Clinical trial NCT03268811
Conditions: Short Bowel Syndrome
Sponsor: Shire
Start date: 2017-08-23; Completion date: 2021-11-02
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this clinical study is to evaluate the long-term safety and tolerability of teduglutide treatment in Japanese pediatric participants with short bowel syndrome (SBS) who completed Study SHP633-302 (NCT02980666).

Detailed description:

Arms: arm 1: Participants will receive teduglutide 0.05 milligram per kilogram (mg/kg) subcutaneous (SC) injection once daily into 1 of the 4 quadrants of the abdomen or either thigh or arm for 24-week intervals. If a participant deteriorates during a follow-up period, the participant may be evaluated immediately for additional teduglutide treatment (24-week interval) until teduglutide is commercially available for each participant, the participant's participation in this study is discontinued, or the study is discontinued.
Interventions: intervention 1: Teduglutide
Intervention descriptions: intervention 1: Teduglutide 0.05 mg/kg SC injection will be administered once daily into 1 of the 4 quadrants of the abdomen or either thigh or arm.

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
NCT Number: 
NCT03268811 
Study Title:  
A Prospective, Open-label, Long-term Safety and Efficacy Study of Teduglutide in 
Japanese Pediatric Subjects with Short Bowel Syndrome Who Completed 
SHP633-302 
Study Number:  
SHP633-305 
Protocol Version and Date:  
Amendment 4: 
06 Nov 2020 
For non-commercial use only


Clinical Trial Protocol: SHP633-305
TITLE:
A Prospective, Open-label, Long-term Safety and Efficacy Study of 
Teduglutide in Japanese Pediatric Subjects with Short Bowel Syndrome 
Who Completed SHP633-302
NUMBER:
SHP633-305 
PHASE:
3 Extension
DRUG:
Teduglutide
IND:
058213
OTHER NO.:
NA
INDICATION:
Short bowel syndrome
SPONSOR:
Shire Human Genetic Therapies, Inc.
Takeda Pharmaceutical Company Limited
1-1, Doshomachi 4-Chrome, Chuo-ku, Osaka-Shi
Osaka
Japan
PROTOCOL 
HISTORY:
Amendment 4: 06 Nov 2020
Amendment 3: 20 Jul 2018
Amendment 2: 24 Jan 2018
Amendment 1: 26 May 2017
Original Protocol: 22 July 2016
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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SHP633-305 Protocol Amendment 4 
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06 Nov 2020 
 
PROTOCOL SIGNATURE PAGE 
Sponsor’s (Shire) Approval 
Signature: 
Date: 
, MD PhD  
, Clinical Science 
 
Investigator’s Acknowledgement 
I have read this protocol for Shire Study SHP633-305. 
Title: A Prospective, Open-label, Long-term Safety and Efficacy Study of Teduglutide in 
Japanese Pediatric Subjects with Short Bowel Syndrome Who Completed SHP633-302 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor’s representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Conference on Harmonization (ICH) guidelines on Good Clinical 
Practice (GCP) and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Address: 
(please hand print or type) 
 
 
 
 
Signature: 
 
Date: 
 
 
12-Nov-2020 | 00:13 JST
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SUMMARY OF CHANGES FROM PREVIOUS PROTOCOL VERSION
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
4
Amendment Date
06 Nov 2020
Global
Description of Change and Rationale
Section(s) Affected by Change
Sponsor Name Changed to include both Shire Human Genetic Therapies, Inc. 
(USA) and Takeda Pharmaceutical Company Limited
The Sponsor name was updated to align more accurately with legal entities 
responsible for study.
Signature Page
Changed name of sponsor protocol signatory to 
, MD, 
PhD. 
Signature Page
Transferred back the role of in-country clinical caretaker from IQVIA 
Services Japan K.K to the sponsor. The sponsor is now responsible for 
notifying the relevant regulatory authorities of related, unexpected serious 
adverse events (SAEs).
Emergency Contact Information
Section 8.2.7
Changed name of Shire medical monitor to 
, MD, PhD, MPH.
(Protocol Administrative Amendment dated 27 Mar 2020)
Emergency Contact Information
Changed the fax number for SAE reporting. The priority should be given to 
reporting SAEs via email, and if not possible, to reporting by fax.
(Clarification Memo dated 04 Feb 2019)
Emergency Contact Information
Updated the end of the planned study period to December 2021.
Synopsis
Expanded the timing to perform a colonoscopy/sigmoidoscopy at the end of a 
teduglutide treatment cycle (CxW24). Subjects who received 2 treatment 
cycles (48 weeks of teduglutide exposure) will undergo a 
colonoscopy/sigmoidoscopy before the next cycle of teduglutide treatment.
Colonoscopy/sigmoidoscopy performed after the Visit CxW24 (±4 days) 
window and before the next cycle of teduglutide treatment will not be 
considered a protocol deviation. All other visit procedures must adhere to the 
(±4 days) visit window.
(Clarification Memos dated 08 Jun 2020 and 11 Jun 2020)
Table 3, Section 7.2.9.2
Specified that the SHP633-305 study will continue as a post-marketing study 
if teduglutide is approved for marketing.
Section 3.2
Clarified that the output diaries should be recorded for subjects during a 
teduglutide treatment period within 1 week of implementing a change in the 
PS prescription.
Section 7.2.10.2
Added a new section entitled “Changes to Study Procedures Due to a 
Pandemic”. The purpose of these changes is to maintain the subject safety, 
confidentiality, and study integrity in the context of healthcare delivery 
challenges presented by the COVID-19 pandemic.
Section 7.3
Clarified the definition of an overdose as the administration of the 
investigational product at a dose or frequency greater than 0.05 mg/kg 
subcutaneous once daily. An overdose occurs if any of the following criteria 
are met: 

More than 0.05 mg/kg is given at any one time

Consecutive doses are spaced less than 12 hours apart
Section 8.1.7
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
4
Amendment Date
06 Nov 2020
Global
Description of Change and Rationale
Section(s) Affected by Change

Any more than 0.05 mg/kg in one day (a day is defined as beginning at 
12:00 AM and ending at 11:59 PM)
(Clarification Memo dated 12 Jun 2019)
Changed the data monitoring committee meeting frequency. The DMC 
members will review the data approximately every 6 months (previously 
3 months) during the study treatment periods (date of the first subject’s first 
dose to date of the last subject’s last dose).
(Protocol Administrative Amendment dated 02 Sep 2020)
Section 9.4
Updated the contact information for the monitoring personnel within Japan 
with the Takeda Pharmaceutical Company Limited address, removed the 
name and contact information for
who is no longer on the 
program, and updated
 phone number.
Appendix 4
See Appendix 1 for protocol history, including all amendments.
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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 and Non-serious AEs as 
Required by Protocol within 24 hours to IQVIA Services Japan K.K. using the details below. 
Pharmacovigilance SAE Reporting:
Email (preferred method):  
 
or
FAX: 
 (Japan domestic line only)
For protocol- or safety-related issues, the investigator should contact:
, MD 
Phone: 
 (24-hour coverage)
Email:
Fax: 
For protocol- or safety-related issues between 8:00 to 20:00 US Eastern Standard 
Time, the investigator may contact the Shire medical monitor:
, MD, PhD, MPH
Shire Medical Monitor
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 (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.
The product quality includes quality of the drug delivery device combination product. As such 
device defects should be reported according to the instructions in this section. The reporting of 
product quality occurrences, when the product does not meet specifications, includes the 
reporting of device defects.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
Ex-US
Telephone numbers (provided for reference, if needed): 
Shire, Lexington, MA (USA)
 
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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS PROTOCOL VERSION..................................3
EMERGENCY CONTACT INFORMATION................................................................................5
PRODUCT QUALITY COMPLAINTS..........................................................................................6
TABLE OF CONTENTS.................................................................................................................7
LIST OF TABLES.........................................................................................................................11
LIST OF FIGURES .......................................................................................................................11
ABBREVIATIONS .......................................................................................................................12
STUDY SYNOPSIS ......................................................................................................................14
STUDY SCHEDULES..................................................................................................................19
1
BACKGROUND INFORMATION.......................................................................................25
1.1
Indication and Current Treatment Options...............................................................25
1.2
Product Background and Clinical Information ........................................................25
2
STUDY OBJECTIVES AND PURPOSE ..............................................................................29
2.1
Rationale for the Study.............................................................................................29
2.2
Study Objectives ......................................................................................................29
2.2.1
Primary Objectives.................................................................................................29
2.2.2
Secondary Objectives.............................................................................................29
3
STUDY DESIGN ...................................................................................................................30
3.1
Study Design and Flow Chart ..................................................................................30
3.2
Duration and Study Completion Definition .............................................................32
3.3
Sites and Regions .....................................................................................................33
4
STUDY POPULATION.........................................................................................................34
4.1
Study Eligibility Criteria ..........................................................................................34
4.1.1
Study Inclusion Eligibility Criteria........................................................................34
4.1.2
Study Exclusion Eligibility Criteria.......................................................................34
4.2
Teduglutide Eligibility Criteria ................................................................................34
4.2.1
Teduglutide Treatment Inclusion Criteria..............................................................34
4.2.2
Teduglutide Treatment Exclusion Criteria.............................................................34
4.3
Follow-up Period Escape Criteria ............................................................................36
4.4
Reproductive Potential .............................................................................................36
4.4.1
Female Contraception............................................................................................36
4.5
Discontinuation of Subjects .....................................................................................37
4.5.1
Permanent Discontinuation of Investigational Product .........................................37
4.5.2
Study Withdrawal ..................................................................................................37
4.5.3
Reasons for Discontinuation..................................................................................37
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4.5.4
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................38
5
CONCOMITANT TREATMENT..........................................................................................39
5.1
Concomitant Medications and Procedures...............................................................39
5.1.1
Permitted Treatment...............................................................................................39
5.1.2
Prohibited Treatment .............................................................................................39
6
INVESTIGATIONAL PRODUCT ........................................................................................40
6.1
Identity of Investigational Product...........................................................................40
6.1.1
Blinding the Treatment Assignment......................................................................40
6.2
Administration of Investigational Product(s)...........................................................40
6.2.1
Allocation of Subjects to Treatment ......................................................................40
6.2.2
Dosing....................................................................................................................40
6.2.2.1
Administration by Parent/Guardian .......................................................41
6.3
Labeling, Packaging, and Storage............................................................................42
6.3.1
Labeling .................................................................................................................42
6.3.2
Storage and Handling.............................................................................................42
6.4
Drug Accountability.................................................................................................43
6.5
Subject Compliance..................................................................................................44
7
STUDY PROCEDURES........................................................................................................45
7.1
Study Schedule.........................................................................................................45
7.1.1
Screening................................................................................................................45
7.1.2
Visits for Subjects Not Receiving Teduglutide .....................................................45
7.1.3
Visits for Subjects Receiving Teduglutide ............................................................45
7.1.3.1
Pretreatment Visit...................................................................................45
7.1.3.2
Teduglutide Treatment Period (CxD1-CxW24).....................................46
7.1.3.3
Phone Visits............................................................................................46
7.1.4
Teduglutide Follow-up Period...............................................................................46
7.1.5
Study Completion/Early Termination Visit (EOS/ET Visit).................................46
7.2
Study Evaluations and Procedures ...........................................................................47
7.2.1
Demographics, Medical History, and SBS History ...............................................47
7.2.2
Physical Examination (Including Height, Weight, and Head Circumference)......47
7.2.3
Vital Signs..............................................................................................................47
7.2.4
Clinical Laboratory Tests.......................................................................................47
7.2.5
Serum Sampling.....................................................................................................49
7.2.6
Antibody Assessment.............................................................................................49
7.2.7
Pregnancy Testing..................................................................................................49
7.2.8
Volume of Blood....................................................................................................49
7.2.9
Gastrointestinal-specific Testing ...........................................................................50
7.2.9.1
Fecal Occult Blood Testing....................................................................50
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7.2.9.2
Colonoscopy or Sigmoidoscopy.............................................................50
7.2.10 Other Study Procedures .........................................................................................50
7.2.10.1
Nutritional Support.................................................................................50
7.2.10.2
Diaries ....................................................................................................50
7.3
Changes to Study Procedures Due to a Pandemic....................................................52
8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................53
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................53
8.1.1
Severity Categorization..........................................................................................53
8.1.2
Relationship Categorization...................................................................................54
8.1.3
Outcome Categorization ........................................................................................54
8.1.4
Symptoms of the Disease under Study ..................................................................55
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................55
8.1.6
Pregnancy...............................................................................................................55
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................56
8.2
Serious Adverse Event Procedures ..........................................................................57
8.2.1
Reference Safety Information................................................................................57
8.2.2
Reporting Procedures.............................................................................................57
8.2.3
Serious Adverse Event Definition .........................................................................57
8.2.4
Serious Adverse Event Collection Time Frame.....................................................58
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................58
8.2.6
Fatal Outcome........................................................................................................58
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................59
8.3
Adverse Events of Special Interest...........................................................................59
8.4
Dose Interruption of Individual Subjects .................................................................59
8.4.1
Dose Interruption Criteria Based on Known or Possible Risks of 
Teduglutide ............................................................................................................60
8.4.2
Dose Interruption Criteria Based on Drug-induced Liver Injury...........................61
8.5
Early Termination of the Clinical Study ..................................................................62
9
DATA MANAGEMENT AND STATISTICAL METHODS...............................................63
9.1
Data Collection.........................................................................................................63
9.2
Clinical Data Management.......................................................................................63
9.3
Statistical Analysis Process......................................................................................63
9.4
Planned Interim Analysis, and Data Monitoring Committee...................................64
9.5
Sample Size Calculation and Power Considerations................................................64
9.6
Study Population ......................................................................................................65
9.7
Efficacy Analyses.....................................................................................................65
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9.8
Safety Analyses........................................................................................................65
10 SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................67
10.1
Sponsor’s Responsibilities .......................................................................................67
10.1.1 Good Clinical Practice Compliance.......................................................................67
10.1.2 Public Posting of Study Information......................................................................67
10.1.3 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................67
10.1.4 Study Suspension, Termination, and Completion..................................................67
10.2
Investigator’s Responsibilities .................................................................................68
10.2.1 Good Clinical Practice Compliance.......................................................................68
10.2.2 Protocol Adherence and Investigator Agreement..................................................68
10.2.3 Documentation and Retention of Records.............................................................68
10.2.3.1
Case Report Forms.................................................................................68
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................69
10.2.3.3
Financial Disclosure...............................................................................69
10.3
Ethical Considerations..............................................................................................69
10.3.1 Informed Consent...................................................................................................69
10.3.2 Institutional Review Board or Ethics Committee..................................................70
10.4
Privacy and Confidentiality......................................................................................71
10.5
Study Results / Publication Policy ...........................................................................71
11 REFERENCES .......................................................................................................................73
12 APPENDICES ........................................................................................................................74
Appendix 1
Protocol History .....................................................................................75
Appendix 2
Guidelines for Nutritional Support Management During the Study ......82
Appendix 3
Weaning Algorithms ..............................................................................83
Appendix 4
Monitoring Personnel.............................................................................86
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LIST OF TABLES
Table 1
Schedule of Events Required for All Subjects ..............................................19
Table 2
Schedule of Events for Subjects Not Receiving Teduglutide .......................20
Table 3
Schedule of Events for Subjects While Receiving Teduglutide....................21
Table 4
Prohibited Treatment.....................................................................................39
Table 5
List of Laboratory Tests ................................................................................48
Table 6
Adverse Events that May Lead to Dose Interruption....................................60
LIST OF FIGURES
Figure 1
Study Design Flow Chart ..............................................................................32
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ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
β-HCG
beta-human chorionic gonadotropin
BMI
body mass index
COVID-19
coronavirus disease 2019
CTCAE
common terminology criteria for adverse events
DILI
drug-induced liver injury
DMC
data monitoring committee
DPP-4
dipeptidyl peptidase 4
EC
ethics committee
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
EMA
European Medicines Agency
EN
enteral nutrition
EOS
end of study
EOT
end of treatment
ET
early termination
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
gastrointestinal
GLP-1
glucagon-like peptide 1
GLP-2
glucagon-like peptide 2
ICH
International Conference on Harmonization
IGF-1
insulin-like growth factor-1
INR
international normalized ratio
IRB
institutional review board
MedDRA
Medical Dictionary for Regulatory Activities
NCI
National Cancer Institute
NTT
no-teduglutide treatment
PDA
patent ductus arteriosus
PS
parenteral support
PT/INR
prothrombin time/international normalized ratio
SAE
serious adverse event
SAP
statistical analysis plan
SBS
short bowel syndrome
SC
subcutaneous
t1/2
elimination half-life
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ULN
upper limit of normal
US(A)
United States
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STUDY SYNOPSIS
Protocol number: SHP633-305
Drug: Teduglutide
Title of the study: A Prospective, Open-label, Long-term Safety and Efficacy Study of Teduglutide in Japanese 
Pediatric Subjects with Short Bowel Syndrome Who Completed SHP633-302
Number of subjects (total and for each treatment arm):
Approximately 7 subjects who completed Study SHP633-302 are expected to enroll in this extension study. This 
study will enroll up to as many subjects who complete Study SHP633-302.
Investigator(s): Multicenter study
Site(s) and Region(s): 
Approximately 5 investigational sites in Japan will participate in this extension study.
Study period (planned):
August 2017 – Dec 2021
Clinical phase:
3 Extension
Objectives:
Primary: To evaluate the long-term safety and tolerability of teduglutide treatment in Japanese pediatric subjects 
with short bowel syndrome (SBS) who completed Study SHP633-302.
Secondary: To evaluate long-term efficacy of teduglutide treatment in Japanese pediatric subjects with SBS who 
completed Study SHP633-302.
Rationale:
This extension study is needed to evaluate long-term safety and efficacy of teduglutide treatment in Japanese 
children with SBS. It also provides the opportunity to offer additional teduglutide treatment to subjects who 
completed Study SHP633-302.
Investigational product, dose, and mode of administration:
Teduglutide 0.05 mg/kg subcutaneous (SC) once daily injection will be administered to eligible pediatric 
subjects who previously received teduglutide 0.05 mg/kg once daily in Study SHP633-302. There is no active 
comparator or reference product.
Methodology:
This is a Phase 3, prospective, open-label, long-term extension study to evaluate the safety and efficacy of 
teduglutide in Japanese pediatric subjects who completed Study SHP633-302 (core study). The study population 
will include 2 cohorts based on age of subjects at the time of entry in the core study: infants 4-<12 months 
corrected gestational age and children 1-15 years of age.
Once informed consent (and if applicable, informed assent) has been obtained, demographics, updates to medical 
history and short bowel syndrome history will be obtained at screening. The first visit after screening (either a 
no-teduglutide treatment [NTT] visit or a pretreatment visit), must occur within 12 weeks of screening. Subjects 
not receiving teduglutide treatment (ie, in an NTT period), will be seen approximately every 12 weeks to collect 
safety and parenteral support (PS) requirements. At any point after screening, including during an NTT period, 
subjects who meet at least one teduglutide treatment inclusion criteria may proceed immediately to a pretreatment 
visit if the investigator and the subject (and/or parent/guardian, as applicable), agree to proceed with teduglutide 
therapy.
At the pretreatment visit, eligibility for teduglutide treatment is confirmed. Subjects who meet at least one of the 
teduglutide treatment inclusion criteria and none of the teduglutide treatment exclusion criteria will start a 28-week 
cycle, consisting of 24 weeks of teduglutide treatment at 0.05 mg/kg SC once daily, followed by a 4-week 
follow-up period, during which no teduglutide is administered. During the 28-week cycle, clinic visits will occur at 
Day 1 and Weeks 1, 2, 4, 6, 9, 12, 16, 20, 24, and 28. Phone visits are required approximately 1 week after each 
adjustment in PS during the teduglutide treatment period (between Weeks 1-24), and weekly during the follow-up 
period (between Weeks 24 and 28). Safety and PS requirements will be evaluated at every visit. A subject may 
“escape” the follow-up period between cycle Week 24 and Week 28 and proceed immediately to another 
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pretreatment visit if the subject meets at least one follow-up period escape criteria. 
Otherwise, following completion of the 28-week treatment cycle, the subject will proceed to an NTT visit (or 
another pretreatment visit, if needed) within 12 weeks. A subject may participate in multiple treatment cycles and 
NTT periods depending on his or her clinical trajectory.
At all site and phone visits, safety will be monitored and nutritional support will be reviewed and adjusted as 
needed. To maintain consistency across centers, all attempts should be made to follow the nutritional support 
adjustment guidelines and weaning algorithm (developed with SBS expert input and provided in Appendix 2 and 
Appendix 3 of the protocol) for decisions regarding PS reduction and advances in enteral feeds based on weight 
gain, urine and stool output, and clinical stability. Departure from the guidelines and weaning algorithms, 
however, is not considered a protocol deviation. 
Study Design Flow Chart 
Figure legend: Safety and efficacy data for subjects not receiving teduglutide treatment are captured approximately every 
12 weeks, but subjects may proceed to the pretreatment visit at any time in order to assess eligibility for teduglutide therapy.
Subjects eligible for teduglutide will enter a 28-week treatment cycle. During this cycle, subjects will return to the site for
safety and efficacy assessments at Day 1 (Week 0) and Weeks 1, 2, 4, 6, 9, 12, 16, 20, 24, and 28 (solid black lines). Phone 
visits are required approximately 1 week after adjustments in PS during the intervening weeks between Weeks 2 and 24 
(dashed grey lines). At Week 24, subjects enter a 4-week follow-up period, where teduglutide is not received, during which 
phone visits will be performed weekly (solid grey lines). If at least 1 escape criterion is met at Week 24 or during the follow-up 
period, subjects may proceed directly to another pretreatment visit.
PS=parenteral support; SC=subcutaneous
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Study Inclusion Criteria: 
The subject will be considered eligible for the study if they meet all of the study inclusion criteria. Teduglutide 
treatment eligibility does not impact study eligibility.
1.
Informed consent by a parent or guardian prior to any study-related procedures.
2.
When applicable, informed assent (as deemed appropriate by the Institutional Review Board) by the 
subject prior to any study-related procedures.
3.
Subject completed Study SHP633-302.
4.
Subject (and/or parent/guardian) understands and is willing and able to fully adhere to study 
requirements as defined in this protocol. 
Study Exclusion Criteria: There are no exclusion criteria for this study.
Teduglutide Eligibility Criteria: Subjects are eligible for teduglutide treatment if at least 1 of the teduglutide 
treatment inclusion criteria, and none of the teduglutide treatment exclusion criteria, are met. In addition, the 
investigator and the subject (and/or parent/guardian, as applicable) must agree to proceed with treatment.
Teduglutide Treatment Inclusion Criteria:
1.
Increasing PS requirements following teduglutide discontinuation.
2.
Decreased PS requirement during prior teduglutide treatment, followed by cessation of improvement 
after teduglutide discontinuation.
3.
Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal tolerated enteral 
nutrition following teduglutide discontinuation.
4.
Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and electrolyte intake 
following teduglutide discontinuation.
5.
Severe diarrhea related to teduglutide discontinuation.
Teduglutide Treatment Exclusion Criteria:
1.
Body weight <5 kg at the pretreatment visit.
2.
Unresected gastrointestinal (GI) polyp, known polyposis condition, premalignant change, or 
malignancy, in the GI tract.
3.
History of cancer in the previous 5 years except surgically curative skin cancers.
4.
Serial transverse enteroplasty or other major intestinal surgery within 3 months preceding the 
teduglutide pretreatment visit. Insertion of a feeding tube, anastomotic ulcer repair, minor intestinal 
resections ≤10 cm, and endoscopic procedures are allowed.
5.
Intestinal or other major surgery planned or scheduled to occur during the 28-week cycle.
6.
Clinically significant intestinal stricture or obstruction.
7.
Clinically significant, active or recurrent pancreatic or biliary disease.
8.
Active, severe, or unstable, clinically significant hepatic impairment or injury, including the following 
laboratory values at the pretreatment visit:
a.
Total bilirubin ≥2 × upper limit of normal (ULN)
b.
Aspartate aminotransferase (AST) ≥7 ×ULN
c.
Alanine aminotransferase (ALT) ≥7 ×ULN
9.
Renal dysfunction shown by results of an estimated glomerular filtration rate (eGFR) below 
50 mL/min/1.73 m2 at the pretreatment visit.
10. Unstable cardiac disease, congenital heart disease or cyanotic disease, with the exception of subjects 
who had undergone ventricular or atrial septal defect repair, or patent ductus arteriosus (PDA) ligation.
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11. Participation in a clinical study using an experimental drug (other than glutamine or intravenous lipid 
emulsions) within 3 months or 5.5 half-lives of experimental drug administration, whichever is longer, 
prior to the pretreatment visit and for the duration of the 28-week cycle.
12. Treatment with analogs of glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2) (not 
including teduglutide), insulin-like growth factor-1 (IGF-1), or growth hormone, within 3 months 
preceding the teduglutide pretreatment visit.
13. Treatment with octreotide or dipeptidyl peptidase 4 (DPP-4) inhibitors within 3 months prior to the 
pretreatment visit.
14. Known or suspected intolerance or hypersensitivity to the investigational product, closely-related 
compounds, or any of the stated ingredients.
15. Known history of alcohol or other substance abuse within 1 year prior to the pretreatment visit.
16. Pregnant or lactating female subjects.
17. Sexually active female subjects of childbearing potential unwilling to use approved contraception 
throughout the study period and for 30 days following the last dose of investigational product.
18. Any condition, disease, illness, or circumstance that in the investigator’s opinion puts the subject at any 
undue risk, prevents completion of the study, or interferes with analysis of the study results.
Follow-up Period Escape Criteria: At the discretion of the investigator, the follow-up period may be 
interrupted or omitted and the subject may proceed directly to the pretreatment visit, if at least 1 of the following 
criteria is met:
1.
Increasing PS requirements following teduglutide discontinuation.
2.
Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal tolerated enteral 
nutrition following teduglutide discontinuation.
3.
Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and electrolyte intake 
following teduglutide discontinuation.
4.
Severe diarrhea related to teduglutide discontinuation.
5.
The subject escaped during the follow-up period of a previous teduglutide treatment cycle within 
SHP633-305.
Maximum duration of subject involvement in the study:
A subject will be considered enrolled in the study once the subject (and/or parent/guardian, as applicable) has 
provided signed consent/assent, and meets all of the study inclusion criteria. Subjects may participate in multiple 
NTT periods and/or multiple 28-week treatment cycles. The study will continue until teduglutide is commercially 
available for each subject, the subject’s participation in this study is discontinued, or the study is discontinued. The 
subject’s maximum duration of participation is expected to be approximately 3 years. A subject will be considered 
as having completed the study if the subject has not withdrawn early from the study for any reason prior to 
completing the end of study (EOS) visit.

