Clinical trial NCT05027308
Conditions: Short Bowel Syndrome
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2022-01-04; Completion date: 2023-09-27
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The main aims of the study are to check for side effects from teduglutide.

Participants will receive a daily injection of teduglutide just under the skin (subcutaneous) for 24 weeks. Then they are followed up for another 4 weeks. Participants may be able to repeat this treatment if they meet specific criteria. The study doctors will check for side effects from teduglutide until it becomes commercially available. The maximum duration of treatment is approximately 51.3 weeks.

Detailed description:
A study of teduglutide in Japanese children with short bowel syndrome aged 4 months or older.

Arms: arm 1: Participants will receive teduglutide 0.05 milligram per kilogram \[mg/kg\] (0.025 mg/kg for participants with moderate or greater renal impairment) subcutaneous \[SC\] injection once daily in a 28-week treatment cycle consisting of a 24-week treatment period followed by a 4-week no treatment follow-up period for a maximum of 3 cycles.
Interventions: intervention 1: Teduglutide
Intervention descriptions: intervention 1: Teduglutide 0.05 mg/kg SC injection

Protocol documents:
Prot_000.pdf: 
 
 
Clinical Study Protocol 
 
NCT Number: NCT05027308 
Title: A Phase 3, Open-label Safety Study of Teduglutide in Japanese Pediatric Patients 
With Short Bowel Syndrome Who are Dependent on Parenteral Support, Aged 4 Months 
of Corrected Gestational Age or Older, and Requiring the Dosing of 1.25 mg 
Formulation 
Study Number: TAK-633-3008 
Document Version and Date: Amendment 2 / 19-May-2022 
 
Certain information within this document has been redacted (ie, specific content is 
masked irreversibly from view) to protect either personally identifiable information or 
company confidential information. 
 
 
 


TAKEDA PHARMACEUTICALS
Protocol:
TAK-633-3008
Title:
A Phase 3, Open-label Safety Study of Teduglutide in Japanese Pediatric 
Patients With Short Bowel Syndrome Who are Dependent on Parenteral 
Support, Aged 4 Months of Corrected Gestational Age or Older, and 
Requiring the Dosing of 1.25 mg Formulation
Short Title:
A Safety Study of Teduglutide in Japanese Patients with Short Bowel 
Syndrome Who are Dependent on Parenteral Support
Study Phase:
Phase 3
Drug:
TAK-633
IND Number:
Non-IND
EUDRACT 
Number:
Non-EUDRACT
Sponsor:
Takeda Pharmaceutical Company Limited
1-1, Doshomachi 4-Chome, Chuo-ku, Osaka-shi, Osaka, Japan
Protocol History:
Original Protocol 1.0     02 Jun 2021
Amendment No. 1         02 Dec 2021
Amendment No. 2         19 May 2022
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PROTOCOL SIGNATURE PAGE 
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this study protocol and also in accordance with the 
following: 

The ethical principles that have their origin in the Declaration of Helsinki.

International Council for Harmonisation (ICH) E6(R2) Good Clinical Practice (GCP):
Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws, clinical
trial disclosure laws, and regulations.

“Ministerial Ordinance Concerning the Standards for the Conduct of Clinical Trials of
Medicinal Products” (Ministry of Health, Labour and Welfare Ordinance No. 28,
27 March 1997; hereinafter referred to as “GCP Ordinance”).

“The Ministerial Ordinance that Partially Revises the Ministerial Ordinance Concerning the
Standards for the Conduct of Clinical Trials of Medicinal Products” (hereinafter referred to
as “the revised GCP Ordinance”).

Pharmaceutical Affairs Law.

Upon marketing approval of the teduglutide 1.25 mg formulation, the study will be continued
as a post-marketing clinical study (phase 4 study), in accordance with GCP and Good
Post-marketing Study Practice (GPSP), until each enrolled subject switches to the 1.25 mg
commercial formulation. In the protocol, the term “clinical study” will be read as
“post-marketing clinical study” after shifting to the post-marketing clinical study.
SIGNATURES 
DocuSign Envelope ID: AC2755ED-D0B5-450F-B94E-33CD638E0D08
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INVESTIGATOR’S ACKNOWLEDGEMENT
I have read this protocol for Study TAK-633-3008.
Title: A Phase 3, Open-label Safety Study of Teduglutide in Japanese Pediatric Patients With 
Short Bowel Syndrome Who are Dependent on Parenteral Support, Aged 4 Months of Corrected 
Gestational Age or Older, and Requiring the Dosing of 1.25 mg Formulation
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor’s representative.
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate.
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Council for Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use guidelines on Good Clinical Practice 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:
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PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints or non-medical 
complaints to Takeda within 24 hours. If requested, defective product(s) will be returned to the 
sponsor for inspection and analysis.
A product quality complaint includes any instances where there is an allegation or report relating 
to Takeda licensed or investigational products, received in writing, electronically, or orally, 
which indicates an impact to a product’s strength, identity, safety, purity, or quality, or which 
suggests that the product did not meet the criteria defined in the regulatory applications, licenses, 
or marketing authorizations for the product. Examples of investigational product quality 
complaints include, but are not limited to, the following:
Unit issues

Capsule fill empty or overage

Bottle/vial fill shortage or overage

Capsule/tablet damaged/broken

Syringe/vial cracked/broken

Syringe leakage

Missing components

Product discoloration

Device malfunction
Labeling

Label missing

Leaflet or Instructions For Use
(IFU) missing

Label illegible

Incomplete, inaccurate, or
misleading labeling

Lot number or serial number
missing
Packaging

Damaged packaging (eg, 
secondary, primary, bag/pouch)

