all urine-only diapers. Urine volume will be calculated 
using the following formula: 1 g (scale weight)=1 mL or 1 cc

At the discretion of the investigator, the parent or legal guardian/study site staff may be 
asked to collect the first void after the daily PN infusion to measure specific gravity
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Stool data (includes diapers with mixed urine and stool):

Record the weight of diapers containing stool (including diapers with mixed urine and 
stool) as stool output and score the stool consistency (see Output diary). Stool volume 
will be calculated using the formula: 1 g (scale weight)=1 mL or 1 cc
All ostomy output volume should be recorded. 
Prescribed Parenteral Nutrition
The prescribed PN weekly total volume and days per week will be recorded. Changes in PN 
prescription that reflect changes in the subject's intestinal absorption are recorded.  
Temporary adjustments to PN that last less than 72 hours should be recorded as concomitant 
medications, not a PN adjustments.  Examples include fluid resuscitation during treatment 
of sepsis or acute gastroenteritis, and modification of PS due to interruption of entral venous 
access.  
Parenteral nutrition prescriptions that last more than 72 hours should be recorded as PN 
adjustments.  Examples include recurrent replacement of fluid losses, titration of PN due to 
changes in intestinal absorptive function, and discontinuation of PN due to achievement of 
enteral autonomy.
Native GLP-2
Blood samples for native GLP-2 should be collected postprandial. Blood samples while subjects 
are receiving teduglutide should be drawn at least 14 hours after the previous dose. Native 
GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject 
weight or at investigator discretion based on weekly/monthly total volume.
7.2.3
Safety Assessments
Laboratory Evaluations
Safety laboratory tests to be performed at site visits consist of clinical chemistry, hematology, 
and urinalysis and will be performed as outlined in the study plan (Table 1 and Table 2). 
Scheduled laboratory testing will be processed by a central lab. All laboratory assays will be 
performed according to the central laboratory’s normal procedures. Reference ranges are to be 
supplied by the laboratory. The investigator should assess out-of-range clinical laboratory values 
for clinical significance, indicating if the value(s) is/are not clinically significant or clinically 
significant. Abnormal clinical laboratory values, which are unexpected or not explained by the 
subject’s clinical condition, may, at the discretion of the investigator or sponsor, be repeated as 
soon as possible until confirmed, explained, or resolved.
During the Treatment Period, subjects will also have safety labs within approximately 
5 to 7 days after a PN adjustment. Safety labs performed after PN adjustment and between site 
visits will consist of clinical chemistry and urinalysis and may be processed by the central 
laboratory or a local laboratory. 
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Local lab results are not required to be entered in the eCRFs; however, if the local lab results 
indicate any new clinically significant changes, they must be reported as an adverse event (see 
Section 8). Urine specimen collection should be attempted as part of the safety labs, but lack of 
urinalysis will not constitute a protocol deviation.
At baseline, blood samples for safety labs and PK will be separated by 1 day. The predose 
sample will not be collected from subjects who weigh <7 kg.
Safety labs at telephone visits will be collected at the discretion of the investigator. 
Hematology will not be collected at Week 1 or at telephone visits. Hematology will not be 
collected at screening for subjects <7 kg.
For all subjects, prothrombin time (PT) and international normalized ratio (INR), tested at 
screening, will be repeated if clinically indicated.
New clinically significant labs should be reported as AEs.
Close Monitoring Criteria Related To Liver Test Abnormalities:
The investigator should contact the medical monitor within 24 hours of their awareness if the 
subject develops any of the following changes in laboratory parameters:

ALT or AST >5x ULN and >2x baseline value

Total or direct bilirubin that is >2x baseline value or an absolute increase of ≥3 mg/dL 
(51.3 µmol/L)
If such changes are observed, the labs should be repeated along with an INR, and an inquiry 
should be made as to the presence of clinical symptoms consistent with new liver injury. The 
subject should be followed closely to determine the trajectory of the laboratory abnormalities and 
appropriate evaluations should be made, such as abdominal ultrasound with Doppler imaging to 
exclude vascular causes and biliary obstruction, consideration of sepsis, liver hypoperfusion, 
acute viral hepatitis (such as hepatitis A, EBV, or HSV), exposure to hepatotoxic medications, 
mitochondrial hepatopathy, or metabolic liver disease (such as hereditary fructose intolerance or 
arginosuccinate synthetase deficiency). Further evaluations can be performed at the discretion of 
the investigator in consultation with the Shire medical monitor.
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The following clinical laboratory assessments will be performed according to the study 
schedules:
Table 4:
List of Laboratory Tests
Biochemistry:

Albumin 

Alkaline phosphatase 

Alanine aminotransferase 

Amylase

Aspartate aminotransferase 

Bicarbonate

Bilirubin (total and indirect)

Blood urea nitrogen 

Calcium (total)

Chloride

Cholesterol

C-reactive proteinc

Creatinine

Estimated Glomerular Filtration Rate 
(Schwartz formula)

Gamma-glutamyl transferase 

Glucose

Lipase

Magnesium

Phosphorus

Potassium 

Sodium 

Triglycerides
Hematologya:

Hematocrit 

Hemoglobin 

Platelet count

Red blood cell count 

Red blood cell morphology, if needed

White blood cell count with differential
Coagulationb:

Prothrombin time

International normalized ratio
Urinalysis: 

Specific gravity  

Urine Sodium
a Hematology will not be collected at Week 1 or at telephone visits.  Hematology will not be collected at screening for subjects 
<7 kg.
b For all subjects in the teduglutide treatment arm, PT and INR will be tested at baseline and repeated only if clinically indicated.
c C-reactive protein will not be collected at screening for all subjects and will not be collected at any visit for subjects <7 kg.
Antibodies to Teduglutide 
Blood samples will be drawn to test for antibodies to teduglutide. Samples will be taken before 
teduglutide administration at the screening visit (Visit -1) and at least 14 hours after the previous 
dose at Week 12 (Visit 12); samples may be drawn from a central line or peripheral access. One 
additional sample will be collected at the EOS 4 weeks after the EOT (ie, Week 28 or EOS). 
Volume of Blood
Efforts will be made to minimize the amount of blood drawn from all pediatric subjects 
participating in this study. The volumes of blood to be drawn from each subject will vary 
depending on clinical status. Approximate volumes of blood to be drawn from each subject are 
shown in Table 5.
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Table 5:
Approximate Volume of Blood to be Drawn from Each Subject 
Assessment
Sample Volume 
(mL)
No. Samples for 
Subjects >7 kg
Total Volume 
(mL)
Subjects Receiving Teduglutide Treatment
Biochemistry (not including CRP)
1.1
12
13.2
CRPa
1.1
11
12.1
Hematologyb
1.2
11
13.2
Coagulation Parametersc
1.4
1
1.4
Antibodies
2.0
3
6.0
Pharmacokineticsd
2.0
4
8.0   
Native GLP-2e
1.5
2
3.0
Total mL:
56.9
Subjects Receiving Standard of Care
Biochemistry (not including CRP)
1.1
12
13.2
CRPa
1.1
11
12.1
Hematologyb
1.2
11
13.2
Coagulation Parametersc
1.4
1
1.4
Native GLP-2 e
1.5
2
3.0
Total mL:
42.9
CRP=C-reactive protein; GLP=glucagon-like peptide; INR=international normalized ratio; PT=prothrombin time
a C-reactive will not be collected at screening for all subjects and will not be collected at any visit for subjects <7 kg.
b Hematology will not be collected at Week 1 or at telephone visits.  Hematology will not be collected at screening for subjects 
<7 kg.
c PT and INR tested at screening only, repeat while on study only if clinically indicated.
dAt baseline, safety labs and PK will be separated by 1 day.  Baseline: 3 timepoints; The predose sample will not be collected 
from subjects who weigh <7 kg. Week 7: 1 timepoint.
e Native GLP-2 may not be collected in some subjects if blood volumes are limiting based on subject weight or at investigator 
discretion based on weekly/monthly total volume.
Note: The amount of blood to be drawn for each assessment is an estimate. Blood volume 
estimates do not include safety labs performed after PN adjustments.  
Consistent with standard medical practice, efforts to minimize pain and discomfort during 
procedures such as peripheral venipuncture should be implemented as applicable. This may 
include oral sucrose solutions, a pacifier, distraction techniques, and the use of topical anesthetic 
such as EMLA.  
Physical Examinations, Vital Signs, Weight, Length, and Head Circumference
Physical examinations will be performed according to the study schedules (Table 1 and Table 2). 
Any new clinically significant findings noted during physical examinations should be recorded 
on the appropriate AE page of the eCRF.
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Vital signs will be measured according to the study schedules. Measurements will include 
systolic and diastolic blood pressure (mmHg), pulse (beats per minute), and body temperature 
(°C/°F). Blood pressure should be determined by the appropriate size cuff (using the same 
method, the same leg, and in the supine position throughout the study, when possible). Blood 
pressure measurements should be attempted as part of the vital signs, but lack of blood pressure 
results will not constitute a protocol deviation. New clinically significant vital sign abnormalities 
should be recorded on the appropriate AE page of the eCRF.
Body weight will also be recorded in the eCRF; subjects should be weighed on the same scale 
at each study visit. Length and head circumference will be measured at selected visits. A height 
z-score, weight Z-score, and weight/length ratio will be calculated by the sponsor using the 
site-provided height and weight data collected at each site visit.
7.2.4
Pharmacokinetic Assessments
Subjects will have blood samples taken for teduglutide PK analysis predose, and 1 hour 
±10 minutes and 4 hours ±10 minutes postdose at baseline (Visit 0). At baseline, safety labs and 
PK will be separated by 1 day. Subjects also will have blood samples taken for teduglutide PK 
analysis 2 hours ±10 minutes postdose at Week 7 (Visit 7) or Week 12 (Visit 12) of the treatment 
period. Blood for PK sampling should be collected via peripheral IV or venipuncture, not from a 
central line. The site of teduglutide administration prior to PK blood draws (arm, thigh, 
abdomen) must be specified as well as the exact date and time of the sample. 
7.2.5
Health Economics and Outcomes Research
Hospitalizations
Each hospitalization that occurs during the study will be recorded, including date of admission, 
date of discharge, reasons for hospitalization, discharge diagnosis, and discharge status. 
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8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.3. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, or 
a symptom is more severe or prolonged than expected given the diagnosis, then symptom(s) 
should be listed individually. All AEs should be captured on the appropriate AE pages in the 
eCRF and in source documents. In addition to untoward AEs, unexpected benefits outside the 
investigational product indication should also be captured on the AE eCRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
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8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of 
the investigational product is compelling and/or follows a known or 
suspected response pattern to that product, and the event cannot be 
explained by the subject’s medical condition, other therapies, or 
accident.
Not Related
The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident and no 
plausible temporal or biologic relationship exists between the 
investigational product and the event.
AEs that are related to IP that are not resolved at EOS will be followed until the event resolves or 
stabilizes, as judged by the investigator.
Laboratory values, vital signs, and clinical findings at the scheduled physical examinations must 
be reported as AEs if the investigator considers the finding to be a clinically significant change 
from the baseline.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the eCRF. Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved with Sequelae 

Recovering/Resolving

Unknown
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8.1.4
Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE. It is assumed that some of the infants participating in this study may be 
hospitalized for planned surgery(ies) that will occur during their participation in the study. Such 
pre-planned, elective surgeries, do not need to be reported as SAEs for this protocol. 
8.1.5
Clinical Laboratory and Other Safety Evaluations
An untoward change in the value of a clinical laboratory parameter, vital sign measure, or ECG 
assessment can represent an AE if the change is clinically relevant or if, during administration of 
investigational product, a shift of a parameter is observed from a value in the normative range to 
a value that is outside the normal range and considered clinically significant, or a further waning 
of an already clinically significant value. Clinical significance is defined as any abnormal finding 
that results in further clinical investigation(s), treatment(s), or the diagnosis of new or 
progression of established condition. When evaluating such changes, the extent of deviation from 
the reference range, the duration until return to the reference range, either while continuing 
administration or after the end of administration with the investigational product, and the range 
of variation of the respective parameter within its reference range, should also be considered.
If, at the end of the treatment phase, there are abnormal clinical laboratory (such as hematology 
panel or clinical chemistry panel),  vital sign, or ECG values which were not present at the 
beginning of the pretreatment evaluation observed closest to the start of study treatment, further 
investigations should be performed until the values return to within the reference range or until a 
plausible explanation (eg, concomitant disease or expected disease evolution) is found for the
abnormal values.
The investigator should assess, based on the above criteria and the clinical condition of a subject, 
whether a change in a clinical laboratory value, vital sign, or ECG parameter is clinically 
significant and represents an AE.
8.1.6
Pregnancy
Not applicable.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for 
a non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner 
that may be detrimental to the individual and/or society.
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
Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol).

Overdose – Administration of a dose greater than the allocated dose of the study 
medication or at a frequency greater than the dosing interval specified by the protocol.

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product. For studies, medication errors are reportable to the sponsor 
only as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error. 
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally-authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator brochure which the sponsor 
has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Drug Safety Department and the Shire Medical Monitor within 24 hours of the first awareness of 
the event. Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, 
misuse, overdose, or medication errors (see Section 8.1.7) unless they result in an SAE.
All Adverse Events of Special Interest, as defined in Section 8.3, must be reported by the 
investigator to the Shire Global Drug Safety Department and the Shire Medical Monitor within 
24 hours of the first awareness of the event even if the event does not fulfill seriousness criterion.
The investigator must complete, sign, and date the Shire Clinical Study Adverse Event Form for 
SAEs and Non-serious AEs as Required by Protocol, and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested). Fax or e-mail the completed form to the Shire Global Drug Safety 
Department. A copy of the completed Shire Clinical Study Adverse Event Form for Serious 
Adverse Events (SAEs) and Non-serious AEs as Required by Protocol (and any applicable 
follow-up reports) must also be sent to the Shire medical monitor or designee using the details 
specified in the emergency contact information section of the protocol.
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8.2.3
Serious Adverse Event Definition
A SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose: 

Results in death

Is life-threatening. Note: The term 'life-threatening' in the definition of "serious" refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for pre 
existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse. 
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to investigational product) are collected from the time the 
subject signs the informed consent until the defined follow-up period stated in Section 7.1.3, and 
must be reported to the Shire Global Drug Safety Department and the Shire Medical Monitor 
within 24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Drug Safety Department within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
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In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death. 
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting 
The Sponsor and/or Clinical Contract Research Organization (CRO) is responsible for notifying 
the relevant regulatory authorities, and US central Institutional Review Boards (IRBs)/EU central 
ethics committees (ECs), of related, unexpected SAEs.
In addition, the Clinical CRO is responsible for notifying active sites of all related, unexpected 
SAEs occurring during all interventional studies across the SHP633 program.
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
8.3
Adverse Events of Special Interest
An AE of special interest is an AE (serious or nonserious) of scientific and medical concern 
specific to the sponsor’s product or program and for which ongoing monitoring and immediate 
notification by the investigator to the sponsor is required.
The AEs of special interest that require expedited regulatory reporting include the following:

Growth of pre-existing polyps of the colon

Benign neoplasia of the GI tract including the hepatobiliary system

Tumor-promoting ability (eg, benign and/or malignant neoplasia of any kind, not limited 
to those of the GI or hepatobiliary system)
For AEs of special interest, the sponsor must be informed within 24 hours of first awareness as 
per the SAE notification instructions described in Section 8.2.2 even if the event does not fulfill 
the seriousness criteria.
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8.4
Dose Interruption Criteria
The investigator is responsible for contacting the sponsor/designee when the subject’s 
teduglutide dosing regimen is interrupted. The length of dose interruption, and whether 
teduglutide administration resumes or is permanently discontinued, depends on the clinical 
situation.
Investigational product must be interrupted if any of the following events occur:

An adverse event of special interest (see Section 8.3) 

Intestinal obstruction

Biliary obstruction

Pancreatic duct obstruction

Heart failure with severe fluid overload determined by the sponsor or investigator to 
be related to IP.
Investigational product must be permanently discontinued if any of the following events occur: 

Severe hypersensitivity, such as anaphylaxis, determined by the investigator to be 
related to IP. 