Planned duration of no teduglutide treatment periods: variable, depending on disease course 

Planned duration of the teduglutide pretreatment visit: 1 to 21 days

Planned teduglutide treatment cycle duration: 28 weeks. Each cycle consists of 24 weeks of 
teduglutide treatment followed by a 4-week follow-up period
Subject Population:
The safety population will consist of all enrolled subjects. The safety population will be used for both safety and 
efficacy analysis.
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Efficacy Endpoints
Efficacy endpoints will be analyzed at the end of each teduglutide treatment period (Week 24 or end of treatment 
[EOT]), and at each study visit, relative to the baseline of the core study (SHP633-302). The following efficacy 
endpoints will be analyzed:

Reduction in PS volume of at least 20%

Absolute and relative change in PS volume

Complete weaning off PS

Change in days per week of PS
Safety Endpoints 
The following safety endpoints will be analyzed: 

Adverse events

Vital signs, including temperature, heart rate, blood pressure

Laboratory safety data (ie, biochemistry, hematology, and urinalysis)

Urine output

Stool output

Antibodies to teduglutide

Gastrointestinal-specific testing, including fecal occult blood testing and colonoscopy or sigmoidoscopy 

Z-scores for weight, height (or length), head circumference (up to 36 months of age), and body mass 
index
Statistical Methods:
Data will be analyzed and presented by subject cohorts according to the subjects’ age at the time of entry in the 
core study: infants 4-<12 months corrected gestational age and children 1-15 years of age.
Efficacy Analysis
No claims of statistical significance will be made; however, 95% confidence intervals will be provided, if 
applicable. Continuous variables, including those assessed on a discrete scale, will be summarized using 
descriptive statistics including number of subjects, mean, median, standard deviation, maximum, and minimum. 
For categorical variables, statistical summaries will include number of subjects and percentages. The derivations 
of the weekly PS volume will be described in the study statistical analysis plan in detail.
Safety Analysis 
Safety data, including laboratory tests and vital signs assessments, will be summarized by visit. Adverse events 
will also be collected and summarized. Descriptive statistics will be calculated for quantitative safety data as 
well as for the difference from baseline, if applicable. Frequency counts will be compiled for classification of 
qualitative safety data.
Sample Size Justification 
As this is an extension study, the maximum number of subjects will be determined by completion of Study 
SHP633-302.
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STUDY SCHEDULES 
Table 1
Schedule of Events Required for All Subjects
Period
Screening
End of Study or Early Termination
EOS/ET
Visit Type
Site
Site
Informed consent/assenta
X
Study eligibility
X
Demographics, medical historyb, SBS historyc
X
Dispense intake and output diaries
X
Evaluate teduglutide treatment inclusion criteriad
X
Adverse events
X
X
Concomitant medications and procedures
X
X
Physical examination and vital signs, including weight
X
Height and head circumferencee
X
Review intake and output diariesf 
X
Record PS prescriptions, and adjust as neededg
X
X
Safety laboratory testsh
X
Antibodies to teduglutide
X
Fecal occult blood testingi
(X)
Colonoscopy/sigmoidoscopyj
(X)
Pregnancy testingk
(X)
EOS=end of study; EN=enteral nutrition; ET=early termination; GI=gastrointestinal; PS=parenteral support; SBS=short bowel 
syndrome 
a In general, subjects (and/or parent or guardian, as applicable) should sign consent (and informed assent, if applicable) to 
participate in Study SHP633-305 within 7 days after completion of Study SHP633-302.
b Updates to the medical history will be collected, consisting of adverse events that were ongoing at the time of completion of
SHP633-302, and events that occurred during the period between completion of SHP633-302 and informed consent/assent to 
SHP-633-305. 
c If the subject has any changes to the SBS history that had been collected at the baseline of the SHP633-302, then the updated 
SBS history will be collected.
d If one or more teduglutide treatment eligibility criteria are satisfied, the first pretreatment visit assessments may begin 
immediately and can be combined with the SHP633-302 Week 28 (EOS) assessments if performed within 7 days of the 
SHP633-302 EOS visit.
e Head circumference will be measured in subjects 36 months of age and younger.
f The intake diary should be completed daily for a minimum of 2 weeks prior to the EOS/ET visit. The output diary should be 
completed daily over a 48-hour period of PS and EN stability before the EOS/ET visit.
g Parenteral support prescription will be collected at the screening visit. PS adjustments should be made after review of the intake 
and output diaries and the safety lab data according to the guidance for nutrition support adjustment provided in Appendix 2 and 
Appendix 3. 
h Safety laboratory assessments at site visits will consist of biochemistry, hematology, and urinalysis, with results processed by a 
central laboratory. Urine specimen collection should be attempted as part of the safety lab tests, but lack of urinalysis will not 
constitute a protocol deviation.
i Fecal occult blood test should be performed on an annual basis, approximately every 48-60 weeks at a minimum.
j The need for colonoscopy/sigmoidoscopy in response to a positive fecal occult blood test during a no-teduglutide treatment 
period is at the discretion of the investigator, but all subjects will undergo colonoscopy/sigmoidoscopy after they have received 
the equivalent of 2 treatment cycles (48 weeks of investigational product exposure).
k Pregnancy testing is required for female subjects of childbearing potential at an ET visit if the subject has not had a pregnancy 
test at least 30 days after investigational product discontinuation.
Note: (X) denotes conditional requirement for a given assessment if the subject meets certain conditions per protocol.
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Table 2
Schedule of Events for Subjects Not Receiving Teduglutide
Visit Number
NTx
Visit Type
Site
Visit Frequency
Every 12 weeks 
Window (days)a
±7
Dispense intake and output diaries
X
Evaluate teduglutide treatment inclusion criteriab
X
Adverse events
X
Concomitant medications and procedures
X
Physical examination and vital signs, including weight
X
Height and head circumferencec
X
Review intake and output diariesd 
X
Record PS prescriptions, and adjust as needede
X
Safety laboratory testsf
X
Antibodies to teduglutideg
(X)
Fecal occult blood testingh
Annually 
Colonoscopy/sigmoidoscopyi
(X)
Serum samplej
Every 24 weeks
EN=enteral nutrition; GI=gastrointestinal; NTx=no treatment; PS=parenteral support
a Window is relative to the first NTx visit in the current no-teduglutide treatment period.
b Subjects who meet at least one teduglutide treatment inclusion criteria, may proceed to the pretreatment visit if the investigator 
and the subject (and/or parent/guardian, as applicable) agree to proceed with teduglutide therapy.
c Head circumference will be measured in subjects 36 months of age and younger.
d The intake diary should be completed daily for a minimum of 2 weeks prior to each NTx visit. The output diary should be 
completed daily over a 48-hour period of PS and EN stability before each NTx visit.
e PS adjustments should be made after review of the intake and output diaries and the safety lab data according to the guidance 
for nutrition support adjustment provided in Appendix 2 and Appendix 3. 
f Safety laboratory assessments at site visits will consist of biochemistry, hematology, and urinalysis, with results processed by a 
central laboratory. Urine specimen collection should be attempted as part of the safety lab tests, but lack of urinalysis will not 
constitute a protocol deviation.
g Subjects who have been treated previously and test positive for antibodies specific to teduglutide should have follow-up samples 
collected every 12 weeks until a negative result is obtained or the study ends. 
h Fecal occult blood test should be performed on an annual basis, approximately every 48-60 weeks at a minimum.
i The need for colonoscopy/sigmoidoscopy in response to a positive fecal occult blood testing during a no-teduglutide treatment 
period is at the discretion of the investigator, but all subjects will undergo colonoscopy/sigmoidoscopy after they have received 
the equivalent of 2 treatment cycles (48 weeks of investigational product exposure).
j Lack of collection of serum samples will not constitute a protocol deviation. Saved serum samples should be omitted for 
subjects weighing less than 10 kg and whenever local blood volume limitations are exceeded.
Note: (X) denotes conditional requirement for a given assessment if the subject meets certain conditions per protocol.
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Table 3
Schedule of Events for Subjects While Receiving Teduglutide
Period
Pretreatment
Teduglutide Treatment
Follow-up
Visit Number
Pxa
Cx
D1
Cx
W1
Cx
W2
Phone visit is required approximately 1 week after PS adjustment
Cx
W4
Phone visit is required approximately 1 week after PS adjustment
Cx 
W6
Phone visit is required approximately 1 week after PS adjustment
Cx 
W9
Phone visit is required approximately 1 week after PS adjustment
Cx 
W12
Phone visit is required approximately 1 week after PS adjustment
Cx 
W16
Phone visit is required approximately 1 week after PS adjustment
Cx 
W20
Phone visit is required approximately 1 week after PS adjustment
Cx 
W24 
(EOT)
CxW25 
CxW26 
CxW27
CxW28c
Visit Type
Site
Site
Site
Site
Site
Site
Site
Site
Site
Site
Site
Phoneb
Site
Cycle Day
-21 to 0
1
8
15
29
43
64
85
113
141
169
176
197
183
190
Window (days)d
±2
±2
±2
±2
±4
±4
±4
±4
±4
±2
±2
Evaluate teduglutide 
eligibility (inclusion 
and exclusion) 
criteria
X
Xe
Dispense intake and 
output diaries
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications and 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical 
examination and 
vital signs, including 
weight
X
X
X
X
X
X
X
X
X
X
X
X
Height and head 
circumferencef
X
X
X
X
Review intake and 
output diariesg
X
X
X
X
X
X
X
X
X
X
X
X
X
Record PS Rx, and 
adjust as neededh
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety laboratory 
testsi
Xi
X
X
X
X
X
X
X
X
X
X
(X)
X
Antibodies to 
teduglutidej
X
X
X
X
Fecal occult blood 
testing
X
X
X
Colonoscopy/
sigmoidoscopyk
(X)
(X)
(X)
Pregnancy testingl
X
X
X
X
X
X
X
X
X
Serum samplem
X
X
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Table 3
Schedule of Events for Subjects While Receiving Teduglutide
Period
Pretreatment
Teduglutide Treatment
Follow-up
Visit Number
Pxa
Cx
D1
Cx
W1
Cx
W2
Phone visit is required 
approximately 1 week 
ft
PS dj
t
t
Cx
W4
Phone visit is required 
approximately 1 week 
ft
PS dj
t
t
Cx 
W6
Phone visit is required 
approximately 1 week 
ft
PS dj
t
t
Cx 
W9
Phone visit is required 
approximately 1 week 
ft
PS dj
t
t
Cx 
W12
Phone visit is required 
approximately 1 week 
ft
PS dj
t
t
Cx 
W16
Phone visit is required 
approximately 1 week 
ft
PS dj
t
t
Cx 
W20
Phone visit is required 
approximately 1 week 
ft
PS dj
t
t
Cx 
W24 
(EOT)
CxW25 
CxW26 
CxW27
CxW28c
Visit Type
Site
Site
Site
Site
Site
Site
Site
Site
Site
Site
Site
Phoneb
Site
Cycle Day
-21 to 0
1
8
15
29
43
64
85
113
141
169
176
197
183
190
Window (days)d
±2
±2
±2
±2
±4
±4
±4
±4
±4
±2
±2
Evaluate escape 
criterian
Xo
X
X
Review study drug 
administration 
diaryp
X
X
X
X
X
X
X
X
X
Dispense 
investigational 
product and study 
drug administration 
diary
X
X
X
X
X
X
X
X
X
Confirm 
administration 
proficiency
Xq
Cx=cycle x; D1=Day 1 of teduglutide treatment cycle; EN=enteral nutrition; ET=early termination; EOS=end of study; EOT=end of treatment; GI=gastrointestinal; PS=parenteral 
support; PT/INR=prothrombin time/international normalized ratio; Rx=prescription; Px=pretreatment; SC=subcutaneous; W=week
a The first pretreatment visit may be combined with the screening visit and Study SHP633-302 EOS visit (Week 28), if the pretreatment visit assessments occur within 7 days of 
the SHP633-302 EOS assessments. If subjects proceed directly from screening to a pretreatment visit, the first pretreatment visit must occur within 12 weeks of screening.
b Phone visits are required approximately 1 week after an adjustment in PS. The assessments to be performed at phone visits are the same as those described for CxW25-27 (except 
for evaluation of escape criteria).
c Whenever possible, subjects who withdraw early from the study during a teduglutide treatment cycle should complete the EOT visit and 4-week follow-up period (CxW25-27) 
and then proceed to the ET visit in Table 1. The ET visit will take place in lieu of the CxW28 visit. The investigator may combine the CxW28 visit with a pretreatment visit if at 
least 1 escape criterion is met at the CxW28 visit.
d Visit windows are relative to the CxD1 visit.
e Eligibility will need to be re-confirmed prior to the first dose in the cycle. Negative urine pregnancy test is required prior to the first dose of teduglutide, but results of other lab 
tests obtained at the CxD1 visit are not required to determine teduglutide treatment eligibility.
f Head circumference will be measured in subjects 36 months of age and younger.
g The intake diary should be completed daily for a minimum of 2 weeks immediately prior to each clinic visit (except at pretreatment visit), for 1 week after PS adjustment, and 
daily during the 4-week follow-up period. The output diary should be completed daily over a 48-hour period of PS and EN stability before each clinic or phone visit and within 
1 week of implementing a change in the PS prescription. See Section 7.2.10.2 for more detail.
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06 Nov 2020
Table 3
Schedule of Events for Subjects While Receiving Teduglutide
Period
Pretreatment
Teduglutide Treatment
Follow-up
Visit Number
Pxa
Cx
D1
Cx
W1
Cx
W2
Phone visit is required 
approximately 1 week 
ft
PS dj
t
t
Cx
W4
Phone visit is required 
approximately 1 week 
ft
PS dj
t
t
Cx 
W6
Phone visit is required 
approximately 1 week 
ft
PS dj
t
t
Cx 
W9
Phone visit is required 
approximately 1 week 
ft
PS dj
t
t
Cx 
W12
Phone visit is required 
approximately 1 week 
ft
PS dj
t
t
Cx 
W16
Phone visit is required 
approximately 1 week 
ft
PS dj
t
t
Cx 
W20
Phone visit is required 
approximately 1 week 
ft
PS dj
t
t
Cx 
W24 
(EOT)
CxW25 
CxW26 
CxW27
CxW28c
Visit Type
Site
Site
Site
Site
Site
Site
Site
Site
Site
Site
Site
Phoneb
Site
Cycle Day
-21 to 0
1
8
15
29
43
64
85
113
141
169
176
197
183
190
Window (days)d
±2
±2
±2
±2
±4
±4
±4
±4
±4
±2
±2
h PS adjustments should be made after review of the intake and output diaries and the safety lab data according to the nutritional support adjustment guidelines and weaning 
algorithms provided in Appendix 2 and Appendix 3, respectively. 
i Safety laboratory assessments at site visits will consist of biochemistry, hematology, and urinalysis, with results processed by a central laboratory. Biochemistry and urinalysis 
must also be performed within approximately 5-7 days of any adjustment to the PS prescription. Safety lab tests performed between clinic visits may be performed at the 
investigational site laboratory. Unscheduled results processed by the investigational site laboratory will not be captured in the eCRFs, but if abnormal results are considered an 
adverse event, an AE form will be completed. PT/INR will be collected at the pretreatment visit. Additional collection will occur if a potential drug-induced liver injury signal is 
observed. Urine specimen collection should be attempted as part of the safety lab tests, but lack of urinalysis will not constitute a protocol deviation.
j Blood samples collected on CxD1 must be drawn prior to first administration of teduglutide. Samples collected while subjects are receiving teduglutide should be drawn at least 
14 hours after the previous dose.
k Subjects of any age with newly positive fecal occult blood test results at the pretreatment visit for which a readily detectable cause cannot be identified (eg, anal fissure) will 
undergo a colonoscopy/sigmoidoscopy prior to receiving teduglutide. If newly positive fecal occult blood test results (for which a readily detectable cause cannot be identified) 
are obtained at the end of a teduglutide treatment cycle (CxW24/EOT), colonoscopy/sigmoidoscopy will be performed. The need for colonoscopy/sigmoidoscopy in response to 
positive fecal occult blood tests at CxW12 is at the discretion of the investigator. Subjects who have received the equivalent of 2 treatment cycles (48 weeks of investigational 
product exposure) will undergo colonoscopy/sigmoidoscopy before the next cycle of teduglutide treatment. Colonoscopy/sigmoidoscopy performed after the Visit CxW24 
(±4 days) window and before the next cycle of teduglutide treatment will not be considered a protocol deviation (all other visit procedures must adhere to the (±4 days) visit 
window).
l Serum pregnancy test at the pretreatment visit, urine pregnancy tests at all other visits as per protocol schedule.
m If the subject met a follow-up period escape criterion, the serum sample will not be collected at the pretreatment visit. Lack of collection of serum samples will not constitute a 
protocol deviation. Saved serum samples should be omitted for subjects weighing less than 10 kg and whenever local blood volume limitations are exceeded.
n If escape criteria are met, the subject may proceed directly to another pretreatment visit at the discretion of the investigator.
o Escape criteria will be assessed for subjects who escaped during the follow-up period of a previous teduglutide treatment cycle at CxW24. The investigator may combine the 
CxW24 visit with the next pretreatment visit if at least 1 escape criterion is met at the CxW24 visit. In order to combine assessments, the pretreatment assessments must occur 
within 7 days of the CxW24 visit.
p The study drug administration diary should be completed daily between CxD1 and CxW24 by the subject or parent/guardian/study site staff. See Section 6.2.2 for dosing 
adjustment.
q The study physician must observe the parent/guardian administer the study drug in compliance with the study drug administration checklist at the beginning of each teduglutide 
treatment cycle before the parent/guardian is allowed to administer the drug without direct observation by the physician. Refer to Section 6.2.2.1.
Note: (X) denotes conditional requirement for a given assessment if the subject meets certain conditions per protocol.
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06 Nov 2020
Table 3
Schedule of Events for Subjects While Receiving Teduglutide
Period
Pretreatment
Teduglutide Treatment
Follow-up
Visit Number
Pxa
Cx
D1
Cx
W1
Cx
W2
Phone visit is required 
approximately 1 week 
ft
PS dj
t
t
Cx
W4
Phone visit is required 
approximately 1 week 
ft
PS dj
t
t
Cx 
W6
Phone visit is required 
approximately 1 week 
ft
PS dj
t
t
Cx 
W9
Phone visit is required 
approximately 1 week 
ft
PS dj
t
t
Cx 
W12
Phone visit is required 
approximately 1 week 
ft
PS dj
t
t
Cx 
W16
Phone visit is required 
approximately 1 week 
ft
PS dj
t
t
Cx 
W20
Phone visit is required 
approximately 1 week 
ft
PS dj
t
t
Cx 
W24 
(EOT)
CxW25 
CxW26 
CxW27
CxW28c
Visit Type
Site
Site
Site
Site
Site
Site
Site
Site
Site
Site
Site
Phoneb
Site
Cycle Day
-21 to 0
1
8
15
29
43
64
85
113
141
169
176
197
183
190
Window (days)d
±2
±2
±2
±2
±4
±4
±4
±4
±4
±2
±2
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Teduglutide (SHP633)
06 Nov 2020
1
BACKGROUND INFORMATION
1.1
Indication and Current Treatment Options 
Short bowel syndrome (SBS) is a rare disorder resulting from congenital abnormalities or severe 
intestinal disease that results in major surgical resections of the small intestine. In children, most 
cases of short bowel syndrome begin in infancy. Based on national surveys, it is estimated that 
the number of patients with SBS who are dependent on parenteral support (PS) is less than 
1000 in Japan (Kitajima et al., 2013; Takagi et al., 1995; Takehara, 2001). Among the 195 SBS 
subjects in the 2011 survey, 99 (51%) developed SBS at <1 years old. Common causes of SBS in 
children include necrotizing enterocolitis, midgut volvulus, intestinal atresia, and gastroschisis 
(Duro et al., 2008; Squires et al., 2012). Similar to adults, new-onset SBS in older children 
usually stems from Crohn’s disease, trauma, or cancer. The diminished absorptive capacity for 
fluids and nutrients often results in dependence on PS (parenteral nutrition or intravenous fluids) 
to maintain energy, fluid, and electrolyte homeostasis. 
After resection or congenital loss, the small intestine is capable of remarkable adaptation. 
Mechanisms for adaptation include up-regulation of nutrient transporters, increased villus height 
and crypt depth, dilation, and delayed intestinal transit. The main principle of management of 
SBS is to provide the minimal necessary PS to maintain energy, fluid, and electrolyte 
homeostasis while maximizing enteral feeding to promote intestinal adaptation. In infants, rapid 
linear growth of the intestines during the first year of life dramatically complements the 
aforementioned adaptive responses. About 30% of infants who develop SBS during the 
neonatal period become independent of PS requirements within 12 months of the initial insult, 
and an additional 10% wean off PS within 24 months. After this time, linear intestinal growth 
slows. About 60% of children with SBS are able to become independent of PS within 5 years 
(Khan et al., 2015; Squires et al., 2012). Nevertheless, despite optimal medical management, 
many children remain dependent on PS.
For this reason, research in the pediatric arena is focused on children with PS-dependent SBS. 
Given intestinal adaption in younger children, the unmet medical need is the greatest in children 
who are 1 year of age and older. 
Complications of long-term PS include liver disease, catheter-related blood stream infections, 
central line-associated venous thrombosis, and dwindling central venous access. Sepsis is the 
leading cause of death in these patients, and quality of life is poor. Accelerating the adaptive 
process is an urgent goal for all patients with SBS who are dependent on PS.
1.2
Product Background and Clinical Information
Intestinal adaptation is driven by hormonal cues in response to nutrient malabsorption 
(Drucker and Yusta, 2014). Chief among these is hormones glucagon-like peptide-2 (GLP-2), 
which is secreted from L-type enteroendocrine cells that reside in the distal ileum and colon. 
Resection of these regions may impair the adaptive response by limiting endogenous production 
of GLP-2.
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In the United States (US) and the European Union (EU), a GLP-2 analog called teduglutide is 
approved for the treatment of SBS in adult patients who are dependent on PS. On 29 June 2016, 
the European Commission approved teduglutide for the treatment of children with SBS who are 
dependent on PS. There are no other approved pharmacological therapies that promote intestinal 
adaptation in children with SBS.
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) of approximately 2 hours in healthy adults and 1.3 hours in SBS adults 
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). 
Teduglutide was designated as an orphan drug indicated for SBS in Japan on 20 Nov 2014.
Adult Studies
Four Phase 3 studies have been completed in adult SBS subjects in US/EU countries. A 
completed adult study (CL0600-004) and its extension (CL0600-005) together evaluated safety 
and tolerability of daily teduglutide dosing for up to 12 months in SBS subjects who were 
dependent on PS. Study CL0600-004, a double-blind, placebo-controlled study in which 
83 subjects were enrolled and 67 dosed with teduglutide, assessed the effects of teduglutide 
(0.05 and 0.10 mg/kg/day) on reductions in PS. There was a statistically significant difference 
favoring the 0.05 mg/kg/day group over placebo (p=0.007) by using a graded response at the end 
of the study. At Week 24, the weekly reduction of PS volume was similar in the 2 active groups 
(2.5 L each). The extension study, CL0600-005, assessed the long-term safety of teduglutide 
(0.05 mg/kg/day and 0.10 mg/kg/day) and the proportion of responders in the CL0600-004 study 
that maintained their response at the end of a further 28 weeks of treatment. The extension study 
also assessed the effects of teduglutide at 28 weeks on those subjects previously receiving 
placebo in Study CL0600-004.
Results from the extension study supported the clinical benefits of the 0.05 mg/kg/day 
teduglutide treatment in the initial Phase 3 study, which included significant reductions in PS. 
Seventy-five percent of the subjects who previously responded to teduglutide treatment in Study 
CL0600-004 maintained this response or experienced further improved benefit from teduglutide 
treatment. More than 60% of the subjects previously receiving placebo in Study CL0600-004 
achieved a clinical response after switching to teduglutide treatment for 6 months. Most of the 
adverse events (AEs) reflected the underlying disease and were not treatment related.
Study CL0600-020 was a randomized, double-blind, placebo-controlled study in which subjects 
were randomized to teduglutide 0.05 mg/kg/day or placebo on a 1:1 ratio. The first stage of the 
study included a screening and optimization period and a stabilization period that demonstrated 
stable administration of PS volume for a minimum of 4 weeks up to a maximum of 8 weeks. 
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The second stage was a dosing period of 24 weeks. Subjects on 0.05 mg/kg/day teduglutide 
achieved a higher responder rate (defined as a 20% to 100% reduction from baseline in PS 
volume at Weeks 20 and 24) than the placebo-treated subjects (27/43 subjects [62.8%] versus 
13/43 subjects [30.2%], respectively). This difference was clinically and statistically significant 
in both the intent-to-treat (p=0.002) and per protocol (p <0.001) populations. Generally, the 
incidence of treatment-emergent AEs was distributed similarly across all treatment groups. The 
treatment-emergent AEs with a higher incidence in the teduglutide group were mainly of GI 
origin. 
A long-term, open-label extension study (CL0600-021) assessed safety and efficacy for up to 
24 additional months (ie, up to 30 months of exposure for subjects who received teduglutide in 
Study CL0600-020). Overall, 30 of 43 subjects who received teduglutide in Study CL0600-020 
and entered Study CL0600-021 completed a total of 30 months of treatment with teduglutide. Of 
these, 28 subjects (93%) achieved a 20% or greater reduction of PS resulting in a PS volume 
reduction of 7.55 L/week, corresponding to a mean reduction of 65.6% relative to baseline prior 
to exposure to teduglutide at the beginning of Study CL0600-020. Parenteral support use was 
reduced by at least one day per week in 21 of 30 subjects (70%) who completed 30 months of 
treatment. Of the 39 subjects who entered Study CL0600-021 after receiving placebo in Study 
CL0600-020, 29 completed 24 months of treatment with teduglutide. The mean reduction in PS 
volume was 3.11 L/week from baseline at the start of Study CL0600-021 (a 28% reduction). 
Sixteen (55.2%) of the 29 completers achieved a 20% or greater reduction of PS. Of the 
12 subjects entering Study CL0600-021 directly, 6 completed 24 months of treatment with 
teduglutide. The mean reduction in PS volume was 4.0 L/week (a 39.4% reduction from baseline 
at the start of Study CL0600-021) and 4 of the 6 completers (66.7%) achieved a 20% or greater 
reduction of PS.
Pediatric Studies
One Phase 3 study, TED-C13-003, was completed in pediatric SBS subjects in US/EU countries. 
In this study, teduglutide was administered to 3 cohorts of children from age 1 through 17. 
Thirty-seven children received teduglutide at doses of 0.0125, 0.025, or 0.05 mg/kg/day for 
12 weeks. Five additional children were enrolled in an observational standard of care cohort.
There were clear dose-dependent effects of teduglutide seen at the 0.025 and 0.05 mg/kg/day 
doses compared to standard of care and the 0.0125 mg/kg/day dose. In the 0.025 mg/kg/day 
cohort there was a reduction in PS volume at Week 12 of 37%, including complete independence 
from PS in 1 subject, and a reduction of 3.94 hours per day infusion time. In the 0.05 mg/kg/day 
cohort there was a reduction in PS volume at Week 12 of 39%, including complete independence 
from PS 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 AEs related to teduglutide 
were reported. No discontinuations from study were due to AEs.
Subjects who completed Study TED-C13-003 will be followed in a long-term retrospective and 
prospective extension study.
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A second Phase 3 pediatric study (TED-C14-006) was recently completed in the US and EU in 
which pediatric subjects through 17 years received 24 weeks of teduglutide treatment followed 
by a 4-week follow-up period. Subjects who completed this study are followed in a long-term 
prospective study.
SHP633-302 is an ongoing open-label Japanese study where subjects receive 0.05 mg/kg/day 
teduglutide treatment once daily. Subjects participate in a 2-week minimum screening period, a 
24-week teduglutide treatment, and a 4-week follow-up period. Subjects who complete Study 
SHP633-302 will be asked to enroll in the SHP633-305 extension study.
Additional information is provided in the investigator’s brochure. 
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2
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study 
This is a Phase 3, prospective, open-label, long-term extension study to evaluate the safety and 
efficacy of teduglutide in Japanese pediatric subjects with SBS who completed Study 
SHP633-302. In addition to evaluating the long-term safety and durability of efficacy after 
24 weeks of treatment, this extension study will evaluate the need for additional teduglutide 
treatment in these subjects.
2.2
Study Objectives
2.2.1
Primary Objectives
The primary objective of the study is to evaluate the long-term safety and tolerability of 
teduglutide treatment in Japanese pediatric subjects with SBS who completed Study 
SHP633-302.
2.2.2
Secondary Objectives
The secondary objective of this study is to evaluate the long-term efficacy of teduglutide 
treatment in Japanese pediatric subjects with SBS who completed Study SHP633-302.
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3
STUDY DESIGN
3.1
Study Design and Flow Chart
This is a Phase 3, prospective, open-label, long-term extension study to evaluate the safety and 
efficacy of teduglutide in Japanese pediatric subjects who completed Study SHP633-302 (core 
study). The study population will include 2 cohorts based on age of subjects at the time of entry
in the core study: infants 4-<12 months corrected gestational age and children 1-15 years of age.
At the time of entry into Study SHP633-302, subjects were dependent on parenteral nutrition to 
provide at least 30% of their caloric and/or fluid/electrolyte needs, and had not been able to 
significantly reduce PS for at least 3 months prior to enrollment. During the core study, subjects 
were to receive 0.05 mg/kg once daily of teduglutide. Study SHP633-302 will also be referred to 
as the core study throughout this protocol.
Approximately 7 subjects who complete the core study are expected to enroll in this extension 
study. To be eligible to additional teduglutide treatment, subjects must meet at least one of the 
teduglutide treatment inclusion criteria and none of the teduglutide treatment exclusion criteria. 
Additional Teduglutide Treatment:
Subjects not receiving teduglutide treatment (ie, in a “no-teduglutide treatment [NTT] period”), 
will be seen approximately every 12 weeks for safety and PS requirements. At any point during 
an NTT period, subjects who meet at least one teduglutide treatment inclusion criterion may 
proceed directly to the pretreatment visit if the investigator and the subject (and/or 
parent/guardian, as applicable) agree to proceed with teduglutide therapy.
Rationale: Some pediatric subjects may have a durable beneficial effect after 24 weeks of 
teduglutide treatment and thus long-term follow-up without additional teduglutide treatment may 
be appropriate. However, there may be some pediatric subjects who deteriorate or stop 
improving after discontinuation of teduglutide treatment. In these pediatric subjects, additional 
teduglutide treatment may be beneficial. 
Dose Selection: 
In this extension study to SHP633-302, eligible subjects will be able to receive daily doses of 
teduglutide 0.05 mg/kg once daily for 24-week periods. 
Rationale: Teduglutide is approved for adult use in the US and EU, and for pediatric use in the 
EU, at a dose of 0.05 mg/kg subcutaneous (SC) once daily. The completed pediatric studies
(TED-C13-003 and TED-C14-006) demonstrated that teduglutide dosing at 0.025 and 
0.05 mg/kg/day was associated with a favorable benefit/risk profile. In addition, population 
pharmacokinetic modeling and simulations were conducted to determine the effective dose to be 
used in pediatric subjects using data from 8 adult clinical studies including adult Phase 1 studies 
and Phases 2/3 studies as well as the pediatric study (TED-C13-003) and suggested that the dose 
in pediatric subjects is likely to be same as the dose in adults (refer to the investigator’s brochure 
for more information). 
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Duration of Treatment:
The duration of teduglutide treatment periods in this study mirrors that of Study SHP633-302, 
consisting of 24 weeks of teduglutide treatment, followed by 4-week follow-up periods. The 
follow-up periods are a mechanism to evaluate whether continued teduglutide is needed. If a 
subject deteriorates during a follow-up period, the subject may be evaluated immediately for
additional teduglutide treatment. Subjects who clinically deteriorate or stop improving at any
time during an NTT period may be immediately assessed for eligibility to additional treatment.
Rationale: During the teduglutide treatment cycle, visit frequency is similar to frequencies 
performed in TED-C13-003 and SHP633-302, to ensure sufficient safety monitoring and 
weaning of PS. During NTT, visits occur approximately every 12 weeks, a frequency that is 
consistent with standard medical practices. To minimize risk to subjects, those who have 
deteriorated quickly after treatment interruption (ie, escaped from a prior follow-up period) may 
be evaluated immediately for eligibility for additional treatment when they reach the Week 24 
visit.
Measures and Parameters:
Following the review and signing of the informed consent (and informed assent, if applicable), 
screening visit procedures will begin, including demographics and updates to medical history 
and short bowel syndrome history. Subjects who meet at least one of the teduglutide treatment 
inclusion criteria may proceed to the pretreatment visit.
After the pretreatment visit, subjects who meet at least one of the teduglutide treatment inclusion 
criteria, and meet none of the teduglutide treatment exclusion criteria, will start a 28-week cycle, 
consisting of 24 weeks of teduglutide treatment at 0.05 mg/kg SC once daily, followed by a 
4-week follow-up (no treatment) period (Figure 1). During the 28-week cycle, clinic visits will 
occur at Day 1 and Weeks 1, 2, 4, 6, 9, 12, 16, 20, 24, and 28. Phone visits are required 
approximately 1 week after adjustments in PS during the teduglutide treatment period (between 
weeks 1 and 24), and weekly during the teduglutide follow-up period (between weeks 24 and 
28).
At all site and phone visits, safety will be monitored and nutritional support will be reviewed and 
adjusted as needed. To maintain consistency across centers, all attempts should be made to 
follow the nutritional support adjustment guidelines and weaning algorithm (developed with SBS 
expert input and provided in Appendix 2 and Appendix 3, respectively) for decisions regarding 
PS reduction and advances in enteral feeds based on weight gain, urine and stool output, and 
clinical stability. Departure from the guidelines (Appendix 2 and Appendix 3), however, is not 
considered a protocol deviation.
Rationale: Measures of long term safety will include AEs, growth parameters, safety laboratory 
tests, and anti-drug antibodies. Measure of long term efficacy will include durability of effect as 
measured by reduction in PS. A reduction in PS volume of at least 20% at end of treatment 
(EOT) was used as the primary endpoint in pivotal Phase 3 adult clinical trials and the completed 
Phase 3 pediatric study (TED-C13-003), and will be used as an endpoint in this extension study. 
In previous clinical studies, a reduction of this magnitude was associated with a reduction in the 
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number of days per week of PS. Reduction in volume and time of PS due to improved enteral 
absorption may provide a pediatric subject with opportunities for more age-appropriate activities 
including oral rehabilitation.
Teduglutide has been found to have a targeted intestinotrophic effect. Taking into account the 
patient population and the pharmacologic effect of teduglutide, GI-specific screening tests, 
including fecal occult blood testing and colonoscopy/sigmoidoscopy, which are commonly part 
of the routine care of these subjects, will be performed to ensure safety. This study captures 
long-term safety data on polyps and other colonic mucosal changes in teduglutide-exposed 
subjects using the surveillance strategy proposed in Section 7.2.9. 
Figure 1
Study Design Flow Chart
PS=parenteral support; SC=subcutaneous
Figure legend: Safety and efficacy data for subjects not receiving teduglutide treatment are captured approximately every 
12 weeks, but subjects may proceed to the pretreatment visit at any time in order to assess eligibility for teduglutide therapy.
Subjects eligible for teduglutide will enter a 28-week cycle. During this cycle, subjects will return to the site for safety and 
efficacy assessments at Day 1 (Week 0) and Weeks 1, 2, 4, 6, 9, 12, 16, 20, 24, and 28 (solid black lines). Phone visits are 
required approximately 1 week after adjustments in PS during the intervening weeks between Weeks 2 and 24 (dashed grey 
lines). At Week 24, subjects enter a 4-week follow-up period, where teduglutide is not received, during which phone visits will 
be performed weekly (solid grey lines). If at least 1 escape criterion is met at Week 24 or during the follow-up period, subjects 
may proceed directly to another pretreatment visit.
3.2
Duration and Study Completion Definition
A subject will be considered enrolled in the study once the subject (and/or parent/guardian, as 
applicable) has provided signed consent (and informed assent, if applicable), and meets all of the 
inclusion criteria at screening. The study will continue until teduglutide is commercially 
available for each subject, the subject’s participation in this study is discontinued, or the study is 
discontinued. A subject will be considered as having completed the study if the subject has not 
withdrawn early from the study for any reason prior to completing the end of study (EOS) visit.
If teduglutide is approved for marketing, this study will be continued as a post-marketing study. 
This protocol will continuously be used. “Clinical Study” mentioned in the protocol will be read 
as “Post-marketing Study” as appropriate.
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The study completion date is defined as the date the final subject, across all sites, completes their 
final protocol-defined assessment. Please note that this includes the follow-up visit or contact
(last safety contact), whichever is later. The study completion date will be used to ascertain 
timing for study results posting and reporting.
3.3
Sites and Regions
This study will be conducted at approximately 5 investigational sites in Japan.
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4
STUDY POPULATION
Each subject (and/or parent or guardian, as applicable) must review and sign the informed 
consent/assent before any study-related procedures specified in the protocol are performed. 
Teduglutide treatment eligibility does not impact study eligibility.
4.1
Study Eligibility Criteria
4.1.1
Study Inclusion Eligibility Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1. Informed consent by a parent or guardian prior to any study-related procedures. 
2. When applicable, informed assent (as deemed appropriate by the Institutional Review 
Board [IRB]) by the subject prior to any study-related procedures.
3. Subject completed Study SHP633-302.
4. Subject (and/or parent/guardian) understands and is willing and able to fully adhere to 
study requirements as defined in this protocol.
4.1.2
Study Exclusion Eligibility Criteria
There are no exclusion criteria for this study.
4.2
Teduglutide Eligibility Criteria
Subjects are eligible for teduglutide treatment if at least 1 of the teduglutide treatment inclusion 
criteria, and none of the teduglutide treatment exclusion criteria, are met. In addition, the 
investigator and the subject (and/or parent/guardian, as applicable) must agree to proceed with 
treatment.
4.2.1
Teduglutide Treatment Inclusion Criteria
1. Increasing PS requirements following teduglutide discontinuation.
2. Decreased PS requirement during prior teduglutide treatment, followed by cessation of 
improvement after teduglutide discontinuation.
3. Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal 
tolerated enteral nutrition following teduglutide discontinuation.
4. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation.
5. Severe diarrhea related to teduglutide discontinuation.
4.2.2
Teduglutide Treatment Exclusion Criteria
1. Body weight <5 kg at the pretreatment visit.
2. Unresected GI polyp, known polyposis condition, premalignant change, or malignancy, 
in the GI tract.
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3. History of cancer in the previous 5 years except surgically curative skin cancers.
4. Serial transverse enteroplasty or other major intestinal surgery within 3 months 
preceding the teduglutide pretreatment visit. Insertion of a feeding tube, anastomotic 
ulcer repair, minor intestinal resections ≤10 cm, and endoscopic procedures are 
allowed.
5. Intestinal or other major surgery planned or scheduled to occur during the 28-week 
cycle.
6. Clinically significant intestinal stricture or obstruction.
7. Clinically significant, active or recurrent pancreatic or biliary disease.
8. Active, severe, or unstable, clinically significant hepatic impairment or injury, 
including the following laboratory values at the pretreatment visit:
a.
Total bilirubin ≥2 × upper limit of normal (ULN)
b. Aspartate aminotransferase (AST) ≥7 ×ULN
c.
Alanine aminotransferase (ALT) ≥7 ×ULN
9. Renal dysfunction shown by results of an estimated glomerular filtration rate (eGFR) 
below 50 mL/min/1.73 m2 at the pretreatment visit.
10. Unstable cardiac disease, congenital heart disease or cyanotic disease, with the 
exception of subjects who had undergone ventricular or atrial septal defect repair, or 
patent ductus arteriosus (PDA) ligation.
11. Participation in a clinical study using an experimental drug (other than glutamine or 
intravenous lipid emulsions) within 3 months or 5.5 half-lives of experimental drug 
administration, whichever is longer, prior to the pretreatment visit and for the duration 
of the 28-week cycle.
12. Treatment with analogs of glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 
(GLP-2) (not including teduglutide), insulin-like growth factor-1 (IGF-1), or growth 
hormone, within 3 months preceding the teduglutide pretreatment visit.
13. Treatment with octreotide or DPP-4 inhibitors within 3 months prior to the 
pretreatment visit.
14. Known or suspected intolerance or hypersensitivity to the investigational product, 
closely-related compounds, or any of the stated ingredients.
15. Known history of alcohol or other substance abuse within 1 year prior to the 
pretreatment visit.
16. Pregnant or lactating female subjects.
17. Sexually active female subjects of childbearing potential unwilling to use approved 
contraception throughout the study period and for 30 days following the last dose of 
investigational product. 
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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4.3
Follow-up Period Escape Criteria
At the discretion of the investigator, the follow-up period may be interrupted or omitted and the 
subject may proceed directly to the pretreatment visit, if at least 1 of the following criteria is 
met:
1. Increasing PS requirements following teduglutide discontinuation.
2. Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal 
tolerated enteral nutrition following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and 
electrolyte intake following teduglutide discontinuation.
4. Severe diarrhea related to teduglutide discontinuation.
5. The subject escaped during the follow-up period of a previous teduglutide treatment 
cycle within SHP633-305.
4.4
Reproductive Potential
4.4.1
Female Contraception
To be eligible for treatment with teduglutide, sexually active females of childbearing potential 
must use an acceptable form of contraception. Females of childbearing potential must be advised 
to use acceptable contraceptives throughout the study period and for 30 days following the last 
dose of investigational product. If hormonal contraceptives are used, they should be administered 
according to the package insert. Females of childbearing potential who are not currently sexually 
active must agree to use acceptable contraception, as defined below, if they become sexually 
active during the period of the study and for 30 days following the last dose of investigational 
product. 
Female children and adolescent subjects should be either:

Premenarchal and either Tanner Stage 1 or less than age 9 years, or

Females of childbearing potential with a negative serum beta-human chorionic gonadotropin 
(β-HCG) pregnancy test at the teduglutide pretreatment visit and a negative urine β-HCG 
pregnancy test prior to enrollment. Females of childbearing potential must agree to abstain 
from sexual activity (ie, true abstinence*) that could result in pregnancy or agree to use 
medically acceptable methods of contraception at all times during the study and for 30 days 
following the last dose of investigational product. 
*Note: True abstinence: Abstention of sexual activity that is in line with the preferred and usual 
lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, 
post-ovulation methods] and withdrawal are not acceptable methods of contraception.)
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4.5
Discontinuation of Subjects 
4.5.1
Permanent Discontinuation of Investigational Product
If the investigational product is discontinued prematurely during a teduglutide treatment cycle 
and the subject wishes to remain in the study, the evaluations listed for the EOT visit are to be 
performed. A 4-week follow-up period will ensue, consisting of weekly phone visits (CxW25 to 
CxW27) and the week 28 clinic visit (CxW28) shown in Table 3. The subject would then enter 
an NTT period.
Comments (spontaneous or elicited) or complaints made by the subject must be recorded in the 
source documents. In all cases, the reason for permanent discontinuation must be recorded in the 
electronic case report form (eCRF) and in the subject’s medical records, as described in 
Section 4.5.3. The investigator is encouraged to discuss withdrawal of a subject from 
investigational product with the medical monitor, when possible.
4.5.2
Study Withdrawal
At any time during the study, the investigator or sponsor may withdraw a subject, or a subject 
may withdraw from the study, for any reason, without prejudice to their future medical care by 
the physician or at the institution.
If a subject withdraws from the study during a teduglutide cycle, the evaluations listed for the 
EOT visit are to be performed as completely as possible. Whenever possible, the subject will 
then be asked to return 4 weeks later for the early termination (ET) visit, and will be contacted 
weekly by phone during the interim period between EOT and ET for safety follow-up.
If a subject withdraws from the study during an NTT period, the evaluations listed for the ET 
visit are to be performed as completely as possible. 
Subjects who withdraw from the study will not be replaced.
4.5.3
Reasons for Discontinuation
The reason(s) for permanent discontinuation of treatment and/or withdrawal from the study must 
be determined by the investigator, and recorded in the subject’s medical record and in the eCRF. 
If a subject is withdrawn for more than 1 reason, each reason should be documented in the source 
document, and the most clinically relevant reason should be entered in the eCRF.
Reasons for discontinuation include, but are not limited to:

Adverse event

Death

Lost to follow-up

Physician decision

Pregnancy
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
Protocol deviation