Tampered seals

Inadequate or faulty closure

Missing components within
package
Foreign 
material

Contaminated product

Particulate in bottle/vial

Particulate in packaging
Please report the product quality complaint using the “Clinical Trial Material Complaint Form” 
via the following email address:
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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE..............................................................................................2
INVESTIGATOR’S ACKNOWLEDGEMENT.........................................................................3
SUMMARY OF CHANGES FROM PREVIOUS PROTOCOL VERSION...........................4
CONTACTS ...................................................................................................................................5
PRODUCT QUALITY COMPLAINTS......................................................................................6
TABLE OF CONTENTS ..............................................................................................................7
LIST OF IN-TEXT TABLES .....................................................................................................11
LIST OF IN-TEXT FIGURES ...................................................................................................11
LIST OF APPENDICES .............................................................................................................11
LIST OF ABBREVIATIONS .....................................................................................................12
Study Definitions.....................................................................................................................13
Corporate Identification.........................................................................................................13
1. PROTOCOL SUMMARY ......................................................................................................14
1.1 Synopsis..............................................................................................................................14
1.2 Schema ...............................................................................................................................18
1.3 Schedule of Activities........................................................................................................19
2. INTRODUCTION....................................................................................................................21
2.1 Indication and Current Treatment Options...................................................................21
2.2 Product Background and Clinical Information .............................................................22
2.3 Study Rationale .................................................................................................................23
2.4 Benefit/Risk Assessment...................................................................................................24
2.5 Compliance Statement......................................................................................................25
3. OBJECTIVES AND ENDPOINTS ........................................................................................26
3.1 Study Objectives................................................................................................................26
3.1.1 Primary Objective ......................................................................................................26
3.1.2 Secondary Objectives .................................................................................................26
3.2 Study Endpoints ................................................................................................................26
3.2.1 Safety Endpoints.........................................................................................................26
3.2.2 Efficacy Endpoints......................................................................................................26
4. STUDY DESIGN......................................................................................................................27
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4.1 Overall Design ...................................................................................................................27
4.2 Justification for Study Design, Dose, and Endpoints.....................................................28
4.3 Duration of Subject Participation and Study Completion Definition..........................29
4.4 Sites and Regions...............................................................................................................29
4.5 Premature Termination or Suspension of Study or Study Site ....................................29
4.5.1 Criteria for Premature Termination or Suspension of the Study..........................29
4.5.2 Criteria for Premature Termination or Suspension of Study Sites.......................30
4.5.3 Procedures for Premature Termination or Suspension of the Study or the
Participation of Study Site(s)....................................................................................30
5. STUDY POPULATION............................................................................................................31
5.1 Inclusion Criteria ...............................................................................................................31
5.2 Exclusion Criteria...............................................................................................................31
5.3 Reproductive Potential .....................................................................................................33
6. STUDY INTERVENTION......................................................................................................34
6.1 Investigational Product.....................................................................................................34
6.1.1 Identity of Investigational Product ...........................................................................34
6.1.1.1 Study Drug............................................................................................................34
6.1.2 Blinding the Treatment Assignment.........................................................................34
6.2 Administration of Investigational Product.....................................................................34
6.2.1 Dose, Regimen, and Administration by Parent or Guardian.................................35
6.2.1.1 Administration by Parent/Guardian..................................................................35
6.2.2 Unblinding the Treatment Assignment ....................................................................38
6.2.3 Dose Modification.......................................................................................................38
6.2.4 Treatment Eligibility Criteria for Initiation of a Next Teduglutide Treatment 
Cycle............................................................................................................................38
6.2.5 Follow-up Period Escape Criteria.............................................................................39
6.2.6 Overdose......................................................................................................................39
6.3 Labeling, Packaging, Storage, and Handling of Investigational Product....................40
6.3.1 Labeling.......................................................................................................................40
6.3.2 Packaging ....................................................................................................................40
6.3.3 Storage.........................................................................................................................40
6.4 Drug Accountability and Destruction of Sponsor-Supplied Drugs..............................40
6.5 Subject Compliance ..........................................................................................................41
6.6 Prior and Concomitant Therapy .....................................................................................41
6.6.1 Prior Treatment..........................................................................................................41
6.6.2 Concomitant Treatment.............................................................................................41
6.6.3 Permitted Treatment..................................................................................................41
6.6.4 Prohibited Treatment.................................................................................................41
7. DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT
DISCONTINUATION/WITHDRAWAL .............................................................................43
7.1 Discontinuation of Study Treatment...............................................................................43
7.2 Reasons for Discontinuation ............................................................................................43
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7.3 Withdrawal from the Study .............................................................................................44
7.4 Subjects “Lost to Follow-up” Prior to the Last Scheduled Visit..................................44
8. STUDY ASSESSMENTS AND PROCEDURES..................................................................45
8.1 Study Procedures ..............................................................................................................45
8.1.1 Informed Consent Procedure ....................................................................................45
8.1.2 Demographics, Medical History, and Medication History Procedure ..................45
8.1.3 Physical Examination Procedure ..............................................................................45
8.1.4 Weight, Height (or length), and Head Circumference............................................46
8.1.5 Vital Sign Procedure ..................................................................................................46
8.1.6 Documentation of Concomitant Medications ..........................................................46
8.1.7 Documentation of Concurrent Medical Conditions................................................46
8.1.8 Procedures for Clinical Laboratory Samples ..........................................................46
8.1.9 Telephone Contacts ....................................................................................................48
8.1.10 Adjustment of Nutritional Support ........................................................................48
8.1.11 Dispense Study Drug ................................................................................................48
8.1.12 Adverse Events Assessment.....................................................................................48
8.1.13 Diaries........................................................................................................................49
8.1.14 Colonoscopy/Sigmoidoscopy....................................................................................50
8.1.15 Documentation of Screen Failure............................................................................50
8.1.16 Documentation of Study Entrance..........................................................................50
8.2 Monitoring Subject Treatment Compliance...................................................................51
8.3 Schedule of Observations and Procedures......................................................................51
8.3.1 Screening .....................................................................................................................51
8.3.2 Study Entrance ...........................................................................................................52
8.3.3 Treatment, Follow-up, and No-teduglutide treatment period................................52
8.3.3.1 Week 1 and Week 2 (Window period ±3 days) .................................................52
8.3.3.2 Weeks 4, 8, 12, 16, 20, and 24 (Window period ±7 days)..................................53
8.3.3.3 Follow-up period (4 weeks) (Window period ±7 days).....................................53
8.3.3.4 No-teduglutide treatment period (every 12 weeks)...........................................54
8.3.4 End of Treatment or Early Termination (Window period ±7 days) .....................54
8.3.5 Alternative Approaches to Study Procedures and Data Collection Due to 
Coronavirus Disease 2019 .........................................................................................55
9. DATA HANDLING AND RECORDKEEPING...................................................................58
9.1 CRFs (Electronic)..............................................................................................................58
9.2 Record Retention...............................................................................................................59
10. STATISTICAL METHODS .................................................................................................60
10.1 Statistical and Analytical Plans......................................................................................60
10.1.1 Analysis Sets..............................................................................................................60
10.1.2 Analysis of Demographics and Other Baseline Characteristics...........................60
10.1.3 Safety Analysis..........................................................................................................60
10.1.4 Efficacy Analysis.......................................................................................................61
10.1.5 Missing Data Analysis..............................................................................................61
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10.2 Interim Analysis and Criteria for Early Termination.................................................61
10.3 Determination of Sample Size........................................................................................62
11. QUALITY CONTROL AND QUALITY ASSURANCE...................................................63
11.1 Study-Site Monitoring Visits..........................................................................................63
11.2 Protocol Deviations .........................................................................................................63
11.3 Quality Assurance Audits and Regulatory Agency Inspections .................................63
12. ETHICAL ASPECTS OF THE STUDY..............................................................................65
12.1 IRB....................................................................................................................................65
12.2 Subject Information, Informed Consent, and Subject Authorization .......................66
12.2.1 Dissemination of New Information .........................................................................67
12.3 Subject Confidentiality...................................................................................................67
12.4 Publication, Disclosure, and Clinical Trial Registration Policy .................................68
12.4.1 Publication and Disclosure ......................................................................................68