Any malignancy 
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9.
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the eCRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered on the eCRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. Once a subject is randomized, it is expected that site 
personnel will complete the eCRF entry within approximately 3 business days of the subject’s 
visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the data management plan. Quality 
control and data validation procedures are applied to ensure the validity and accuracy of the 
clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Statistical Analysis Process
The study will be analyzed by the sponsor or designee. All statistical analyses will be performed 
using SAS® (SAS Institute, Cary, NC, US) version 9.3 or higher.
The statistical analysis plan (SAP) will provide the definitions and statistical methods  for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed.
9.4
Planned Interim Analysis, and Data Monitoring Committee 
Interim analysis will be conducted for regulatory submissions, as needed. Analyses will be 
descriptive in nature. No formal comparisons are planned and no hypotheses will be formally 
tested.  Due to the open-label nature of this study, personnel involved in conducting the interim 
analyses will have access to treatment assignments. 
A data monitoring committee (DMC) will be involved in the management of this study. The 
DMC members will review the data approximately every 3 months according to the DMC 
Charter. The DMC review will include all cumulative safety data (ie, AEs, laboratory 
assessments, physical examinations, etc.) from study assessments through each cutoff period. 
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Further details regarding the DMC can be found in the DMC charter, which will be available 
prior to the administration of investigational product. 
The DMC for this study will be conducted in accordance with the FDA Guidance for Clinical 
Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees 
(March 2006).
The DMC will be an external, independent board comprised of physicians with relevant training. 
The DMC will be restricted to individuals free of significant conflicts of interest, including, but 
not limited to, financial, scientific, or regulatory in nature. The DMC will be governed by a 
Charter agreed to by members of the Board and the sponsor. Members of the Board may not be 
study investigators or be employed at the same institution as a study investigator, individuals 
employed by the sponsor, independent contractors hired by the sponsor, or members of 
regulatory agencies. The DMC may make recommendations to the sponsor regarding study 
aspects including stopping, modifying or continuing the study; however, the sponsor will have 
the final responsibility to determine whether the study should be modified or temporarily or 
permanently stopped. If the DMC recommends termination of this pediatric study, the 
recommendations will be communicated to the relevant regulatory agencies within 7 calendar 
days.
9.5
Sample Size Calculation and Power Considerations
The sample size is determined based on enrollment feasibility for this rare condition and the age 
of the study population. 
9.6
Study Population
Intent to treat (ITT) population: All subjects randomized in the study.
Safety analysis population: The safety analysis set will contain all subjects who meet the 
following criteria:

Teduglutide treatment arm: subjects who receive at least 1 dose of teduglutide and 
have undergone at least 1 post-baseline safety assessment; analyses will be performed 
according to dose group as appropriate.  

Standard of care treatment arm: subjects who have undergone at least 1 post-baseline 
safety assessment.
Per-protocol population: All subjects in the ITT population without any major protocol deviation 
that affects interpretation of efficacy results.
Pharmacokinetic analysis population: All subjects who received at least 1 dose of teduglutide 
and have at least 1 evaluable postdose PK concentration value.  
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9.7
Efficacy Analyses
9.7.1
Efficacy Endpoints
Efficacy endpoints consist of the following:
9.7.1.1
Primary Efficacy Endpoint 

Reduction in weight-normalized PN fluid volume by at least 20% from baseline at 
Week 24/EOT
9.7.1.2
Secondary Efficacy Endpoints

Reduction in weight-normalized parenteral calories by at least 20% from baseline to 
Week 24/EOT

Achievement of enteral autonomy by Week 24

Time to achieve enteral autonomy

Change in weight-normalized parenteral fluid volume from baseline to each visit

Change in weight-normalized parenteral calories from baseline to each visit

Change in weight-normalized enteral fluid volume from baseline to each visit

Change in weight-normalized enteral caloric intake from baseline to each visit

Increase in weight-normalized enteral fluid intake by at least 20% from baseline to 
week 24/EOT

Increase in weight-normalized enteral caloric intake by at least 20% from baseline to 
week 24/EOT
9.7.2
Method of Analysis-Efficacy Endpoints
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 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.
Analyses of weekly PN support will be based on 2 data sources: the subject diary data (also 
referred to as actual data) and the investigator prescribed data. 
The number and percentage of subjects who achieve at least a 20% reduction from baseline in 
weight-normalized average daily PN volume at Week 24/EOT and the number and percentage of 
subjects who achieve at least a 20% reduction from baseline in weight-normalized parenteral 
calories at Week 24/EOT will be summarized by treatment arm.
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During the treatment period, a subject will be considered to have achieved enteral autonomy 
(completely weaned off PN) at a given visit if the investigator prescribes no PN at that visit and 
for the remainder of the treatment period, and there is no use of PN recorded in the subject diary 
during the week prior to that visit and for the remainder of the treatment period. During the 
follow-up period, a subject will be considered to have achieved enteral autonomy at a given visit 
if the investigator prescribes no PN at that visit and for the remainder of the follow-up period and 
there is no use of PN recorded in the subject diary during the week prior to that visit and for the 
remainder of the follow-up period. The number and percentage of subjects who achieve enteral 
autonomy at each scheduled visit, as well as at EOT, will be summarized by treatment arm. 
Descriptive statistics will be used to summarize time to achievement of enteral autonomy by 
treatment arm.
The absolute and percent change in weight-normalized weekly PN volume, parenteral calories, 
enteral fluid volume, and enteral caloric intake, from baseline to each scheduled visit, as well as 
at EOT, will be summarized by treatment arm using descriptive statistics.
The number and percentage of subjects who demonstrate an increase in weight-normalized 
enteral fluid intake by at least 20% from baseline to Week 24/EOT and the number and 
percentage of subjects who demonstrate an increase in weight-normalized enteral caloric intake 
by at least 20% from baseline to week 24/EOT will be summarized by treatment arm.
9.8
Safety Analyses
9.8.1
Safety Endpoints
Safety endpoints consist of the following:

Adverse events

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for 
gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output

Stool (including mixed) output

Antibodies to teduglutide
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9.8.2
Method of Analysis-Safety Endpoints
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Treatment-emergent AEs will be summarized by system organ class and preferred 
term using descriptive statistics (eg, number and percentage of subjects). Adverse events will be 
summarized by severity and relationship to treatment. In addition, SAEs will also be tabulated by 
overall and treatment-related events. AEs leading to treatment discontinuation and death will 
also be summarized.
For laboratory tests; vital signs; urine and stool output; weight, length, and head circumference 
Z-scores, and descriptive statistics (eg, n, mean, standard deviation, median, minimum and 
maximum values, and the number and percentage of subjects in specified categories) will be 
used to summarize the absolute values and change from baseline at each visit.
The number and percentage of subjects classified as having antibodies to teduglutide will be used 
to summarize the presence of antibodies. 
9.9
Health Economics and Outcomes Research Analyses
Health economics and outcomes research endpoints consist of the following:

Cumulative number of hospitalization days during the study
Health economics and outcomes research endpoints will be summarized using descriptive 
statistics (number, mean and standard deviation) at nominal time points. 
9.10
Pharmacokinetics Analyses
Plasma concentrations will be summarized using descriptive statistics (number, mean, standard 
deviation, geometric mean, coefficient of variation, minimum, median, and maximum ) at 
nominal time points. 
Pharmacokinetic parameters will be estimated using a population PK modeling approach as 
appropriate and will be reported separately.
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10.
SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements. 
The name and address of each third-party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH Good Clinical Practice (GCP) Guideline E6 (1996), EU 
Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study. An insurance certificate is supplied as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. 
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This requirement will be fulfilled within 6 months of the end of the study completion date for 
pediatric studies and within 1 year for non-pediatric studies as per guidance. The sponsor will 
provide the ECs with a copy of the same summary.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly. The sponsor will make an end-of-study declaration to the relevant competent 
authority as required by Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator will be appointed to review the final clinical study report 
for multicenter studies. Agreement with the final clinical study report is documented by the 
signed and dated signature of the principal investigator (single-site study) or coordinating 
principal investigator (multicenter study), in compliance with Directive 2001/83/EC as amended 
by Directive 2003/63/EC and ICH Guidance E3 (1995).
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
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If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Electronic Case Report Forms
Electronic case report forms are supplied by the sponsor or designee and should be handled in 
accordance with instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Electronic case report forms 
must be completed by the investigator or designee as stated in the site delegation log. All data 
will have separate source documentation; no data will be recorded directly onto the eCRF.
All data sent to the sponsor must be endorsed by the investigator. 
The study monitor will verify the contents against the source data per the monitoring plan. If the 
data are unclear or contradictory, queries are sent for corrections or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject diaries, and original clinical laboratory reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF entries 
against the source documents. The consent form includes a statement by which the 
parent/guardian agrees to the monitor/auditor from the sponsor or its representatives, national or 
local regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical 
file, appointment books, original laboratory reports, X-rays etc). Non-study site personnel will 
not disclose any personal information or personal medical information.
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These records must be made available within reasonable times for inspection and 
duplication, if required, by a properly authorized representative of any regulatory agency 
(eg, the US FDA, EMA, UK Medicines and Healthcare products Regulatory Agency) or an 
auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the European Medicines Agency (EMA), the 
Medicines and Healthcare products Regulatory Agency, other regulatory authorities, the sponsor 
or its representatives, and the IRB/EC for each site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for
1 year after, whereby the outcome of the study could be influenced by the value of the 
compensation for conducting the study, or other payments the investigator received from 
the sponsor. The following information is collected: any significant payments from the 
sponsor or subsidiaries such as a grant to fund ongoing research, compensation in the form of 
equipment, retainer for ongoing consultation or honoraria; any proprietary interest in 
investigational product; any significant equity interest in the sponsor or subsidiaries as defined in 
21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent, where applicable, 
from the parent(s)/guardian(s) of all study subjects prior to any study-related procedures 
including screening assessments. All consent documentation must be in accordance with 
applicable regulations and GCP. Each subject’s legally authorized representative is requested to 
sign and date the subject informed consent form or a certified translation if applicable, after the 
subject’s parent or guardian has received and read (or been read) the written subject information 
and received an explanation of what the study involves, including but not limited to: the 
objectives, potential benefits and risk, inconveniences, and the subject’s rights and 
responsibilities. A copy of the informed consent documentation (ie, a complete set of subject 
information sheets and fully executed signature pages) must be given to the subject’s legally 
authorized representative, as applicable. This document may require translation into the local 
language. Signed consent forms must remain in each subject’s study file and must be available 
for verification at any time.
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The principal investigator provides the sponsor with a copy of the consent form  that was 
reviewed by the IRB/EC and received their favorable opinion/approval. A copy of the IRB/EC’s 
written favorable opinion/approval of these documents must be provided to the sponsor prior to 
the start of the study unless it is agreed to and documented (abiding by regulatory guidelines and 
national provisions) prior to study start that another party (ie, sponsor or coordinating principal 
investigator) is responsible for this action. Additionally, if the IRB/EC requires modification of 
the sample subject information and consent document provided by the sponsor, the 
documentation supporting this requirement must be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the sponsor/designee has received 
written IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB/EC informed of any serious and 
significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996. A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the sponsor/designee.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
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After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market teduglutide; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2 to 4 and certain other studies as determined by Shire. The purpose of 
the publication steering committee is to act as a non-commercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, royalty 
free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
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Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.
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11.
REFERENCES
Beattie, L. M., Barclay, A. R. & Wilson, D. C. 2010. Short bowel syndrome and intestinal failure 
in infants and children. Paediatrics and Child Health, 20, 485-491.
Carter, Cohran, Cole, Corkins, Dimmitt, Duggan, Hill, Horslen, Lim, Mercer, Merritt, Nichol, 
Sigurdsson, Teitelbaum, Thompson, Vanderpool, Vaughan, Li, Youssef, Venick & 
Kocoshis 2017. Outcomes from a 12-Week, Open-Label, Multicenter Clinical Trial of 
Teduglutide in Pediatric Short Bowel Syndrome. Journal of Pediatrics, The, 181, 102-
111.e5.
Gonzalez-Hernandez, Prajapati, Ogola, Channabasappa, Drews & Piper 2017. Predicting time to 
full enteral nutrition in children after significant bowel resection. Journal of Pediatric 
Surgery, 52, 764-767.
Goulet, O. & Ruemmele, F. 2006. Causes and Management of Intestinal Failure in Children. 
Gastroenterology, 130, S16-S28.
Huisman-de Waal, G., Schoonhoven, L., Jansen, J., Wanten, G. & van Achterberg, T. 2007. The 
impact of home parenteral nutrition on daily life-A review. Clinical Nutrition, 26, 275-
288.
Khan, F. A., Squires, R. H., Litman, H. J., Balint, J., Carter, B. A., Fisher, J. G., Horslen, S. P., 
Jaksic, T., Kocoshis, S., Martinez, J. A., Mercer, D., Rhee, S., Rudolph, J. A., Soden, J., 
Sudan, D., Superina, R. A., Teitelbaum, D. H., Venick, R., Wales, P. W. & Duggan, C. 
2015. Predictors of Enteral Autonomy in Children with Intestinal Failure: A Multicenter 
Cohort Study. J Pediatr, 167, 29-34.e1.
Marier, J., Kassir, N., Martin, P. & Wang, Y. 2017. Population pharmacokinetic modeling of 
teduglutide to support dosing in pediatric patients with short bowel syndrome. Clinical 
Pharmacology & Therapeutics, 101, S91.
Martin, G.-R., Beck, P.-L. & Sigalet, D.-L. 2006. Gut hormones, and short bowel syndrome: the 
enigmatic role of glucagon-like peptide-2 in the regulation of intestinal adaptation. World 
Journal of Gastroenterology, 12, 4117-29.
O'Keefe, S. J., Buchman, A. L., Fishbein, T. M., Jeejeebhoy, K. N., Jeppesen, P. B. & Shaffer, J. 
2006. Short bowel syndrome and intestinal failure: consensus definitions and overview. 
Clin Gastroenterol Hepatol, 4, 6-10.
Sigalet, D. L., Martin, G., Meddings, J., Hartman, B. & Holst, J. J. 2004. GLP-2 levels in infants 
with intestinal dysfunction. Pediatr Res, 56, 371-6.
Spencer, A. U., Neaga, A., West, B., Safran, J., Brown, P., Btaiche, I., Kuzma-O'Reilly, B. & 
Teitelbaum, D. H. 2005. Pediatric Short Bowel Syndrome: Redefining Predictors of 
Success. Annals of Surgery, 242, 403-412.
Squires, R. H., Duggan, C., Teitelbaum, D. H., Wales, P. W., Balint, J., Venick, R., Rhee, S., 
Sudan, D., Mercer, D., Martinez, J. A., Carter, B. A., Soden, J., Horslen, S., Rudolph, J. 
A., Kocoshis, S., Superina, R., Lawlor, S., Haller, T., Kurs-Lasky, M. & Belle, S. H. 
2012. Natural history of pediatric intestinal failure: initial report from the Pediatric 
Intestinal Failure Consortium. J Pediatr, 161, 723-8.e2.
Tappenden, K. A., Edelman, J. & Joelsson, B. 2013. Teduglutide enhances structural adaptation 
of the small intestinal mucosa in patients with short bowel syndrome. J Clin 
Gastroenterol, 47, 602-7.
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Thymann, T., Stoll, B., Mecklenburg, L., Burrin, D. G., Vegge, A., Qvist, N., Eriksen, T., 
Jeppesen, P. B. & Sangild, P. T. 2014. Acute effects of the glucagon-like peptide 2 
analogue, teduglutide, on intestinal adaptation in short bowel syndrome. J Pediatr 
Gastroenterol Nutr, 58, 694-702.
Wales, P. W., de Silva, N., Kim, J., Lecce, L., To, T. & Moore, A. 2004. Neonatal short bowel 
syndrome: population-based estimates of incidence and mortality rates. J Pediatr Surg,
39, 690-5.
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12.
APPENDICES
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Appendix 1
Protocol History
Document
Date
Global/Country/Site Specific
Original Protocol
03 Oct 2017
Global
Amendment 1
18 Jan 2018
Global
Amendment 1.1
07 Aug 2018
France-specific
Amendment 2.1
04 Dec 2018
France-specific
Amendment 3.1
24 May 2019
France-specific
Amendment 4.1
17 Dec 2019
France-specific
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change and Rationale
Section(s) Affected by Change
Updated emergency contact information to reflect the change of the 
Contract Research Organization’s name.
Emergency Contact Information
Clarified the duration of the screening period and total time on study. 
Provided a clear definition of study completion.
Synopsis, Section 3.1, Section 3.2
Updated the study schematic to reflect the study design changes.
Revised the telephone and clinic visit schedule to assure laboratory 
measurement could be collected without exceeding weekly/monthly total 
blood volume restrictions. 
Synopsis, Table 1, Section 3.1.2
Moved the PK sampling from Week 6 to Week 7 so that the samples 
could be collected without exceeding weekly/monthly total blood volume 
restrictions.
Synopsis, Table 1, Section 3.1.2, 
Section 7.2.4, Table 5
Clarified that blood for pharmacokinetic samples of postdose may be 
taken within ± 10 minutes of the time pre-specified.
Clarified that end jejunostomy or ileostomy are examples  of small bowel 
ostomy rather than the stratification factors.
Synopsis, Section 3.1.2, Section 6.2.2
Clarified that all subjects regardless of treatment arm are eligible for the 
extension study.
Synopsis, Section 3.1.3
Clarified that if a subject treated with teduglutide meets the escape 
criteria, the assessments scheduled for the EOS visit should be conducted.
Synopsis, Table 2, Section 3.1.3, 
Section 6.2.3
Clarified that subjects must be 4 to 12 months corrected gestational age at 
screening.
Synopsis, Section 4.1
Changed dose adjustments to Week 12 rather than at every clinic visit to 
reduce site burden.
Synopsis, Table 1, Section 6.2.3
Clarified the definition of enteral autonomy.
Synopsis, Section 9.7.2
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
18 Jan 2018
Global
Description of Change and Rationale
Section(s) Affected by Change
Updated the pharmacokinetic endpoint and analysis to reflect that only 
descriptive statistics will be calculated on plasma teduglutide 
concentration values. Pharmacokinetic parameters will be estimated using 
a population PK modeling approach as appropriate and reported 
separately.
Synopsis, Section 9.10
Removed assessment of the 5-level EuroQol five dimensions 
questionnaire to reduce caregiver burden.
Synopsis, Table 1, Section 7.2.5, 
Section 9.9
Clarified that native GLP-2 samples drawn while subjects are receiving 
teduglutide should be drawn at least 14 hours after the previous dose.
Table 2, Section 7.2.2
Inserted a footnote to clarify that parenteral support and parenteral 
nutrition are used interchangeably.
Section 1.1
Removed the 5 mg vial of teduglutide as this size vial will not be 
supplied for this study.
Section 6.1
Clarified the procedures for assessing subject compliance. 
Section 6.5
Specified that it is acceptable to only enroll subjects who have already
had an upper GI series with small bowel follow through performed since 
the subject’s most recent surgery. 
Section 7.2.1
Corrected the volume of blood to be collected for native GLP-2.
Table 5
Removed references to subject assent as assent is not possible in a study 
of infants. 
Section 7.1.1, Section 10.3.1
Clarified the definitions of the analysis sets.
Section 9.6
Clarified that an adjustment to enteral nutrition as appropriate is part of 
the PN/IV adjustment algorithm.
Figure A-1
Minor editorial changes and corrections to typographical errors (which do 
not modify content and/or intent of the original document) were made.
Throughout protocol.
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1.1
Amendment Date
07 Aug 2018
France-specific
Description of Change and Rationale
Section(s) Affected by Change
The Shire contact was updated to 
.
Emergency Contact Information
Added an exclusion criterion for Gilbert’s disease and liver failure 
based on the values of the transaminases and of total bilirubin as 
requested by Agence Nationale de Sécurité du Medicament et des 
Produits de Santé (ANSM).
Synopsis, Section 4.2
Added an exclusion criterion for hypersensitivity to trace residues of 
tetracycline to be consistent with the European Summary of Product 
Characteristics of teduglutide as requested by ANSM.
Synopsis, Section 4.2
Added text to specify that efforts to minimize pain and discomfort 
during procedures such as peripheral venipuncture will be implemented.
Section 7.2.3
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2.1
Amendment Date
04 Dec 2018
France-specific
Description of Change and Rationale
Section(s) Affected by Change
The fax number currently used to send the Shire Medical Monitor a 
copy of the Shire Clinical Study Adverse Event Form for Serious 
Adverse Events (SAEs) and Non-serious AEs as Required by Protocol 
is now retired; a copy of the form must be sent by email only.
Updated emergency contact information to reflect the change of Shire 
medical monitor to 
, IQVIA back up medical support 
to 
, and IQVIA phone number for medical 
emergencies.
Emergency Contact Information
A single email address (
) is now used to report a 
Product Quality Complaint, independently from where it has originated.  
Product Quality Complaints
Added the new secondary efficacy endpoint “Time to achieve enteral 
autonomy” and statistical methodology to be used.
Synopsis, Section 9.7.1.2, 
Section 9.7.2
Updated  the information on the clinical studies with teduglutide in 
pediatric subjects to include the results of TED-C14-006.
Section 1.2
Clarified that teduglutide is the investigational product for this study.
Section 6.1
Updated the dose selection rationale with results from a simulation 
work using the previous population pharmacokinetic model. Based on 
the totality of clinical data, 0.05 mg/kg once daily is  expected to 
provide comparable Cmax concentrations in infants as compared to 
pediatric patients with SBS and was recommended as an evaluation 
dosing regimen in Study SHP633-301.
Section 6.2.5
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2.1
Amendment Date
04 Dec 2018
France-specific
Description of Change and Rationale
Section(s) Affected by Change
Clarified that rescreening of subjects in the study will not be allowed. 
(Administrative amendment dated 03 Oct 2018)
Section 7.1.1
Clarifications were made to the definition of adverse events.
Section 8.1, Section 8.1.5, 
Section 8.2.4
Added heart failure with severe fluid overload, determined by the 
sponsor or investigator to be related to the investigational product, to 
the list of events leading to interruption of investigational product 
administration. This addition is in alignment with the warnings and
special precautions listed in the investigator brochure.
Section 8.4
As recommended by the FDA, specified that if the DMC recommends 
termination of this pediatric study, the recommendations will be 
communicated to the relevant regulatory agencies within 7 calendar 
days.
Section 9.4
Minor editorial changes and corrections to typographical errors (which 
do not modify content and/or intent of the original document) were 
made.
Throughout the protocol
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
3.1
Amendment Date
24 May 2019
France-specific
Description of Change and Rationale
Section(s) Affected by Change
Deleted Inclusion Criteria #6, Lack of terminal ileum and ileocecal valve, 
due to difficulties in enrollment. 
Synopsis, Section 4.1
Minor editorial changes and corrections to typographical errors (which do 
not modify content and/or intent of the original document) were made.
Throughout the protocol
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Appendix 2
Guidelines for Nutritional Support Management During the Study
The nutritional support adjustment guidelines are designed to standardize management of 
parenteral and enteral nutritional support in this study. Adjustments to nutritional support should 
be considered at every scheduled clinic visit. Adjustments at phone visits may also be performed, 
but nutritional assessments at phone visits serve primarily to confirm that nutritional adjustments 
at prior clinic visits were tolerated.
All attempts should be made to follow the guidelines, but departure from the guidelines will not 
constitute a protocol deviation.
Clinical judgment is required within the algorithm. Each decision point requires integrating 
multiple sources of information into a yes/no decision. When individual data points are 
conflicting, the investigator must use their best judgment in the assessment.
If intestinal adaptation is occurring, reductions in parenteral support volume and calories are 
expected to be in decrements of 5 to 10% relative to baseline values. Parenteral support 
components are at the discretion of the investigator, but care should be taken to balance 
carbohydrate, fat, and protein. Likewise, if intestinal adaptation is occurring, enteral nutrition 
volume and calories should be increased in increments of approximately 10% relative to baseline 
values.
Assessment of the severity of malabsorption may require estimation of stool output for children 
who have mixed stool and urine output.
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.
During the 48-hour output measurement period prior to the subject’s scheduled visit, no further 
changes to the prescribed nutritional support should be made.
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Figure A-1:
Parenteral Nutrition/Intravenous Adjustment Algorithm for All Subjects  
BUN=blood urea nitrogen; Cr=creatinine; PN=parenteral nutrition; UNa=urine sodium; UOP=urine output; USpGr=Urine specific gravity; VS=vital signs; vol=volume
Adequately hydrated?
•
Normal exam and VS
•
Weight stable
•
UOP > 1 ml/kg/h
•
USpGr < 1.020
•
UNa > 20 meq/L
•
Stable, normal BUN/Cr
yes
no
Adequate weight gain 
and linear growth?
↑ PN kcal or no change
↓PN vol and kcal
↑ PN vol +/- kcal
yes
no
Assess severity of malabsorption and adjust EN as appropriate
For non-commercial use only

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
 
 
NCT Number:   
NCT03571516 
 
Study Title:  
A Randomized, Open-label, 24-Week Safety, Efficacy, and Pharmacokinetic 
Study of Teduglutide in Infants 4 to 12 Months of Age With Short Bowel 
Syndrome Who Are Dependent on Parenteral Support 
 
Study Number:  
SHP633-301 
 
 
SAP Version and Date:   
Version 1.1:  
 