Study terminated by sponsor

Withdrawal by parent/guardian

Withdrawal by subject

Lack of efficacy 

Other 
If the reason is not known, the subject must be followed-up to establish whether the reason was 
an AE and, if so, the AE must be reported in accordance with the procedures described in 
Section 8.1. 
4.5.4
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact (site or phone visit). At least one 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
CONCOMITANT TREATMENT
5.1
Concomitant Medications and Procedures
Concomitant treatment refers to all treatment taken between the dates of informed consent/assent 
and EOS, inclusive. Concomitant medications and procedures will be assessed at each site visit, 
and include all nonstudy treatments (medications, herbal treatments, vitamins, invasive, and 
diagnostic procedures). Concomitant treatment information must be recorded on the appropriate 
eCRF page. Details of medication changes and/or dosages will be recorded on the eCRF. See 
also nutritional support in Section 7.2.10.1.
The mechanism of action of teduglutide may increase enteral absorption of drugs (eg, motility 
medication including narcotics and opioids used for the management of SBS, warfarin, 
psychotropics, metronidazole, digoxin), so consideration should be given to modifying 
concomitant enteral medication regimens. Titration of concomitant enteral medications should be 
considered when drugs, especially those with a narrow therapeutic index, are given.
5.1.1
Permitted Treatment
Standard medical therapy for SBS should be continued.
5.1.2
Prohibited Treatment
The following medications are prohibited during teduglutide treatment and within the provided 
timeframe prior to the pretreatment visit (Table 4):
Table 4
Prohibited Treatment
Prior Therapy
Time Restriction Prior to 
the Pretreatment Visit
Native/synthetic glucagon-like peptide-2 (not-including teduglutide)
Any
Glucagon-like peptide-1 analog or human growth hormone
3 months
Octreotide or dipeptidyl peptidase 4 inhibitors
3 months
Biological therapy used to treat inflammatory bowel disease (eg, 
antitumor necrosis factor)
6 months
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6
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product 
The test product is teduglutide, which will be provided in sterile, single-use 3 mL vials 
containing 5 mg or 1.25 mg teduglutide as a white lyophilized powder to be reconstituted before 
use with 0.5 mL sterile water for injection. In addition to the active ingredient (teduglutide), each 
vial of teduglutide contains L-histidine, mannitol, monobasic sodium phosphate monohydrate, 
and dibasic sodium phosphate as excipients. Additional information is provided in the current 
SHP633 investigator’s brochure.
6.1.1
Blinding the Treatment Assignment
Not applicable.
6.2
Administration of Investigational Product(s) 
6.2.1
Allocation of Subjects to Treatment 
This is an open-label study where subjects may receive teduglutide 0.05 mg/kg/day as described 
in Section 6.2.2. Subjects will retain their assigned subject number from Study SHP633-302. 
Assessment of need for teduglutide treatment should be guided by the teduglutide treatment 
inclusion criteria. If the investigator and the subject (and/or parent/guardian, as applicable) agree 
to proceed with treatment, a formal evaluation of teduglutide inclusion and exclusion criteria will 
be performed at the pretreatment visit (Table 3). 
6.2.2
Dosing
If teduglutide treatment eligibility is established at the pretreatment visit and again confirmed at 
the Cycle Day 1 (CxD1) visit, the subject will start a teduglutide treatment period, consisting of 
24 weeks of teduglutide treatment at 0.05 mg/kg SC once daily. The initial dose will be 
calculated based on body weight measured at the teduglutide pretreatment visit, and adjusted as 
needed, based on body weight measured at Week 12 (CxW12). No other adjustments to dose will 
be made during the teduglutide treatment period, unless discussed with the sponsor’s medical 
monitor. 
Following reconstitution, teduglutide will be administered by SC injection once daily into 1 of 
the 4 quadrants of the abdomen (in subjects without a stoma) or into either the thigh or arm. Each 
day, the injection site should be rotated. For subjects with a stoma, the quadrant of the abdomen 
containing the stoma should not be used. 
The subject should be dosed at approximately the same time each day. Consecutive doses should 
be separated by at least 12 hours. 
Detailed instructions for reconstitution and injection of the investigational product can be found 
in the Instructions for Use. Teduglutide should be used as soon as possible after reconstitution, 
but no more than 3 hours later.
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At the end of each 24-week teduglutide treatment period, subjects will be evaluated for the need 
for additional teduglutide treatment. During the 4-week follow-up, the investigator will assess 
the subject via weekly phone visits. At Week 24 or any time during the follow-up period, if 
escape criteria are met, the subject may proceed directly to another pretreatment visit to assess 
treatment eligibility for another cycle (Section 4.3). Following the completion of the 4-week 
follow-up, the subject will continue in the study off teduglutide until teduglutide treatment 
eligibility criteria are again met. Additional 28-week cycles may be repeated if treatment 
eligibility is established each time. 
If the investigational product is discontinued prematurely during a teduglutide treatment cycle 
and the subject wishes to remain in the study, the evaluations listed for the EOT visit are to be 
performed. A 4-week follow-up period will ensue, consisting of weekly phone visits (CxW25 to 
CxW27) and the week 28 clinic visit (CxW28) shown in Table 3. The subject would then enter 
an NTT period and could be evaluated for subsequent teduglutide treatment eligibility according 
to the study schedules.
6.2.2.1
Administration by Parent/Guardian
The processes for training the parent/guardian to administer teduglutide and for providing 
oversight of study drug administration are described in the Site Training Guide. Before a 
parent/guardian is permitted to administer teduglutide, the study physician must observe the 
parent/guardian administering the study drug at least twice in compliance with the teduglutide 
administration checklist. The checklist is included as an Appendix to the Site Training Guide. It 
is expected that most parents/guardians of subjects enrolled in study SHP633-305 will have 
already been deemed proficient to administer teduglutide in study SHP633-302. Those who have 
already demonstrated proficiency need only to be observed once by a study physician at the 
beginning of each teduglutide treatment cycle (CxD1 visit, see Table 3) as long as they continue 
to prepare and administer teduglutide in compliance with the study drug administration checklist. 
If a parent/guardian fails to administer teduglutide in compliance with the checklist, they must 
perform this procedure correctly on 2 consecutive observations by the study physician in order to 
be deemed proficient to administer the study drug unsupervised. Refer to the Site Training Guide 
for details regarding this training. This process ensures that the parent/guardian continues to 
administer the study drug correctly and safely throughout the dosing period.
If at any time a study physician suspects that the parent/guardian is no longer capable of 
administering the study drug safely and accurately, the parent/guardian should be re-assessed by 
a study physician using the teduglutide administration checklist. If the parent/guardian is deemed 
unable to administer the study drug, dosing must be performed by a study physician until the 
parent/guardian is re-trained and proficiency is confirmed using the teduglutide administration 
checklist. 
Eligibility for teduglutide to be administered by a parent/guardian will be judged by a study 
physician using the following criteria. Refer to the checklist included as an appendix to the Site 
Training Guide.
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Criteria to Initiate Teduglutide Administration by the Parent/Guardian:

The subject’s condition is stable.

The parent/guardian has been sufficiently trained and is able to administer teduglutide 
in compliance with the checklist.
Criteria to Discontinue Teduglutide Administration by the Parent/Guardian:

The parent/guardian is unable to administer teduglutide in compliance with the 
checklist.

The subject’s condition has deteriorated such that the study physician assesses it is 
inappropriate for the subject to have teduglutide administered by their 
parent/guardian. In addition to discontinuing administration of teduglutide by the 
parent/guardian, if a subject sustains an adverse drug reaction where the symptoms 
are considered intolerable, dose interruption or study drug discontinuation should be 
considered (see Section 8.4). 

In the study physician’s judgment, it is inappropriate for the parent/guardian to
continue administration of the study drug for any other reason.
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
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 and 8°C 
until dispensed to a subject. The prefilled sterile water for injection syringes will be stored at a 
temperature between 2 and 25°C. Once dispensed/supplied to a subject, the investigational 
product can be stored refrigerated up to a controlled room temperature (acceptable range of 2 to 
25°C). A parent/guardian will be instructed to keep the subject’s investigational product and 
sterile water diluent at controlled room temperature. If there are concerns that the controlled 
room temperature cannot be maintained, the investigational product may be refrigerated. The 
study drug is for single use only, and should be used within 3 hours following reconstitution.
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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 (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 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 his/her treatment assignment. 
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.
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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
Subject compliance with investigational product dosing will be monitored by the sponsor or 
designee by counting and examining used and unused vials. In addition, compliance will be 
checked by site personnel at every visit by reviewing the subject diaries and asking the subject,
the subject’s parent or guardian, or study site staff 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.
Compliance with study drug is calculated from subject diaries. Of those subjects eligible for 
teduglutide treatment, subjects who have received 80% of the planned doses administered will be 
assessed as being compliant with the study protocol.
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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, Table 2, and Table 3) and must be referred to in 
conjunction with the instructions provided in this section. 
7.1.1
Screening 
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent/assent from the subject 
and/or parent/guardian, as applicable. In general, consent/assent to participate in Study 
SHP633-305 should be obtained within 7 days after completion of Study SHP633-302. The first 
visit after screening (either an NTT visit or a pretreatment visit), must occur within 12 weeks of 
screening.
The screening visit (Scr) assessments and procedures, beginning with informed consent/assent, 
will be performed as outlined in Table 1.
7.1.2
Visits for Subjects Not Receiving Teduglutide
While outside of the 28-week teduglutide-treatment cycle, subjects will be followed 
approximately every 12 weeks for safety and efficacy assessments. No-teduglutide treatment 
visits are numbered sequentially (NT1, NT2, etc.), even if interrupted by the treatment cycles. 
When subjects proceed from screening to the first NTT visit, the first NTT visit must occur
within 12 weeks of screening. Assessments will be performed as outlined in Table 2. 
7.1.3
Visits for Subjects Receiving Teduglutide
7.1.3.1
Pretreatment Visit
Subjects who meet at least one of the teduglutide treatment inclusion criteria during the 
screening visit or during the NTT period may proceed to the pretreatment visit immediately if the 
investigator and the subject (and/or parent/guardian, as applicable) agree to proceed with 
teduglutide therapy. Similarly, subjects who meet escape criteria at cycle Week 24 or during the 
teduglutide follow-up period may proceed to the pretreatment visit immediately. Pretreatment 
visits cannot occur consecutively and must be scheduled at least 12 weeks apart.
The first pretreatment visit may be combined with the screening visit and the Study SHP633-302 
EOS visit (Week 28), if the pretreatment visit assessments occur within 7 days of the 
SHP633-302 EOS assessments. If subjects proceed directly from screening to a pretreatment 
visit, the first pretreatment visit must occur within 12 weeks of screening. 
In general, pretreatment assessments should occur within 21 days. The teduglutide pretreatment 
visit (Px) assessments and procedures will be performed as outlined in Table 3. 
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7.1.3.2
Teduglutide Treatment Period (CxD1-CxW24)
The open-label teduglutide treatment period will comprise 24 weeks, during which all 
assessments and procedures listed for visits CxD1-CxW24 in Table 3 shall be completed. Cycles 
are numbered sequentially, such that the first visit of the first cycle is C1D1, and the first visit of 
the second cycle is C2D1, etc. Every effort should be made to complete 2 weeks of intake diary 
entries prior to each clinic visit and to complete 48 hours of output diary entries during a period 
of PS stability prior to each clinic visit. 
Following the CxD1 visit, subjects will return for clinic visits on Cycle Weeks 1, 2, 4, 6, 9, 12, 
16, 20, and 24/EOT. Assessments and procedures at these visits will be performed as outlined in
Table 3.
At the CxW24 visit, a serum sample is collected and stored for future analysis. This sample will 
not be used for genetic testing and lack of collection will not constitute a protocol deviation.
Saved serum samples should be omitted for subjects weighing less than 10 kg and whenever 
local blood volume limitations are exceeded.
Escape criteria are also evaluated at CxW24. The investigator may combine the CxW24 
assessments with the next pretreatment visit assessments if at least 1 escape criterion is met at the 
CxW24 visit and the pretreatment assessments occur within 7 days of the CxW24 visit.
7.1.3.3
Phone Visits 
Phone visits are required approximately 1 week after an adjustment in PS during the teduglutide 
treatment period and weekly during the 4-week follow up period. Phone visit assessments and 
procedures are outlined in Table 3. 
7.1.4
Teduglutide Follow-up Period
The safety follow-up period is 4 weeks (Weeks 25–28 of the cycle). During this period, phone 
visits will occur on Cycle Weeks 25, 26, and 27, and a clinic visit will occur at Week 28. 
Follow-up period assessments and procedures are outlined in Table 3.
If escape criteria are met at any time during the follow-up period, the subject may proceed 
directly to another pretreatment visit at the investigator’s discretion. The investigator may 
combine the CxW24 or CxW28 visit with the next pretreatment visit if at least 1 escape criterion 
is met at the CxW24 or CxW28 visit, and the pretreatment assessments occur within 7 days of 
the CxW24 or CxW28 visit. 
7.1.5
Study Completion/Early Termination Visit (EOS/ET Visit) 
All subjects will return to the study site for the EOS/ET. Assessments and procedures at this visit 
will be performed as outlined in Table 1. If a subject discontinues the study prematurely, the 
assessments for the EOS/ET Visit are to be performed as completely as possible.
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7.2
Study Evaluations and Procedures
All evaluations and procedures will be performed as outlined in the study schedules (Table 1, 
Table 2, and Table 3). 
7.2.1
Demographics, Medical History, and SBS History
Demographics, medical history, and SBS history will be obtained at screening. Medical history 
for purposes of this extension study will consist of the following:

Adverse events that were ongoing at the time of completion of Study SHP633-302.

Events that occurred during the period between completion of Study SHP633-302 and 
informed consent/assent to Study SHP633-305. 
Updates to medical history will supplement the medical history information collected at the start 
of the SHP633-302 core study. If the subject has any changes to the SBS history collected at the 
baseline visit of Study SHP633-302, that information (updated SBS history) will be collected.
7.2.2
Physical Examination (Including Height, Weight, and Head Circumference)
Physical examinations will be performed according to the study schedules to assess the subject’s 
physical status. New clinically significant abnormalities that are detected or diagnosed after 
study evaluations have begun (after signing of the informed consent/assent) should be recorded 
on the appropriate AE page of the eCRF.
Subjects should be weighed on the same scale at each study visit. Height (or length [cm]) and 
head circumference (for subjects ≤36 months of age [cm]) will be measured at selected visits. 
Body mass index (BMI) and z-scores for weight, height (or length), head circumference, and 
BMI will be calculated by the sponsor using the site-provided height and weight data collected at 
each site visit.
7.2.3
Vital Signs
Vital signs will be measured according to the study schedules. Measurements will include 
systolic and diastolic blood pressure (mmHg), pulse rate, and body temperature (°C). Blood 
pressure should be determined by cuff (using the same method, the same extremity, and in the 
same position throughout the study, whenever possible).
New clinically significant vital sign abnormalities should be recorded on the appropriate AE 
page of the eCRF.
7.2.4
Clinical Laboratory Tests
Safety laboratory tests are to be performed at site visits with results processed by a central 
laboratory. They consist of biochemistry, hematology, coagulation, and urinalysis and will be 
performed as outlined in the study schedules. 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. 
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Abnormal clinical laboratory values, which are unexpected or not explained by the subject’s 
clinical condition, may, at the discretion of the investigator or sponsor, be repeated as soon as 
possible until confirmed, explained, or resolved. 
During the teduglutide treatment period, subjects will also have safety lab tests within 
approximately 5-7 days after a PS adjustment. Safety lab tests performed after PS adjustment and 
between site visits will consist of biochemistry and urinalysis to be performed at the 
investigational site laboratory. Urine specimen collection should be attempted as part of the 
safety lab tests, but lack of urinalysis will not constitute a protocol deviation.
New clinically significant lab tests results should be reported as AEs (see Section 8.1).
All laboratory testing will be processed at the investigational site and performed according to the 
study schedules. Tests include the following (Table 5): 
Table 5
List of Laboratory Tests
Hematology:
Hematocrit 
Hemoglobin 
Platelet count
Red blood cell (RBC) count 
RBC morphology, if needed
White blood cell count with differential
Coagulation:
Prothrombin time/International normalized ratio
Urinalysis: 
Blood
Glucose
Leukocytes
pH
Protein
Specific gravity 
Microscopic analysis
Pregnancy tests (females of childbearing potential):
Serum β-HCG (pretreatment)
Urine β-HCG (all other visits)
Biochemistry:
Albumin 
Alkaline phosphatase 
Alanine aminotransferase 
Amylase
Aspartate aminotransferase 
Bicarbonate
Bilirubin (total, direct and indirect)
Blood urea nitrogen 
Calcium (total)
Chloride
Cholesterol
C-reactive protein 
Creatinine
Estimated glomerular filtration rate 
(Schwartz formula)
Gamma-glutamyl transferase 
Glucose
Lipase
Magnesium
Phosphorus
Potassium 
Sodium 
Triglycerides
Uric acid
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7.2.5
Serum Sampling
Serum samples will be collected and stored for future analysis at the following times: 

At the pretreatment visit. If the subject arrived at the pretreatment visit by meeting an escape 
criterion, the serum sample will not be repeated at the pretreatment visit, because it will have 
been collected recently at the CxW24 visit.

At the CxW24 (EOT) visit

During NTT: Approximately every 24 weeks
The serum sample will not be used for genetic testing. Lack of collection will not constitute a 
protocol deviation. Saved serum samples should be omitted for subjects weighing less than 10 kg 
and whenever local blood volume limitations are exceeded.
The sponsor, sponsor’s representatives, biorepositories, and any specialty laboratories will be 
blinded to the subject’s identity. The sample and/or extracted material will otherwise be stored 
for up to 15 years from the end of the study after which time it will be destroyed. Upon written 
request, subjects will be permitted to withdraw their sample from the analysis and have their 
sample and/or extracted material destroyed. Any results already generated from the samples will 
not be removed from any analyses that have already been performed.
7.2.6
Antibody Assessment
Blood samples will be drawn for the analysis of antibodies to teduglutide according to the study 
schedules. Blood samples for antibodies may be drawn from a central line or peripheral access. 
The sample drawn on CxD1 must be drawn prior to administration of the first dose of 
teduglutide. Once the subject has started teduglutide treatment, samples must be drawn at least 
14 hours after dosing. Subjects who test positive for antibodies to teduglutide will also be tested 
for neutralizing antibody. Subjects who have been previously treated with teduglutide, and who 
test positive for antibodies to teduglutide, will have follow-up blood draws for antibodies to 
teduglutide every 12 weeks until a negative result is obtained or the study ends.
7.2.7
Pregnancy Testing
A serum pregnancy test will be performed on all female subjects of child bearing potential 
(Section 4.4.1) at the teduglutide pretreatment visit. Urine pregnancy tests will be performed at 
all other visits according to the study schedules, or if pregnancy is suspected, or as specified per 
protocol upon withdrawal of the subject from the study.
7.2.8
Volume of Blood
During this study, efforts will be made based on Japanese manufacturer or laboratory regulations 
and guidelines to minimize the amount of blood drawn from all pediatric subjects enrolled in this 
study. 
The amount of blood to be drawn may vary according to instructions provided by the 
manufacturer or laboratory for an individual assessment. 
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When more than one blood assessment is to be done at the same time point, the assessments 
should be combined if they require the same type of tube.
7.2.9
Gastrointestinal-specific Testing
7.2.9.1
Fecal Occult Blood Testing
Fecal occult blood testing must be performed on all subjects at the pretreatment visit, Week 12, 
and Week 24 of the teduglutide cycle. During NTT periods, fecal occult blood testing must be 
performed on a roughly annual basis (approximately every 48-60 weeks). Actions to be taken in 
response to a positive fecal occult blood testing are described below.
7.2.9.2
Colonoscopy or Sigmoidoscopy
Subjects of any age with newly positive fecal occult blood testing results at the pretreatment visit 
for which a readily detectable cause cannot be identified (eg, anal fissure) will undergo a 
colonoscopy/sigmoidoscopy prior to receiving teduglutide. If newly positive fecal occult blood 
test results (for which a readily detectable cause cannot be identified) are obtained at the end of a 
teduglutide treatment cycle (CxW24/EOT), colonoscopy/sigmoidoscopy will be performed. The 
need for colonoscopy/sigmoidoscopy in response to positive fecal occult blood tests at any other 
point during the study, or to reevaluate persistently positive fecal occult blood tests is at the 
discretion of the investigator. 
Subjects who have received the equivalent of 2 treatment cycles (48 weeks of investigational 
product exposure) will undergo colonoscopy/sigmoidoscopy before the next cycle of teduglutide 
treatment. While receiving additional teduglutide treatment, subjects will undergo 
colonoscopy/sigmoidoscopy at 5 year intervals or more often as needed. 
Upper endoscopy may be performed along with any colonoscopy/sigmoidoscopy at the 
investigator’s discretion. If a polyp is found, adherence to current polyp follow-up guidelines is 
recommended. Subjects with unresected GI polyps, polyposis conditions, pre-malignant change 
or malignancy in the GI tract will be excluded from teduglutide treatment.
7.2.10
Other Study Procedures
7.2.10.1
Nutritional Support
Nutritional support includes PS, EN, and other food and fluids. Reductions to PS will be based 
on clinical status, including weight, linear growth, hydration status, and safety laboratory results. 
Intake and output diaries will include data to be considered in the adjustment of each subject’s 
nutritional support. Guidelines for nutritional support management and weaning algorithms are 
provided in Appendix 2 and Appendix 3, respectively.
7.2.10.2
Diaries
Study Drug Administration Diary:
A study drug administration diary will record administration of teduglutide. This diary should be 
completed by the subject, parent/guardian, or study site staff) daily during the teduglutide 
treatment period (between visits CxD1 and CxW24).
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Intake Diary:
An intake diary will be used to record administration of PS. Every effort should be made to 
complete the intake diary for 2 weeks prior to each scheduled site visit (except at pretreatment 
visit), for 1 week following PS adjustment during the teduglutide treatment period (CxD1 to 
CxW24), and daily during the 4-week follow-up period (CxW24 to CxW28). The subject, 
parent/guardian, or study site staff will record:

Volume and infusion duration.

Site personnel will determine the actual PS 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 PS 
stability before every clinic visit; in addition, output should be recorded for subjects during a 
teduglutide treatment period within 1 week of implementing a change in the PS prescription.
Urine data:

Toilet-trained subjects (who do not wear diapers) 
Measure and record all urine output in mL or cc. 

Nontoilet-trained subjects (who wear diapers)
Measure and record the weight of all urine-only diapers. Urine volume will be calculated 
using the following formula: 1 g (scale weight) = 1 mL or 1 cc. 

At the discretion of the investigator, the parent may be asked to collect the first void after the 
daily PS infusion to measure specific gravity.
Stool data (includes diapers with mixed urine and stool):

Toilet-trained subjects (who do not wear diapers)
Record the occurrence of each bowel movement and score the stool consistency using the 
Bristol Stool Form Scale (see output diary).

Nontoilet-trained subjects (who wear diapers)
Record the weight of diapers containing stool (including diapers with mixed urine and stool) 
as stool output and score the stool consistency using the Bristol Stool Form Scale (see output 
diary). Stool volume will be calculated using the formula: 1 g (scale weight) = 1 mL or 1 cc.
All ostomy output volume should be recorded. Ostomy output will not be scored using the 
Bristol Stool Form Scale.
All available diary data will be reviewed by the investigator or their designee at each clinic and 
phone visit to assess clinical status and opportunity for PS reduction and advance in feeds.
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7.3
Changes to Study Procedures Due to a Pandemic
The following information provides guidance regarding changes to the study procedures that 
could be implemented for study participants or study sites that are impacted by a pandemic (eg, 
coronavirus disease 2019 [COVID-19] or other future similar unexpected public health concerns) 
that require physical distancing that may result in subjects missing their visits. This guidance 
takes references from the Food and Drug Administration (FDA) Guidance on Conduct of 
Clinical Trials of Medical Products during COVID-19 Public Health Emergency Guidance for 
Industry, Investigators, and Institutional Review Boards, March 2020 and updated on 
02 July 2020, the European Medicines Agency (EMA) Guidance on the Management of Clinical 
Trials During the COVID 19 (Coronavirus) Pandemic, Version 3 (28 April 2020), and the EMA 
Points to consider on implications of Coronavirus disease (COVID-19) on methodological 
aspects of ongoing clinical trials, dated 26 June 2020.
Because a pandemic (eg, COVID-19) may peak in different regions at different times and 
restrictions implemented by local laws and recommendations may vary, any decision on 
procedural changes should be made on a case-by-case basis by the principal investigator, in 
consultation with the study team (and the medical team as needed), while maintaining patient 
safety and confidentiality as the priority.
Procedural changes due to COVID-19 (or other similar pandemic) may include the following:

Informed Consent Form Procedure: If necessary, informed re-consent from a current study 
participant may be obtained via electronic informed consent capabilities, or an electronic 
face-to-face consent interview when these individuals are unable to travel to the site, based 
on local regulations or requirements.

Clinic / Telephone Visits:   In situations where a clinic visit is not completed due to a 
COVID-19 (or other similar pandemic) concern, a telephone visit may be conducted as an 
unscheduled safety assessment on subject well-being. The on-site visit will be recorded as 
“Not Done” with a free text comment referencing COVID-19 (or similar pandemic) and the 
telephone visit will be documented in the study records and recorded as an unscheduled visit 
in the eCRF, with a free text comment indicating “Telephone visit”.

Deviations from protocol-specified procedures, eg, missing visits, missing data, alternative 
visits, etc. will be recorded as related to a pandemic (eg, COVID-19 or other similar 
pandemic).

Secure direct-to-patient delivery of the study drug from the investigational site to subjects 
may be implemented, as per investigational site and sponsor agreement.