12.4.2 Clinical Trial Registration.......................................................................................68
12.4.3 Clinical Trial Results Disclosure.............................................................................69
12.5 Insurance and Compensation for Injury ......................................................................69
12.6 Payment............................................................................................................................69
13. STUDY-SPECIFIC COMMITTEES...................................................................................70
14. REFERENCES.......................................................................................................................71
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LIST OF IN-TEXT TABLES
Table 1. Schedule of Study Procedures......................................................................................19
Table 2. Adverse Events that May Lead to Dose Interruption................................................37
Table 3. Common Excluded Treatments and Associated Washout Period............................42
Table 4. Clinical Laboratory Tests.............................................................................................47
LIST OF IN-TEXT FIGURES
Figure 1. Study Schematic Diagram...........................................................................................18
LIST OF APPENDICES
Appendix 8 Protocol History.......................................................................................................94
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LIST OF ABBREVIATIONS
AE
adverse event
AESI
adverse event of special interest
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANA
anti-nuclear antibody
ASMA
anti-smooth muscle antibody
AST
aspartate aminotransferase
CI
confidence interval
CL/F
apparent clearance (clearance [CL] divided by bioavailability [F])
COVID-19
coronavirus disease 2019
(e)CRF
case report form (electronic)
CRO
contract research organization
EA
early antigen
EBNA
nuclear antigen
EEA
European Economic Area
EN
enteral nutrition
EOT
end of treatment
ET
early termination
EU
European Union
FAS
full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
gastrointestinal
GLP
glucagon-like peptide
GPSP
Good Post-marketing Study Practice
HBsAg
hepatitis B virus surface antigen
HCV
hepatitis C virus
ICH
International Council for Harmonisation
IgG
immunoglobulin G
IgM
immunoglobulin M
INR
international normalized ratio
IRB
institutional review board
Ka
absorption rate constant
LKM
liver-kidney microsomal antibody
MedDRA
Medical Dictionary for Regulatory Activities
NTT
no-teduglutide treatment
PK
pharmacokinetic
PN/IV
parenteral nutrition/intravenous fluid
PS
parenteral support
PT
prothrombin time
PTE
pretreatment event
SAE
serious adverse event
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SAP
statistical analysis plan
SAS
safety analysis set
SBS
short bowel syndrome
SC
subcutaneous
SD
standard deviation
SUSAR
suspected unexpected serious adverse reaction
t1/2
elimination half-life
TBili
total bilirubin
TEAE
treatment-emergent adverse event
TNF
tumor necrosis factor
ULN
upper limit of normal
US
United States
VCA
viral capsid antigen
Vc/F
apparent central volume of distribution
WHO
World Health Organization
Study Definitions
Study completion
A subject would be considered as completing the study if the subject completed the end 
of treatment (EOT) visits, and does not withdraw from the study for any reason prior to 
the EOT visit, or the date when the study is discontinued, the subject’s body weight is 
≥15 kg, or the commercial teduglutide of 1.25 mg formulation is available.
Corporate Identification
TDC Japan
Takeda Development Center Japan
TDC Asia
Takeda Development Center Asia, Pte Ltd
TDC Europe
Takeda Development Centre Europe Ltd.
TDC Americas
Takeda Development Center Americas, Inc.
TDC
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
Takeda
TDC Japan, TDC Asia, TDC Europe and/or TDC Americas, as applicable
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1. PROTOCOL SUMMARY
1.1 Synopsis
Protocol number: TAK-633-3008
Drug: Teduglutide 
Title of the study: A Phase 3, Open-label Safety Study of Teduglutide in Japanese Pediatric Patients With Short 
Bowel Syndrome Who are Dependent on Parenteral Support, Aged 4 Months of Corrected Gestational Age or 
Older, and Requiring the Dosing of 1.25 mg Formulation
Short title: A Safety Study of Teduglutide in Japanese Patients with Short Bowel Syndrome Who are Dependent 
on Parenteral Support
Study phase: Phase 3
Number of subjects (total and per treatment arm):
Approximately 5 subjects are planned to be enrolled into the study.
Investigator(s): 
Multicenter study.
Site(s) and Region(s): 
Approximately 6 sites in Japan
Duration of Treatment:
Until subject with ≥15 kg of body weight (or ≥30 kg 
of body weight if a subject has moderate or greater 
renal impairment), transition to 1.25 mg formulation 
when commercially available or subject 
discontinuation, or study termination. The maximum 
duration of treatment is expected to be approximately 
18 months.
Period of Evaluation:
Until subject with ≥15 kg of body weight (or ≥30 kg of 
body weight if a subject has moderate or greater renal 
impairment), transition to 1.25 mg formulation when 
commercially available or subject discontinuation, or 
study termination.
Objectives:
Primary: To evaluate the safety of the 1.25 mg formulation of teduglutide in Japanese pediatric patients with 
short bowel syndrome (SBS) who are dependent on PS, aged 4 months (corrected gestational age) or older, and 
requiring the dosing of 1.25 mg formulation.
Secondary: To evaluate the efficacy of the 1.25 mg formulation of teduglutide in Japanese pediatric patients with 
SBS who are dependent on PS, aged 4 months (corrected gestational age) or older, and requiring the dosing of 
1.25 mg formulation.
Investigational product, dose, and mode of administration:
Teduglutide 0.05 mg/kg (0.025 mg/kg for patients with moderate or greater renal impairment) once daily via 
subcutaneous injection
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Methodology:
This study is designed to allow access and administration of 1.25 mg formulation of teduglutide to pediatric 
patients with SBS of <10 kg body weight (or <20 kg of body weight if a subject has moderate or greater renal 
impairment) for whom the 5 mg formulation cannot be dosed.
This is a phase 3, open-label study to evaluate the safety of teduglutide in Japanese pediatric patients with SBS 
who are dependent on parenteral support (PS), aged 4 months (corrected gestational age) or older, and <10 kg of 
body weight (or <20 kg of body weight if a subject has moderate or greater renal impairment). A 2 to 4-week 
screening period will be used to verify eligibility. Subjects who fail screening may be re-screened with prior 
sponsor approval. After screening, subjects, who meet the inclusion criteria and meet none of the exclusion 
criteria, will start a 28-week treatment cycle, consisting of 24 weeks of teduglutide treatment at 0.05 mg/kg 
(0.025 mg/kg for patients with moderate or greater renal impairment) subcutaneous once daily, followed by a 
4-week follow-up (no treatment) period. Each subject will visit the site at baseline, weekly for the first 2 weeks
(Week 1 and Week 2), and every 4 weeks after Week 4 (Weeks 4, 8, 12, 16, 20, 24, and 28). Telephone contacts
will be made as needed during the treatment period. At all site visits and during all telephone contacts, safety will
be evaluated and nutritional support will be reviewed and adjusted, as needed. A subject may “escape” the
follow-up period between Week 24 and Week 28 and proceed immediately to another screening visit if the
subject meets at least 1 of the follow-up period escape criteria. Otherwise, following completion of the 28-week
treatment cycle, the subject will proceed to a no-teduglutide treatment (NTT) period. The subject in the NTT
period may proceed to another screening visit at any time if at least 1 of the treatment eligibility criteria are met.
The subjects will start a next cycle of teduglutide treatment if the eligibility is confirmed at another screening
visit and baseline visit. A subject may participate in multiple treatment cycles and NTT periods depending on his
or her clinical trajectory. The screening period for another treatment cycle following the NTT or follow-up period
will be -28 to -1 days.
All attempts will be made to follow the nutritional support adjustment guidelines and weaning algorithms 
(developed with SBS expert input and to be provided in the protocol) for decisions regarding parenteral 
nutrition/intravenous fluid (PN/IV) (or PS) reduction and advances in enteral feeds based on weight gain, urine, 
and stool output in the setting of clinical stability. Any departure from the nutritional support adjustment 
guidelines and weaning algorithms will not constitute a protocol deviation.
The teduglutide treatment will continue until the teduglutide 1.25 mg formulation is commercially available and 
each subject is able to transition to the commercially available product, the subject’s body weight increases to 
≥15 kg (or ≥30 kg of body weight if a subject has moderate or greater renal impairment) requiring them to 
transition to the 5 mg formulation, the subject’s participation in this study is discontinued, or the study is 
discontinued, whichever comes first. The 1.25 mg formulation can be used in subjects with <15 kg body weight 
(or <30 kg of body weight if a subject has moderate or greater renal impairment) in this study, depending on the 
subjects’ condition, such as the status of the subjects’ weight fluctuation. 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 treatment (EOT) visit. The benefit of teduglutide treatment will be assessed at Week 24. If no benefit is 
observed at Week 24, as determined by the investigator, the treatment should be discontinued, and the subject 
should be discontinued from the study; otherwise, the subject may continue on the study at the discretion of the 
investigator and per the above guidance.
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Inclusion and Exclusion Criteria
Inclusion Criteria:
Subject eligibility is determined according to the following criteria prior to entry into the study and the first dose:
1.
In the opinion of the investigator, a parent/guardian is capable of understanding and complying with protocol
requirements.
2.
A parent or guardian signs and dates a written, informed consent form and any required privacy authorization
prior to the initiation of any study procedures.
3.
Male or female pediatric patient of corrected gestational age 4 months or older.
4.
Body weight at the time of screening and baseline visits of at least 5 kg and <10 kg for subjects with normal
renal function or mild renal impairment (estimated glomerular filtration rate ≥50* mL/min/1.73 m2), OR at
least 10 kg and <20 kg for subjects with moderate or greater renal impairment (estimated glomerular
filtration rate <50* mL/min/1.73 m2).
5.
Diagnosis of SBS with intestinal failure, defined as dependence on parenteral support (PS) to provide at least
30% of fluid or caloric needs.
6.
Subjects to have stable PS for at least 1 month prior to screening as assessed by the investigator. Stable PS is
defined as inability to significantly reduce parenteral nutrition/intravenous fluid (PN/IV) support, usually
associated with minimal or no advance in enteral feeds (ie, 10% or less change in PN or advance in feeds),
assessed by the investigator.
*This criterion is based on “Guidance for Industry: Pharmacokinetics in Patients with Impaired Renal Function:
Study Design, Data Analysis, and Impact on Dosing and Labeling. Food and Drug Administration. May 1998.”
Exclusion Criteria:
Any subject who meets any of the following criteria will not qualify for entry into the study:
1.
A parent/guardian who is not capable of understanding or not willing to adhere to the study visit schedule
and other protocol requirements.
2.
Clinically significant intestinal obstruction, active or recurrent pancreatic or biliary disease, or dysmotility
that prevents the advancement of enteral intake.
3.
Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus inclusion disease,
etc.
4.
Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, active
gastroschisis-related dysmotility, that is the primary contributing factor to feeding intolerance and inability
to reduce PS, prior to screening. Dysmotility is defined as severe if it is expected to limit the advancement
of enteral feeding.
5.
Major gastrointestinal (GI) surgical intervention including significant intestinal resection or bowel
lengthening procedure within 3 months prior to screening (insertion of feeding tube, anastomotic ulcer
repair, minor intestinal resections ≤10 cm and endoscopic procedures are allowed).
6.
Cardiac disease that makes the patient vulnerable to changes in fluid status.
7.
History of cancer or known cancer predisposition syndrome, such as juvenile polyposis or
Beckwith-Wiedemann syndrome, or first degree relative with early onset of GI cancer (including
hepatobiliary and pancreatic cancer).
8.
Concurrent treatment with glucagon-like peptide-2 (GLP-2), human growth hormone, or analogs of these
hormones (not including teduglutide) within 6 months prior to the screening visit, or concurrent treatment
with octreotide or GLP-1 analogs within 30 days prior to the screening visit.
9.
Concurrent treatment with biological therapy (eg, anti-tumor necrosis factor [anti-TNF]) for active Crohn’s
disease within 6 months prior to the screening visit.
10.
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 the experimental drug, whichever is longer, prior to the
screening visit and for the duration of the study.
11.
Known or suspected intolerance or hypersensitivity to the study drug, closely related compounds, or any of
the stated ingredients.
12.
Signs of active, severe, or unstable clinically significant hepatic impairment during the screening period as
meeting at least 2 of any of the following parameters:
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a.
International normalized ratio >1.5 not corrected with parenteral vitamin K
b.
Platelet count <100×103/μL due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d.
Cirrhosis
e.
Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 μmol/L) over a 2-week period
during screening
f.
Total bilirubin ≥2x upper limit of normal (ULN)
g.
Aspartate aminotransferase (AST) ≥3x ULN
h.
Alanine aminotransferase (ALT) ≥3x ULN
13.
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.
Statistical Considerations
Safety Analysis
Adverse events will be summarized using the safety analysis set. Counts and percentages for subjects with 
treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) (any SAE, regardless of 
relationship to study drug) will be summarized descriptively by System Organ Class and Preferred Term using 
Medical Dictionary for Regulatory Activities terminology. Serious adverse events will also be summarized by 
severity and by relationship to study drug. For clinical laboratory tests, body weight, height (or length), and head 
circumferences, vital signs, urine, and fecal output, descriptive statistics will be used to summarize the absolute 
values and changes from baseline by visit.
Efficacy Analysis
For the continuous endpoints, the following statistics will be presented: non-missing values, mean, median, 
standard deviation, minimum, maximum, and 95% confidence interval (CI). 