24 Mar 2020 


STATISTICAL ANALYSIS PLAN
Teduglutide
PHASE 3
A Randomized, Open-label, 24-Week Safety, Efficacy, and
Pharmacokinetic Study of Teduglutide in Infants 4 to 12 Months of Age
with Short Bowel Syndrome Who are Dependent on Parenteral Support
PROTOCOL IDENTIFIER: SHP633-301
Study Sponsor(s):
Shire Human Genetic Therapies, Inc.
300 Shire Way
Lexington, MA 02421 USA
Author:
Protocol Version #:
Amendment 4: 17 Dec 2019
Amendment 3: 24 May 2019
Amendment 2: 04 Dec 2018
Amendment 1: 18 Jan 2018
Original Protocol: 03 Oct 2017
SAP Version #:
1.1
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Statistical Analysis Plan v1.1
Protocol Number: SHP633-301
24Mar2020
SAP Date:
24Mar2020
Status:
v1.1
REVISION HISTORY
Version
Issue Date
Summary of Changes
1.0
11Dec2018
New Document
1.1
24Mar2020
See detailed summary of changes in Appendix 14.3
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Page 3 of 50
Statistical Analysis Plan v1.1
Protocol Number: SHP633-301
24Mar2020
TABLE OF CONTENTS
REVISION HISTORY ......................................................................................................2
TABLE OF CONTENTS ..................................................................................................3
ABBREVIATIONS............................................................................................................7
1.
INTRODUCTION..................................................................................................9
2.
OBJECTIVES, ESTIMANDS, AND ENDPOINTS ...........................................9
2.1
Objectives............................................................................................................9
2.2
Estimands............................................................................................................9
2.3
Endpoints ..........................................................................................................12
2.3.1
Primary Endpoint.......................................................................................12
2.3.2
Secondary Endpoints .................................................................................12
2.3.3
Other Efficacy Endpoints...........................................................................12
2.3.4
Safety Endpoints........................................................................................12
2.3.5
Pharmacokinetic Endpoints .......................................................................13
2.3.6
Healthcare Resource Utilization Endpoint.................................................13
3.
STUDY DESIGN..................................................................................................13
3.1
General Description ..........................................................................................13
3.2
Randomization ..................................................................................................14
3.3
Blinding.............................................................................................................14
3.4
Sample Size and Power Considerations............................................................14
4.
STATISTICAL ANALYSIS SETS.....................................................................15
4.1
Screened Set......................................................................................................15
4.2
Intent-to-Treat Set.............................................................................................15
4.3
Safety Set ..........................................................................................................15
4.4
Per-protocol Set.................................................................................................15
4.5
Pharmacokinetic Set..........................................................................................16
5.
STUDY SUBJECTS.............................................................................................16
5.1
Disposition of Subjects .....................................................................................16
5.2
Demographic and Other Baseline Characteristics.............................................17
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Statistical Analysis Plan v1.1
Protocol Number: SHP633-301
24Mar2020
5.3
Surgical and Medical History............................................................................18
5.4
Short Bowel Syndrome History ........................................................................18
5.5
Upper Gastrointestinal Series with Small Bowel Follow-through....................19
5.6
Prior Medication and Procedure........................................................................19
5.7
Concomitant Medications and Procedures........................................................19
5.8
Exposure to Investigational Product .................................................................20
5.9
Measurements of Treatment Compliance .........................................................20
5.10
Protocol Deviations...........................................................................................21
6.
EFFICACY ANALYSES ....................................................................................22
6.1
Analyses of Primary Efficacy Endpoint............................................................22
6.1.1
Sensitivity Analyses of Primary Efficacy Endpoint ..................................23
6.2
Analyses of Secondary Efficacy Endpoints......................................................23
6.2.1
Reduction in PS Caloric Intake from Baseline to Week 24/EOT..............23
6.2.2
Complete Weaning Off PS Support...........................................................23
6.2.3
Time to Achieve Enteral Autonomy..........................................................24
6.2.4
Change and Percent Change from Baseline in PS Support at Each Visit..24
6.2.5
Change and Percent Change from Baseline in Enteral Nutritional 
Support at Each Visit .................................................................................24
6.2.6
Increase in Enteral Nutritional Support from Baseline to Week 
24/EOT.......................................................................................................25
6.2.7
Supplementary Analyses of Secondary Efficacy Endpoints......................25
6.3
Analysis of Other Efficacy endpoints ...............................................................25
6.3.1
Native GLP-2.............................................................................................25
6.3.2
Change and Percent Change from Baseline in Hours per Day and Days 
per Week of PS Support.............................................................................25
6.3.3
Escape Criteria During Follow up Period..................................................26
6.4
Multiplicity Adjustment....................................................................................26
6.5
Subgroup Analysis ............................................................................................26
7.
SAFETY ANALYSIS...........................................................................................26
7.1
Adverse Events..................................................................................................26
7.1.1
All TEAEs..................................................................................................27
7.1.2
Serious Adverse Events .............................................................................27
7.1.3
AEs Leading to Discontinuation of Study Drug........................................28
7.1.4
Adverse Events Leading to Death..............................................................28
7.1.5
Adverse Events of Special Interest ............................................................28
7.2
Clinical Laboratory Data...................................................................................29
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Statistical Analysis Plan v1.1
Protocol Number: SHP633-301
24Mar2020
7.2.1
Reference Ranges.......................................................................................30
7.2.2
Markedly Abnormal Laboratory Criteria...................................................30
7.3
Antibodies to Teduglutide.................................................................................32
7.4
Vital Signs.........................................................................................................32
7.5
Physical Examination........................................................................................33
7.6
Fecal and Urine Output.....................................................................................33
8.
PHARMACOKINETIC ANALYSIS.................................................................34
8.1
Drug Concentration...........................................................................................34
8.2
Handling Below Limit of Quantitation (BLQ) Values .....................................34
8.3
Pharmacokinetic Parameters.............................................................................34
8.4
Statistical Analysis of Pharmacokinetic Data ...................................................34
9.
OTHER ANALYSES...........................................................................................34
9.1
Health-related Quality of Life Analyses ...........................................................34
10.
DATA MONITORING COMMITTEE/INTERIM ANALYSIS.....................34
11.
DATA HANDLING CONVENTIONS ..............................................................35
11.1
General Data Reporting Conventions ...............................................................35
11.2
Common calculations........................................................................................35
11.3
Reference Start Date and Study Day.................................................................35
11.4
Definition of Baseline .......................................................................................36
11.5
Definition of Visit Windows.............................................................................36
11.6
Derived Efficacy Endpoints..............................................................................36
11.7
Repeated or Unscheduled Assessments ............................................................38
11.8
Handling of Missing, Unused, and Spurious Data............................................38
11.8.1 Missing Date of Investigational Product....................................................38
11.8.2 Missing Date Information for Prior or Concomitant Medications 
(Therapies/Procedures) ..............................................................................38
11.8.3 Missing Date Information for Adverse Events..........................................41
11.8.4 Missing Severity Assessment for Adverse Events.....................................43
11.8.5 Missing Relationship to Investigational Product for Adverse Events .......43
11.8.6 Character Values of Clinical Laboratory Variables...................................43
11.8.7 Unused data................................................................................................44
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Statistical Analysis Plan v1.1
Protocol Number: SHP633-301
24Mar2020
12.
ANALYSIS SOFTWARE ...................................................................................44
13.
CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL............................44
14.
APPENDICES......................................................................................................45
14.1
Decimal Places and Rounding Rules ................................................................45
14.2
Identified Tables/Figures/Listings for Interim Analysis...................................45
14.3
Changes in the Statistical Analysis Plan...........................................................48
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Statistical Analysis Plan v1.1
Protocol Number: SHP633-301
24Mar2020
ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
BLQ
Below the Lower Limit of Quantification
BUN
Blood Urea Nitrogen
CTMS
Clinical Trial Management System
DMC
Data Monitoring Committee
eCRF
Electronic Case Report Form
EN
Enteral Nutrition
EOS
End of Study
EOT
End of Treatment
GI
Gastrointestinal
GLP-2
Glucagon-Like Peptide 2 
ICF
Informed Consent Form
INR
International Normalized Ration
IP
Investigational Product
ITT
Intent-to-Treat
IWRS
Interactive Web Response System
M
Months
MedDRA
Medical Dictionary for Regulatory Activities
LLN
Lower Limit of Normal
LOCF
Last Observation Carried Forward
LOV
Last Observed Value
LVOT
Last Value on Treatment
PCS
Potentially Clinically Significant
PD
Pharmacodynamic
PK
Pharmacokinetic
PP
Per-Protocol
PS
Parenteral Support
Pt
Prothrombin Time
PT
Preferred Term (MedDRA)
Q1
25th Percentile
Q3
75th Percentile
RBC
Red Blood Cells
SAF
Safety 
SAE
Serious Adverse Event
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Statistical Analysis Plan v1.1
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SAP
Statistical Analysis Plan
SBS
Short Bowel Syndrome
SC
Subcutaneous
SD
Standard Deviation
SEM
Standard Error of the Mean
SI
Standard International
SMQ
Standardized MedDRA Query
SOC
System Organ Class
SRN
Screened
TEAE
Treatment-Emergent Adverse Event
TESAE
Treatment-Emergent Serious Adverse Event
ULN
Upper Limit of Normal
ULQ
Upper Limit of Quantification
WBC
White Blood Cells
WHO
World Health Organization
WHODD
WHO Drug Dictionary
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Statistical Analysis Plan v1.1
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1.
INTRODUCTION
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the 
statistical analyses of safety, efficacy and pharmacokinetic data. The SAP version 1.0
was developed based on protocol amendment 2 dated 2018-Dec-04. This SAP version 1.1 
was updated based on protocol amendment 4 dated 2019-Dec-17. Specifications for 
tables, figures, and listings are contained in separate documents and updated as needed.
2.
OBJECTIVES, ESTIMANDS, AND ENDPOINTS
2.1
Objectives
The objectives of this study are to evaluate the safety, efficacy/pharmacodynamics (PD) 
and pharmacokinetics (PK) of teduglutide treatment in infants with Short Bowel 
Syndrome (SBS) dependent on parenteral support.
2.2
Estimands
There is no specified hypothesis testing. The selected estimands are described in Table 1.
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Table 1: List of Selected Estimands
Estimand
Definition
Attributes
A: 
Population
B: Variable 
(or endpoint)
C: Strategy for 
addressing 
intercurrent 
event
D: Population-level summary
Primary
The primary 
estimand is the 
effect of 
teduglutide 
compared to 
standard of care 
on weight-
normalized 
parenteral support 
(PS) volume at 
Week 24
ITT set,
4-12 months 
old infants 
with SBS 
who are 
dependent 
on 
parenteral 
support 
At least 20% 
reduction in 
weight-
normalized PS 
volume at 
Week 24 
compared to 
baseline based 
on diary data
Evaluated 
regardless of 
treatment 
received or 
protocol 
violations
Number/percentage of subjects who achieved 
at least 20% decrease in weight-normalized PS 
volume at Week 24 compared to baseline, 
where percent reduction in PS volume is define 
as [(average daily value at the scheduled visit -
average daily value at baseline) / average daily 
value at baseline] * 100
And average daily value is defined as: [(sum of 
non-missing daily values in the diary / number 
of days with non-missing values)] / last 
available body weight prior to the visit
Secondary
Reduction in 
weight-
normalized 
parenteral calories 
by at least 20% 
from baseline to 
Week 24/ End of 
ITT set, 4-
12 months 
old infants 
with SBS 
who are 
dependent 
on 
parenteral 
At least 20% 
reduction in 
weight-
normalized PS 
calories at 
Week 24 
compared to 
baseline based 
Evaluated 
regardless of 
treatment 
received or 
protocol 
violations
Number/percentage of subjects who achieved 
at least 20% decrease in weight-normalized PS 
calories at Week 24 compared to baseline, 
where percent reduction in PS calories is 
define as [(average daily value at the scheduled 
visit - average daily value at baseline) / 
average daily value at baseline] * 100
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Statistical Analysis Plan v1.1
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Treatment (EOT)
support
on diary data
And average daily value is defined as: 
(prescribed weekly PS volume / 7) / last 
available weight prior to or on the date of visit
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Statistical Analysis Plan v1.1
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2.3
Endpoints
2.3.1
Primary Endpoint

Reduction in weight-normalized PS volume by at least 20% from baseline at
Week 24/EOT
2.3.2
Secondary Endpoints

Reduction in weight-normalized PS caloric intake by at least 20% from baseline
to Week 24/EOT

Achievement of enteral autonomy by Week 24

Time to achieve enteral autonomy

Change in weight-normalized PS volume from baseline to each visit

Change in weight-normalized PS caloric intake from baseline to each visit

Change in weight-normalized enteral nutrition (EN) volume from baseline to each
visit

Change in weight-normalized EN caloric intake from baseline to each visit

Increase in weight-normalized EN volume by at least 20% from baseline to week
24/EOT

Increase in weight-normalized EN caloric intake by at least 20% from baseline to
week 24/EOT
2.3.3
Other Efficacy Endpoints

Native glucagon-like peptide 2 (GLP-2)

Change and percent change from baseline to each visit in hours per day of PS
support

Change and percent change from baseline to each visit in days per week of PS
support

Escape criteria during follow up period
2.3.4
Safety Endpoints

Adverse events (AEs)

Physical examinations

Vital signs

Weight, length, head circumference, and weight-for-length Z-scores (corrected for
gestational age)

Laboratory safety data (biochemistry and hematology)

Urine output
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Statistical Analysis Plan v1.1
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
Stool (including mixed) output

Antibodies to teduglutide
2.3.5
Pharmacokinetic Endpoints

Summary of plasma teduglutide concentration at nominal time point
2.3.6
Healthcare Resource Utilization Endpoint

Cumulative number of hospitalization days during the study
3.
STUDY DESIGN
3.1
General Description
This is a randomized, multicenter, open-label study, consisting of a 2 to 4-week screening 
period, a 24-week treatment period and a 4-week follow-up period. A schematic 
representation of the study design is presented in Figure 1.
Figure 1: Study Schematic
*At EOS all subjects regardless of treatment arm may enroll in an extension study if that study is open to enrollment at
the time of the SHP633-301 EOS that will capture long-term safety data and provide the opportunity for additional 
teduglutide treatment. The follow-up period for subjects in the teduglutide treatment arm may be interrupted and the 
subjects may proceed immediately to the EOS if at least one“escape”criteria is met.
Once patients sign the informed consent they will be screened for a minimum of two and 
maximum of four weeks to determine their study eligibility.
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Statistical Analysis Plan v1.1
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At the baseline visit (Week 0), subjects will be randomized to the teduglutide or standard 
of care treatment arm. During the 24-week treatment period, subjects in the standard of 
care treatment arm will receive standard medical therapy for SBS, while those in the 
teduglutide arm will receive 0.05 mg/kg by subcutaneous (SC) injection once daily in 
addition to standard medical therapy.
Subjects in both arms will follow the same visit schedule and assessments. Subjects will 
be monitored weekly with phone or clinic visits. Clinic visits will occur at Weeks 1, 3, 5, 
7, 9, 12, 16, 20, 24, and 28. At all site visits and telephone contacts, safety will be 
monitored and nutritional support will be reviewed and adjusted as needed.
To maintain consistency across all centers, sites and subjects should be made to follow 
the nutritional support adjustment guidelines (developed with SBS expert input and 
provided in the protocol) for decisions regarding PS reduction and advances in enteral 
feeds based on weight gain, urine and stool output, and clinical stability.
At the end of the treatment period (Week 24/EOT), all subjects will enter a 4-week 
follow-up period until the end of study (Week 28/End of Study [EOS]) during which time 
subjects will receive standard medical therapy, but no investigational product (IP) will be 
administered. At EOS, all subjects regardless of treatment arm may enroll in an extension 
study if that study is open to enrollment at the time of the SHP633-301 EOS. The follow-
up period for subjects in the teduglutide treatment arm may be interrupted and the 
subjects may proceed immediately to the EOS visit if at least one of the “escape” criteria 
highlighted in protocol section 3.1.3.
Schedule of events can be found in Study Schedule Section (Table 1 and Table 2) of the 
protocol.
Study completion is defined as the last subject, last visit. This is the visit date at which 
the last subject on the study has his or her last follow-up visit on the study (whether 
during the 24-week treatment period or the 4-week follow-up period).
3.2
Randomization
Subjects who meet all the inclusion criteria and none of the exclusion criteria will be 
randomized (1:1 ratio) to either teduglutide or standard of care arm using the interactive 
web response system (IWRS).  The randomization will be stratified per the presence of a 
small bowel ostomy (e.g., end jejunostomy or ileostomy).
3.3
Blinding
Not applicable for this open label study.
3.4
Sample Size and Power Considerations
Sample size is determined based on enrollment feasibility for this rare condition and the 
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Statistical Analysis Plan v1.1
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age of the study population.
In this study, at least 10 subjects will be randomized: at least 5 subjects in a teduglutide 
treatment arm and at least 5 subjects in an standard of care comparator arm.
4.
STATISTICAL ANALYSIS SETS
Analysis of efficacy and safety endpoints will be performed based on the analysis sets 
defined in this section and as specified for each endpoint throughout this SAP.  
If two analysis sets are the same, then only one set of tables will be generated.  
Therefore, if ITT set is same as Safety Set, only ITT set of tables will be generated. 
4.1
Screened Set
The Screened (SRN) set will consist of all subjects who have signed informed consent. 
Data for subjects who fail to pass the screening period will be included in the listings, but 
will not be included in any analyses.
4.2
Intent-to-Treat Set
The Intent-to-Treat (ITT) set will consist of all subjects randomized in the study. 
Whenever using ITT set, subjects will be presented in the treatment regimen to which 
they were randomized at the start of the treatment period (even if the treatment they 
received was different).  
All efficacy analyses will be conducted on this population, unless otherwise specified.
4.3
Safety Set
The Safety (SAF) set will contain all subjects who met the following criteria:
Teduglutide treatment arm: subjects who receive at least 1 dose of teduglutide and have 
undergone at least 1 post-baseline safety assessment.
Standard of care treatment arm: subjects who have undergone at least 1 post-baseline 
safety assessment.
Subjects will be classified according to treatment they actually received. All safety 
analyses will be conducted on this population, unless otherwise specified.
4.4
Per-protocol Set
The Per-protocol (PP) set will contain all subjects in the ITT set who complete the 
study treatment period without any major protocol deviations or other situations that 
could potentially affect the efficacy conclusions of the study.
The situations that may affect inclusion in the PP set include, but are not limited to:
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
Non-compliance to study drug for the treatment group as defined in Section 5.9.