In the event a monitor cannot visit the site in a timely manner due to the COVID-19 
pandemic or other similar pandemic, alternative monitoring approaches such as remote 
source data verification or telephone contact may be used to maintain patient safety and 
ensure data quality and integrity. Alternative monitoring approaches should be used only 
where allowed by applicable local regulations and permitted by the IRB/IEC.
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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 
(International Conference on Harmonisation [ICH] Guidance E2A 1995). 
All AEs are collected from the time the informed consent/assent is signed until the defined 
follow-up period stated in Section 7.1.4. This includes events occurring during the screening 
phase of the study, regardless of whether or not investigational product is administered. Where 
possible, a diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not 
been made, then each symptom should be listed individually. All AEs should be captured on the 
appropriate AE pages in the eCRF and in source documents. In addition to untoward AEs, 
unexpected benefits outside the investigational product indication should also be captured on the 
AE eCRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pretreatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate eCRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
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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.
Note that the severity of AEs listed in Table 6 that may lead to dose interruption based on known 
or possible risks of teduglutide will also be evaluated using the National Cancer Institute’s (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) grading criteria (Section 8.4.1).
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related.” The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected 
response pattern to that product, and the event cannot be explained by the 
subject’s medical condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident and no 
plausible temporal or biologic relationship exists between the investigational 
product and the event.
AEs that are related to investigational product that are not resolved at EOT will be followed until 
the event resolves or stabilizes, as judged by the investigator.
Laboratory values, vital signs, and clinical findings at the scheduled physical examinations must 
be reported as AEs if the investigator considers the finding to be a clinically significant change 
from the baseline. 
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the eCRF. Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved
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
Recovered/Resolved

Recovered/Resolved with Sequelae 

Recovering/Resolving

Unknown
8.1.4
Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE.
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory or vital sign can represent an AE if the change is 
clinically relevant or if, during treatment with investigational product, 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 
EOT with the investigational product, and the range of variation of the respective parameter 
within its reference range, must be taken into consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory values or vital signs 
which were not present at the pretreatment value 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) is found for the abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory or vital sign is clinically significant and 
therefore represents an AE.
8.1.6
Pregnancy
All pregnancies are to be reported from the time informed consent/assent is signed until the 
defined follow-up period stated in Section 7.1.4.
Any report of pregnancy for any female study participant must be reported within 24 hours to 
IQVIA Services Japan K. K. using the Shire Investigational and Marketed Products Pregnancy 
Report Form. A copy of the Shire Investigational and Marketed Products Pregnancy Report 
Form (and any applicable follow-up reports) must also be sent to the CRO/Shire Medical 
Monitor using the details specified in the emergency contact information section of the protocol. 
In the event a subject becomes pregnant during the study, teduglutide administration must be 
immediately and permanently discontinued. 
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days postpartum.
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Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered serious adverse events (SAEs) and must be reported using the Shire Clinical 
Study Adverse Event Form for Serious Adverse Events and Non-serious AEs as Required by 
Protocol. Note: An elective abortion is not considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Adverse Event Form for SAEs and 
Non-serious AEs as Required by Protocol as well as the Shire Investigational and Marketed 
Products Pregnancy Report Form. The test date of the first positive serum/urine β-HCG test or 
ultrasound result will determine the pregnancy onset date.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for a 
non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner that 
may be detrimental to the individual and/or society.

Misuse – Intentional use of investigational product other than as directed or indicated at any 
dose (Note: this includes a situation where the investigational product is not used as directed 
at the dose prescribed by the protocol).

Overdose – Administration of the investigational product at a dose or frequency greater than 
0.05 mg/kg subcutaneous once daily. An overdose occurs if any of the following criteria are 
met:

More than 0.05 mg/kg is given at any one time

Consecutive doses are spaced less than 12 hours apart

Any more than 0.05 mg/kg in one day (a day is defined as beginning at 12:00 AM and 
ending at 11:59 PM)

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. 
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All investigational product provided to pediatric subjects should be supervised by the 
parent/guardian.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator’s 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 IQVIA Services
Japan K.K. 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 IQVIA Services Japan K.K. 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 
Serious Adverse Events 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.) The investigator must fax or email the completed 
form to IQVIA Services Japan K.K. A copy of the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol From (and any applicable follow-up reports) 
must also be sent to the CRO/Shire Medical Monitor using the details specified in the emergency 
contact section of the protocol and the form (sent under separate cover).
8.2.3
Serious Adverse Event Definition
An 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 
preexisting 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.
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
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 one of the outcomes listed in this definition. Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; 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 informed 
consent/assent is obtained until the defined follow-up period stated in Section 7.1.4, and must be 
reported to IQVIA Services Japan K.K. and the CRO/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 IQVIA Services
Japan K.K. within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed 
consent/assent 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.
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8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting 
The sponsor is responsible for notifying the relevant regulatory authorities and central 
IRBs/ethics committees (ECs), of related, unexpected SAEs. 
In addition, the sponsor and/or designee is responsible for notifying active sites of all related, 
unexpected SAEs occurring during all interventional studies across the teduglutide program.
The investigator is responsible for notifying the local IRB 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 for this study include the 
following:

Growth of preexisting 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, IQVIA Services Japan K.K. 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 seriousness criterion.
8.4
Dose Interruption of Individual Subjects
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 interruptions may include but 
are not limited to hospitalization and AEs, a lapse in investigational product delivery, etc.
Investigational product must be discontinued if any of the following events occur:

Pregnancy

Severe hypersensitivity, such as anaphylaxis determined by the investigator to be related to 
investigational product. This does not include the presence of anti-teduglutide antibodies, 
mild injection site reactions or mild symptoms that according to the investigator do not pose 
a significant risk to the subject.
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
An AE listed in (Table 6) that is of NCI CTCAE severity Grade 3 or 4 and considered to be 
related to investigational product administration (see Section 8.4.1)

Confirmed drug-induced liver injury (DILI) related to teduglutide (see Section 8.4.2)
8.4.1
Dose Interruption Criteria Based on Known or Possible Risks of Teduglutide
The investigational product may be discontinued if the subject experiences an AE listed in 
Table 6 that is of severity ≥Grade 3 per the NCI CTCAE. All such AEs should be discussed with 
the medical monitor or designee as soon as possible. Teduglutide administration must be 
discontinued if the AE is considered related to the investigational product. The length of dose 
interruption, and whether teduglutide administration resumes or is permanently discontinued, 
depends on the clinical situation.
Investigators and the Data Monitoring Committee (DMC) should be guided by the descriptions 
of Grade 3 and 4 events, as they relate to known or possible risks associated with the 
administration of teduglutide (Table 6). 
Table 6
Adverse Events that May Lead to Dose Interruption
Adverse Event
Grade 3 Description
Grade 4 Description
Gastrointestinal Disorders
Colorectal polyps
Severe or medically significant but not 
immediately life threatening; 
hospitalization or prolongation of existing 
hospitalization indicated; disabling; 
limiting self-care activities of daily living
Life-threatening consequences; urgent 
intervention indicated
Intestinal obstruction
Hospitalization indicated; elective 
operative intervention indicated; limiting 
self-care activities of daily living; 
disabling
Life-threatening consequences; urgent 
operative intervention indicated
Gallbladder and Bile Duct Disease
Cholecystitis
Severe symptoms; radiologic,
endoscopic or elective operative 
intervention indicated
Life-threatening consequences; urgent 
operative intervention indicated
Gallbladder perforation
Not Applicable
Life-threatening consequences; urgent 
intervention indicated
Gallbladder obstruction
Symptomatic and severely altered 
gastrointestinal function; tube feeding, 
total parenteral nutrition or hospitalization 
indicated; nonemergent operative 
intervention indicated
Life-threatening consequences; urgent 
operative intervention indicated
Gallbladder infection
Intravenous antibiotic, antifungal, or 
antiviral intervention indicated; radiologic, 
endoscopic, or operative intervention 
indicated
Life-threatening consequences; urgent 
intervention indicated
Alkaline phosphatase 
increased
>5.0 to 20.0x ULN
>20.0x ULN
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Table 6
Adverse Events that May Lead to Dose Interruption
Adverse Event
Grade 3 Description
Grade 4 Description
Blood bilirubin increased
>3.0 to 10.0x ULN
>10.0x ULN
Bile duct stenosis
Severely altered gastrointestinal function; 
radiologic, endoscopic or elective 
operative intervention indicated
Life-threatening consequences; urgent 
operative intervention indicated
Pancreatic Disease
Pancreatitis
Severe pain; vomiting; medical 
intervention indicated (eg, analgesia, 
nutritional support)
Life-threatening consequences; urgent 
intervention indicated
Pancreatic duct stenosis
Severely altered gastrointestinal function; 
tube feeding or hospitalization indicated; 
elective operative intervention indicated
Life-threatening consequences; urgent 
operative intervention indicated
Pancreas infection
Intravenous antibiotic, antifungal, or 
antiviral intervention indicated; radiologic 
or operative intervention indicated
Life-threatening consequences; urgent 
intervention indicated
Serum amylase increaseda
>2.0 to 5.0x ULN
>5.0x ULN
Lipase increaseda
>2.0 to 5.0x ULN
>5.0x ULN
Cardiovascular Disease
Heart failure
Severe with symptoms at rest or with 
minimal activity or exertion; intervention 
indicated
Life-threatening consequences; urgent 
intervention indicated (eg, continuous 
intravenous therapy or mechanical 
hemodynamic support)
ULN=upper limit of normal
a In the setting of clinically acute and symptomatic pancreatitis
Source: Common Terminology Criteria for Adverse Events, version 4.03, 14 June 2010
8.4.2
Dose Interruption Criteria Based on Drug-induced Liver Injury
Teduglutide administration for an individual subject may need to be discontinued if the subject 
has clinical and laboratory evidence of potential DILI, in the absence of an alternative 
explanation, as identified by the following criteria:

Subjects with normal (or low) values of ALT and AST at baseline:

ALT or AST >8x ULN

ALT or AST >5x ULN for more than 2 weeks

ALT or AST >3x ULN and (total bilirubin >2x ULN or INR>1.5)

ALT or AST >3x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
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
Subjects with baseline elevations of values of ALT and/or AST over ULN:

ALT or AST >8x ULN

ALT or AST >5x ULN and >2x baseline value for more than 2 weeks

(ALT or AST >3x ULN and >2x baseline value) and (total bilirubin >2x ULN or 
INR>1.5)

ALT or AST >3x ULN and >2x baseline value with the appearance of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
All laboratory values suggestive of potentially new DILI should be repeated and verified within 
3 days. INR should be measured with this set of verification laboratory assessments and an 
inquiry should be made as to the presence of clinical symptoms consistent with new liver injury. 
The subject should be followed closely to determine the trajectory of the laboratory 
abnormalities and to evaluate the cause of liver injury. 
This evaluation may include, as clinically indicated, consideration of sepsis, acute viral hepatitis 
(eg, hepatitis A immunoglobulin M [IgM], hepatitis B surface antigen, hepatitis C antibodies, 
cytomegalovirus IgM, Epstein-Barr virus antibody panel), hepatobiliary obstruction (ultrasound), 
autoimmune hepatitis (anti-nuclear, anti-smooth muscle, anti-actin, or anti-liver kidney 
microsomal antibodies), intestinal failure associated liver disease, cardiovascular causes such as 
ischemic hepatitis, and concomitant hepatotoxic treatments.
Additional evaluations may be performed at the discretion of the investigator in consultation 
with the medical monitor or designee.
Teduglutide administration must be discontinued if DILI is confirmed and deemed related to 
investigational product.
8.5
Early Termination of the Clinical Study
The DMC may recommend stopping the study if:

At least 2 subjects develop the same event listed in Table 6 of severity CTCAE Grade 3 
or

1 subject develops an event listed in Table 6 of severity CTCAE Grade 4 which is
attributable to investigational product or is not reasonably related to the underlying disease 
process
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9
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigator or investigators’ authorized site personnel must enter the information required
by the protocol in the eCRF. A study monitor will visit each site in accordance with the 
monitoring plan and review the eCRF data against the source data for completeness and 
accuracy. Discrepancies between source data and data entered on the eCRF will be addressed by 
the investigator or qualified site personnel. When a data discrepancy warrants correction, the 
correction will be made by the investigator or authorized site personnel. The investigator must 
verify that all data entries in the eCRF are accurate and correct. Original diary data should be 
entered into the eCRF and take precedence over data collected over the phone. 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 enrolled, it is expected that the investigator or authorized site 
personnel will complete the eCRF entry in a timely manner following the subject’s visit.
Unscheduled safety follow-up assessments (conducted after EOS) are not required to be 
collected.
9.2
Clinical Data Management 
Training will occur at an investigator meeting or at the site initiation visit or both, and instruction 
manuals will be provided to aid consistency in data collection and reporting across sites.
The required data will be captured in a validated clinical data management system that is 
compliant with the US FDA 21 CFR Part 11 Guidance. The clinical trial database will include an 
audit trail to document any evidence of data processing or activity on each data field by each 
user. 
Data will be entered into a clinical database as specified in the Data Management Plan. Quality 
control and data validation procedures will be applied to ensure the validity and accuracy of the 
clinical database. Users will be trained and given restricted access, based on their role(s) in the 
study, through a password-protected environment.
Data will be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification will 
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.
Serious adverse event information captured in the clinical trial database will be reconciled with 
the information captured in the Shire Global Drug Safety database.
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.
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The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. 
Data will be analyzed and presented by subject cohorts according to the subjects’ age at the time 
of entry in the core study: infants 4-<12 months corrected gestational age and children 1-15 years 
of age.
9.4
Planned Interim Analysis, and Data Monitoring Committee 
Interim analyses may be conducted during the study, 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 DMC will be involved in the management of this study. The DMC members will review the 
data approximately every 6 months during the study treatment periods (date of the first subject’s 
first dose to date of the last subject’s last dose). The DMC review will include cumulative safety 
data (ie, AEs, laboratory assessments, physical examinations, etc.) through each cutoff period. 
Further details regarding the DMC can be found in the DMC charter, which will be available 
prior to the administration of investigational product. 
The DMC for this study will be conducted in accordance with the FDA Guidance for Clinical 
Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees 
(March 2006).
The DMC will be an external, independent board comprised of physicians with relevant training. 
The DMC will be restricted to individuals free of significant conflicts of interest, including, but 
not limited to, financial, scientific, or regulatory in nature. The DMC will be governed by a 
Charter agreed to by members of the Committee and the sponsor. Members of the Committee 
may not be study investigators or be employed at the same institution as a study investigator, 
individuals employed by the sponsor (or designee), independent contractors hired by the sponsor 
(or designee), or members of regulatory agencies. The DMC may make recommendations to the 
sponsor (or designee) regarding stopping, modifying or continuing the study; however, the 
sponsor will have the final responsibility to determine whether the study should be modified or 
temporarily or permanently stopped. 
9.5
Sample Size Calculation and Power Considerations 
The number of subjects in this study is not based on statistical power considerations as this is an 
extension study of the core study SHP633-302. The maximum number of subjects will be 
determined by the completion of Study SHP633-302.
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9.6
Study Population
The safety population will include all enrolled subjects in the study. A subject will be considered 
enrolled in the study once the informed consent/assent has been obtained and the subject meets 
all of the study inclusion criteria at screening. Safety population will be used for both safety and 
efficacy analyses.
9.7
Efficacy Analyses 
No claims of statistical significance will be made; however, 95% confidence intervals will be 
provided, if applicable. Continuous variables, including those assessed on a discrete scale, will 
be summarized using descriptive statistics including number of subjects, mean, median, standard 
deviation, maximum, and minimum. For categorical variables, statistical summaries will include 
number of subjects and percentages. The derivations of the weekly PS volume will be described 
in the study SAP in detail.
Efficacy Endpoints:
Efficacy endpoints will be analyzed at the end of each teduglutide treatment period (Week 24 or 
EOT), and at each study visit, relative to the baseline of the core study (SHP633-302). The 
following efficacy endpoints will be analyzed:

Reduction in PS volume of at least 20%

Absolute and relative change in PS volume

Complete weaning off PS

Change in days per week of PS
9.8
Safety Analyses 
Safety Endpoints:
The following safety endpoints will be analyzed:

Adverse events

Vital signs, including temperature, heart rate, blood pressure

Laboratory safety data (ie, biochemistry, hematology, and urinalysis)