Change from baseline in PS volume by each visit and EOT

Percent change from baseline in PS volume by each visit and EOT

Change from baseline in days per week of PS by each visit and EOT
For the binary endpoint, the following statistics will be presented: count, proportion, and 95% Clopper Pearson 
CI.

Number and percent of subjects achieving at least 20% reduction in PS volume from baseline by each
visit and EOT

Number and percent of subjects achieving enteral autonomy, defined as complete weaning off PS by
each visit and EOT
Analyses of PS will be based on 2 data sources: the subject diary data (also referred to as actual data) and the 
investigator prescribed data.
No formal statistical test will be performed due the limited sample size. Details of the analysis methods will be 
specified in the statistical analysis plan.
Sample Size Justification
The sample size is determined based on enrollment feasibility of this rare population in children in Japan, rather 
than statistical power calculation.
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1.2 Schema
Figure 1. Study Schematic Diagram
SC=subcutaneous
Figure legend: Subjects eligible for the study will enter a 28-week treatment cycle. During this cycle, subjects will 
return to the site for safety and efficacy assessments at baseline (Week 0) and Weeks 1, 2, 4, 8, 12, 16, 20, 24, and 
28. If at least 1 of the follow-up period escape criteria (Section 6.2.5) is met during the 4-week follow-up period,
where teduglutide is not received, subjects may proceed directly to another screening visit. Otherwise, following
completion of the 28-week treatment cycle, the subject will proceed to a no-teduglutide treatment period. Safety and
efficacy data for subjects not receiving teduglutide treatment are captured approximately every 12 weeks, but
subjects may proceed to another screening visit at any time in order to assess eligibility (Section 6.2.4). Subject will
start a next cycle of teduglutide treatment if at least 1 of the treatment eligibility criteria and none of the exclusion
criteria are met. At Week 24, if the efficacy (eg, PS volume reduction from baseline) is confirmed, or the
continuation of teduglutide treatment is appropriate as determined by the investigator, subjects may proceed directly
to the screening visit without entering to follow-up period, otherwise subjects will enter the 4-week follow-up
period.
The teduglutide treatment will continue until the following situations, whichever comes first:
•
The teduglutide 1.25 mg formulation is commercially available, and each subject is able to transition to the
commercially available product,
•
The subject’s body weight increases to ≥15 kg (or ≥30 kg of body weight if a subject has moderate or greater
renal impairment) requiring them to transition to the 5 mg formulation,
•
The subject’s participation in this study is discontinued, or
•
The study is discontinued.
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1.3 Schedule of Activities
Table 1. Schedule of Study Procedures
Procedures
Screening
Baseline
(Week 
0)
Week 
1
Week 
2
Week 
4
Week 
8
Week 
12
Week 
16
Week 
20
Week 
24
Follow-up
(4 weeks)
NTTp
(every 
12 
weeks)
After 52 
weeks of 
treatment
EOT/ETr
Visit number
1
2
3
4
5
6
7
8
9
10
11
-
Study day
±window (days)
-28 to
-14g
0
7
±3
14
±3
28
±7
56
±7
84
±7
112
±7
140
±7
168
±7
196
±7
±7
±7
Informed consenta
Xh
Eligibility
Xi
Xk
Demographics, medical and 
surgical history, SBS history
Xh
Adverse events assessment
X
Xl
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications/procedures
X
Xl
X
X
X
X
X
X
X
X
X
X
X
Physical examination/vital 
signs/weight
X
Xl
X
X
X
X
X
X
X
X
X
X
X
Height (or length) and head 
circumferenceb
X
Xl
X
X
X
X
X
X
X
X
Safety laboratory testsc
X
Xl
X
X
X
X
X
X
X
X
X
X
X
Provide intake and output 
diaries
X
Xl
X
X
X
X
X
X
X
X
X
X
Review diariesd
Xj
Xl
X
X
X
X
X
X
X
X
X
X
X
Adjust nutritional support as 
needede
Xj
Xj
X
X
X
X
X
X
X
X
X
X
X
Dispense investigational 
productf
Xl
X
X
X
X
X
X
X
Confirm administration 
proficiency
Xl, m
X
X
Evaluation of escape criteria
Xn
Xo
Colonoscopy/sigmoidoscopy
Xq
Assessment of eligibility for 
additional treatment
Xj
X
X
X
X
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Table 1. Schedule of Study Procedures
(e)CRF=case report form (electronic); EOT=end of treatment; ET=early termination; GI=gastrointestinal; NTT=no-teduglutide treatment; PS=parenteral support; SBS=short
bowel syndrome; SC=subcutaneous
a.
Informed consent and, if applicable, informed assent must be obtained prior to performing any study-related procedure.
b.
Head circumference will be measured in subjects 36 months of age and younger.
c.
Safety lab assessments (see Table 4) at site visits will consist of biochemistry, hematology (not required at Week 1 and Week 2), and urinalysis (not required at Week 1 and
Week 2), with results processed by a central lab. At the discretion of the investigator, safety labs may be performed between study visits following adjustments to PS. Urine
specimen collection should be attempted as part of the safety lab tests, but lack of urinalysis will not constitute a protocol deviation.
d.
The volume of PS and oral/enteral intake will be recorded on the intake diary every day during the study by the subject or parent/guardian/study site staff (Section 8.1.13).
Urine and stool output should be recorded in the output diary over the 48-hour period preceding every clinic visit. (Section 8.1.13 for more details).
e.
Nutritional support adjustments should be made after review of the intake and output diaries and safety lab data, and according to the guidelines for nutrition support
management and weaning algorithms provided in Guidelines for Nutritional Support Management During the Study (Appendix 5) and Weaning Algorithms (Appendix 6),
respectively.
f.
The first SC injection will be administered under the supervision of the investigator/designee. The subject will be observed for possible hypersensitivity reactions for at least
4 hours after administration during their initial dosing visit. The site of administration (arm, thigh, abdomen) must be specified and recorded in the (e)CRF. The dose of study
medication will be adjusted per body weight at Week 12 in each treatment cycle.
g.
The screening period for another treatment cycle following the NTT or follow-up period will be -28 to -1 days.
h
Not applicable for another treatment cycle.
i.
Only exclusion criteria is needed for another treatment cycle.
j.
Applicable only for another treatment cycle.
k.
Subject eligibility will need to be re-confirmed before the first dose in the cycle.
l.
The procedures will be performed before the administration of the study drug.
m.
The first dose of teduglutide will be administered by a study physician. The study physician must observe the parent/guardian administer the study drug in compliance with
the study drug administration checklist before the parent/guardian is allowed to administer the drug without direct observation by the physician. Refer to Section 6.2.1.1.
n.
If the efficacy (eg, PS volume reduction from baseline) is confirmed, or the continuation of teduglutide treatment is appropriate as determined by the investigator, subjects
may proceed directly to the screening visit without entering to follow-up period, otherwise subjects will enter the 4-week follow-up period. For the subjects who skip the
follow-up period, the screening period will be -28 to -1 days. The Week 24 visit and the next round of screening visit may be combined.
o.
If at least 1 escape criterion (Section 6.2.5) is met during the follow-up period, subjects may proceed directly to another screening visit.
p.
Safety and efficacy data for subjects not receiving teduglutide treatment are captured approximately every 12 weeks, but subjects may proceed to the screening visit at any
time in order to assess eligibility for the study, if at least 1 of the treatment eligibility criteria is met (Section 6.2.4).
q.
Colonoscopy/sigmoidoscopy to identify colorectal polyps is recommended in each subject after 52 weeks of treatment while on continuous treatment with teduglutide, and/or
if the subject has new or unexplained GI bleeding. Fecal blood test may be performed as needed.
r.
If a subject terminates from the study prematurely, all EOT procedures should be done at the time of termination. In the case of ET, a phone contact should be done every
week before the ET visit.
Note: Telephone contacts will be made as needed during the treatment period. A visit to the site may be undertaken, if necessary, instead of a phone contact and completed as an 
unscheduled visit.
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2. INTRODUCTION
Short bowel syndrome (SBS) is a rare disorder resulting from congenital abnormalities or severe 
intestinal disease, which usually results in major surgical resections of the small intestine. In 
children, most cases of SBS begin in infancy. 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, and cancer. The diminished absorptive capacity for fluids and nutrients 
often results in dependence on parenteral support (PS) to maintain energy and 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 by 12 months of age, and an additional 
10% wean off PS by 24 months of age. After this time, linear intestinal growth slows. About 
60% of 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.
It is highly unlikely that children with less than 10% of the expected length of small intestine 
reach enteral independence. These subjects reach a plateau in their ability to advance oral/enteral 
feeds or decrease PS (ie, are “stuck”) and are not expected to achieve spontaneous adaptation. 
Subjects who have not progressed to full enteral adaptation by 12 months after their intestinal 
insults are very unlikely to demonstrate spontaneous improvement in their enteral function 
(Sigalet et al. 2011).
2.1 Indication and Current Treatment Options 
Intestinal adaptation is driven by hormonal cues in response to nutrient malabsorption. Chief 
among these is hormones glucagon-like peptide-2 (GLP-2), which is secreted from L-type 
enteroendocrine cells in the distal ileum and colon. Resection of these regions impairs the 
adaptive response by limiting endogenous production of GLP-2.
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There are no approved pharmacological therapies that promote intestinal adaptation in children 
with SBS in Japan. In the United States (US) and European Union (EU), a GLP-2 analog called 
teduglutide is approved for the treatment of SBS in adult patients who are dependent on 
parenteral nutrition/intravenous fluid (PN/IV) support or PS.
2.2 Product Background and Clinical Information
Teduglutide (TAK-633, SHP633, ALX-0600) 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 and therefore 
maintains a longer elimination half-life (t1/2) of approximately 2 hours compared to the native 
peptide, which has a t1/2 of approximately 7 minutes. Teduglutide is approved for the treatment 
of patient aged 1 year and above with SBS in the US and EU at a dose of 0.05 mg/kg 
subcutaneous (SC) once daily. In Japan, it was approved in June 2021 for the treatment of 
patients aged 4 months by corrected gestational age and above with SBS.
An overseas phase 3 study, Study SHP633-301, has been completed in infants 4 to 12 months of 
age with SBS who were dependent on PS, where the safety, efficacy/pharmacodynamics and 
pharmacokinetics (PK) of teduglutide treatment were evaluated. Subjects were randomized 
(1:1 ratio) to the teduglutide (0.05 mg/kg SC once daily) or standard of care treatment (standard 
medical therapy for SBS) arm. Based on subject diary data and prescribed data, overall data 
showed a reduction of PS volume and caloric intake, and of days per week of PS infusions over 
time, in infant subjects treated with teduglutide compared with the subjects receiving the 
standard of care. This reduction was similar to the results observed in previous pediatric studies. 
Teduglutide treatment was also demonstrated to be generally safe and well tolerated, and no new 
safety issues were identified. The safety profile was favorable and consistent with the safety 
profile seen in other pediatric studies.
A pediatric phase 3 study, Study SHP633-302, has been completed in Japanese pediatric patients 
with SBS. In that study, teduglutide 0.05 mg/kg was subcutaneously administered once daily for 
24 weeks in 10 Japanese pediatric patients with SBS who were dependent on PS of 4 months 
(corrected gestational age) to 15 years (specifically, 8 children aged 1 to 15 years old and 
2 infants aged 4 to <12 months [corrected gestational age]). Within the analyzed group of 
8 subjects (6 children and 2 infants) who began treatment after Protocol Amendment 3 where the 
training process of self-injection has been changed, the ratios of subjects who achieved at least 
20% reduction in weekly PS volume from baseline for the children group and the infant group 
were 66.7% (4/6 subjects) and 50.0% (1/2 subjects).
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Change in PS volume (average±standard deviation [SD]) to end of treatment (EOT) from 
baseline and change rate were −14.5±8.03 mL/kg/day and −35.7±33.18% for children and 
−26.2±13.61 mL/kg/day and −26.7±15.14% for infants. The treatment responses observed in
Japanese patients with SBS in this study were similar to those observed in previous
non-Japanese-conducted studies in pediatric patients with SBS. Teduglutide was generally
well-tolerated by Japanese pediatric subjects with SBS; the nature and frequency of the reported
treatment-emergent adverse events (TEAEs) in Study SHP633-302 were generally consistent
with the underlying disease and those reported in previous studies in pediatric patients with SBS.
Additional information is provided in the Investigator’s Brochure.
2.3 Study Rationale
Teduglutide was designated as an orphan drug indicated for SBS in Japan on 20 Nov 2014. The
total number of patients with SBS who are dependent on PS is estimated to be <1,000 patients in 
Japan. There is no established standard of care and there is a high unmet medical need.
The present TAK-633-3008 study in Japanese pediatric and infant subjects is designed 
 