Clinically significant discrepancies between planned and actual treatment.

Missing baseline or week 24 efficacy data.
4.5
Pharmacokinetic Set
All subjects who received at least one dose of teduglutide and have at least one 
evaluable and interpretable post-dose PK concentration value.
5.
STUDY SUBJECTS
5.1
Disposition of Subjects
All subjects who provide informed consent will be accounted for in this study. 
Assessment of eligibility to the inclusion and exclusion criteria will be performed at 
Screening and re-confirmed at the Baseline visit.
The reason(s) for permanent discontinuation of treatment and/or withdrawal from the 
study must be determined by the investigator, and recorded in the subject’s medical 
record and in the electronic case report form (eCRF). If a subject is withdrawn for more
than one reason, each reason should be documented in the source document, and the 
most clinically relevant reason should be entered in the eCRF. Overall reasons for 
discontinuation of treatment and withdrawal from study will be summarized separately 
based on the following categories:

Adverse event

Failure to meet enrollment criteria

Non-compliance with study drug

Protocol deviation

Lack of efficacy

Physician decision

Withdrawal by Parent/Guardian

Lost to follow-up

Study terminated by sponsor

Site terminated by sponsor

Technical Problems

Death
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
Other
The following summary tables are planned for presentation:

Subject disposition (SRN set)

Analysis Sets (ITT set)

Protocol deviations (ITT set)

Protocol deviations (SAF set)

Enrollment duration by site (SRN set)
The presentation of planned listings will include the following:

Subject Disposition (SRN set)

Study inclusion and exclusion criteria violations (SRN set)

Screen Failure Data (Screen Failures)

Protocol deviations (SRN set)

Subjects excluded from Per Protocol Set (SRN set)

Subjects assignment to analysis sets (SRN set)

Follow-up Period Escape Criteria (SAF set)
5.2
Demographic and Other Baseline Characteristics
Descriptive summaries of demographic and other baseline characteristics will be 
presented by treatment assignment for the ITT, Safety, and PP sets.
The following demographic and other baseline characteristics will be summarized in the 
following order in the tables:

Corrected gestational age (months)

Corrected gestational age category (months):
o
4 - < 6 months
o
6 - 12 months

Chronological age (months)

Sex

Ethnicity
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
Race

Weight Z-scores at Baseline

Length Z-scores at Baseline

Weight/ length ratio Z-score at Baseline

Head circumference Z-scores at Baseline
The demographic data collected in the eCRF will be listed by subject.
5.3
Surgical and Medical History
Medical and Surgical History conditions are defined as those conditions which began 
prior to informed consent. Medical and surgical history includes all relevant past medical 
diagnoses and surgeries other than related to the cause or diagnosis of SBS. Medical and 
Surgical history will be collected at the Screening Visit (Visit -1) and will be coded using 
Medical Dictionary for Regulatory Activities (MedDRA). A table based on ITT and 
Safety sets, and a listing will be provided.
Data captured on the Medical and Surgical History page of the CRF will be presented by 
System Organ Class (SOC) and Preferred Term (PT). SOC will be sorted alphabetically 
and PT within SOC will be sorted by descending frequency in the teduglutide treatment 
arm.
5.4
Short Bowel Syndrome History
The following SBS History will be collected at screening and will be summarized and 
listed using the ITT and Safety sets:

Primary reason for the diagnosis of SBS

Secondary reason for the diagnosis of SBS

Presence of stoma; if Y, stoma type

Presence of any remaining colon; if Y, estimated percent colon remaining and
whether the colon is in continuity with the small bowel

Estimated length of remaining small intestine

Presence of Distal/Terminal Illeum and ileocecal valve
Date of first major surgical resection, date of last major surgical resection, date of 
diagnosis of SBS and method of determining the length of remaining anatomy will be 
presented in the listing only.
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5.5
Upper Gastrointestinal Series with Small Bowel Follow-through
An upper gastrointestinal (GI) contrast series with small bowel follow-through collected 
at screening will be only listed as:

Normal

Abnormal, not clinically significant

Abnormal, clinically significant
Any abnormal results or reason for positive result will be specified within the listing also.
5.6
Prior Medication and Procedure
Prior medications will be coded using the World Health Organization Drug Dictionary 
(WHODD). Prior therapies and procedures will be coded using MedDRA.
Prior medications (therapies/procedures) are defined as any medications
(therapies/procedures) received prior to and discontinued before the reference start date 
(see section 11.3 for definition of reference start date). 
The prior medication usage will be summarized by the number and proportion of subjects 
in each treatment group within each preferred term for the Safety set. The prior 
medication will be sorted alphabetically by preferred name. Multiple medication usage by 
a subject in the same category will be counted only once.
The diagnostic, surgical, or therapeutic procedures during the study that are recorded in 
the eCRF will be presented only in a listing.
5.7
Concomitant Medications and Procedures
Concomitant medications will be coded using the WHODD. Concomitant procedures will 
be coded using MedDRA.
Concomitant medication (therapy/procedure) is defined as any medication taken on or 
after the first dose for the subjects teduglutide treatment arm, and on or after the 
randomization date for the subjects in standard of care treatment arm.
The concomitant therapies and medication usage will be summarized by the number and 
proportion of subjects in each treatment group receiving each medication within each 
preferred term for the Safety set. The concomitant therapies or medication will be sorted 
alphabetically by preferred name. Multiple concomitant therapies or medication usage by 
a subject in the same category will be counted only once.
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A listing of all medications, both prior and concomitant will be presented. The listing 
will be sorted by treatment group and subject identifier and will include reported name, 
dose, route of administration, dosing frequency, start date, end date, indication and 
period of medication (prior only, concomitant only, prior and concomitant). 
Investigator verbatim as well as coded terms will be included in the listings.
The diagnostic, surgical, or therapeutic procedures recorded during the study will be 
presented only in a listing.
5.8
Exposure to Investigational Product
Exposure to investigational product for the Safety, ITT and PP sets will be summarized in 
terms of treatment duration, which is calculated as the number of days from the date of 
first dose of investigational product taken to the date of the last dose of investigational 
product taken, inclusively:
Extent of exposure (days) = (date of last study drug administration – date of 
first study drug administration) + 1.
The date of first study drug administration is collected on the eCRF “First SC 
Injection” form. The date of last study drug is collected on the eCRF “End of 
Treatment” form.
The number and percentages of subjects will be tabulated for extent of exposure 
categorized into weeks (<4, 4-<12, 12-<24, >=24). Descriptive statistics (n, mean, 
standard deviation (SD), median, 25th Percentile (Q1), 75th Percentile (Q3), minimum, 
and maximum) will be presented to describe the exposure to investigational product for 
teduglutide treatment group (excluding the standard of care treatment arm).
Compliance and dose interruptions are not considered when determining the extent of 
exposure.
Information about interruptions of study drug by investigator decision (start date of 
interruption, date study drug resumed, and reason for interruption) will be included in 
data listing. Separate listings summarizing the study drug accountability and its 
administration will be produced. 
5.9
Measurements of Treatment Compliance
Study drug administration diary data will be used to measure study drug compliance. 
The first SC Injection page and the diary entries with “Yes” in response to the question:
“Was the study drug administered per instructions today?” will be counted towards 
compliance.
Subjects will be considered compliant overall for study drug administration if the 
calculated compliance is >=80%.
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Compliance with investigational drug will be calculated as the number of doses 
administered divided by the planned number of doses expressed as a percentage. This 
can be summarized as:
Overall percent compliance = (Total number of diary days marked “Yes” for 
study drug administration and the first injection page/ Number of days on 
treatment) * 100
where number of days on treatment will be calculated as (Date of last study drug – Date 
of first study drug + 1) and dose interruption days will be excluded, the sum of (Date of 
study drug resumed – start date of interruption +1).
Overall treatment compliance will be presented for percent compliance calculations 
using descriptive statistics and the number and percentage of subjects who are >=80% 
compliant by treatment group for the ITT and PP sets.
5.10
Protocol Deviations
Protocol deviations from the CTMS will be coded to categories and provided as part of 
the CTMS transfer to Biostatistics. Protocol deviation categories from CTMS include:

Informed Consent

Eligibility and Entry

Concomitant Medication

Laboratory Assessment

Study Procedures

Serious Adverse Event

Randomization

Visit Schedule

Investigational Product Compliance

Efficacy

Administrative

Source Document

Regulatory or Ethics Approvals

Other
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Confirmed protocol deviations will be summarized by category for each treatment group 
(Teduglutide and standard of care) and overall, for the ITT and Safety sets. All protocol 
deviations will be listed including the site of origin, type, class and description.
6.
EFFICACY ANALYSES
All efficacy analyses will be based on the ITT set. Baseline for all efficacy analyses is 
defined as the last observed value for the efficacy assessment prior to taking the first dose 
of investigational product (based on dates or date/times) or baseline visit for standard of 
care arm. All efficacy analyses will be conducted as per the treatment assigned. Given the 
small sample size, no hypothesis testing will be conducted. Endpoints will be evaluated 
descriptively. Therefore, there will be no adjustment for alpha level.
Efficacy endpoints will be evaluated separately based on:

Subject diary data (also referred to as “diary”)