Urine output

Stool output

Antibodies to teduglutide

Gastrointestinal-specific testing, including fecal occult blood testing and colonoscopy or 
sigmoidoscopy 
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
Z-scores for weight, height (or length), head circumference (up to 36 months of age), and 
BMI 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). The number of events and percentage of AEs will be calculated overall, by System 
Organ Class and by preferred term. Serious adverse events will be further summarized by 
severity and relationship to investigational product. Adverse events related to investigational 
product, AEs leading to withdrawal, SAEs, and deaths will be similarly summarized/listed.
Prior and concomitant medications will be coded using the World Health Organization-Drug 
Dictionary with regard to drug class and drug name. The number and percentage of subjects with 
specific prior medications will be summarized. Medical history (including surgical history) will 
be coded using MedDRA. The number and percentage of subjects with specific histories will be 
summarized by system organ class and preferred term. 
For clinical laboratory tests, vital signs, and body weight, descriptive statistics (mean, median, 
standard deviation, minimum and maximum values, the number and percentage of subjects in 
specified categories) will be calculated to summarize the observed values and change from 
baseline at each scheduled visit.
The number and percentage of subjects classified as having positive specific or neutralizing 
antibodies to teduglutide will be used to summarize the presence of antibodies. 
Additional safety parameters and measures will include change in body weight, height (or 
length) and head circumference (up to 36 months of age). Derived variables will include height 
z-score, weight z-score, BMI, and BMI z-score. Descriptive statistics (mean, median, standard 
deviation, minimum and maximum values, the number and percentage of subjects in specified 
categories) will be calculated to summarize the absolute values and change from baseline at each 
scheduled visit.
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10
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
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 
international government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor or designee 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
Public Posting of Study Information
The sponsor or designee is responsible for posting appropriate study information on applicable 
websites. Information included in clinical study registries may include participating 
investigators’ names and contact information.
10.1.3
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. 
10.1.4
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.
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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/assent, inform them of the subject’s participation in the study.
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 international regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable contract research 
organization, investigator, or for multicenter studies, the coordinating principal investigator 
according to national provisions and will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Case Report Forms
Electronic case report forms will be 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. 
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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 
solely onto the eCRF.
All data transmitted to the sponsor or designee 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 will be 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, original clinical laboratory reports, and imaging 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/assent form includes a statement by which the subject 
agrees to the monitor/auditor from the sponsor or its representatives, national or local regulatory 
authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, appointment 
books, original laboratory reports, X-rays etc.).
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 
Pharmaceuticals and Medical Devices 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
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 receives 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 or designee to obtain written informed consent from 
all subjects or parents/guardian, and assent from subjects where applicable, prior to any 
study-related procedures including screening assessments. 
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All consent and assent documentation must be in accordance with applicable regulations and 
GCP. Each subject or the subject’s parent or guardian, as applicable, is requested to sign and date 
the informed consent form/assent 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/assent documentation (ie, a complete set of subject information sheets and fully executed 
signature pages) must be given to the subject or the subject’s parent or guardian, as applicable. 
This document requires translation into the local language. Signed consent/assent forms must 
remain in each subject’s study file and must be available for verification at any time.
Within the source documents, site personnel should document instruction of and understanding 
by the parent/guardian of the safe, responsible storage and administration of investigational 
product to the study subject.
The principal investigator provides the sponsor with a copy of the blank consent form, and assent 
form where applicable, which was reviewed by the IRB/EC and which received their favorable 
opinion/approval. A copy of the IRB/EC’s written favorable opinion/approval of these 
documents must be provided to the sponsor, prior to the start of the study unless it is agreed to 
and documented (abiding by regulatory guidelines and national provisions) prior to study start 
that another party (ie, sponsor or coordinating principal investigator) is responsible for this 
action. Additionally, if the IRB/EC requires modification of the sample subject information and 
consent/assent 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
It is the responsibility of the investigator to submit this protocol, the informed consent/assent 
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.
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/assent documents and amendments to the protocol unless there 
is a subject safety issue.
Investigational product supplies will not be released until the Sponsor or designee has received 
written IRB/EC approval and copies of revised documents.
The investigator is responsible for keeping the IRB/EC apprised of the progress of the study and 
of any changes made to the protocol, but in any case at least once a year; for multicenter studies, 
this 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.
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10.4
Privacy and Confidentiality
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After consent/assent to take part in the study is received, the sponsor and/or its representatives 
will review their medical records and data collected during the study. These records and data 
may, in addition, be reviewed by others including the following: independent auditors who 
validate the data on behalf of the sponsor; third parties with whom the sponsor may develop, 
register, or market teduglutide; national or local regulatory authorities; and the IRBs/ECs which 
gave approval for the study to proceed. The sponsor and/or its representatives accessing the 
records and data will take all reasonable precautions in accordance with applicable laws, 
regulations, and guidelines to maintain the confidentiality of subject’s 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. 
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 
current standards. Participation as an investigator does not confer any rights to authorship of 
publications.
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11
REFERENCES
Drucker, D. J. & Yusta, B. 2014. Physiology and pharmacology of the enteroendocrine hormone 
glucagon-like peptide-2. Annu Rev Physiol, 76, 561-83.
Duro, D., Kamin, D. & Duggan, C. 2008. Overview of pediatric short bowel syndrome. J Pediatr 
Gastroenterol Nutr, 47 Suppl 1, S33-6.
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.
Kitajima, M., Shamizu, M., Wakabayashi, G., Hoshino, K., Tanabe, M. & Kawachi, S. 2013. 
Current Issues in Liver and Small Bowel Transplantation, Springer Science & Business 
Media.
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.
Takagi, Y., Okada, A., Sato, T., Fukushima, T., Shirotani, N., Osawa, Y., Takeyama, H., 
Taniguchi, M., Takehara, H. & Mizote, H. 1995. Report on the first annual survey of 
home parenteral nutrition in Japan. Surg Today, 25, 193-201.
Takehara, H. 2001. Home parenteral nutrition for pediatric patients. Nihon Rinsho, 59 Suppl 5,
848-51.
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.
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APPENDICES
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APPENDIX 1
PROTOCOL HISTORY
Document
Date
Global/Country/Site Specific
Original Protocol
22 Jul 2016
Global
Amendment 1
26 May 2017
Global
Amendment 2
24 Jan 2018
Global
Amendment 3
20 Jul 2018
Global
Amendment 4
06 Nov 2020
Global
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
3
Amendment Date
20 Jul 2018
Global
Description of Change and Rationale
Section(s) Affected by Change
Changed Quintiles Transnational Japan K.K. to IQVIA Services Japan K.K. to 
reflect a corporate name change.
Emergency Contact
Information
Section 8.1.6, Section 8.2.2, 
Section 8.2.4, Section 8.2.7, 
Section 8.3
Changed name of Shire medical monitor to 
, MD, PhD, FAAP.
(Protocol Administrative Amendment dated 15 Mar 2018)
Emergency Contact
Information
Updated the approximate number of subjects to be enrolled in the SHP633-305 
study from 5 to 7. This change reflects the addition of a minimum of 2 subjects 
to be enrolled in the core study (SHP633-302). Also added that the study 
population will include 2 cohorts based on age of subjects at the time of entry 
in the core study: infants 4-<12 months corrected gestational age and children 
1-15 years of age.
Synopsis, Section 3.1
To minimize risk to subjects, a new escape criterion was added, allowing those 
who had escaped during the follow-up period of a previous teduglutide 
treatment cycle to omit the follow-up period during subsequent teduglutide 
treatment cycles.
For subjects who previously escaped the follow-up period, CxW24 assessments 
can be combined with the next pretreatment visit assessments.
Synopsis, Table 3, Figure 1, 
Section 3.1, Section 4.3, 
Section 6.2.2, Section 7.1.3.1, 
Section 7.1.3.2, Section 7.1.4, 
Section 7.2.5
Modified teduglutide treatment exclusion criterion 1 on subject’s body weight 
to accommodate younger children (exclude subjects if weight <5 kg).
Synopsis, Section 4.2.2
Specified that results for subjects enrolled as infants in the core study will be 
analyzed separately in the SHP633-305 study.
Synopsis, Section 3.1, Section 9.3
Specified that saved serum samples should be omitted for subjects weighing 
less than 10 kg and whenever local blood volume limitations are exceeded.
Table 2, Table 3, Section 7.1.3.2, 
Section 7.2.5
Updated the status of the clinical study TED-C14-006 which is now completed. 
Section 1.2
Deleted text that was duplicated in the same paragraph.
Section 5.1
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
3
Amendment Date
20 Jul 2018
Global
Description of Change and Rationale
Section(s) Affected by Change
Deleted the requirements for the first dose of teduglutide to be administered by 
a study physician and the subject to be observed for possible hypersensitivity 
reactions for at least 4 hours during their initial dosing visit. Subjects enrolled 
in the study have already received teduglutide in the core study.
(Clarification memo #2 dated 17 May 2018)
Section 6.2.2.1
Clarified requirement for the study physician to observe the parent/guardian 
administering the study drug at least twice in compliance with the teduglutide 
administration checklist before permitting the parent/guardian to administer 
teduglutide.
Parents/guardians who have already demonstrated proficiency need only to be 
observed once by a study physician at each CxD1 visit as long as they continue 
to prepare and administer teduglutide in compliance with the study drug 
administration checklist. If a parent/guardian fails to administer teduglutide in 
compliance with the checklist, they must perform this procedure correctly on 2 
consecutive observations by the study physician in order to be deemed 
proficient to administer the study drug unsupervised.
(Clarification memo #2 dated 17 May 2018)
Section 6.2.2.1
Clarified that compliance with study drug is calculated from subject diaries.
Section 6.5
Specified that blood pressure should be collected in the same extremity rather 
than in the same arm as blood pressure is not collected using the arm in small 
children.
Section 7.2.3
Added the contact information for the monitoring personnel.
Appendix 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
2
Amendment Date
24 Jan 2018
Global
Description of Change and Rationale
Section(s) Affected by Change
Updated Emergency Contact Information.
Emergency Contact Information
Updated the product quality complaint section to address the drug delivery 
device.
Product Quality Complaints
Revised study drug administration language for clarity.
Section 6.2.2
As requested by PMDA, updated text to specify the process for training 
parent/guardian and measures to be taken to provide oversight on study drug 
administration.
Table 3, Section 6.2.2.1
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2
Amendment Date
24 Jan 2018
Global
Description of Change and Rationale
Section(s) Affected by Change
Clarified that the study drug administration diary can be completed by study site 
staff.
Table 3, Section 6.5, 
Section 7.2.10.2
Added direct bilirubin to the list of laboratory tests.
Table 5
Replaced the term “legally authorized representative” with guardian.
Throughout protocol.
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
26 May 2017
Global
Description of Change and Rationale
Section(s) Affected by Change
The Pharmacovigilance SAE Reporting fax number and email address 
have been updated. A sentence has been removed from the emergency 
contact information to eliminate a redundancy with the information 
provided under the Pharmacovigilance SAE Reporting heading. The title 
of 
 MD PhD is now 
; his email address 
has been changed and fax number removed as contact.
Protocol Signature Page
Emergency Contact Information
The planned study period has been updated with the initiation in August 
2017. 
Synopsis
Clarification has been made that medical history and short bowel 
syndrome (SBS) history collected at entry of Study SHP633-305 are 
updates to the medical history and SBS history collected at the start of 
SHP633-302. 
The statement ‘This period will be less than 7 days’, referring to the 
period between completion of Study SHP633-302 and the signing of the 
informed consent/assent in Study SHP633-305, has been deleted as 
inconsistent with the protocol. 
Synopsis
Section 3.1
Section 7.2.1
Clarification has been made that during the no-teduglutide treatment 
period, visits will take place approximately every 12 weeks.
Synopsis
Section 3.1
Figure 1
Section 7.1.2
Text was revised for consistency and clarity on the type of visits 
performed during the study:  at the clinic and by phone. Phone contacts 
were renamed phone visits.
Synopsis
Table 3
Section 3.1; Section 4.5.1; 
Section 4.5.4; Section 6.2.2; 
Section 7.2.10.2
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
26 May 2017
Global
Description of Change and Rationale
Section(s) Affected by Change
The text on the signing of informed consent and assent was revised for 
consistency throughout the protocol:  subjects (and/or parent or legally 
authorized representative, as applicable) are to sign an informed consent 
(and informed assent, if applicable). 
Synopsis
Table 1 
Section 3.2; Section 4; Section 5.1; 
Section 7.1.1; Section 7.2.1; 
Section 7.2.2; Section 8.2.4; 
Section 9.6
Teduglutide treatment exclusion criterion 11 has been revised to broaden 
experimental drug to any intravenous lipid emulsions (not only to 
Omegaven) 
Synopsis
Section 4.2.2
Teduglutide treatment exclusion criterion 17 has been revised for 
consistency with information on female contraception in Section 4.4.1 of 
the protocol. Use of approved contraception is throughout the study 
period and for 30 days following the last dose of investigational product.
Synopsis
Section 4.2.2
Section 4.4.1
The timeframe for the study completion has been reworded to ‘until 
teduglutide is commercially available for each subject, the subject’s 
participation in this study is discontinued, or the study is discontinued’. It 
was previously ‘until regulatory approval and commercial availability of 
teduglutide in Japan’.
Synopsis
Section 3.2
Language on safety endpoints has been clarified.
Synopsis; Section 9.8
Clarification has been made that no results from gastro-intestinal 
procedures are to be recorded: ‘GI procedures’ was changed to 
‘procedures’ in all study schedules tables (and the corresponding footnote 
deleted) and in Section 5.1 header. The statement on ‘GI procedures’ was 
deleted in Section 5.1. 
Table 1; Table 2; Table 3
Section 5.1
Clarification has been made that parenteral support prescription is to be 
collected at the screening visit.
Table 1
The requirement for urine specimen collection has been revised so that a 
lack of urinalysis will not constitute a protocol deviation for any pediatric 
subjects (not only for subjects wearing diapers).
Table 1; Table 2; Table 3
Section 7.2.4
For consistency within the protocol, sigmoidoscopy has been added as the 
alternate to colonoscopy throughout the protocol.
Table 1; Table 2; Table 3
Section 3.1; Section 7.2.9.2
A new footnote (now footnote ‘a’) has been added to the pretreatment 
visit to clarify that it may be combined with the screening visit and Study 
SHP633-302 EOS visit (Week 28), if the pretreatment visit assessments 
occur within 7 days of the SHP633 302 EOS assessments; and that if 
subjects proceed directly from screening to a pretreatment visit, the first 
pretreatment visit must occur within 12 weeks of screening.
Table 3
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
26 May 2017
Global
Description of Change and Rationale
Section(s) Affected by Change
Footnote ‘c’ (formerly ‘a’) in ‘CxW28 visit’ has been revised to clarify 
that when a subject withdraws from the study during the treatment period, 
the early termination visit will be performed in lieu of the CxW28 visit. 
Former footnote ‘p’ “The investigator may combine the CxW28 visit with 
a pretreatment visit if at least 1 escape criterion is met at the CxW28 
visit.” has been moved into footnote ‘c’.
Table 3
Footnote ‘g’ in “Review intake and output diaries” has been clarified. It 
also specifies that completion of the intake diary is not required for 
2 weeks prior to the pretreatment visit.
Table 3
Section 7.2.10.2
Clarification that unscheduled laboratory tests will be performed at the 
investigational site laboratory. Scheduled laboratory tests will be 
performed at the central laboratory.
Table 3
Section7.2.4
Former footnote ‘k’, stating that fecal occult blood testing should be 
performed on an annual basis (approximately every 48-60 weeks), has 
been removed from Table 3 as not relevant during the treatment period 
when fecal blood test is performed approximately every 12 weeks.
Table 3
Clarification on timing of blood collection for antibody testing at visit 
CxD1 has been added to footnote ‘j’.
Table 3
Footnote ‘l’ (formerly ‘m’) has been revised to clarify that serum urine 
pregnancy tests will be performed as per protocol schedule.
Table 3
Clarifications have been made to the indication, product, and clinical 
background information.
Section 1.1; Section 1.2
The in-text citation for ‘O’Keefe et al. 2006’ has been deleted from the 
rationale for dose selection (it now refers to the investigator’s brochure); 
and the corresponding full citation deleted from the list of references.
Section 3.1; Section 11
The definition of enrollment has been clarified; the timing when all of the 
study inclusion criteria must be met by a subject is at screening.
Section 3.2; Section 9.6
Clarifications have been made to discontinuation of treatment. A new 
header entitles Section 4.5.1 ‘Permanent Discontinuation of 
Investigational Product’ has been added and includes the 2 paragraphs 
formerly under the Section 4.5 header with the following changes: the 
subjects cannot be evaluated for subsequent teduglutide treatment 
eligibility and ‘withdrawal’ has been replaced with ‘permanent 
discontinuation’.
Section 4.5; Section 4.5.1
The last paragraph has been deleted for clarity. It was redundant with 
information presented in Sections 4.5.1 and 4.5.2 and not necessary here.
Section 4.5.3 (formerly Section 4.5.2)
Clarification has been made to the titration instructions for concomitant 
enteral medications with a narrow therapeutic index when given with 
teduglutide.
Section 5.1
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
26 May 2017
Global
Description of Change and Rationale
Section(s) Affected by Change
Clarification that biological therapy prohibited during teduglutide 
treatment and within 6 months prior to the pretreatment visit refers to 
biological therapy used to treat inflammatory bowel disease.
Section 5.1.2
Clarification has been made that all subjects may receive teduglutide 
0.05 mg/kg/day as described in Section 6.2.2 Dosing.
Section 6.2.1
Clarification has been made on visit schedule when a subject prematurely 
discontinues investigational product during a teduglutide treatment cycle. 
Clarification that subjects, and/or any designated person who will be 
administering the investigational product, will be trained on 
investigational product preparation and administration before the first 
dose of teduglutide or the implementation of any change in ancillary kit 
components.
Section 6.2.2
Language on labelling of ancillary kits has been revised.
Section 6.3.1
Clarification has been made on handling of study drug, which is for single 
use only and should be used within 3 hours following reconstitution. 
‘Handling’ was added to the section header for clarity.
Section 6.3.2
The text has been corrected for consistency with other sections of the 
protocol.
Section 7.1.3.1
Clarification that following the Cycle Day 1 visit, subjects will return to 
the clinic visits on Cycle Weeks 1 through 24.
Section 7.1.3.2
The Fahrenheit (°F) temperature scale is not used in Japan. The body 
temperature will only be recorded in the Celsius (°C) scale. Also, ‘pulse 
(beats per minute)’ has been changed to ‘pulse rate’ for translation 
purpose.
Section 7.2.3
Urine sodium has been removed from the list of urinalysis parameters to 
be tested. This parameter is not needed as safety parameter nor required 
for the decision to adjust a subject’s nutritional support. 
Also, a typographical error for serum β-HCG testing has been corrected, it 
is performed at the pretreatment visit.
Table 5
‘Specific’ has been deleted from ‘positive/specific anti-teduglutide 
antibodies’ to eliminate the redundancy. By definition, positive samples 
must be specific (as assessed in the confirmatory assay), or otherwise 
considered negative.
Section 7.2.6
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
26 May 2017
Global
Description of Change and Rationale
Section(s) Affected by Change
The estimated blood volume to be collected during the study has been 
removed because it may vary according to instructions provided by the 
manufacturer or laboratory for an individual assessment. Efforts will be 
made based on Japanese manufacturer or laboratory regulations and 
guidelines to minimize the amount of blood drawn from all pediatric 
subjects enrolled in this study.
Section 7.2.8
Performance of dipstick specific gravity tests by the subject at home on 
the first urine produced after the daily infusions of PS has been removed. 
It is now at the discretion of the investigator for all subjects, not just those 
in diapers. This change is to align with standard medical practice.
Section 7.2.10.2
Clarification has been made that only available diary data will be 
reviewed at each clinic and phone visit.
Section 7.2.10.2
The name of Shire Global Pharmacovigilance and Risk Management 
department has been changed to Shire Global Drug Safety. 
Section 9.2
The incidence of adverse events has been deleted from the summarized 
data to be presented in the safety analysis for translation purpose. 
Percentage of adverse events will be summarized.
Descriptive statistics will not be calculated for fluid balance variables.
Section 9.8
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APPENDIX 2
GUIDELINES FOR NUTRITIONAL SUPPORT MANAGEMENT 
DURING THE STUDY
Nutritional support adjustment in volume and calories should be considered at all planned visits. 
Please consider the following clinical parameters identified as markers for adequate management
of pediatric SBS. These parameters should be considered for managing nutritional support (PS 
and/or oral/enteral feeding) in terms of volume and calories during the treatment period: 

Growth trajectory, including weight, height (or length), and head circumference (for subjects 
up to 36 months of age)

Other clinical evaluations

Serum electrolytes

Blood urea nitrogen /creatinine levels

Changes in stool frequency or volume, including mixed output

Stool consistency (ie, Bristol Stool Form Scale)

Urine specific gravity

General consideration to possible clinical deterioration in SBS

Inability to maintain weight and growth velocity

Diarrhea (≥10 bowel movements per day, ≥80 mL/kg/day from an ostomy, or 
≥75 mL/kg/day mixed output)

Colic/vomiting frequency increased

Electrolyte changes or imbalance

Skin breakdown 

Adjustments should be based on the actual nutritional support in volume and calories the 
subject infuses. Subjects should remain compliant with the nutritional support prescription in 
volume and calories during the study.

Nutritional support constituents may be adjusted at the discretion of the investigator.

During the 48-hour intake/output measurement period prior to the subject’s scheduled visit, 
no further changes to the prescribed nutritional support should be made.

If there is a change in EN or other food or fluid intake, the investigator should consider this 
when adjusting the PS/EN support in volume and calories.
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APPENDIX 3
WEANING ALGORITHMS
Figure A-1
Weaning Algorithm for Subjects Who are NOT Toilet Trained and in 
Diapers
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Figure A-2
Weaning Algorithm for Subjects Who are Toilet Trained and NOT in 
Diapers
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Figure A-3
Clinical Dehydration Assessment and PS/EN Adjustment
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06 Nov 2020
APPENDIX 4
MONITORING PERSONNEL
Takeda Pharmaceutical Company Limited
1-1, Doshomachi 4-Chome, Chuo-ku, Osaka-shi, Osaka, Japan
Name: 
Contact info: TEL: 
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SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
NCT Number: 
NCT03268811 
Study Title:  
A Prospective, Open-label, Long-term Safety and Efficacy Study of Teduglutide in 
Japanese Pediatric Subjects with Short Bowel Syndrome Who Completed 
SHP633-302 
Study Number:  
SHP633-305 
SAP Version and Date:  
Final 1.0: 
25 Jul 2019 
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STATISTICAL ANALYSIS PLAN
SHP633-305
A PROSPECTIVE, OPEN-LABEL, LONG-TERM SAFETY AND EFFICACY STUDY OF 
TEDUGLUTIDE IN JAPANESE PEDIATRIC SUBJECTS WITH SHORT BOWEL SYNDROME 
WHO COMPLETED SHP633-302
AUTHOR:
VERSION NUMBER AND DATE: FINAL 1.0, 25JUL2019
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
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Author: 
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Company: 
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Signature 
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Plan, authorizing that the content is acceptable for the reporting of this study, 
Name 
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MODIFICATION HISTORY
Unique 
Identifier 
for 
this 
Version
Date of the 
Document 
Version
Author
Significant 
Changes 
from 
Previous Authorized Version
Final 1.0
25Jul2019
Not Applicable – First Version
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TABLE OF CONTENTS
1.
LIST OF ABBREVIATIONS..............................................................................................................7
2.
INTRODUCTION AND BACKGROUND INFORMATION..........................................................8
2.1.
Study Design............................................................................................................................................8
2.2.
Objectives................................................................................................................................................9
2.2.1.
Efficacy Assessments ..................................................................................................................................9
2.2.2.
Safety Assessments ....................................................................................................................................9
3.
DETERMINATION OF SAMPLE SIZE ........................................................................................10
4.
UNBLINDING PROCEDURES.......................................................................................................10
5.
DATA MANAGEMENT...................................................................................................................10
6.
STATISTICAL/ANALYTICAL ISSUES........................................................................................10
6.1.
General Methodology............................................................................................................................10
6.2.
Baseline .................................................................................................................................................11
6.3.
Visit Summaries.....................................................................................................................................11
6.4.
Windowing Visits...................................................................................................................................12
6.5.
Reference Start Day and Study Day........................................................................................................12
6.6.
Adjustments for Covariates/Prognostic Variables..................................................................................12
6.7.
Handling of Dropouts or Missing Data ...................................................................................................13
6.8.
Interim Analyses and Data Monitoring ..................................................................................................13
6.9.
Multicenter Studies ...............................................................................................................................14
6.10.
Multiple Comparisons/Multiplicity........................................................................................................14
6.11.
Active-Control Studies Intended to Show Equivalence...........................................................................14
6.12.
Examination of Subgroups.....................................................................................................................14
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7.
ANALYSIS POPULATIONS...........................................................................................................14
7.1.
Screened Population..............................................................................................................................14
7.2.
Enrolled Population ...............................................................................................................................14
7.3.
Safety Population ..................................................................................................................................14
8.
STUDY SUBJECTS...........................................................................................................................15
8.1.
Subjects Screened..................................................................................................................................15
8.2.
Study Analysis Populations....................................................................................................................15
8.3.
Protocol Deviations ...............................................................................................................................15
8.4.
Disposition of Subjects...........................................................................................................................15
9.
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS..........................................16
9.1.
Analysis of Demographic and Other Baseline Characteristics.................................................................16
10. MEASUREMENTS OF TREATMENT COMPLIANCE ..............................................................18
11. EFFICACY/PHARMACODYNAMIC EVALUATION.................................................................18
11.1.
Analysis of Efficacy and Pharmacodynamic Variables ............................................................................18
12. SAFETY EVALUATION..................................................................................................................21
12.1.
Extent of Exposure.................................................................................................................................21
12.2.
Adverse Events ......................................................................................................................................22
12.3.
Clinical Laboratory Evaluation ...............................................................................................................23
12.4.
Vital Signs ..............................................................................................................................................26
12.4.1.
Z-scores of height for age and weight for age for children 1-15 years of age and subjects in the infant 
cohort ≥2 years corrected gestational age..............................................................................................................28
12.4.2.
Z-scores of length for age and weight for age for subjects in the infant cohort < 2 years corrected 
gestational age .........................................................................................................................................................29
12.4.3.
Z-scores of head circumference for all study subjects ≤36 months of age ..........................................29
12.4.4.
Z-scores of BMI for all study subjects 2-15 years of age.......................................................................29
12.4.5.
Z-scores of weight for length for infants ..............................................................................................29
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12.5.
Physical Examination .............................................................................................................................30
12.6.
Antibodies to Teduglutide .....................................................................................................................30
12.7.
Gastrointestinal-Specific Testing............................................................................................................30
12.8.
Fecal and Urine Output..........................................................................................................................30
12.9.
Concomitant Medications......................................................................................................................31
13. CHANGES IN THE STATISTICAL METHODOLOGY PRESENTED IN THE PROTOCOL31
14. GENERAL PROGRAMMING INFORMATION...........................................................................32
14.1.
General..................................................................................................................................................32
14.2.
Format of Tables/Listings.......................................................................................................................32
14.3.
Data Formats .........................................................................................................................................33
15. TABLE, FIGURE AND DATA LISTING SHELLS.......................................................................33
15.1.
Table Shells............................................................................................................................................33
15.2.
Figure Shells...........................................................................................................................................33
15.3.
Data Listing Shells..................................................................................................................................34
16. REFERENCES...................................................................................................................................34
MARKEDLY ABNORMAL LABORATORY CRITERIA .........................35
APPENDIX 1.
L, M AND S VALUES OF HEIGHT, BODY WEIGHT, BMI AND HEAD 
APPENDIX 2.
CIRCUMFERENCE FOR AGE FOR JAPANESE ......................................................................37
MEDDRA TERMS CORRESPONDING TO EACH GROUPING OF 
APPENDIX 3.
ADVERSE EVENTS OF SPECIAL INTEREST...........................................................................42
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1. LIST OF ABBREVIATIONS
AE
Adverse Event
ALT
Alanine Aminotransferase 
AST
Aspartate Aminotransferase 
BMI
Body Mass Index 
CDC
Centers for Disease Control and Prevention 
CTMS
Clinical Trial Management System
DMC
Data Monitoring Committee 
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EOS
End of Study 
EOT
End of Treatment 
GI
Gastrointestinal
HLGT
Higher Level Group Term
ICH
International Conference on Harmonisation
MedDRA
Medical Dictionary for Regulatory Activities 
MOS
Months
NA
Not Applicable
NTT
No-Teduglutide Treatment
PS
Parenteral Support
PT
Preferred Term 
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan 
SBS
Short Bowel Syndrome 
SC
Subcutaneous
SE
Standard Error
SI
Standard International
SOC
Standard of Care 
TEAE
Treatment-Emergent Adverse Event
TESAE
Treatment-Emergent Serious Adverse Event
ULN
Upper Limit of Normal
WHO
World Health Organization
YRS
Years
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2. INTRODUCTION AND BACKGROUND INFORMATION
This document describes the rules and conventions to be used in the presentation and 
analysis of efficacy and safety data for Protocol SHP633-305. It describes the data to be 
summarized and analyzed, including specifics of the statistical analyses to be performed. 
This statistical analysis plan (SAP) is based on protocol amendment 3, dated 20 July 2018.
2.1.
STUDY DESIGN
This is a Phase 3, prospective, open-label, long-term extension study to evaluate the safety 
and efficacy of teduglutide in Japanese pediatric subjects who completed Study SHP633-302 
(core study). The study population will include 2 cohorts based on age of subjects at the time 
of entry in the core study: infants 4-<12 months corrected gestational age and children 1-15 
years of age. A schematic representation of the study design is presented in Figure 1. The 
study schedule of events can be found in Table 1, 2 and 3 of the protocol.
Figure 1
Study Diagram
Subjects not receiving teduglutide treatment, i.e., in a no-teduglutide treatment (NTT) period, will 
be seen approximately every 12 weeks to collect safety and parenteral support (PS) 
requirements. At any point after screening, including during an NTT period, subjects who meet 
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at least one teduglutide treatment inclusion criteria may proceed directly to a pretreatment visit if 
the investigator and the subject (and/or parent/guardian, as applicable), agree to proceed with 
teduglutide therapy.
At the pretreatment visit, subjects who meet at least one of the teduglutide treatment inclusion 
criteria and none of the teduglutide treatment exclusion criteria will start a 28-week cycle, 
consisting of 24 weeks of teduglutide treatment at 0.05 mg/kg subcutaneous (SC) once daily, 
followed by a 4-week follow-up period, during which no teduglutide is administered.
A subject may “escape” the follow-up period between cycle Week 24 and Week 28 and proceed 
directly to another pretreatment visit if the subject meets at least one follow-up period escape 
criteria. Otherwise, following completion of the 28-week treatment cycle, the subject will proceed 
to an NTT visit (or another pretreatment visit, if needed) within 12 weeks. A subject may 
participate in multiple treatment cycles and NTT periods depending on his or her clinical 
trajectory.
2.2.
OBJECTIVES
The primary objective of the study is to evaluate the long-term safety and tolerability of 
teduglutide treatment in Japanese pediatric subjects with Short Bowel Syndrome (SBS) who 
completed Study SHP633-302.
The secondary objective of this study is to evaluate the long-term efficacy of teduglutide 
treatment in Japanese pediatric subjects with SBS who completed Study SHP633-302.
2.2.1.
EFFICACY ASSESSMENTS
The following efficacy endpoints will be analyzed at the end of each teduglutide treatment 
cycle , Week 24 or End of Treatment (EOT), and at each study visit, relative to the baseline of 
the core study (SHP633-302):

Reduction in PS volume of at least 20%

Absolute and relative change in PS volume

Complete weaning off PS

Change in days per week of PS
2.2.2.
SAFETY ASSESSMENTS
The following safety endpoints will be analyzed:

Adverse events
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
Vital signs, including temperature, heart rate, blood pressure

Laboratory safety data (i.e., biochemistry, hematology, and urinalysis)

Urine output

Stool output

Antibodies to teduglutide

Gastrointestinal-specific testing, including fecal occult blood testing and colonoscopy or 
sigmoidoscopy