 There are 2 options of the teduglutide drug 
product for injection: 5 mg and 1.25 mg formulations, which were used in the SHP633-301, the 
SHP633-302, and SHP633-305 studies based on the subjects’ body weight (only 1.25 mg 
formulation was used in the SHP633-301 study). From the viewpoint of dose accuracy, however, 
the 5 mg formulation is not recommended for use in patients with a body weight of <10 kg who 
require a dose of <0.5 mg of teduglutide. The 1.25 mg formulation is for patients <10 kg to 
receive an accurate dose at such low body weight. In the clinical package, the lowest body 
weight in pediatric patients was 5.2 kg. The 1.25 mg formulation can also be used in patients 
who weight up to 15-20 kg. An application for this additional dosage form (1.25 mg formulation) 
is planned to be filed in Japan after the approval of the 5 mg formulation. If a subject has 
moderate or greater renal impairment, body weight should be considered as 2 times as a subject 
has normal renal function or mild renal impairment.
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The teduglutide dose of 0.05 mg/kg daily is supported by results from a completed 12-week 
pediatric study. Teduglutide is approved for adult use in over 40 countries at a dose of 
0.05 mg/kg SC once daily. The completed 12-week pediatric study (TED-C13-003, A 12-Week 
Pharmacokinetic, Safety, and Pharmacodynamic Study of Teduglutide in Pediatric Subjects
Aged 1 Year through 17 Years, with SBS who are Dependent on Parenteral Support) and the 
28-week infant study (SHP633-301, A Randomized, Open-label, 24-Week Safety, Efficacy, and
Pharmacokinetic Study of Teduglutide in Infants 4 to 12 Months of Age with Short Bowel
Syndrome Who are Dependent on Parenteral Support) demonstrated that teduglutide dosing at
0.025 and 0.05 mg/kg/day was associated with a favorable benefit/risk profile. In addition,
population PK 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 phases 1, 2, and
3 studies as well as the pediatric study (TED-C13-003); they suggested that the dose in pediatric
subjects is likely to be the same as the dose in adults (O'Keefe et al. 2006).
Effect of renal impairment on PK have been investigated by a dedicated renal study 
(CL0600-018) and population PK analyses using data collected in subjects and SBS patients 
(adults and pediatrics) with and without various degrees of renal impairment. Results of these 
evaluations have recommended 50% dose reduction (from 0.05 mg/kg to 0.025 mg/kg) in 
patients with moderate or greater renal impairment, which were included in the approved drug 
labels of teduglutide across regions.
2.4 Benefit/Risk Assessment
The aim of teduglutide treatment is to increase absorptive capacity in order to yield decreases in 
PS. In addition, experts anticipate that there will be several direct benefits from decreased PS and 
advances in enteral feeds, including less exposure to PN/IV constituents, less central line 
manipulation with lower risk of infection, and more time to focus on oral rehabilitation 
strategies. Results of studies have confirmed these expectations (see Investigator’s Brochure for 
study results).
The study is designed to allow access and administration of 1.25 mg formulation of teduglutide 
to pediatric patients with SBS of <10 kg body weight (or <20 kg body weight if a subject has 
moderate or greater renal impairment) for whom the 5 mg formulation cannot be dosed.
Always refer to the latest version of the teduglutide investigator’s brochure (IB) for the overall 
benefit/risk assessment and the most accurate and current information regarding drug 
metabolism, pharmacokinetics, efficacy, and safety of teduglutide.
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2.5 Compliance Statement
This study will be conducted in accordance with this protocol, the International Council for 
Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP, 1996; ICH E6 R2, 2016), 
Title 21 of the US Code of Federal Regulations (US CFR), the EU Directives (2001/20/EC; 
2005/28/EC), and applicable national and local regulatory requirements.
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3. OBJECTIVES AND ENDPOINTS
3.1 Study Objectives
3.1.1 Primary Objective
To evaluate the safety of the 1.25 mg formulation of teduglutide in Japanese pediatric patients 
with SBS who are dependent on PS, aged 4 months (corrected gestational age) or older, and 
requiring the dosing of 1.25 mg formulation.
3.1.2 Secondary Objectives
To evaluate the efficacy of the 1.25 mg formulation of teduglutide in Japanese pediatric patients 
with SBS who are dependent on PS, aged 4 months (corrected gestational age) or older, and 
requiring the dosing of 1.25 mg formulation.
3.2 Study Endpoints
3.2.1 Safety Endpoints
The following safety endpoints will be analyzed:
Incidence of TEAEs, serious adverse events (SAEs), and adverse events of special
interest (AESIs)
Physical examinations
Vital signs, including body temperature, respiratory rate, blood pressure, and pulse
Body weight, height (or length), head circumference and weight-for-length Z-scores
(corrected for gestational age)
Laboratory safety data (biochemistry, hematology, and urinalysis)
Urine output
Fecal output
3.2.2 Efficacy Endpoints
The following efficacy endpoints will be analyzed:
Change from baseline in PS volume by each visit and EOT
Percent change from baseline in PS volume by each visit and EOT
Number and percent of subjects achieving at least 20% reduction in PS volume from
baseline by each visit and EOT
Number and percent of subjects achieving enteral autonomy, defined as complete
weaning off PS by each visit and EOT
Change from baseline in days per week of PS by each visit and EOT
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4. STUDY DESIGN
4.1 Overall Design
This study is designed to allow access and administration of 1.25 mg formulation of teduglutide 
to pediatric patients with SBS of <10 kg body weight (or <20 kg of body weight if a subject has 
moderate or greater renal impairment) for whom the 5 mg formulation cannot be dosed.
This is a phase 3, open-label study to evaluate the safety of teduglutide in Japanese pediatric 
patients with SBS who are dependent on PS, aged 4 months (corrected gestational age) or older, 
and <10 kg of body weight (or <20 kg of body weight if a subject has moderate or greater renal 
impairment). A 2 to 4-week screening period will be used to verify eligibility. Subjects who fail 
screening may be re-screened with prior sponsor approval. After screening, subjects, who meet 
the inclusion criteria and meet none of the exclusion criteria, will start a 28-week treatment 
cycle, consisting of 24 weeks of teduglutide treatment at 0.05 mg/kg (0.025 mg/kg for patients 
with moderate or greater renal impairment) SC once daily, followed by a 4-week follow-up (no 
treatment) period. Each subject will visit the site at baseline, weekly for the first 2 weeks 
(Week 1 and Week 2), and every 4 weeks after Week 4 (Weeks 4, 8, 12, 16, 20, 24, and 28). 
Telephone contacts will be made as needed during the treatment period. At all site visits and 
during all telephone contacts, safety will be evaluated, and nutritional support will be reviewed 
and adjusted, as needed. A subject may “escape” the follow-up period between Week 24 and 
Week 28 and proceed immediately to another screening visit if the subject meets at least 1 of the 
follow-up period escape criteria (Section 6.2.5). Otherwise, following completion of the 28-week 
treatment cycle, the subject will proceed to a no-teduglutide treatment (NTT) period. The subject 
who escapes the follow-up period and immediately proceeds to another screening visit will start 
a next cycle of teduglutide treatment if at least 1 of the treatment eligibility criteria and none of 
the exclusion criteria are met. The subject in the NTT period may proceed to another screening 
visit at any time if at least 1 of the treatment eligibility criteria are met, and may start a next 
cycle of teduglutide treatment if at least 1 of the treatment eligibility criteria and none of the 
exclusion criteria are met. A subject may participate in multiple treatment cycles and NTT 
periods depending on his or her clinical trajectory. The screening period for another treatment 
cycle following the NTT or follow-up period will be -28 to -1 days.
All attempts will be made to follow the nutritional support adjustment guidelines and weaning 
algorithms (developed with SBS expert input and to be provided in the protocol) for decisions 
regarding PN/IV (or PS) reduction and advances in enteral feeds based on weight gain, urine, 
and stool output in the setting of clinical stability. Any departure from the nutritional support 
adjustment guidelines and weaning algorithms will not constitute a protocol deviation.
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The teduglutide treatment will continue until the teduglutide 1.25 mg formulation is 
commercially available and each subject is able to transition to the commercially available
product, the subject’s body weight increases to ≥15 kg (or ≥30 kg of body weight if a subject has 
moderate or greater renal impairment) requiring them to transition to the 5 mg formulation, the 
subject’s participation in this study is discontinued, or the study is discontinued, whichever 
comes first. The 1.25 mg formulation can be used in subjects with <15 kg body weight (or 
<30 kg of body weight if a subject has moderate or greater renal impairment) in this study, 
depending on the subjects’ condition, such as the status of the subjects’ weight fluctuation. 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 EOT visit. The benefit of teduglutide 
treatment will be assessed at Week 24. If no benefit is observed at Week 24, as determined by 
the investigator, the treatment should be discontinued, and the subject should be discontinued 
from the study; otherwise, the subject may continue on the study at the discretion of the 
investigator and per the above guidance.
Since the subjects will be exposed to teduglutide with the 1.25 mg formulation under 
development, safety will be evaluated during the study as the primary endpoint, including 
TEAEs, SAEs, AESIs, vital signs, urine/fecal outputs, and laboratory values. Efficacy will be 
also evaluated as secondary endpoints, including the reduction in PS volume from baseline to 
each visit, achievement of enteral autonomy by each visit and EOT, and reduction in days per 
week of PS from baseline to each visit.
Refer to Section 1.2 for a study design schematic and Section 1.3 for the study schedule of 
assessments.
4.2 Justification for Study Design, Dose, and Endpoints
The study population is defined as “Japanese pediatric patients with SBS who are dependent on 
PS, aged 4 months (corrected gestational age) or older, and requiring the dosing of 1.25 mg 
formulation”. The inclusion criterion defined 5 kg as the lower limit of body weight (or 10 kg for 
subjects with moderate or greater renal impairment) because no clinical trials in children with 
below 5 kg body weight have been performed.
The dosage and administration of teduglutide for adult patients and pediatric patients aged 
1 years or older in all countries approved overseas is 0.05 mg/kg/day. The result of the Japanese 
clinical studies in adults appeared similar to the results observed in the overseas studies (see 
Investigator’s Brochure), and a population PK analysis using modeling and simulation was 
performed using the Japanese and foreign adult and pediatric data (17 clinical studies), showing 
that race (Japanese vs Non-Japanese) does not affect the absorption rate constant (Ka), apparent 
clearance (CL/F), or apparent central volume of distribution (Vc/F). 
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However, the dose should be reduced by 50% (ie, 0.025 mg/kg/day) in patients with moderate or 
greater renal impairment based on the PK data from the clinical studies. These renal impaired 
patients with 10 to <20 kg of body weight are applicable for the teduglutide administration with 
the 1.25 mg formulation.
The teduglutide 0.05 mg/kg/day was administered for infant patients with SBS in the 
SHP633-301, the SHP633-302, and SHP633-305 studies. The treatment response was similar to 
the results observed in previous pediatric studies. Teduglutide treatment was also demonstrated 
to be generally safe and well tolerated, and the safety profile was favorable and consistent with 
the safety profile seen in other pediatric studies.
4.3 Duration of Subject Participation and Study Completion Definition
The subject’s maximum duration of participation is expected to be until the subject with ≥15 kg 
of body weight (or ≥30 kg of body weight if a subject has moderate or greater renal impairment), 
transitions to 1.25 mg formulation commercially available, subject discontinuation, or study 
termination. The maximum duration of treatment is expected to be approximately 18 months.
A subject will be considered as completing the study if the subject completed the EOT visits, and 
does not withdraw from the study for any reason prior to the EOT visit, or the date when the 
study is discontinued, the subject’s body weight is ≥15 kg, or the commercial teduglutide of 
1.25 mg formulation is available.
4.4 Sites and Regions
The study is planned for approximately 6 sites in Japan.
4.5 Premature Termination or Suspension of Study or Study Site
4.5.1 Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless 1 or more of the following criteria are satisfied 
that require temporary suspension or early termination (ET) of the study. The study completion 
date is defined as the date when the final subject, across all sites, completes their final 
protocol-defined assessment.