Investigator-prescribed data (referred to as “prescribed”)
PS/EN support will be reported in both subject diary data and the investigator-
prescribed data in the eCRF. Investigator-prescribed data are the most recent PS/EN 
prescription (from either baseline or prescription adjustments) prior to or on the date of 
visit, captured in the PS/EN history and PS/EN adjustments eCRF pages.
PS/EN diary data are collected over 24-hour periods that start on the assigned date. 
Depending on the time of day at which the 24-hour period begins, which can vary by 
subject, overnight PS infusion volumes after midnight may be associated with prior the 
date. Baseline diary PS/EN parameters will be calculated using all the diary data 
collected within 14 days prior to the first dose or baseline visit. Calculation of post-
baseline diary PS/EN parameters will be based on the daily support recorded in 
subjects’ diaries within 7 days prior to the date of each scheduled post-baseline visit.
For the definitions and derivations of average daily values, refer to section 11.6.
6.1
Analyses of Primary Efficacy Endpoint
The primary efficacy endpoint is the reduction in weight-normalized PS volume of at 
least 20% at Week 24/EOT compared to baseline. Subjects who achieve at least 20% 
reduction in weight normalized PS support are considered responders. 
The number and percentage of subjects who achieve ≥20%, ≥50%, ≥75%, and 100% 
reduction in weight-normalized average daily diary PS volume at EOT will be 
summarized by treatment arm. The denominator will be the number of subjects for the 
ITT set in each treatment arm.
The same descriptive statistics will also be summarized based on investigator 
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prescribed data.
For the definition and derivation of percent reduction and weight-normalized average 
daily value, refer to section 11.6.
6.1.1
Sensitivity Analyses of Primary Efficacy Endpoint
A sensitivity analysis will also be performed using the PP set for both the subject diary 
data and the investigator prescribed data.
6.2
Analyses of Secondary Efficacy Endpoints
6.2.1
Reduction in PS Caloric Intake from Baseline to Week 24/EOT
Similar to the primary analysis, PS caloric intake reduction at week 24/EOT compared 
to baseline will be calculated. The number and percentage of subjects who achieve ≥
20%, ≥50%, ≥75%, and 100% reduction in weight-normalized PS caloric intake at 
week 24/EOT visit will be summarized by treatment group for diary data as well as 
prescribed data.
6.2.2
Complete Weaning Off PS Support
During the treatment period:
A subject will be considered to have achieved enteral autonomy (completely weaned 
off PS support) at a given visit if the investigator prescribes no PS at that visit and for 
the remainder of the treatment period and there is no use of PS recorded in the subject 
diary during the week prior to that visit and for the remainder of the treatment period.
During the follow-up period: 
A subject will be considered to have achieved enteral autonomy (completely weaned 
off PS support) at a given visit if the investigator prescribes no PS at that visit and for 
the remainder of the follow-up period and there is no use of PS recorded in the subject 
diary during the week prior to that visit and for the remainder of the follow-up period.
During the overall study period:
A subject will be considered to have achieved enteral autonomy (completely weaned 
off PS support) at a given visit if the investigator prescribes no PS at that visit and for 
the remainder of the overall study period and there is no use of PS recorded in the 
subject diary during the week prior to that visit and for the remainder of the overall 
study period.
The number and percentage of subjects, who achieve enteral autonomy at each scheduled 
visit, including EOT, follow up visits and EOS, will be summarized by treatment arm.
A supporting listing summarizing PS support status at week 28, escape criteria and last 
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visit date will be produced.
6.2.3
Time to Achieve Enteral Autonomy
Descriptive statistics will be used to summarize time to achievement of enteral autonomy 
(complete weaning off PS support) during treatment period, where the time to 
achievement of enteral autonomy is defined as the time from the reference start date until 
the date a subject is considered to have achieved enteral autonomy during a specific 
period:
Time to achievement of enteral autonomy (weeks) = (date subject meets all 
enteral autonomy criteria – reference start date +1) / 7
Data permitting, time to achievement of enteral autonomy during the treatment period
will be analyzed using Kaplan Meier method including Kaplan Meier plot. Log-rank test 
p-value will be provided as a supportive analysis. Subjects who will not achieve the 
enteral autonomy at the end of a specific period (treatment period, overall study period)
or subjects who discontinue the treatment during the treatment period or the study during 
the overall study period will be censored. 
A supporting listing of subjects achieving enteral autonomy and its durations during 
treatment period and overall study period will be produced.
6.2.4
Change and Percent Change from Baseline in PS Support at Each Visit
Changes in average daily weight-normalized diary and prescribed PS volume at each
post-baseline visit during the 24-week treatment period and 4-week follow-up period 
will be derived using the same formulas as for primary efficacy calculations.
Analogous calculations will be used to calculate changes in weight-normalized diary 
and prescribed PS calories. Mean ± SE plots of percent change from baseline in PS
volume (mL/kg/day) and caloric intake (kcal/kg/day) based on prescribed and diary 
data will be generated.
Baseline values, post-baseline values, change from baseline and percent change from 
the baseline in PS support and PS calories will be summarized by visit and treatment 
arm for diary data and prescribed data using descriptive statistics including number of 
subjects, mean, SD, median, Q1, Q3, minimum and maximum.
There will be subject level figures for PS support and PS calories based on diary data.
6.2.5
Change and Percent Change from Baseline in Enteral Nutritional Support
at Each Visit
The change and percent change from baseline in average daily weight-normalized diary
and prescribed EN volume and EN calories at each post-baseline visit during the 24-
week treatment period and 4-week follow-up period will be calculated and summarized 
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using analogous methods used for PS parameters. 
Baseline values, post-baseline values, change from baseline and percent change from 
the baseline in EN support and EN calories will be summarized by visit and treatment 
arm for diary data and prescribed data using descriptive statistics including number of 
subjects, mean, SD, median, Q1, Q3, minimum and maximum.
There will be subject level figures for EN support and EN calories based on diary data.
6.2.6
Increase in Enteral Nutritional Support from Baseline to Week 24/EOT
EN volume and caloric intake increase at week 24/EOT compared to baseline will be 
calculated. The number and percentage of subjects who achieve ≥20%, ≥50%, ≥75%, 
and 100% increase in weight-normalized EN volume or EN caloric intake at week 
24/EOT visit will be summarized by treatment group for diary data and prescribed data
using analogous methods used for PS parameters.
6.2.7
Supplementary Analyses of Secondary Efficacy Endpoints
There are no supplementary analyses of secondary efficacy endpoints planned.
6.3
Analysis of Other Efficacy endpoints
Since diary and prescribed PS and EN data will be analyzed separately, visit-level listing 
for average daily weight-normalized PS/EN volume, caloric intake, days per week and 
hours per day of PS support, will present diary and prescribed data side-by-side.
6.3.1
Native GLP-2
Native GLP-2 at baseline will be graphically summarized using scatter plots by percent 
change in PS Volume at Week 24/EOT for the ITT analysis set with a regression line 
and r-value by responder and non-responder. 
Native GLP-2 at baseline will be summarized by percent change in PS Volume 
(responder/non-responder) at Week 24/EOT for the ITT analysis set.
A listing of collected GLP-2 will be produced.
6.3.2
Change and Percent Change from Baseline in Hours per Day and Days per 
Week of PS Support 
Change and percent change of diary and prescribed PS hours per day and PS days per 
week from baseline to each visit during 24-week treatment period and the 4-week 
follow-up period will be summarized. These summaries will be presented by treatment 
arm using descriptive statistics.
Prescribed PS hours per day for each visit (including baseline) will be taken from the 
most recent prescription data prior to or at that visit.
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For the derivations of hours per day and days per week parameters, refer to section 
11.6.
6.3.3
Escape Criteria During Follow up Period
A table summarizing the number and percentages of subjects who escaped during 
follow up period as well as the escape reasons will be produced. This table will also 
display descriptive statistics (n, mean, SD, median, Q1, Q3, minimum and maximum) 
of the escape duration, where the time to escape is defined as the time from the last 
teduglutide dose to the date subject meets escape criteria:
Time to escape (days)= (date subject meets escape criteria – date of last 
teduglutide dose) +1
6.4
Multiplicity Adjustment
There is no statistical testing due to the small sample size. Therefore, no adjustment to 
the p-value to control Type I error is necessary.
6.5
Subgroup Analysis
There are no subgroup analyses for efficacy endpoints.
7.
SAFETY ANALYSIS
The safety analysis will be performed using the Safety set. Safety variables include AEs, 
clinical laboratory variables, and vital signs. For each safety variable where applicable, 
the last value collected before the first dose of investigational product for teduglutide 
treatment arm or the last value collected at baseline visit for standard of care treatment 
arm will be used as baseline for all analyses of that safety variable. Last Value on 
Treatment (LVOT) will be defined as the last valid assessment obtained after Baseline 
and whilst on investigational product (until Week 24/EOT visit for standard of care 
treatment arm). Last Observed Value (LOV) will be defined as the last valid assessment 
obtained after Baseline for both: standard of care treatment arm and teduglutide treatment 
arm.
All safety analyses will be conducted according to the treatment the subject actually 
received.
7.1
Adverse Events
Adverse events will be coded using MedDRA.
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7.1.1
All TEAEs
Treatment-emergent adverse event (TEAE) is defined as any adverse event on or after the 
first dose for the subjects teduglutide treatment arm, and on or after the randomization 
date for the subjects in standard of care treatment arm.
If more than 1 AE with the same preferred term is reported before the date of the first 
dose of investigational product (date of baseline visit for standard of care treatment arm), 
then the AE with the greatest severity will be used as the benchmark for comparison to 
the AEs occurring during the treatment period under the preferred term. In the case where 
it is not possible to define an AE as treatment-emergent or not, the AE will be classified 
by the worst case; i.e. treatment-emergent.
An overall summary of the number of subjects with TEAEs as well as the number of
events will be presented, including the number and percentage of subjects with any 
TEAEs and serious TEAEs (TESAEs), TEAEs and serious TEAEs related to 
investigational product, TEAE highest severity and TEAEs leading to discontinuation of 
investigational product or death.
Incidence of TEAEs will be also presented by SOC and PT as well as analyzed by 
relationship to study drug and maximum severity, respectively. Summaries by SOC and 
PT will present SOC in alphabetical order and PT within the SOC in descending order of 
incidence in the teduglutide treatment arm.
If more than 1 AE occurs with the same preferred term for the same subject, then the 
subject will be counted only once for that preferred term using the most severe and most 
related occurrence for the summarization by severity and by relationship to 
investigational product. Presentation by SOC and PT will present SOC sorted 
alphabetically and PT within SOC by descending incidence in the teduglutide treatment 
arm.
Listings will include both TEAEs and Non-TEAEs (unless specified otherwise) and 
will also list serious adverse events, adverse events leading to death, and adverse events 
leading to discontinuation of study drug. Listings will indicate whether an AE is 
treatment emergent or not and whether it is related to study drug or not.
7.1.2
Serious Adverse Events
Serious adverse events (SAEs) are those events recorded as “Serious” on the Adverse 
Events Form of the eCRF. Any SAE that occurs from the time of the signing of the 
informed consent form (ICF) through last study visit (week 28 or EOS) will be 
captured. A summary of TESAEs by SOC and PT will be prepared, as well as 
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summaries by event and causal relationship to study drug. A listing of SAEs will be 
presented.
7.1.3
AEs Leading to Discontinuation of Study Drug
AEs leading to permanent discontinuation of study drug will be identified by the 
“Study drug discontinued” response for action taken with study treatment in the 
Adverse Events Form of the eCRF.
Separate listings will be provided for AEs leading to permanent discontinuation of 
study drug.
7.1.4
Adverse Events Leading to Death
AEs leading to Death are those events which are recorded as “Fatal” on the Adverse 
Events Form of the eCRF. A listing of AEs leading to death will be presented.
7.1.5
Adverse Events of Special Interest
Separate summary table will be provided for the selected adverse events of special 
interest (AESI) that will be determined in accordance with Table 2.

Growth of pre-existing polyps of the colon

Benign neoplasia of the GI tract including the hepatobiliary system

Tumor-promoting ability (e.g., benign and/or malignant neoplasia of any kind, not
limited to those of the GI or hepatobiliary system)
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Table 2 AESI Categories 
AESI Categories
System Organ 
Class (SOC)
Preferred Terms (PT)
Higher Level Group 
Terms (HLGTs)
Tumor-promoting 
ability
Neoplasms benign, 
malignant and 
unspecified
Growth of pre-
existing polyps of 
the colon
Duodenal polyp
Intestinal polyp
Rectal Polyp
Large intestine polyp
Gastrointestinal polyp
Benign neoplasia 
of the GI tract
Gastrointestinal 
neoplasms benign
Hepatic and biliary 
neoplasms benign
Note: MedDRA terms are based on MedDRA version 21.0.
A supporting listing will be provided.
7.2
Clinical Laboratory Data
Laboratory evaluations that are done at study site visits will be collected and processed 
via a central laboratory, including panels for Hematology, Clinical Chemistry, 
Coagulation and Urinalysis.
The central laboratory data will be transferred to IQVIA for analyses. Laboratory 
evaluations that are required at intervals that do not coincide with study site visits may be 
obtained by a local laboratory. The local laboratory data will be collected on the local
laboratory tests form of eCRF. The summaries will be based on central laboratory results 
only, while all reported data will be listed including local laboratory data.
Descriptive statistics for clinical laboratory values in standard international (SI) units
from central lab and changes from baseline at each assessment time point will be 
presented by treatment group.
Hematology
Hemoglobin, hematocrit, red blood cells (RBC), platelet count, white 
blood cell count (WBC), neutrophils, lymphocytes, monocytes, 
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eosinophils, basophils, neutrophils/leukocytes, lymphocytes/leukocytes, 
monocytes/leukocytes, eosinophils/leukocytes, basophils/leukocytes
Biochemistry
Albumin, alkaline phosphatase, aspartate transaminase, alanine 
aminotransferase, amylase, aspartate aminotransferase, bicarbonate, 
indirect bilirubin, total bilirubin, blood urea nitrogen, calcium (total), 
chloride, cholesterol, C-creative protein, creatinine, estimated 
glomerular filtration rate (Schwartz formula), gamma glutamyl 
transferase, glucose, lipase, magnesium, phosphorus, potassium, 
sodium, triglycerides
Urinalysis
    Specific gravity, urine sodium
Coagulation      Prothrombin time (Pt), international normalized ration (INR)
Liver enzyme parameters, namely alkaline phosphatase, aspartate transaminase, alanine 
aminotransferase, aspartate aminotransferase, total and direct bilirubin and gamma 
glutamyl transferase will be presented graphically by visit. 
7.2.1
Reference Ranges
Quantitative laboratory measurements will be compared with the relevant laboratory 
reference ranges in SI units and categorized as:

Low: Below the lower limit of the laboratory reference range.

Normal: Within the laboratory reference range (upper and lower limit
inclusive).

High: Above the upper limit of the laboratory reference range.
Quantitative laboratory measurements reported as “< X”, i.e. below the lower limit of 
quantification (BLQ), or “> X”, i.e. above the upper limit of quantification (ULQ), will 
be categorized as per above instruction, taking into account the direction sign. That is if 
the reported value is <3 and the lower limit of the laboratory reference range equals 3 
then the reported value will be categorized as low.
7.2.2
Markedly Abnormal Laboratory Criteria 
Markedly abnormal laboratory tests will be identified in accordance with the predefined 
potentially clinically significant criteria (PSC) presented in Table 3.
The number and percentage of subjects with post-baseline PCS values will be tabulated 
by treatment group. The percentages will be calculated relative to the number of 
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subjects in the Safety Population. A listing of subjects will be provided for a parameter 
if there was a markedly abnormal laboratory value at any timepoint during the study. 
Table 3:
PSC Criteria for Markedly Abnormal Laboratory Tests
Parameter
SI Unit
Lower Limit
Higher Limit
Biochemistry
Albumin
g/L
<20
>68
Alkaline Phosphatase (ALP)
U/L
>5*ULN
Alanine Aminotransferase (ALT)
U/L
>8*ULN
Aspartate Aminotransferase (AST)
U/L
>8*ULN
Amylase
U/L
>3*ULN
Bilirubin Total
umol/L
>5*ULN
Direct Bilirubin
umol/L
>68.4147
Blood Urea Nitrogen (BUN)
mmol/L
> 12.495
Calcium
mmol/L
< 1.5
> 3
Creatinine
μmol/L
>132.6
C Reactive Protein
mg/L
>=100
Glucose
mmol/L
< 2.22
> 13.875
Lipase
U/L
>3*ULN
Magnesium
mmol/L
< 0.4114
> 1.2342
Phosphorus
mmol/L
<0.644
> 2.254
Potassium
mmol/L
< 2.5
> 6.5
Sodium
mmol/L
< 120
> 160
Triglycerides
mmol/L
>5.65
Hematology
Hemoglobin
g/L
< 70
>200
Hematocrit
fraction of 1
<0.21
>0.60
Platelets
10^9/L
< 75
>700
Leukocytes
10^9/L
< 2
>30
Neutrophils, absolute
10^9/L
<0.5
Coagulation
International normalized ration (INR)
NA
> 1.5
LLN:  Lower limit of normal value provided by the laboratory
ULN:  Upper limit of normal value provided by the laboratory
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7.3
Antibodies to Teduglutide
The number and percentage of subjects with an antibody finding (Antibodies to 
Teduglutide Negative/Positive, Neutralizing Antibodies Present/ No Neutralizing 
Antibodies Present) will be summarized at baseline, Week 12 and Week 28/EOS. Non-
specific antibodies will be categorized as Negative.
If at a specific visit a screening value as well as a confirmation value is present for a 
subject, the confirmed antibody value will be used in the table summary.
The follow-up antibody assessments after study completion will not be transferred from 
the lab vendor for any statistical analysis.
7.4
Vital Signs
The following vital signs measurements will be reported for this study:

Systolic Blood Pressure (mmHg)

Diastolic Blood Pressure (mmHg)

Pulse Rate (bpm)

Temperature (°C)

Weight (kg)

Length (cm)

Head circumference (cm)
The following vital signs parameters will be derived for this study:

Weight Z-score

Length Z-score

Head circumference Z-score

Weight/length ratio Z-score
Descriptive statistics will be used to summarize vital signs measurements and derived 
parameters in actual value and change from baseline for each treatment group, only 
vital signs (not derived parameters) by age group (4-< 6 months and 6-12 months) at 
study site visits where associated parameters are collected. The Weight, Length,
Weight/Length ratio and Head Circumference Z-scores will be graphed.  A listing will 
also be provided.  
For Weight, Length, Weight/Length ratio and Head Circumference Z-scores
Official and validated SAS programs created by WHO will be used to calculate z-
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scores:
http://www.who.int/childgrowth/software/en/
7.5
Physical Examination
Physical examination dates and reason that an examination was not done will be 
presented in data listings. Any clinically significant findings for physical examination 
are recorded as adverse events.
7.6
Fecal and Urine Output
Urine and stool output data is recorded over a 48-hour period of PS and EN stability 
before every scheduled site visit and within 1 week of implementing any PS
prescription adjustment.
The average daily urine output (mL/kg/day) at the scheduled site visit will be calculated 
as follows:
(Total urine output over 48 hours / 2) / body weight (kg) at the scheduled visit
where total urine output is calculated as the sum of the urine output in mL and the 
urine-only diaper weights in g (1g = 1mL) for the subject collected on the output diary 
form of eCRF.
If there are two or more days reported (Monday, Wednesday, Friday) the most recent 
two days will be summed up (Wednesday, Friday) and divided by 2 and then divided 
by body weight. The days do not have to be consecutive, so if (Tuesday, Wednesday, 
Friday) is available, then Wednesday and Friday would be selected as the two most 
recent days. Values will not be calculated if at least two urine outputs are not available 
at the visit. If the body weight at the scheduled visit is missing, the last available weight 
assessment will be used.
The average daily fecal output will be summarized separately by the average number of 
stools per day, the average total daily stool/mixed stool diaper weight (g/kg/day) and 
the average ostomy output per day (mL/kg/day) for each visit. The average number of 
stools per day will be calculated as (sum of the daily data in a 48-hour period / 2). The 
body weight will be used to calculate the daily stool/mixed stool diaper weight 
(g/kg/day) and the total ostomy output per day (mL/kg/day) using the same formula as 
we use to calculate the average daily urine output.
The change in average daily output for stool and urine from baseline to each scheduled 
visit, as well as at EOT, will be presented by treatment group using descriptive 
statistics. The change and the percent change in average daily output for fecal and urine 
output from baseline to each scheduled visit, as well as at EOT, will be presented by 
treatment group using descriptive statistics. A listing will also be provided.
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8.
PHARMACOKINETIC ANALYSIS
8.1
Drug Concentration
Descriptive statistics (mean, SD, CV%, median, Q1, Q3, minimum and maximum values, 
Geometric mean and Geometric mean CV%) of plasma teduglutide concentration will be 
calculated to summarize the observed values at each nominal timepoint. When analysis at 
one timepoint will occur, only the observed values will be summarized at the nominal 
timepoint.
Mean teduglutide plasma concentrations will be visually presented over time. 
Pharmacokinetic concentration data will be summarized based on the Pharmacokinetic set 
defined in section 4.5.
8.2
Handling Below Limit of Quantitation (BLQ) Values
In the calculation of summary statistics of concentrations at individual time point the 
BLQ concentration will be considered to be zero for pre-dose time point and set to 
missing for any other time point.
8.3
Pharmacokinetic Parameters
Pharmacokinetic parameters will be analyzed separately and reported separately.
8.4
Statistical Analysis of Pharmacokinetic Data
Statistical analysis of PK data will be documented separately.
9.
OTHER ANALYSES
9.1
Health-related Quality of Life Analyses
Cumulative number of hospitalization days during the treatment period and during the 
follow up period will be summarized separately using descriptive statistics (number, 
mean, median, SD, Q1, Q3, minimum and maximum).
A supporting listing presenting the date of admission, date of discharge, primary reason 
for hospitalization, discharge diagnosis and discharge status will be produced.
10.
DATA MONITORING COMMITTEE/INTERIM ANALYSIS
A Data Monitoring Committee (DMC) was set up to review the safety during the course 
of the trial.  For further details of the DMC can be found in the separate DMC SAP.
Interim analysis will be conducted for regulatory submissions, as needed.  The interim 
analysis will focus on the ITT set and Safety set. The Per-Protocol Analysis Set will not 
be in the scope.
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Analyses will be descriptive in nature. No formal comparisons are planned, and no 
hypotheses will be formally tested.
11.
DATA HANDLING CONVENTIONS
11.1
General Data Reporting Conventions
Continuous variables will be summarized using the following descriptive statistics: n, 
mean, median, standard deviation, interquartile ranges (Q1, Q3), minimum, maximum. 
Categorical and count variables will be summarized by the number of subjects (n) and the 
percentage of subjects in each category and treatment arm.
See Appendix 14.1 for rules on the number of decimal places to present data.
11.2
Common calculations
For quantitative measurements, change from baseline will be calculated as:
Test Value at Visit X – Baseline Value
Percent change from baseline will be calculated as:
((Test Value at Visit X – Baseline Value) / Baseline Value) *100
Change (or percent change) from baseline tables will be calculated based on the 
number of subjects in the treatment group with a non-missing value at baseline and at 
the time point being analyzed unless otherwise specified.
11.3
Reference Start Date and Study Day
Study Day will be calculated from the reference start date, and will be used to show 
start/stop day of assessments and events.
Reference start date for teduglutide arm is defined as the day of the first dose of study 
drug, while for standard of care treatment arm it is defined as the day of the baseline 
visit date. Study days before the first dose of study drug (or baseline) will be negative.
If the date of the event is on or after the reference start date then:
Study Day = (date of event – reference start date) + 1.
If the date of the event is prior to the reference start date then:
Study Day = (date of event – reference start date).
In the situation where the event date is partial or missing, the date will appear partial or 
missing in the listings, and Study Day.
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11.4
Definition of Baseline
Unless otherwise specified, baseline is defined as the last non-missing measurement 
taken prior to or on the reference start date (including unscheduled assessments). For 
AEs or concomitant medications that start on the reference start date, the time of onset 
will be compared to the time of the first dose of study drug to determine if the AE or 
medication was pre-baseline or post-baseline. If the timing relative to the first dose of 
study drug is unknown, AEs and medications commencing on the reference start date 
will be considered post-baseline. Actual PS and EN administration on the day of the 
reference start will be considered post-baseline.
11.5
Definition of Visit Windows
Nominal visits will occur within two days of the scheduled week 1 and week 2 visits, 
within three days of the scheduled week 3 to week 15 visits and within four days of the 
scheduled week 16 to week 28 (EOS) visit. There will be no windowing of scheduled 
visits based on study day, and unscheduled visits will not be included in by-visit 
summaries. Early termination data will be mapped to a scheduled visit if it falls into the 
appropriate visit window as defined in the protocol and if that scheduled visit did not 
occur.
An EOT time point, defined as the last determination of endpoint or last available 
measurement after the date of first dose during the 24-week treatment period, will be 
analyzed in addition to the scheduled visits.
11.6
Derived Efficacy Endpoints
The calculation of diary PS/EN parameter normalized to weight will follow the formula 
below unless otherwise specified:
Baseline values:
Baseline average daily value = [(sum of non-missing daily values in the diary within 14 
days prior to the first dose or baseline visit / number of days with non-missing values 
within 14 days prior to the first dose or baseline visit)] / last available weight prior to
the first dose or baseline visit
Days per week of diary PS support at baseline = (number of days with non-zero values 
for PS intake within the 14 days prior to the first dose or baseline visit / number of days 
for which any PS intake data is recorded within the 14 days prior to the first dose or 
baseline visit) *7
Hours per day of diary PS support at baseline = (sum of hours per day for each day 
that PS intake data is recorded within the 14 days prior to the first dose or baseline visit 
/ number of days that PS hours per day data is recorded within the 14 days prior to the 
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first dose or baseline visit)
A Sensitivity Analysis will be added for Hours per day of diary PS:
Hours per non-zero day of diary PS support at baseline = (sum of non-zero hours per 
day for each day that PS intake data is recorded within the 14 days prior to the first 
dose or baseline visit / number of days with non-zero that PS hours per day data is 
recorded within the 14 days prior to the first dose or baseline visit)
If more than 7 days’ values in two weeks prior to the first dose or baseline visit are 
missing, the baseline average daily value will be set to missing.
Post-baseline values:
Post-baseline average daily value = [(sum of non-missing daily values in the diary
within 7 days prior the date of each scheduled post-baseline visit / number of days with 
non-missing values within 7 days prior the date of each scheduled post-baseline visit)] / 
last available weight prior to the visit
Days per week of diary PS support post-baseline = (number of days with non-zero 
values for PS intake within the 7 days prior the date of each scheduled post-baseline 
visit / number of days for which any PS intake data is recorded within the 7 days prior 
the date of each scheduled post-baseline visit) *7 
Hours per day of diary PS support post-baseline = (sum of hours per day for each day 
that PS intake data is recorded within the 7 days prior the date of each scheduled post-
baseline visit / number of days that PS hours per day data is recorded within the 7 days 
prior the date of each scheduled post-baseline visit 
A Sensitivity Analysis will be added for Hours per day of diary PS:
Hours per non-zero day of diary PS support post-baseline = (sum of non-zero hours per 
day for each day that PS intake data is recorded within the 7 days prior the date of each 
scheduled post-baseline visit / number of days that PS hours per day with non-zero data 
is recorded within the 7 days prior the date of each scheduled post-baseline visit
If more than 2 days’ values in a week are missing, the post-baseline average daily value 
will not be calculated and will be assigned as missing. Week 1 visit calculations will 
exclude any pre-baseline diary data.
The calculation of prescribed PS/EN parameter normalized to weight for baseline and 
post-baseline average daily values will follow the formula below unless otherwise 
specified:
Average daily value = (most recent prescribed weekly PS/EN parameter prior to or on 
the date of visit / 7) / last available weight prior to or on the date of visit
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Prescribed PS hours per day and PS days per week for each visit (including baseline) 
will be taken from the most recent prescription data prior to or at that visit.
Percent reduction in weight-normalized diary and prescribed PS/EN parameter from 
baseline at the scheduled visit will be calculated using the formula below:
% reduction in PS/EN value at the visit = [(average daily value at the scheduled visit -
average daily value at baseline) / average daily value at baseline] * 100
11.7
Repeated or Unscheduled Assessments
In general, for by-visit summaries, data recorded at the nominal visit will be presented. 
Unscheduled measurements will not be included in by-visit summaries, but can 
contribute to the best/worst case value where applicable. Unscheduled PS or EN 
prescription adjustments carry forward until the next adjustment, and hence may 
contribute to data assigned to subsequent visits.
Listings will include scheduled, unscheduled, retest and early discontinuation data.
11.8
Handling of Missing, Unused, and Spurious Data
No imputation for missing data (e.g., last observation carried forward [LOCF]) will be 
applied except for the partial dates for adverse events and prior/concomitant medications.
Imputation will be performed for partial dates of AEs and medications solely for the 
purpose of defining treatment emergence for AEs, determining whether an AE started in 
the treatment period and prior/concomitant status for medications. Details on how to 
handle partial dates for adverse events and prior/concomitant medications are described 
below.
Details for the imputation algorithm for the missing endpoint values for PS support 
parameters (volume, calories and etc.) are described in Section 6 of this analysis plan.
11.8.1 Missing Date of Investigational Product
No imputations will be done for the investigational product. 
11.8.2 Missing Date Information for Prior or Concomitant Medications 
(Therapies/Procedures)
Imputation of Partial Medication Dates
START 
DATE
STOP 
DATE
ACTION
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Statistical Analysis Plan v1.1
Protocol Number: SHP633-301
24Mar2020
START 
DATE
STOP 
DATE
ACTION
Known
Partial
If medication stop year and month are known and the reference end 
date during that month and year: Impute stop date as the reference 
end date if medication start date <= the reference end date;
Else if medication stop year and month are known and are not the 
month and year of the reference start date: Impute stop date as the 
last day of the month;
Else if only medication stop year is known and is the year of the 
reference end date: Impute stop date as the reference end date if 
medication start date <= the reference end date;
Else if only medication stop year is known and is prior to the year 
of the reference end date: Impute stop date as the last day of the 
year (31st December).
Missing
If medication stop date is unknown leave as missing.
Partial
Known
If medication start year and month are known and it is the month 
and year of the reference start date: Impute start date as the 
reference start date if medication stop date > the reference start 
date;
Else if medication start year and month are known and it is the 
month and year of the informed consent: Impute start date as the 
informed consent date if medication start year and month < the year 
and month of the reference start date;
Else if medication start year and month are known and are not the 
month and year of the reference start date or informed consent: 
Impute start date as the first day of the month;
Else if only medication start year is known and is the year of the 
reference start date: Impute start date as the reference start date if 
medication stop date > the reference start date;
Else if only medication start year is known and is the year of the 
informed consent date: Impute start date as the informed consent 
date if medication start year < the year of the reference start date;
Else if only medication start year is known and is after year of the 
reference start date: Impute start date as the first day of the year (1st 
January).
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Statistical Analysis Plan v1.1
Protocol Number: SHP633-301
24Mar2020
START 
DATE
STOP 
DATE
ACTION
Partial
If medication start year and month are known and it is the month 
and year of the reference start date: Impute start date as the 
reference start date if medication stop year and month are known 
and >= the year and month of the reference start date Or If only AE 
stop year is known and >= year of the reference start date;
Else if medication start year and month are known and it is the 
month and year of the informed consent: Impute start date as the 
informed consent date if medication start year and month < the year 
and month of the reference start date;
Else if medication start year and month are known and are not the 
month and year of the reference start date or informed consent: 
Impute start date as the first day of the month;
Else if only medication start year is known and is the year of the 
reference start date: Impute start date as the reference start date if 
medication stop year and month are known and >= the year and 
month of reference start date Or If only AE stop year is known and 
>= year of reference start date;
Else if only medication start year is known and is after year of the 
reference start date: Impute start date as the first day of the year (1st 
January).
If medication stop year and month are known and study drug 
stopped during that month and year: Impute stop date as the stop 
date of study drug if medication start date <= the stop date of study 
drug;
Else if medication stop year and month are known and are not the 
month and year of the reference start date: Impute stop date as the 
last day of the month;