Z-scores for weight, height (or length), head circumference (up to 36 months of age), and 
Body Mass Index (BMI)
3. DETERMINATION OF SAMPLE SIZE
The number of subjects in this study is not based on statistical power considerations as this is 
an extension study of the core study SHP633-302. The maximum number of subjects will be 
determined by the completion of Study SHP633-302.
4. UNBLINDING PROCEDURES
No unblinding procedures apply as this is an open-label study.
5. DATA MANAGEMENT
IQVIA is responsible for data management activities for this study. Details about data 
management, including the electronic case report form (eCRF) design, the Electronic Data 
Capture (EDC) system, data validation and discrepancy management, reconciliation of data 
from different sources, and electronic data transfer, are included in the Data Management Plan 
for this study.
6. STATISTICAL/ANALYTICAL ISSUES
6.1.
GENERAL METHODOLOGY
All statistical procedures will be completed using SAS version 9.4 or later.
Due to the limited size of the study population descriptive statistics will be used with a goal of 
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summarizing the sample which discourages the use of inferential statistics. Accordingly, no 
claims of significance will be made for any of the data.
Continuous variables, including those assessed on a discrete scale, will be summarized using 
descriptive statistics including number of subjects, mean, median, standard deviation, 
maximum, and minimum. For efficacy parameters, as well as body weight, height (or length), 
BMI, head circumference and weight for length, standard errors (SE) will be presented in the 
corresponding tables. For categorical variables, descriptive statistical summaries will include 
number of subjects and percentages.
Subjects will be classified in cohorts based on age of subjects at the time of entry in the 
SHP633-302 core study as recorded on the demographics page of the SHP633-305 eCRF:

Infants: 4-<12 months corrected gestational age

Children: 1-15 years of age
Unless otherwise specified, analyses will be done for all subjects, and subset of subjects who 
were enrolled after SHP633-305 protocol amendment 2.0. Main conclusions will be based on 
subjects who were enrolled after implementation of protocol amendment 2.0.
6.2.
BASELINE
For summary purposes, the baseline value will be defined as the last available pre-dose value 
in the core study SHP633-302. 
6.3.
VISIT SUMMARIES
Scheduled visits will be summarized as provided in the eCRFs. 
Visits will be summarized within the associated pre-treatment period or treatment cycle or NTT 
period. For teduglutide treatment cycles, Cycle x Day 1, Cycle x Week 1, …, Cycle x Week 24, 
Cycle x Week 25 Follow-up, Cycle x Week 26 Follow-up, Cycle x Week 27 Follow-up and 
Cycle x Week 28 Follow-up data will be collected according to the schedule of events.
If the first pre-treatment visit is indicated in the eCRF to have been combined with the 
SHP633-302 core study’s End of Study (EOS) visit, data from the SHP633-302 EOS visit will 
be presented for the SHP633-305 first pre-treatment visit. For subsequent treatment cycles, if 
the pre-treatment visit is indicated to be combined with Week 24 or Week 28 of the previous 
treatment cycle, that pre-treatment visit will not be in the tables. All data will be in the listings.  
For NTT periods, NTx data will be collected approximately every 12 weeks. Data for 
teduglutide treatment periods and NTT periods will be presented in separate tables.
For each treatment cycle, an EOT time point, defined as the last determination of endpoint or 
last available measurement after the date of first dose during that 24-week treatment period 
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will be analyzed in addition to the scheduled visits. An EOT endpoint will also be presented for 
the last treatment cycle, defined as the last determination of endpoint or last available 
measurement on treatment. 
Similarly, a last NTx endpoint, defined as the last determination of endpoint or last available 
measurement during any NTT period, will be presented.
Unscheduled measurements will not be included in by-visit summaries, but can contribute to 
the EOT value where applicable. Datasets and listings will include data collected at both 
scheduled and unscheduled visits.
6.4.
WINDOWING VISITS
Although there is a visit window from 2 to 7 days around the expected visit date, nominal visits 
will be used for the per-visit analyses. Therefore, no windowing of visits by study day will be 
done for data obtained at the scheduled visits. 
The end of treatment visit within a teduglutide treatment cycle will be mapped to a scheduled 
visit within that treatment cycle if it falls into the appropriate visit window as defined in the 
protocol and if that scheduled visit did not occur.
For subjects who withdraw from the study prematurely, if the early termination visit falls into 
the window of a scheduled visit as defined in the protocol, the early termination visit is also 
summarized for that scheduled visit, unless the scheduled visit already took place.
6.5.
REFERENCE START DAY AND STUDY DAY
Reference start date is defined as the date of first study drug administration in SHP633-302 
core study.
Study Day will be calculated as follows:

If the date of the evaluation is on or after the reference start date then: 
                Study Day = (date of the evaluation – reference start date) + 1.

If the date of the evaluation is prior to the reference start date then: 
                Study Day = (date of the evaluation – reference start date).
In the situation where the event date is partial or missing, the date will appear partial or 
missing in the listings, and Study Day will be missing.
6.6.
ADJUSTMENTS FOR COVARIATES/PROGNOSTIC VARIABLES
No adjustments for covariates are planned in the statistical analyses.
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6.7.
HANDLING OF DROPOUTS OR MISSING DATA
All subjects in the analysis population defined in Section 7 will be included in the associated 
analyses.
No imputation for missing data (e.g., last observation carried forward [LOCF]) will be applied 
except for the partial dates for adverse events.
Details on how to handle partial dates for adverse events are described below.
Complete dates will be imputed from partial dates of adverse events solely for the purpose of 
calculating the onset time of adverse events (Imputed dates will not be presented in the 
listings). Dates will be defined using the hierarchy of derivations below.

Adverse event start date (references to month and year are the month and year of 
the start date):
1.
If year and month are known, and it is the month and year of the informed consent/assent 
date, use the informed consent/assent date.
2.
If year and month are known, and it is not the month and year of the informed 
consent/assent date, use the first day of the month.
3.
If only year is known, and it is the year of the informed consent/assent date, use the 
informed consent/assent date.
4.
If only year is known, and it is not the year of the informed consent/assent date, use the 
first day of the year (1st January).
5.
Should any of the previous start dates created be after a complete stop date provided, use 
the stop date as the start date, instead of the date that would otherwise be created.
6.
Otherwise, if start date is unknown leave as missing.

Partial adverse event stop date will not be imputed.
6.8.
INTERIM ANALYSES AND DATA MONITORING
Interim analyses may be conducted during the study, as needed. Analyses will be descriptive 
in nature. No formal comparisons are planned and no hypotheses will be formally tested.
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 during the study treatment 
periods (date of the first subject’s first dose to date of the last subject’s last dose). The DMC 
review will include cumulative safety data (ie, AEs, laboratory assessments, physical 
examinations, etc.) through each cutoff period.
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6.9.
MULTICENTER STUDIES
Because a small number of subjects are expected at each center, data from all centers will be 
pooled.
6.10. MULTIPLE COMPARISONS/MULTIPLICITY
Not Applicable.
6.11. ACTIVE-CONTROL STUDIES INTENDED TO SHOW EQUIVALENCE
Not applicable.
6.12. EXAMINATION OF SUBGROUPS
No subgroup analyses will be conducted given the small number of patients in this study.
7. ANALYSIS POPULATIONS
7.1.
SCREENED POPULATION
All subjects who provided signed informed consent/assent will be included in the Screened 
population.
7.2.
ENROLLED POPULATION
The enrolled population will include all enrolled subjects. A subject will be considered enrolled 
in the study once the informed consent/assent has been obtained and the subject meets all of 
the study inclusion criteria at screening.
7.3.
SAFETY POPULATION
The safety population will include all enrolled subjects in the study and who received at least 
one dose of teduglutide (in study SHP633-302 or SHP633-305). Safety population will be used 
for both safety and efficacy analyses.
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8. STUDY SUBJECTS
8.1.
SUBJECTS SCREENED
The number of subjects screened will be presented.
8.2.
STUDY ANALYSIS POPULATIONS
The number of subjects in the Enrolled population and Safety population will be presented for 
the Screened population.
8.3.
PROTOCOL DEVIATIONS
Protocol deviations as obtained from a clinical trial management system (CTMS) will be 
assessed throughout the study. All identified deviations will be reported in the CTMS. Protocol 
deviations from the CTMS will be coded to severity categories (“minor”, “important” and 
“priority”) and provided as part of the CTMS transfer to Biostatistics. Protocol deviations will be 
summarized for the Safety population. A listing of protocol deviations by subject will be 
presented in the data listings.
8.4.
DISPOSITION OF SUBJECTS
The number and percentage of subjects who received teduglutide during the study as well as 
number and percentage of subjects who completed all treatment periods or prematurely 
discontinued from any of the treatment period will be presented. Reasons for premature 
permanent treatment discontinuation as recorded on the end of treatment page of the eCRF 
will be summarized (number and percentage). 
The number and percentage of subjects who completed the study or discontinued early will be 
presented. Reasons for early study discontinuation based on the end of study page of the 
eCRF will be summarized (number and percentage).
All percentages will be calculated based on the Safety population. 
A subject data listing will present subject disposition for the Screened population. A subject 
data listing will present subject disposition by teduglutide-treatment cycle and NTT visit for the 
Screened population. Inclusion criteria violations, if any, will be presented in a listing for the 
Screened population. In addition, treatment eligibility criteria and follow-up period escape 
criteria will be listed for the Safety population.
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9. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
9.1.
ANALYSIS OF DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
The baseline and demographic characteristics will be summarized with descriptive statistics 
defined in Section 6.1 for the Safety population. Demographic and baseline characteristics to 
be presented include:

Age (years) at informed consent/assent date of SHP633-302 study for the cohort of 
children 1-15 years of age.

Chronological (actual) age (months) at informed consent/assent date of SHP633-302 
study for the infant cohort.
Corrected gestational age (months) at informed consent/assent date of SHP633-302 study 
for the infant cohort.

Sex

Race

Ethnicity

Height or length for age Z-score and percentile at Baseline of SHP633-302 study

Weight for age Z-score and percentile at Baseline of SHP633-302 study 

Head Circumference for age Z-score and percentile at Baseline of SHP633-302 study 
(only for subjects who are <= 36 months of age at Baseline of SHP633-302 study)

BMI for age Z-score and percentile at Baseline of SHP633-302 study only for children 2-
15 years of age at Baseline of SHP633-302 study

Weight for length Z-score and percentile at Baseline of SHP633-302 study only for the 
infant cohort
Age will be rounded to 1 decimal place for reporting. BMI, Z-score of weight, height or length, 
BMI and head circumference for age as well as weight for length Z-score will be calculated 
based on the method described in Section 12.4. Z-scores will be rounded and presented to 2 
decimal places. Percentiles will be calculated as the corresponding probability of Z-scores 
from the standard normal distribution. Percentiles will be rounded and presented to 1 decimal 
places. 
Any update in SBS history since SHP633-302 core study’s screening visit will be collected and 
summarized. If there is no update in the SBS history from the core study, the data from 
SHP633-302 screening visit will be used in the SBS history summary below. 
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The following SBS history will be summarized with descriptive statistics defined in Section 6.1
for the Safety population:

Duration of SBS at baseline of the core study

Primary reason for the diagnosis of SBS (necrotizing enterocolitis, midgut volvulus, intestinal 
atresia, gastroschisis, trauma, cancer, Crohn’s disease, long-segment Hirschprung disease, 
other)

Secondary reason for the diagnosis of SBS (Yes/No), secondary reason (necrotizing 
enterocolitis, midgut volvulus, intestinal atresia, gastroschisis, trauma, cancer, Crohn’s 
disease, long-segment Hirschprung disease, other)

Stoma (Yes/No), stoma type (jejunostomy, ileostromy, colostomy, other)

Remaining colon (Yes/No), estimated percent of colon remaining, and colon in continuity 
(Yes/No)

Colonoscopy in the last 12 months (Yes/No/NA [Not Applicable]) as collected at the screening 
visit of SHP633-302 core study

Total estimated remaining small intestinal length (cm)

Presence of the distal/terminal ileum (Yes/No) and ileocecal valve (Yes/No)

Method to determine remaining anatomy length (surgery, radiology, other)
For the cohort of children 1-15 years of age, duration of SBS in years will be calculated as 
(Date of informed consent/assent form signed for SHP633-302 study – Date of diagnosis of 
SBS +1) / 365.25 and rounded to 1 decimal place for reporting.
For the cohort of infants, duration of SBS in months will be calculated as (Date of informed 
consent/assent form signed for SHP633-302 study – Date of diagnosis of SBS +1) / 
(365.25/12) and rounded to 1 decimal place for reporting.
Partial dates for the date of diagnosis of SBS will use the first day of the month if only the day 
is missing. If both the day and month are missing, the first day of January will be used.
Medical and surgical history will supplement the medical history information collected at the 
start of the SHP633-302 core study and will consist of the following:

New medical conditions not related to SBS since core study participation 

Ongoing adverse events (AE) at the time of core study completion

Updates to a previously reported medical history
Medical and surgical history will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). Type of medical or surgical history, severity for ongoing AEs from the 
core study, investigator verbatim as well as preferred terms and system organ class will be 
included in the listings. The medical and surgical history will be summarized by system organ 
class (SOC) and preferred term (PT) within system organ class for the Safety population, with 
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SOC sorted alphabetically and PT within SOC by descending incidence.
10.
MEASUREMENTS OF TREATMENT COMPLIANCE
Treatment compliance will be presented both overall and by treatment cycle. 
Percent compliance for Cycle X will be calculated as 100 times the number of days the study 
treatment was administered per instructions between Cycle X Day 1 and Cycle X Week 24 
(EOT) divided by the number of days on treatment in Cycle X. Number of days on treatment in 
Cycle X is calculated as (last visit date on or before Cycle X Week 24 (EOT) – Cycle X Day 1 + 
1). 
Overall compliance will be calculated as 100 times the total number of days the study 
treatment was administered per instructions across all cycles divided by the total number of 
days on treatment across all cycles.
The information whether the study treatment was administered per instructions is captured on 
the study drug administration daily diary. Administration of the study treatment by the 
investigator will be considered per instructions. 
Subjects will be considered compliant for study medication if the calculated compliance is ≥ 
80%. Overall and by-cycle treatment compliance will be presented for both percent compliance 
calculations using descriptive statistics and the number and percentage of subjects who are ≥ 
80% compliant for the Safety population.
11.
EFFICACY/PHARMACODYNAMIC EVALUATION
11.1. ANALYSIS OF EFFICACY AND PHARMACODYNAMIC VARIABLES
Primary efficacy analyses will be conducted on the Safety population.
Parenteral support will be reported in both subject diary data and the investigator-prescribed 
data in the eCRF. Diary and prescribed PS volume/calories will be normalized to weight in 
order to facilitate comparability of results across patients in this pediatric population. 
Data will be summarized separately for treatment periods and NTT periods. For treatment 
periods, PS data will be presented by cycle and by scheduled visit within each cycle (Day 1 to 
Week 28). An EOT time point and a last NTx time point will also be presented as defined in 
Section 6.3. The baseline value of the SHP633-302 core study will also be presented as 
applicable. Data collected at unscheduled time points will be included in the listings but will not 
be summarized at those unscheduled time points.
Pre-treatment visits will not be analyzed for efficacy.
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For prescribed data, the most recent PS prescription prior to or on the date of visit will be 
used. 
Average daily values normalized to weight will be calculated for PS volume and calories as 
follows:
Average prescribed daily value = (prescribed weekly value / 7) / last available body weight 
prior to or on the visit
Baseline prescribed PS values (volume, calories, hours per day and days per week) will be 
obtained from the analysis datasets of the SHP633-302 core study.
Calculation of diary PS parameters (including hours per day and days per week of PS) will be 
based on the daily support recorded in subjects’ diaries within 7 days prior to the date of each 
scheduled visit. 
Average daily values normalized to weight will be calculated for PS volume and calories as 
follows:
Average diary daily value = (sum of non-missing daily values in the diary / number of days with 
non-missing values) / last available body weight prior to the visit
If more than 2 days’ values in a week are missing, the average daily value will not be 
calculated and will be assigned as missing. This missing data handling rule will be used to 
calculate all other diary average diary parameters, including PS hours per day and PS days 
per week.
Baseline diary PS values (volume, calories, hours per day and days per week) will be 
calculated using the most recent 14 days of diary data collected prior to the first dose of the 
SHP633-302 core study. If more than 5 days’ values are missing in two weeks before the first 
dose of the core study, the baseline values are missing.
Percent reduction in weight-normalized diary and prescribed PS values from baseline at the 
scheduled visit will be calculated using the formula below: 
% reduction in PS value at the visit = [(average daily value at the scheduled visit - average 
daily value at baseline of the core study) / average daily value at baseline of the core study] * 
100 
Percent reduction calculation will be performed on both diary and prescribed PS data.
Change and percent change from baseline in PS volume and calories
The absolute and percent change from baseline in average daily values for PS volume and 
calories to each scheduled visit, separately for NTT (including last NTx) and each treatment 
cycle (including EOT), will be presented using descriptive statistics defined in Section 6.1.
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Mean ± standard error (SE) plots of percent change in PS volume and caloric intake will be 
generated by scheduled visit for each treatment cycle.
Plots of PS volume and caloric intake by scheduled visit in each treatment cycle will be 
presented for each individual subject in the Safety population.
≥ 20% Reduction in PS volume at each study visit
PS volume reduction at each scheduled visit compared to baseline will be calculated using 
average daily values. The number and percentage of subjects who achieve at least a 20% 
reduction in PS volume will be presented at each scheduled visit separately for NTT (including 
last NTx) and each treatment cycle (including EOT).
Enteral autonomy (completely weaned off PS)
Enteral autonomy (completely weaned off PS) is defined as the first visit where there is no use 
of PS for the 7 days prior to the visit and there is no prescribed PS at that visit, and the patient 
remains off PS for the remainder of the treatment period of that cycle.
The enteral autonomy (completely weaned off PS) will be summarized by visits. 
For each treatment cycle, a listing will present the study week when enteral autonomy was 
achieved for these subjects who achieved enteral autonomy during the teduglutide treatment 
cycles.
Change and percent change from baseline in hours per day and days per week of PS 
Change and percent change from baseline in hours per day and days per week of PS to each 
scheduled visit, separately for NTT (including last NTx) and each treatment cycle (including 
EOT), will be presented using descriptive statistics defined in Section 6.1.
Hours per day of diary PS for all visits except the baseline visit will be calculated as follows: 
Hours per day of diary PS = (sum of hours per day for each day that PS intake data is 
recorded within the 7 days prior to the visit / number of days that PS hours per day data is 
recorded within the 7 days prior to the visit)
Days per week of diary PS for all visits except the baseline visit will be calculated as follows: 
Days per week of diary PS = (number of days with non-zero values for PS volume within the 7 
days prior to the visit / number of days for which any PS intake data is recorded within the 7 
days prior to the visit) * 7 
Prescribed PS hours per day and days per week for each visit will be taken from the most 
recent prescription data prior to or at that visit.
In addition, the number and percentages of subject will be tabulated for the reduction in 
number of days per week of PS usage from baseline at Week 24 and Week 28 categorized 
into days: >=1, >=2, >=3, >=4, >=5, >=6 and =7 days. 
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12.
SAFETY EVALUATION
All safety evaluations will be conducted on the Safety population. By-visit summaries will be 
presented separately for treatment periods and NTT periods. For each treatment cycle, all 
protocol scheduled visits during the 24-week treatment period and Week 28 visit will be 
presented. An EOT time point and a last NTx time point will also be presented as defined in 
Section 6.3. The baseline value of the SHP633-302 core study will also be presented as 
applicable.
12.1. EXTENT OF EXPOSURE
The extent of exposure will be presented both overall and by treatment cycle for the Safety 
population. 
The extent of exposure in days for Cycle X will be calculated as (last visit date on or before 
Cycle X Week 24 (EOT) – Cycle X Day 1 + 1). 
The overall extent of exposure in weeks will include the extent of exposure in both the 
SHP633-302 core study and the extension study. It will be calculated as [the exposure in days 
in the core study (date of last dose - date of first dose + 1) + the sum of extents of exposure 
across all cycles in the extension study] / 7.
Overall and by-cycle extent of exposure will be presented using descriptive statistics. In 
addition, the number and percentages of subject will be tabulated for the overall extent of 
exposure categorized into weeks: 0-<12, 12-<24, 24-<48, 48-<72, 72-<96, 96-<120, 120-<144, 
144-<168 and  >=168 weeks.
The overall extent of observation will be presented for the Safety population using descriptive 
statistics. The overall extent of observation in weeks will be calculated as (last date of follow-
up or interim analysis cut-off date – SHP633-305 inform consent/assent date + 1) / 7. The last 
date of follow-up is defined as the date of the last available follow-up visit. 
The overall time to start cycle 1 will be presented for the Safety population using descriptive 
statistics. The overall time to start cycle 1 in weeks will be calculated as (Cycle 1 Day 1 –
SHP633-305 inform consent/assent day + 1) / 7. 
The gap in treatment between each treatment cycle will be presented for the Safety population 
using descriptive statistics. The gap in treatment in weeks for Cycle X will be calculated as 
[Cycle X Day 1 – EOT of Cycle (X-1) + 1] / 7. The gap in treatment in weeks for Cycle 1 will be 
calculated as (Cycle 1 Day 1 – last dose date in SHP633-302 study + 1) / 7.
The overall number of cycles on teduglutide during the extension study will also be 
summarized as a numeric variable.
The information related to the study drug accountability, study drug interruption and study drug 
training provided by the study physician will be listed for all subjects in the Safety population.
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12.2. ADVERSE EVENTS
Adverse Events will be coded using MedDRA. Investigator verbatim as well as preferred term 
and system organ class will be included in the listings. Only AEs recorded in the SHP633-305 
eCRF will be used for the analysis.
Treatment emergent AEs (TEAEs) are defined as AEs whose onset occurs, severity worsens 
or intensity increases on or after the date of first study drug administration in SHP633-302 core 
study. AEs with an unknown date of onset and a stop date on or after the date of first study 
drug administration in SHP633-302 core study or unknown will be included as treatment 
emergent AEs. If any AE records contain only partial dates, these will be handled by 
imputation, as described in Section 6.7. AEs which are not treatment emergent, if any, will be 
flagged in listings.
An overview summary of AEs for the categories below will be provided using descriptive 
statistics (e.g., number and percent of subjects). The number of events will also be presented. 
Categories summarized will include any TEAE (Yes/No), severity of TEAEs (any and highest 
category), investigator assessment of relationship of TEAEs to study treatment, treatment 
emergent serious AEs (TESAEs), severity of TESAEs, investigator assessment of relationship 
of TESAEs to study treatment, TEAEs leading to death, TEAEs leading to discontinuation, and 
TEAEs of special interest.
Treatment emergent AEs will be summarized using number and percentage of subjects. 
Subject incidence for AEs within each SOC and PT will be presented, unless otherwise 
specified. The number of events will also be summarized. Categories summarized will be the 
same as those summarized in the overview tabulations, except that no summary table will be 
provided for TEAEs leading to death. Presentation by SOC and PT will present SOC sorted 
alphabetically and PT within SOC by descending incidence.
Summaries of TEAEs, TEAEs by relationship, TESAEs and TESAEs by relationship will also 
be presented by PT. These presentations will be sorted by descending incidence.
For the summaries described above, TEAEs with a missing severity will be classified as 
severe and TEAEs with a missing relationship to study drug will be regarded as related to 
study drug.
In addition, AEs of special interest will be considered. An AE of special interest is an AE 
(serious or nonserious) of scientific and medical concern specific to the sponsor’s product or 
program. The AEs of special interest will include the following groupings:

Growth of pre-existing polyps of the colon

Benign neoplasia of the gastrointestinal (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)
The MedDRA terms corresponding to each grouping of events of special interest are included 
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in APPENDIX 3. 
The number and percentage of subjects with at least one TEAE of special interest will be 
presented. The number of events of special interest will also be summarized.
Listings will be provided for serious adverse events (SAEs), AEs leading to death, AEs leading 
to discontinuation of study drug and AEs of special interest. 
TEAEs will be summarized by AE onset time in 3 month increments (i.e., 6<-9 months, 9<-12
months, 12<-15 months, etc.). The denominator for each interval will be the number of 
subjects who reached same interval of observation duration. It will be displayed where data 
available. 
AE onset time in months will be calculated as (AE start date – Date of first dose in SHP633-
302 Study + 1) / 30.4375. The observation duration in months, used for the denominators, will 
be calculated as (Last date of follow-up or interim analysis cut-off date – Date of first dose in 
SHP633-302 Study + 1) / 30.4375. The last date of follow-up is defined as the date of the last 
available follow-up visit.
12.3. CLINICAL LABORATORY EVALUATION
Laboratory evaluations that are done at study site visits will be collected and processed via a 
central laboratory, and presented in standard international (SI) units. 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.
Clinical laboratory evaluations include, but not limited to, the following:
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
Chemistry:
o
Albumin
o
Alkaline phosphatase
o
Alanine aminotransferase
o
Amylase
o
Aspartate aminotransferase
o
Bicarbonate
o
Bilirubin (total, direct and indirect)
o
Blood urea nitrogen
o
Calcium (total)
o
Chloride
o
Cholesterol
o
C-reactive protein
o
Creatinine
o
Estimated glomerular filtration rate (Schwartz formula)
o
Gamma-glutamyl transferase
o
Glucose
o
Lipase
o
Magnesium
o
Phosphorus
o
Potassium
o
Sodium
o
Triglycerides
o
Uric acid
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
Hematology:
o
Hematocrit
o
Hemoglobin
o
Platelet count
o
Red blood cell (RBC) count
o
RBC morphology, if needed
o
White blood cell count with differential