New information or other evaluation regarding the safety or efficacy of the study drug that
indicates a change in the known risk/benefit profile for teduglutide, such that the risk /benefit
is no longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practices (GCP) that compromises the ability to
achieve the primary study objectives or compromises subject safety.
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4.5.2 Criteria for Premature Termination or Suspension of Study Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) 
is found in significant violation of GCPs, the study protocol, or the contractual agreement, is 
unable to ensure adequate performance of the study, or as otherwise permitted by the contractual 
agreement.
4.5.3 Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Site(s)
In the event that the sponsor, an institutional review board (IRB) or regulatory authority elects to 
terminate or suspend the study or the participation of a study site, a study-specific procedure for 
ET or suspension will be provided by the sponsor; the procedure will be followed by applicable 
study sites during the course of termination or study suspension.
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5. STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed 
consent/assent before any procedures specified in the protocol are performed.
5.1 Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below. 
Subject eligibility is determined according to the following criteria prior to entry into the study 
and the first dose:
1. In the opinion of the investigator, a parent/guardian is capable of understanding and complying
with protocol requirements.
2. A parent or guardian signs and dates a written, informed consent form and any required privacy
authorization prior to the initiation of any study procedures.
3. Male or female pediatric patient of corrected gestational age 4 months or older.
4. Body weight at the time of screening and baseline visits of at least 5 kg and <10 kg for subjects
with normal renal function or mild renal impairment (estimated glomerular filtration rate
≥50* mL/min/1.73 m2), OR at least 10 kg and <20 kg for subjects with moderate or greater renal
impairment (estimated glomerular filtration rate <50* mL/min/1.73 m2).
5. Diagnosis of SBS with intestinal failure, defined as dependence on PS to provide at least 30% of
fluid or caloric needs.
6. Subjects to have stable PS for at least 1 month prior to screening as assessed by the investigator.
Stable PS is defined as inability to significantly reduce parenteral nutrition/intravenous fluid
(PN/IV) support, usually associated with minimal or no advance in enteral feeds (ie, 10% or less
change in PN or advance in feeds), assessed by the investigator.
* This criterion is based on “Guidance for Industry: Pharmacokinetics in Patients with Impaired
Renal Function: Study Design, Data Analysis, and Impact on Dosing and Labeling. Food and
Drug Administration. May 1998.”
5.2 Exclusion Criteria
The subject will be excluded from the study if any of the following exclusion criteria are met.
1. A parent/guardian who is not capable of understanding or not willing to adhere to the study visit
schedule and other protocol requirements.
2. Clinically significant intestinal obstruction, active or recurrent pancreatic or biliary disease, or
dysmotility that prevents the advancement of enteral intake.
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3. Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus inclusion
disease, etc.
4. Severe, known dysmotility syndrome, such as pseudo-obstruction or persistent, severe, active
gastroschisis-related dysmotility, that is the primary contributing factor to feeding intolerance and
inability to reduce PS, prior to screening. Dysmotility is defined as severe if it is expected to limit
the advancement of enteral feeding.
5. Major GI surgical intervention including significant intestinal resection or bowel lengthening
procedure within 3 months prior to screening (insertion of feeding tube, anastomotic ulcer
repair, minor intestinal resections ≤10 cm and endoscopic procedures are allowed).
6. Cardiac disease that makes the patient vulnerable to changes in fluid status.
7. History of cancer or known cancer predisposition syndrome, such as juvenile polyposis or
Beckwith-Wiedemann syndrome, or first degree relative with early onset of GI cancer
(including hepatobiliary and pancreatic cancer).
8. Concurrent treatment with GLP-2, human growth hormone, or analogs of these hormones
(not including teduglutide) within 6 months prior to the screening visit, or concurrent
treatment with octreotide or GLP-1 analogs within 30 days prior to the screening visit.
9. Concurrent treatment with biological therapy (eg, anti-tumor necrosis factor [anti-TNF]) for
active Crohn’s disease within 6 months prior to the screening visit.
10. 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 the experimental drug,
whichever is longer, prior to the screening visit and for the duration of the study.
11. Known or suspected intolerance or hypersensitivity to the study drug, closely related
compounds, or any of the stated ingredients.
12. Signs of active, severe, or unstable clinically significant hepatic impairment during the
screening period as meeting at least 2 of any of the following parameters:
a.
International normalized ratio (INR) >1.5 not corrected with parenteral vitamin K
b. Platelet count <100×103/μL due to portal hypertension
c.
Presence of clinically significant gastric or esophageal varices
d. Cirrhosis
e.
Persistent cholestasis defined as conjugated bilirubin >4 mg/dL (>68 μmol/L) over a
2-week period during screening
f.
Total bilirubin ≥2x upper limit of normal (ULN)
g. Aspartate aminotransferase (AST) ≥3x ULN
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h. Alanine aminotransferase (ALT) ≥3x ULN
13. 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.
5.3 Reproductive Potential
Not applicable to this study in infants.
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6. STUDY INTERVENTION
This section contains information regarding all medications and materials provided directly by 
the sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of study material.
6.1 Investigational Product
6.1.1 Identity of Investigational Product
In this protocol, the term study drug refers to teduglutide.
The study drug will be packaged, labeled, and shipped to the study site by the sponsor or 
designee. Kits containing 7 vials of study drug will be provided for this study. The study drug 
will be labeled in accordance with applicable regulatory requirements.
Ancillary kits, containing supplies needed for the reconstitution and administration of the study 
drug will also be provided and labeled in accordance with the applicable regulatory 
requirements.
All study drug used in this study will be manufactured, tested, labeled, and released according to 
current legal requirements and Good Manufacturing Practices. Further details are described 
separately in a “Pharmacy manual.”
6.1.1.1 Study Drug
Teduglutide (TAK-633, SHP633, ALX-0600) for SC injection is provided in 3 mL vials 
containing 1.25 mg teduglutide as a lyophilized powder that must be reconstituted using 0.5 mL 
of 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 Investigator’s 
Brochure.
6.1.2 Blinding the Treatment Assignment
Not applicable.
6.2 Administration of Investigational Product
This is an open-label study; all subjects will receive teduglutide 0.05 mg/kg/day 
(0.025 mg/kg/day for patients with moderate or greater renal impairment) as described in 
Section 6.2.1.1. Subject numbers are assigned to all subjects as consent to take part in the study 
is provided. Within each site (numbered uniquely within a protocol), the subject numbers are 
assigned to subjects according to the sequence of presentation for study participation. 
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These numbers will be used to identify the subjects throughout the study period. 
Once a number/unique identifier has been assigned, that number must not be used again if, for 
example, a subject is withdrawn from the study. If a unique identifier is assigned incorrectly, the 
study monitor must be notified as soon as the error is discovered.
6.2.1 Dose, Regimen, and Administration by Parent or Guardian 
A dose of 0.05 mg/kg/day of teduglutide will be administered once daily to subjects. However, 
the 0.025 mg/kg/day (a 50% reduced dosing) will be administered for patients with moderate or 
greater renal impairment. If a subject develops moderate or greater renal impairment during the 
study, the dose can be reduced to 0.025 mg/kg/day and continued after discussion with the 
sponsor’s medical monitor. However, the subject’s body weight must be at least 10 kg (see 
inclusion criteria 4). The dose calculation will be based on body weight measured at the baseline 
visit (Week 0) and will be adjusted per body weight at Week 12 in each treatment cycle. No 
other adjustments to dose will be made during the study period, unless discussed with Medical 
Monitor or designee.
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. For 
subjects with a stoma, the quadrant of the abdomen containing the stoma should not be used. 
Each day, the injection site should be rotated. The site of administration (arm, thigh, abdomen) 
of the first teduglutide dose must be specified and recorded in the (e)CRF.
Teduglutide should be used as soon as possible after reconstitution, but no more than 3 hours 
later. Detailed instructions for reconstitution and injection of the study drug can be found in the 
Instructions for Use.
The subject should be dosed at approximately the same time each day. If a dose is delayed, that 
day’s dose should be administered as soon as possible, but consecutive doses should be separated 
by at least 12 hours. Do not administer more than 0.05 mg/kg (0.025 mg/kg for patients with 
moderate or greater renal impairment) in one day (a day is defined as beginning at 12:00 AM and 
ending at 11:59 PM).
6.2.1.1 Administration by Parent/Guardian
The first dose of teduglutide will be administered by a study physician and the subject will be 
observed for possible hypersensitivity reactions for at least 4 hours after administration during 
their initial dosing visit.
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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.
After the study physician certifies that the parent/guardian can safely administer the study drug, 
subsequent doses may be administered by the parent/guardian at home without direct supervision 
by the physician. However, at selected study visits (refer to Section 1.3), administration of the 
study drug must be performed under direct supervision by the study physician, and the 
teduglutide administration checklist must be completed again. This 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 reassessed 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 retrained 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.
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:

No benefit of teduglutide is observed at Week 24, as determined by the investigator.

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 his/her 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.
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
The subject experiences an adverse event (AE) listed in Table 2 that is of severity
≥Grade 3 per the National Cancer Institute’s Common Terminology Criteria for Adverse
Events. All such AEs should be discussed with sponsor’s medical monitor or designee as
soon as possible.

In the study physician’s judgment, it is inappropriate for the parent/guardian to continue
administration of the study drug for any other reason.
Table 2. 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; 
limiting self-care activities of daily living
Life-threatening consequences; urgent 
intervention indicated
Intestinal obstruction
Hospitalization indicated; invasive 
intervention indicated; limiting self-care 
activities of daily living
Life-threatening consequences; urgent 
operative intervention indicated
Gallbladder and Bile Duct Disease
Cholecystitis
Severe symptoms; invasive 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; invasive 
intervention indicated
Life-threatening consequences; urgent 
intervention indicated
Alkaline phosphatase 
increased
>5.0 to 20.0x ULN if baseline was
normal; >5.0 to 20.0 x baseline if
baseline was abnormal
>20.0x ULN if baseline was normal;
>20.0 x baseline if baseline was
abnormal
Blood bilirubin increased
>3.0 to 10.0x ULN if baseline was
normal; >3.0 to 10.0 x baseline if
baseline was abnormal
>10.0x ULN if baseline was normal;
>10.0 x baseline if baseline was
abnormal
Bile duct stenosis
Severely altered gastrointestinal function; 
invasive intervention indicated
Life-threatening consequences; urgent 
operative intervention indicated
Pancreatic Disease
Pancreatitis
Severe pain; vomiting; medical 
intervention indicated (eg, analgesia, 
nutritional support)
Life-threatening consequences; urgent
intervention indicated
Pancreatic duct stenosis
Severely altered gastrointestinal function; 
tube feeding or hospitalization indicated; 
elective operative intervention indicated
Life-threatening consequences; urgent 
operative intervention indicated
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Table 2. Adverse Events that May Lead to Dose Interruption
Adverse Event
Grade 3 Description
Grade 4 Description
Pancreas infection
Intravenous antibiotic, antifungal, or 
antiviral intervention indicated; invasive 
intervention indicated
Life-threatening consequences; urgent 
intervention indicated
Serum amylase increaseda
>2.0 to 5.0x ULN with signs or
symptoms; >5.0 x ULN and
asymptomatic
>5.0x ULN and with signs or symptoms
Lipase increaseda
>2.0 to 5.0x ULN with signs or
symptoms; >5.0 x ULN and
asymptomatic
>5.0x ULN and with signs or symptoms
Cardiovascular Disease
Heart failure
Symptoms at rest or with minimal 
activity or exertion; hospitalization; new 
onset of symptoms
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 5.0, 27 November 2017
6.2.2 Unblinding the Treatment Assignment
Not applicable.
6.2.3 Dose Modification
For dose adjustment, see Section 6.2.1.
6.2.4 Treatment Eligibility Criteria for Initiation of a Next Teduglutide Treatment Cycle
Subjects are eligible for a next cycle of teduglutide treatment if at least 1 of the following 
criteria, and none of the exclusion criteria (Section 5.2), are met. In addition, the investigator and 
the parent/guardian must agree to proceed with treatment.
If subjects in the NTT meet at least 1 of the following criteria, they may proceed to another 
screening visit at any time. The screening period for another treatment cycle following the NTT 
or follow-up period will be -28 days to -1 days.
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 (EN) following teduglutide discontinuation.
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4. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and electrolyte
intake following teduglutide discontinuation.
5. Severe diarrhea related to teduglutide discontinuation.
6.2.5 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 another screening visit, if at least 1 of the following criteria is 
met. The screening period for another treatment cycle following the NTT or follow-up period 
will be -28 days to -1 days.
At Week 24, if the efficacy (eg, PS volume reduction from baseline) is confirmed, or the 
continuation of teduglutide treatment is appropriate as determined by the investigator, subjects 
may proceed directly to the screening visit without entering to follow-up period, otherwise 
subjects will enter the 4-week follow-up period. For the subjects who skip the follow-up period, 
the screening period will be also from -28 days to -1 days. The Week 24 visit and the next round
of screening visit may be combined.
1. Increasing PS requirements following teduglutide discontinuation.
2. Deteriorating nutritional status (eg, weight loss or growth failure) despite maximal tolerated
EN following teduglutide discontinuation.
3. Deteriorating fluid or electrolyte status despite maximal tolerated enteral fluid and electrolyte
intake following teduglutide discontinuation.
4. Severe diarrhea related to teduglutide discontinuation.
5. The subject escaped during the follow-up period of a previous teduglutide treatment cycle of
the study.
6.2.6 Overdose
An overdose is defined as a known deliberate or accidental administration of study drug at a dose 
above that which is assigned to that individual subject according to the study protocol. All cases 
of overdose (with or without associated AEs) will be documented on an Overdose page of the 
(e)CRF, in order to capture this important safety information consistently in the database. Cases
of overdose without manifested signs or symptoms are not considered AEs. Adverse events
associated with an overdose will be documented on AE CRF(s) according to Appendix 7.
Serious adverse events associated with overdose should be reported according to the procedure 
outlined in Appendix 7.
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In the event of drug overdose, the subject should be treated by the investigator based on 
symptoms.
6.3 Labeling, Packaging, Storage, and Handling of Investigational Product
6.3.1 Labeling
Labels containing study information and pack identification are applied to the investigational 
product(s) container. Additional labels may not be added without the sponsor’s prior full 
agreement.
6.3.2 Packaging
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
6.3.3 Storage
Study drug must be kept in a locked area with access restricted to specific study personnel. Study 
drug will be stored refrigerated at a temperature between 2 and 8°C until dispensed to a subject. 
The pre-filled sterile water for injection syringes will be stored at a temperature between 2 and 
25°C. Once dispensed/supplied to a subject, the study drug can be stored refrigerated up to a 
controlled room temperature (acceptable range of 2 to 25°C). Parent/guardian will be instructed 
to keep the subject’s study drug and sterile water diluent at controlled room temperature. If there 
are concerns that the controlled room temperature cannot be maintained, the study drug may be 
refrigerated.
6.4 Drug Accountability and Destruction of Sponsor-Supplied Drugs
Drug supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee.
The on-site pharmacist (site designee) will receive the pharmacy manual created by the sponsor, 
according to which the site designee will appropriately manage the sponsor-supplied drug. The 
investigator will also receive those procedures from the sponsor. The procedures include those 
for ensuring appropriate receipt, handling, storage, management, dispensation of the 
sponsor-supplied drug, and collection of unused medications from the subject’s parent/guardian 
as well as return of them to the sponsor or destruction of them. 