Else if only medication stop year is known and is the year of the 
reference end date: Impute stop date as the reference end date if 
medication start date <= the reference end date;
Else if only medication stop year is known and is prior to the year 
of the reference end date: Impute stop date as the last day of the 
year (31st December).
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Statistical Analysis Plan v1.1
Protocol Number: SHP633-301
24Mar2020
START 
DATE
STOP 
DATE
ACTION
Missing
If medication start year and month are known and it is the month 
and year of the reference start date: Impute start date as the 
reference start date;
Else if medication start year and month are known and it is the 
month and year of the informed consent: Impute start date as the 
informed consent date if medication start year and month < the year 
and month of the reference start date;
Else if medication start year and month are known and are not the 
month and year of the reference start date or informed consent: 
Impute start date as the first day of the month;
Else if only medication start year is known and is the year of the 
reference start date: Impute start date as the reference start date;
Else if only medication start year is known and is after year of the 
reference start date: Impute start date as the first day of the year (1st 
January).
If medication stop date is unknown leave as missing.
Missing
Known
If medication stop date is unknown leave as missing.
Partial
If medication stop date is unknown leave as missing.
Missing
If medication stop date is unknown leave as missing.
11.8.3 Missing Date Information for Adverse Events
Imputation of Partial AE Dates
START 
DATE
STOP 
DATE
ACTION
Known
Partial
If AE start year and month are known, impute stop date as latest 
possible date (that is the last day of the month if day is unknown or 
31st December if day and month are unknown).
Missing
If AE stop date is unknown leave as missing.
Partial
Known
If AE start year and month are known and it is the month and year 
of the reference start date: Impute start date as the reference start 
date if AE stop date > the reference start date;
Else if AE start year and month are known and it is the month and 
year of the informed consent: Impute start date as the informed 
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Statistical Analysis Plan v1.1
Protocol Number: SHP633-301
24Mar2020
START 
DATE
STOP 
DATE
ACTION
consent date if AE start year and month < the year and month of the 
reference start date;
Else if AE start year and month are known and are not the month 
and year of the reference start date or informed consent: Impute 
start date as the first day of the month;
Else if only AE start year is known and is the year of the reference 
start date: Impute start date as the reference start date if AE stop 
date > the reference start date;
Else if only AE start year is known and is after year of the reference 
start date: Impute start date as the first day of the year (1st January).
Partial
If AE start year and month are known and it is the month and year 
of the reference start date: Impute start date as the reference start 
date if AE stop year and month are known and >= the year and 
month of the reference start date Or If only AE stop year is known 
and >= year of the reference start date;
Else if AE start year and month are known and it is the month and 
year of the informed consent: Impute start date as the informed 
consent date if AE start year and month < the year and month of the 
reference start date;
Else if AE start year and month are known and are not the month 
and year of the reference start date or informed consent: Impute 
start date as the first day of the month;
Else if only AE start year is known and is the year of the reference 
start date: Impute start date as the reference start date if AE stop 
year and month are known and >= the year and month of the 
reference start date Or If only AE stop year is known and >= year of 
the reference start date;
Else if only AE start year is known and is after year of the reference 
start date: Impute start date as the first day of the year (1st January).
Impute stop date as latest possible date (that is the last day of the 
month if day is unknown or 31st December if day and month are 
unknown).
Missing
If AE start year and month are known and it is the month and year 
of the reference start date: Impute start date as the reference start 
date;
Else if AE start year and month are known and it is the month and 
year of the informed consent: Impute start date as the informed 
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Statistical Analysis Plan v1.1
Protocol Number: SHP633-301
24Mar2020
START 
DATE
STOP 
DATE
ACTION
consent date if AE start year and month < the year and month of the 
reference start date;
Else if AE start year and month are known and are not the month 
and year of the reference start date or informed consent: Impute 
start date as the first day of the month;
Else if only AE start year is known and is the year of the reference 
start date: Impute start date as the reference start date;
Else if only AE start year is known and is after year of the reference 
start date: Impute start date as the first day of the year (1st January).
If AE stop date is unknown leave as missing.
Missing
Known
If AE start date is unknown leave as missing; event will be 
considered treatment-emergent if stop date >= the reference start 
date.
Partial
If AE start date is unknown leave as missing; event will be 
considered treatment-emergent if stop date partial stop date >= 
same partial portions of the reference start date
Missing
If AE start or stop date is unknown leave as missing; event will be 
considered treatment-emergent.
11.8.4 Missing Severity Assessment for Adverse Events
If the severity is missing for a TEAE, a severity of “Severe” will be assigned. The 
imputed values for severity assessment will be used for incidence summaries, while both 
the actual and imputed values will be presented in data listings.
11.8.5 Missing Relationship to Investigational Product for Adverse Events
If the relationship to investigational product is missing for a TEAE, a causality of 
“Related” will be assigned. The imputed values for relationship to investigational product 
will be used for incidence summaries, while both the actual and the imputed values will 
be presented in data listings.  
For subjects in standard of care treatment arm, missing causality will not be imputed as 
subjects in this arm did not receive any investigational product. AE summaries by 
relationship will exclude the standard of care treatment arm.
11.8.6 Character Values of Clinical Laboratory Variables
Quantitative laboratory measurements reported as “< X”, i.e. below the lower limit of 
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Statistical Analysis Plan v1.1
Protocol Number: SHP633-301
24Mar2020
quantification (BLQ), or “> X”, i.e. above the upper limit of quantification (ULQ), will 
be converted to X for the purpose of quantitative summaries, but will be presented as 
recorded, i.e. as “< X” or “> X” in the listings.
11.8.7
Unused data
Other than select fields that capture reason an assessment is not done, all comments and 
specified text fields captured in the eCRF will be displayed in appendix listings only. 
These variables will not be summarized or presented, but will be available in the 
clinical study database, SDTM and/or ADaM datasets.
Other data collected in eCRF, IRT system or any other clinical trial data collection 
system which is not described above will be presented in the appendix listings, such as 
randomization information, IE criteria not met and procedures.
12.
ANALYSIS SOFTWARE
Statistical analyses will be performed using Version 9.4 (or newer) of SASon a suitably 
qualified environment.
13.
CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL
The protocol specifies that the stool consistency will be scored. However, this 
information is not captured on the eCRF hence its evaluation is not included in this SAP.
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Statistical Analysis Plan v1.1
Protocol Number: SHP633-301
24Mar2020
14.
APPENDICES
14.1
Decimal Places and Rounding Rules
1. For measures of median and mean, use 1 decimal place beyond those used for the
measurement.
2. For measures of standard deviation and standard error of the mean, use 2 decimal
places beyond those used for the measurement.
3. For measures of minimum and maximum values, use the same number of decimal
places as those used for the measurement.
4. >=5 is rounded up away from zero, whereas <5 is rounded down toward zero to
account for rounding of negative numbers.
5. Derived questionnaire scores, and other similar efficacy parameters recorded as
integers, should be rounded to 1 decimal place for reporting.
6. For PK Related shells, display as reported.
14.2
Identified Tables/Figures/Listings for Interim Analysis 
All Listings except Listing 16.2.3.1 for Subjects Excluded from the Per Protocol Set 
would be generated for the interim analysis.  
The following Figures would be generated for the interim analysis 
Figure 14.2.3.4.1 – Individual Percent Change in PS Volume (mL/kg/day) by Visit Based 
on Diary Data – Intent-to-treat Set
Figure 14.2.3.6.1 – Individual Percent Change in PS Caloric Intake (kcal/kg/day) by Visit 
Based on Diary Data – Intent-to-treat Set
Figure 14.2.3.12.1 – Individual PS Volume (mL/kg/day) Based on Diary Data Over Time 
– Intent-to-treat Set
Figure 14.2.3.13.1 – Individual PS Calories (kcal/kg/day) Based on Diary Data Over 
Time – Intent-to-treat Set
Figure 14.3.5.3.1 – Individual Weight, Length, Weight/Length Ratio and Head 
Circumference Z-score by Visit – Safety Set
The following Tables would be generated for the interim analysis:
Table 14.1.1.1: Subject Disposition (Screened Set)
Table 14.1.1.2: Analysis Sets (Enrolled Set)
Table 14.1.2.2: Protocol Deviations (Safety Set)
Table 14.1.4.1.3: Demographic Characteristics (Safety Set)
Table 14.1.4.2.3: Baseline Characteristics (Safety Set)
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Statistical Analysis Plan v1.1
Protocol Number: SHP633-301
24Mar2020
Table 14.1.4.3.2: Medical and Surgical History by System Organ Class and Preferred 
Term (Safety Set)
Table 14.1.4.4.2: Short Bowel Syndrome History (Safety Set)
Table 14.1.4.5: Prior Medications (Safety Set)
Table 14.1.4.6: Concomitant Medications (Safety Set)
Table 14.1.5.1: Study Drug Compliance (Intent-to-treat Set)
Table  14.2.2.2.1: Summary of Complete Weaning off PS Support by Visits (Intent-to-
treat Set)
Table  14.2.2.3: Change from Baseline in PS Volume (mL/kg/day) by Visit (Intent-to-
treat Set)
Table  14.2.2.4: Change from Baseline in PS Caloric Intake (kcal/kg/day) by Visit 
(Intent-to-treat Set)
Table  14.2.2.5: Change from Baseline in EN Volume (mL/kg/day) by Visit (Intent-to-
treat Set)
Table  14.2.2.6: Change from Baseline in EN Caloric Intake (kcal/kg/day) by Visit 
(Intent-to-treat Set)
Table  14.2.2.9: Summary of ≥ 20% Reduction  in PS Volume (mL/kg/day) by Visit 
(Intent-to-treat Set)
Table  14.2.2.10: Summary of ≥ 20% Reduction in PS Caloric Intake (kcal/kg/day) by 
Visit (Intent-to-treat Set)
Table  14.2.2.11: Change from Baseline in Days per Week of PS Support (days/week) by 
Visit (Intent-to-treat Set)
Table  14.2.2.12: Change from Baseline in Hours per Day of PS Support (hours/day) by 
Visit (Intent-to-treat Set)
Table  14.2.2.14: Summary of Escape Criteria During Follow-up Period (Safety Set)
Table  14.2.2.15: Summary of Teduglutide Plasma Concentrations by Timepoints 
(Pharmacokinetic Set)
Table  14.3.1.1: Overall Treatment-Emergent Adverse Events (TEAEs) by Treatment 
Group (Safety Set)
Table  14.3.1.2: Treatment-Emergent Adverse Events by System Organ Class, Preferred 
Term and Treatment Group (Safety Set)
Table  14.3.1.3: Treatment-Emergent Adverse Events Considered Related to 
Investigational Product by System Organ Class, Preferred Term and Treatment Group 
(Safety Set)
Table  14.3.1.4: Treatment-emergent Serious Adverse Events by System Organ Class, 
Preferred Term and Treatment Group (Safety Set)
Table  14.3.1.5: Treatment-emergent Serious Adverse Events Considered Related to 
Investigational Product by System Organ Class, Preferred Term and Treatment Group 
(Safety Set)
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Statistical Analysis Plan v1.1
Protocol Number: SHP633-301
24Mar2020
Table  14.3.1.6: Adverse Events of Special Interest by System Organ Class, Preferred 
Term and Treatment Group (Safety Set)
Table  14.3.1.7: Treatment-Emergent Adverse Events by Maximum Severity, System 
Organ Class, Preferred Term and Treatment Group (Safety Set)
Table  14.3.2.1: Listing of Serious Adverse Events (Safety Set)
Table  14.3.2.2: Listing of Adverse Events Leading to Treatment Discontinuation (Safety 
Set)
Table 14.3.2.3: Listing of Adverse Events Leading to Death (Safety Set)
Table  14.3.3.1: Listing of Adverse Events of Special Interest (Safety Set)
Table  14.3.4.1: Quantitative Clinical Laboratory Results by visit and Treatment Group: 
Chemistry (Safety Set)
Table  14.3.4.2: Quantitative Clinical Laboratory Results by visit and Treatment Group: 
Hematology (Safety Set)
Table  14.3.4.3: Quantitative Clinical Laboratory Results by visit and Treatment Group: 
Urinalysis (Safety Set)
Table  14.3.4.4: Markedly abnormal Laboratory Results by Treatment Group: Chemistry 
(Safety Set)
Table  14.3.4.5: Markedly abnormal  Laboratory Results by Treatment Group: 
Hematology (Safety Set)
Table  14.3.4.6: Markedly abnormal  Laboratory Results by Treatment Group: 
Coagulation (Safety Set)
Table  14.3.4.7: Listing of Subjects who met Markedly Abnormal Criteria: Chemistry 
(Safety Set)
Table  14.3.4.8: Listing of Subjects who met Markedly Abnormal Criteria: Hematology 
(Safety Set)
Table  14.3.4.9: Listing of Subjects who met Markedly Abnormal Criteria: Coagulation 
(Safety Set)
Table  14.3.5.1: Actual Values and Change from Baseline in Vital Signs by visit, age and 
Treatment Group (Safety Set)
Table  14.3.5.2: Summary of Body Weight, Length, Weight/Length Ratio and Head 
Circumference Z-Score by Visit (Safety Set)
Table  14.3.6.1: Summary of Antibody Results by Visit (Safety Set)
Table  14.3.7.1: Summary of Fecal Output by Visit (Safety Set)
Table  14.3.7.2: Summary of Urine Output by Visit (Safety Set)
Table  14.3.8.3: Investigational Product Exposure by Treatment Group (Safety Set)
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Statistical Analysis Plan v1.1
Protocol Number: SHP633-301
24Mar2020
14.3
Changes in the Statistical Analysis Plan
Changes from the SAP v1.0 dated 11Dec2018 to this current version 1.1 is summarized 
below. 
Section
Change
Rationale
1.0 Introduction
Addition and mention of 
Protocol Amendment 4 dated 
2019 Dec 17
To be consistent with amendments 
to the protocol made in Protocol 
version 4.0, dated 2019 Dec 17
3.4 Sample Size
Added details from the 
Protocol
Added details from Study 
Population Section of Protocol.
4 Statistical Analysis Set
Added details for when ITT 
Set equals Safety Set, only 
one set of outputs will be 
generated for tables that are 
repeated
To narrow down programming 
work, when there are repeat tables 
but Analysis Sets are equal. 
4.2 Intent-to-Treat Set
Updated ITT Set to 
The Intent-to-Treat (ITT) set 
will consist of all subjects 
randomized in the study.
To be consistent with amendments 
to the protocol made in Protocol 
version 4.0, dated 2019 Dec 17
5.6 Prior Medication
Added clarification for 
reference date
To add hyperlink to location of 
details
5.7 Concomitant 
Medications
Updated con med definition 
to include all medications 
after reference date
To be consistent with other Gattex 
SAPs – i.e. TED-C14-006 Study.
6.2.7 Supplementary 
Analyses of Secondary 
Efficacy Endpoints
Added sentence to clarify 
blank section.  
Clarified nothing applicable for 
this section.
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Statistical Analysis Plan v1.1
Protocol Number: SHP633-301
24Mar2020
6.3.1 Native GLP-2
Added details around 
analysis timepoint, and 
percentage change
To add details in analysis.
7.1.1 All TEAEs
Updated TEAE definition to 
include all AEs after 
reference date
To be consistent with other Gattex 
SAPs – i.e. TED-C14-006 Study.
7.1.5 Adverse Events of 
Special Interest
Added Specific AESI terms
To add clarity to analysis with the 
confirmed MedDRA version 21.0
10. DATA
MONITORING 
COMMITTEE/INTERIM 
ANALYSIS
Updated Interim Analysis 
Section
To be consistent with amendments 
to the protocol made in Protocol 
version 4.0, dated 2019 Dec 17
11.6 Derived Efficacy 
Endpoints
Added analysis for Hours per 
non-zero day of diary PS
To be sensitivity analysis 
11.6 Derived Efficacy 
Endpoints
Updated allowance of 
missing days for diary inputs
Because seven days value within a 
two-week period would provide a 
good estimate for baseline and 
would not introduce bias from 
previous method.
11.8.2 Missing Date 
Information for Prior or 
Concomitant Medications 
(Therapies/Procedures)
Added more details to 
imputation algorithm and 
changed to tabular format
To complete the algorithm rules
11.8.4 Missing Severity 
Assessment for Adverse 
Events
Clarified Missing TEAE will 
be classified as Severe
To be consistent with other Gattex 
SAPs – i.e. TED-C14-006 Study.
11.8.5 Missing 
Relationship to 
Investigational Product 
Clarified Missing TEAE 
relationship will be classified 
as ‘related’ and SoC 
relationship analysis will be 
To be consistent with other Gattex 
SAPs – i.e. TED-C14-006 Study.
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Statistical Analysis Plan v1.1
Protocol Number: SHP633-301
24Mar2020
for Adverse Events
excluded
Section Titles
Editorial changes made to 
this section, e.g, Upper Case 
and Lower case, ITT 
Population vs ITT Set
Text revised for purposes of 
improved clarity, completeness, 
and transparency.
For non-commercial use only


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