Coagulation:
o
Prothrombin time/International normalized ratio

Urinalysis:
o
Blood
o
Glucose
o
Leucocytes
o
Microscopic analysis
o
pH
o
Protein
o
Specific gravity
The laboratory summaries will be based on central lab results only and be presented 
separately for treatment periods and NTT periods. For treatment periods, laboratory data will 
be presented by cycle and by scheduled visit within each cycle, i.e., day 1, weeks 1, 2, 4, 6, 9, 
12, 16, 20, 24 and 28. In addition, laboratory results will also be presented at EOT and at last 
NTx time points. The baseline value of the SHP633-302 core study will also be presented as 
applicable.
Quantitative results will be summarized for hematology, serum chemistry, and selected 
urinalysis parameters by scheduled visit. Both observed values and change from the SHP633-
302 core study baseline will be summarized with descriptive statistics defined in Section 6.1. 
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 
converted to X for the purpose of quantitative summaries, but will be presented as recorded, 
i.e. as “< X” or “> X” in the listings.
Markedly abnormal laboratory values are defined in APPENDIX 1. These criteria are based on 
lab normal ranges. The number and percentage of subjects with post-baseline results 
qualifying as markedly abnormal as defined in this table will be summarized by parameter and 
a subject level listing will be presented. 
Laboratory results will be presented in an appendix data listing for each lab panel (chemistry, 
hematology, urinalysis) by subject, parameter, and date of collection. Laboratory values 
outside of the normal range will be flagged. Local lab test results, categorical test results and 
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urine/serum pregnancy test results will be presented in appendix data listings only.
12.4. 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)

Height or length (cm)

Head circumference (cm) for subjects ≤ 36 months of age
The following vital signs parameters will be derived for this study:

BMI (kg/m2) for subjects 2-15 years of age in the children and infant cohorts

Weight for length ratio (kg/cm) for infants 4-<12 months corrected gestational age

Height or length for age Z-score and percentile

Weight for age Z-score and percentile

BMI for age Z-score and percentile for subjects 2-15 years of age
Weight for length Z-score and percentile for infants 4-<12 months corrected gestational age
Head circumference for age Z-score and percentile for subjects ≤ 36 months of age
The vital sign summaries will be presented separately for treatment periods and NTT periods. 
For treatment periods, vital signs will be presented by cycle and by scheduled visit within each 
cycle. In addition, vital sign results will also be presented at EOT and at last NTx time points. 
The baseline value of the SHP633-302 core study will also be presented.
Descriptive statistics (e.g., mean, standard deviation, median, minimum and maximum values, 
the number and percent of subjects in specified categories) will be used to summarize the vital 
signs at each scheduled study visit. Both observed value and change from baseline of the 
SHP633-302 core study will be summarized with descriptive statistics defined in Section 6.1. 
Mean ± SE plots of body weight, height or length, BMI and head circumference for age Z-
scores and weight for length Z-score will be generated by scheduled visit for each treatment 
cycle. 
The following specific derivations will be used:

BMI
BMI = 10000* Body weight (kg)/body height (cm)2, where both body weight and body height 
data are available at the same scheduled visit. BMI will only be presented for subjects 2-15 
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years of age.

Weight for length ratio
Weight for length ratio = Body weight (kg)/length (cm), where both body weight and length 
data are available at the same scheduled visit. Weight for length ratio will only be presented 
for the subjects in the infant cohort <2 years corrected gestational age.

Height or length, Weight, Head Circumference, BMI for age Z-scores and weight for length Z-
score
A z-score is the deviation of the value for an individual from the mean value of the reference 
population divided by the standard deviation for the reference population.
Z-scores are calculated using the formula below:
Z-score= [((observed value / M) ^ L) – 1] / (S * L), for L≠0
Z-score= ln(observed value / M) / S, for L=0
In which ‘observed value’ is the child’s height or length, weight, head circumference or derived 
BMI. The L, M, and S values vary according to the child’s sex, age or length. The following 
data tables containing the L, M and S values for child’s height or length, weight, head 
circumference, derived BMI for age and weight for length will be used. 
Ag
e
Height or Length
Weight
BMI [3]
Weight 
for 
Length 
[4]
Head 
Circumference
Child 
1-15 
yrs [1]
Infants 
4-<12 
mos 
[2]
Child 
1-15 
yrs [1]
Infants 
4-<12 
mos 
[2]
Child 
1-15 
yrs 
[1]
Infants
4-<12 
mos 
[2]
Infants 
4-<12 
mos 
[2]
Child 
1-15 
yrs [1]
Infants 
4-<12 
mos 
[2]
0-
<12 
mo
s
NA
WHO
NA
WHO
NA
NA
WHO
NA
Kato 
2014
1-
<2 
yrs
Isojima 
2016
WHO
Isojima 
2016
WHO
NA
NA
WHO
Kato 
2014
Kato 
2014
2-3 
yrs
Isojima 
2016
Isojima 
2016
Isojima 
2016
Isojima 
2016
Kato 
2011
Kato 
2011
NA
Kato 
2014
Kato 
2014
>3 
yrs
Isojima 
2016
Isojima 
2016
Isojima 
2016
Isojima 
2016
Kato 
2011
Kato 
2011
NA
NA
NA
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[1] Actual (chronological) age at the time of assessment is used for Z-score calculation.
[2] Corrected gestational age at the time of assessment is used for Z-score calculation.
[3] BMI is only calculated for subjects 2-15 years of age.
[4] Weight for length is only calculated for the cohort of infants <2 years corrected gestational age.
NA = Not applicable; mos = Months; yrs = Years; child = children; WHO = World Health Organization
To obtain the L, M, and S values using these data tables, the corrected gestational age will be 
used for infants and the actual (chronological) age for children 1-15 years of age. Note that the 
calculated age at each vital sign assessment date will be obtained using the date of birth as 
reference date for actual (chronological) age and (date of birth + difference in days between 
corrected gestational age and actual age at informed consent/assent) as reference date for 
corrected gestational age.  
Details of the Z-score calculation are provided in subsections below.
Z-scores will be rounded to 2 decimal places for reporting.
Percentiles will be calculated as the corresponding probability of Z-scores from the standard 
normal distribution. Percentiles will be rounded and presented to 1 decimal places.
For more information on the LMS method, see
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC27365/.
Official and validated SAS programs created by Centers for Disease Control and Prevention 
(CDC) will be used to calculate the Z-scores for a child’s sex and age (up to 20 years of age) 
for BMI, weight, height, and head circumference based on the L, M, S values referred above. 
For 
more 
information 
on 
the 
CDC 
SAS 
programs, 
see 
http://www.cdc.gov/growthcharts/computer_programs.htm.
12.4.1.
Z-SCORES OF HEIGHT FOR AGE AND WEIGHT FOR AGE FOR CHILDREN 1-15 YEARS OF AGE AND SUBJECTS 
IN THE INFANT COHORT ≥2 YEARS CORRECTED GESTATIONAL AGE
The L, M and S values of height and weight for age for Japanese population as given in
Isojima et al. (2016) will be used. These values are also given in Table 1 (for height) and Table 
2 (for weight) of APPENDIX 2.
For ages (in years) that fall between two age categories given in Table 1 and Table 2, the 
following interpolation will be used to calculate the L, M, S values:
LMS value=LMS_lower + [(actual age in years – age_lower) * (LMS_upper – LMS_lower)] / 
(age_upper – age_lower).
Where LMS_lower is the L, M or S value corresponding to the lower age category in the age 
interval, i.e., age_lower, and LMS_upper is the L, M or S value corresponding to the upper age 
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category in the age interval, i.e., age_upper.
For example, according to Table 1 in APPENDIX 2, the M values of height are 135.9 for a 10 
years old male and 138.8 for a 10.5 years old male. Therefore, to obtain the M value of height 
for a 10.2 years old male, the following calculation is applied:
M=135.9 + [(10.2 – 10) * (138.8 – 135.9)] / (10.5 – 10) = 137.06
Corrected gestational age will be used for infants and the actual (chronological) age for 
children.
12.4.2.
Z-SCORES OF LENGTH FOR AGE AND WEIGHT FOR AGE FOR SUBJECTS IN THE INFANT COHORT < 2 YEARS 
CORRECTED GESTATIONAL AGE 
L, M, S values for WHO growth charts will be used:
https://www.cdc.gov/growthcharts/who_charts.htm
12.4.3.
Z-SCORES OF HEAD CIRCUMFERENCE FOR ALL STUDY SUBJECTS ≤36 MONTHS OF AGE
The L, M and S values of head circumference for age for Japanese population as given in 
Kato et al. (2014) will be used. These values are also given in Table 5 of APPENDIX 2.
Corrected gestational age will be used for infants and the actual (chronological) age for 
children 1-3 years of age.
For ages (in months) that fall between two age categories given in Table 5, a similar 
interpolation as described in Section 12.4.1 will be used to calculate the L, M, S values.
12.4.4.
Z-SCORES OF BMI FOR ALL STUDY SUBJECTS 2-15 YEARS OF AGE
The L, M and S values of BMI for age for Japanese population as given in Kato et al. (2011) 
will be used. These values are also given in Table 3 (for male) and Table 4 (for female) of 
APPENDIX 2. BMI for age Z-scores will only be presented for subjects 2-15 years of age. 
Corrected gestational age will be used for infants and the actual (chronological) age for 
children.
12.4.5.
Z-SCORES OF WEIGHT FOR LENGTH FOR INFANTS
L, M, S values for WHO growth charts will be used:
https://www.cdc.gov/growthcharts/who_charts.htm
Weight for length Z-scores will only be presented for the infant cohort.
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12.5. PHYSICAL EXAMINATION
Physical exam findings will be presented in the listings for the Safety population.
12.6. ANTIBODIES TO TEDUGLUTIDE
A summary table will provide the number of subjects with a sample analyzed for Day 1, Week 
12, Week 24 and Week 28 of each treatment cycle. In addition, results will also be presented 
at EOT. The baseline value of the SHP633-302 core study will also be presented. The 
summary table will also provide the number of subjects with an antibody finding (Antibodies to 
teduglutide Negative/Positive and No Neutralizing Antibodies Present/Neutralizing Antibodies 
Present) at each of those visits. All antibody results, including those based on samples 
collected in NTT periods, will be presented in the listings.
Observed value, change and percentage change from baseline for selected efficacy endpoints 
(Diary PS Volume, Prescribed PS Volume, Diary Days per Week of PS, Prescribed Days per 
Week of PS) will be analysed by antibody to teduglutide result (positive/negative) for 
scheduled visit Day 1, Week 12, Week 24 and Week 28 of each treatment cycle and EOT, 
relative to the baseline of the core study (SHP633-302).
12.7. GASTROINTESTINAL-SPECIFIC TESTING
The results of GI-specific testing including fecal occult blood testing and colonoscopy/ 
sigmoidoscopy will be reported as ‘Normal’, ‘Abnormal, not clinically significant’, ‘Abnormal, 
clinically significant’ or ‘Negative’, ‘Positive, not clinically significant’, ‘Positive, clinically 
significant’. The number of patients and percentage for each GI-specific testing parameter and 
result category will be presented by scheduled visit for each treatment cycle. GI-specific 
testing conducted during NTT periods will be included in the listings only.
12.8. FECAL AND URINE OUTPUT
Output diary data is recorded over a 48 hour period of PS stability before every scheduled visit 
and, for subjects that are in a teduglutide treatment cycle, within 1 week of implementing any 
PS prescription adjustment. For the analysis, the latest 48-hour period of output diary data 
entered prior to each visit will be used (The 48-hour period does not need to be within 48 
hours of the visit). Any additional output diary data collected out of this 48-hour window will 
only be presented in the listings.
The output diary summaries will be presented separately for treatment periods and NTT 
periods. For treatment periods, output diary data will be presented by cycle and by scheduled 
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visit within each cycle. In addition, results will also be presented at EOT and at last NTx time 
points. The baseline value of the SHP633-302 core study will also be presented.
The average daily urine output (mL/kg/day) at the scheduled visit will be calculated as follows:
(Total urine output over 48 hours / 2) / most recent body weight (kg) prior to or on 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 over 
48 hours. Values will not be calculated if the urine output is not available at the visit.   
The average daily fecal output will be summarized separately by the number of stools per day, 
the typical stool form score using Bristol Stool Form Scale, the total daily stool/mixed stool 
diaper weight (g/kg/day) and the total ostomy output per day (mL/kg/day). The number of 
stools per day and the average typical stool form score will be calculated as (sum of the daily 
data in a 48-hour period / 2). The body weight will be used to calculate the daily stool/mixed 
stool diaper weight (g/kg/day) and the total ostomy output per day (mL/kg/day) using a formula 
analogous to that used to calculate the average daily urine output.
The change and the percent change in average daily output for urine and fecal from baseline
of the SHP633-302 core study to each scheduled visit will be presented using descriptive 
statistics defined in Section 6.1.
12.9. CONCOMITANT MEDICATIONS
Concomitant medications will be coded to indication-specific preferred name using the WHO 
Drug Dictionary. Investigator verbatim as well as coded terms will be included in the listings.
Concomitant medications are defined as any medication taken during the SHP633-305 study.
Concomitant medication use will be summarized by preferred name using the number and 
percentage of subjects. Medications will be sorted alphabetically by preferred name. Subjects 
with multiple occurrences of a medication in preferred name will only be counted once within 
each preferred name.
A listing of all medications will be presented. The listing will be sorted by subject identifier and 
will include reported name, dose, route of administration, dosing frequency, start date, end 
date and indication.
The diagnostic, surgical, or therapeutic procedures during the study as recorded in the eCRF 
will only be presented in a listing.
13.
CHANGES IN THE STATISTICAL METHODOLOGY PRESENTED IN THE PROTOCOL
There is no change of analysis from protocol.
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14.
GENERAL PROGRAMMING INFORMATION
14.1. GENERAL
All programmed table, figure and listing outputs, unless specified otherwise, will be generated 
using the SAS version 9.4 or later. The programmed outputs will be similar to the 
format/appearance of the table and listing shells. However, space/formatting limitations may 
dictate changes in the programmed output. The footnotes specified in the table and listing 
shells may be changed as necessary for clarifying table entries or the explanation of 
algorithms or methods used for producing the entries. Significant changes in footnotes will be 
discussed prior to their implementation.
14.2. FORMAT OF TABLES/LISTINGS
Tables will present subject cohorts, including all subjects and subset of subjects who were 
enrolled after protocol amendment 2.0, in the following order: “Children (1 - 15 years) After 
Amendment 2”, “Total Children (1 - 15 years)”, and “Infants (4 - <12 months)”, unless 
otherwise specified. Note that all subjects in the infant cohort will be enrolled after protocol 
amendment 2.0 and thus the subset of subjects who were enrolled after protocol amendment 
2.0 will not be presented for the infant cohort. The following footnote will be presented in all 
tables/listings: "Infants are of 4 - <12 months corrected gestational age”.
All output should have a 1-line footer with the SAS program name, including the path, and the 
date and time the output was produced at the lower left margin of the footer.
Tables and listings should be internally paginated in relation to the total length for that table or 
listing (i.e., Page n of N, where n is the page number within the table or listing and N is the 
total number of pages for that table or listing).
The table, figure and listing numbering will be based on the International Conference on 
Harmonization (ICH) guidelines.
A number should identify each table/listing, and the table designation (e.g., Table 1) should be 
centered above the title. A decimal system (e.g., x, x.y, x.y.z) should be used to identify 
tables/listings with related contents. The title should be centered and in mixed-case 
characters. The title and table/listing designation should be single-spaced, but are separated 
from the content of the table/listing by a space and a solid underline. The study population 
and/or subgroup (e.g., Safety population) should be identified on the line immediately following 
the title.
Column headings should be in title case characters. For numeric variables, the unit should be 
included in the column heading when appropriate.
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Footnotes should be single spaced, but separated by an underline and a space from the text 
of the table/listing. The notes should be aligned vertically by the left vertical border of the 
table/listing. Numeric references, which can be confused with data, should not be used. Rather 
asterisks and other non-numeric symbols should be used to refer to footnotes.
The dictionary (e.g., MedDRA, WHO-DRUG) and the dictionary version numbers should be 
identified in the footnotes to the tables/listings for data coded with a dictionary.
For summarizations of categorical data, an Unknown or Missing category should be added to 
any variable for which information is not available for all subjects. The default denominator will 
be all subjects in the analysis set unless otherwise specified in the SAP. For both tables and 
listings where there are no observations (and hence there would be no output), the table/listing 
should be produced with all titles and footnotes as per its shell, but with the text showing no 
observations in the body of the output.
Individual data listings will be sorted and presented by cohort, subject number, parameter (if 
applicable) and visit/collection date.
14.3. DATA FORMATS
Unless otherwise specified, means (arithmetic and geometric) and medians will be rounded 
and presented to 1 decimal place more than the raw data and standard deviations and 
standard errors to 2 decimal places more than the raw data. Minimum and maximum values 
will be presented to the same number of decimal places as the raw data. Coefficient of 
variation shall always be reported as a percent with 1 decimal.
Unless otherwise specified, percentages should be presented to one decimal place. Less than 
signs (i.e., ‘<’) should be presented as appropriate (e.g., 0.04% should be presented as < 
0.1%, not 0.0%).
Standard deviations will be calculated when the number of subjects is 2 or more.
15.
TABLE, FIGURE AND DATA LISTING SHELLS
15.1. TABLE SHELLS
See separate file.
15.2. FIGURE SHELLS
See separate file.
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15.3. DATA LISTING SHELLS
See separate file.
16.
REFERENCES

Isojima, T., Kato, N., Ito, Y., Kanzaki, S., and Murata, M. (2016). Growth standard charts for 
Japanese children with mean and standard deviation (SD) values based on the year 2000 
national survey. Clin Pediatr Endocrinol 2016; 25(2), 71–76.

Kato, N., Takimoto, H., and Sudo, N. (2011). The Cubic Functions for Spline Smoothed L, S 
and M Values for BMI Reference Data of Japanese Children. Clin Pediatr Endocrinol 2011; 
20(2), 47-49.

Kato, N., Takimoto, H., Yokoyama, T., Yokoya, S., Tanaka, T., and Tada, H. (2014). Updated 
Japanese growth references for infants and preschool children, based on historical, ethnic 
and environmental characteristics. Acta Paediatrica 2014; 103, e251-e261. 
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MARKEDLY ABNORMAL LABORATORY CRITERIA  
APPENDIX 1.
Lab Parameter
Unit
Lower Limit Criteria
Upper Limit Criteria
Chemistry
Albumin 
g/L
<20
>68
Alkaline 
Phosphatase 
U/L
>5 x ULN
Alanine 
Aminotransferas
e (ALT)
U/L
>8 x ULN
Aspartate 
Aminotransferas
e (AST)
U/L
>8 x ULN
Amylase
U/L
>3 x ULN
Lipase
U/L
>3 x ULN
Bilirubin Total
umol/L
>3 x ULN
Direct Bilirubin
umol/L
>34.208
Blood 
Urea 
Nitrogen 
mmol/L
>12.495
Calcium 
mmol/L
<1.5
>3
Creatinine
umol/L
>132.6 if age < 10 y;
>150.28 if age 10-<13 y;
>176.8 if age 13-<16 y;
>221 if age 16+
C 
Reactive 
Protein 
mg/L
>=100
Glucose
mmol/L
<2.22
>13.875
Magnesium 
mmol/L
<0.4114
>1.2342
Phosphorus 
mmol/L
<0.644
>2.254
Potassium 
mmol/L
<2.5
>6.5
Sodium 
mmol/L
<120
>160
Triglycerides 
mmol/L
>5.65
Hematology
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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
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L, M AND S VALUES OF HEIGHT, BODY WEIGHT,
APPENDIX 2.
BMI AND HEAD CIRCUMFERENCE FOR AGE FOR JAPANESE 
Table 1
L, M and S Values of Height for Age for Japanese Children 1-15 Years of Age and Subjects 
in the Infant Cohort ≥2 Years Corrected Gestational Age
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Table 2
L, M and S Values of Weight for Age for Japanese Children 1-15 Years of Age and Subjects 
in the Infant Cohort ≥2 Years Corrected Gestational Age
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Table 3
L, M and S Values of BMI for Age for Japanese Subjects ≥2 Years of Age (Male)
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Table 4
L, M and S Values of BMI for Age for Japanese Subjects ≥2 Years of Age (Female)
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Table 5
L, M and S Values of Head Circumference for Age for Japanese Subjects ≤36 Months of Age
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MEDDRA TERMS CORRESPONDING TO EACH 
APPENDIX 3.
GROUPING OF ADVERSE EVENTS OF SPECIAL INTEREST 
Groupings
System Organ 
Class (SOC)
Preferred Terms (PT)
Higher Level Group 
Terms (HLGT)
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 
including the 
hepatobiliary 
system 
Gastrointestinal 
neoplasms benign
Hepatic and biliary 
neoplasms benign
Abdominal wall cyst
Abdominal wall neoplasm 
benign
Benign abdominal 
neoplasm
Benign gastrointestinal 
neoplasm
Benign mesenteric 
neoplasm
Benign pancreatic 
neoplasm
Benign peritoneal 
neoplasm
Benign small intestinal 
neoplasm
Gastric haemangioma
Gastrointestinal polyp
Gastrointestinal polyp 
haemorrhage
Gastrointestinal tract 
adenoma
Gingival cyst
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Groupings
System Organ 
Class (SOC)
Preferred Terms (PT)
Higher Level Group 
Terms (HLGT)
Intestinal angioma
Intestinal cyst
Intestinal polyp
Intra-abdominal 
haemangioma
Intraductal papillary 
mucinous neoplasm
Large intestine benign 
neoplasm
Mesenteric cyst
Pancreatic cyst
Pancreatic cyst rupture
Peutz-Jeghers syndrome
Retroperitoneum cyst
Small intestine polyp
Stoma site polyp
Adenolymphoma
Ameloblastoma
Benign keratocystic 
odontogenic neoplasm
Benign salivary gland 
neoplasm
Buccal polyp
Cementoblastoma
Dental cyst
Gingival polyp
Lip neoplasm benign
Mouth cyst
Odontogenic cyst
Oral fibroma
Oral haemangioma
Oral neoplasm benign
Oral papilloma
Papillary cystadenoma 
lymphomatosum
Pleomorphic adenoma
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Groupings
System Organ 
Class (SOC)
Preferred Terms (PT)
Higher Level Group 
Terms (HLGT)
Salivary gland adenoma
Salivary gland cyst
Tongue cyst
Tongue neoplasm benign
Tongue polyp
White sponge naevus
Anal polyp
Appendix adenoma
Benign anorectal 
neoplasm
Colon adenoma
Large intestine fibroma
Large intestine polyp
Rectal adenoma
Rectal polyp
Benign duodenal 
neoplasm
Benign gastric neoplasm
Benign oesophageal 
neoplasm
Duodenal polyp
Gastric adenoma
Gastric cyst
Gastric polyps
Oesophageal cyst
Oesophageal papilloma
Oesophageal polyp
Biliary cyst
Biliary polyp
Choledochal cyst
Congenital cystic disease 
of liver
Gallbladder polyp
Haemorrhagic hepatic cyst
Hepatic cyst
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Groupings
System Organ 
Class (SOC)
Preferred Terms (PT)
Higher Level Group 
Terms (HLGT)
Hepatic cyst infection
Hepatic cyst ruptured
Benign biliary neoplasm
Benign hepatic neoplasm
Benign hepatobiliary 
neoplasm
Benign neoplasm of 
ampulla of Vater
Biliary adenoma
Biliary hamartoma
Cholangioadenoma
Focal nodular hyperplasia
Gallbladder adenoma
Gallbladder papilloma
Haemangioma of liver
Hepatic adenoma
Hepatic haemangioma 
rupture
Note: MedDRA terms are based on MedDRA version 20.0.
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