The on-site pharmacist (site designee) will immediately return unused study drugs to the sponsor 
after the study is closed at the study site.
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6.5 Subject Compliance
Subjects must be instructed how to have unused investigational product and empty/used 
investigational product packaging assessed for drug accountability. Drug accountability must be 
assessed at the container/packaging level for unused investigational product that is contained 
within the original tamper-evident sealed container (eg, bottles, trays, vials) or at the individual 
count level for opened containers/packaging. The pharmacist/nominated person will record 
details on the drug accountability form.
6.6 Prior and Concomitant Therapy
All non-study treatment received within 30 days prior to the screening visit (Visit 1) (or 
pharmacokinetic equivalent of 5 half-lives, whichever is longer) and through the final study 
contact (including protocol-defined follow-up period) must be recorded in the subject’s source 
document.
6.6.1 Prior Treatment
Prior treatment includes all treatment received within 30 days of the date of first dose of 
investigational product. Prior treatment information must be recorded in the subject’s source 
document.
6.6.2 Concomitant Treatment 
Concomitant treatment refers to all treatment taken between the dates of the first dose of 
investigational product and the end of the follow-up period, inclusive. Concomitant treatment 
information must be recorded in the subject’s source document.
6.6.3 Permitted Treatment
Treatments not listed in Section 6.6.4 are considered allowable. 
6.6.4 Prohibited Treatment
The following medications in Table 3 are prohibited during teduglutide treatment and within the 
provided timeframe prior to the screening visit. Because the teduglutide 5 mg formulation is the 
same GLP-2 analog as study drug, and study drug is not known for interactions with various GI 
growth factors, the medications in Table 3 are excluded.
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, and digoxin), so consideration should be given to 
modifying concomitant enteral medication regimens. 
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Titration of concomitant enteral medications should be considered when drugs, especially those 
with a narrow therapeutic index, are given.
Table 3. Common Excluded Treatments and Associated Washout Period
Prior Therapy
Time Restriction Prior to the 
Screening Visit
Teduglutide (5 mg formulation)
Any
GLP-2, human growth hormone, or analogs of these hormones (not including 
teduglutide)
6 months
Octreotide or GLP-1 analogs
30 days
Biological therapy (eg, anti-tumor necrosis factor [anti-TNF]) for active 
Crohn’s disease
6 months
GLP=glucagon-like peptide
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7. DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT
DISCONTINUATION/WITHDRAWAL
7.1 Discontinuation of Study Treatment
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
ET/EOT Visit will be performed as completely as possible. Whenever possible, all discontinued 
subjects should also undergo the protocol-specified evaluations at the ET/EOT Visit. Comments 
(spontaneous or elicited) or complaints made by the subject must be recorded in the source 
documents. The reason for discontinuation, date of discontinuation of the investigational product, 
and the total amount of investigational product administered must be recorded in the source 
documents.
The investigator may discontinue a subject’s study participation at any time during the study 
when the subject meets the study termination criteria described in Section 7.2. In addition, a 
subject may withdraw his or her participation without giving a reason at any time during the 
study, as described in Section 7.3.
7.2 Reasons for Discontinuation
The reason for discontinuation must be determined by the investigator and recorded in the 
subject’s source document. If a subject is discontinued for more than 1 reason, each reason 
should be documented in the source and the most clinically relevant reason should be indicated.
The primary reason for discontinuation or withdrawal of the subject from the study or study drug 
should be recorded in the case report form ([e]CRF) using the following categories. For screen 
failure subjects, refer to Section 8.1.15.
1. Adverse event (AE).
Subjects who experience an AE may require ET because continued participation imposes
an unacceptable risk to the subject’s health, or the subject is unwilling to continue
because of the pretreatment event (PTE) or AE.
Subjects with abnormal liver test results should be evaluated to determine whether study
drug should be continued, interrupted, or discontinued. See Appendix 3.
2. Significant protocol deviation. The discovery after the first dose of study drug that the
subject failed to meet protocol entry criteria or did not adhere to protocol requirements, and
continued participation poses an unacceptable risk to the subject’s health.
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3. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject
were unsuccessful. Attempts to contact the subject must be documented in the subject’s
source documents.
4. Voluntary withdrawal. The subject (or subject’s parent/guardian) wishes to withdraw from
the study. The reason for withdrawal, if provided, should be recorded in the (e)CRF.
Note: All attempts should be made to determine the underlying reason for the withdrawal
and, where possible, the primary underlying reason should be recorded (ie, withdrawal due to
an AE should not be recorded in the “voluntary withdrawal” category. Similarly, lack of
efficacy should not be recorded in the “voluntary withdrawal” category).
5. Study termination. The sponsor, IRB, or regulatory agency terminates the study.
6. Physician Decision. The investigator has determined that the subject is not benefiting from
study treatment; and, continued participation would pose an unacceptable risk to the subject.
7. Lack of efficacy.
8. Other.
Note: The specific reasons should be recorded in the “specify” field of the (e)CRF.
7.3 Withdrawal from the Study
A subject may withdraw from the study at any time and for any reason without prejudice to 
his/her future medical care by the physician or at the institution, or may be withdrawn at any 
time at the discretion of the investigator or sponsor (eg, in the interest of subject safety). The 
investigator is encouraged to discuss withdrawal of a subject with the medical monitor when 
possible.
Should a subject withdraw from the study, the primary criterion for termination must be recorded 
by the investigator, as described in Section 7.2. In addition, efforts should be made to perform all 
procedures scheduled for the EOT/ET visit.
7.4 Subjects “Lost to Follow-up” Prior to the Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject who is lost to 
follow-up at any time point prior to the last scheduled contact (in person or by phone or video). 
At least 1 of these documented attempts must include a written communication sent to the 
subject’s last known address via courier or mail (with an acknowledgement of receipt request) 
asking that the subject be assessed for final safety evaluations and return any unused 
investigational product.
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8. STUDY ASSESSMENTS AND PROCEDURES
The following sections describe the study procedures and data to be collected. For each 
procedure, subjects are to be assessed by the same investigator or site personnel whenever 
possible. The Schedule of Study Procedures is located in Section 1.3.
8.1 Study Procedures
8.1.1 Informed Consent Procedure
The requirements of the informed consent are described in Section 12.2.
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed.
A unique subject identification number (subject number) will be assigned to each subject at the 
time the signed informed consent is obtained; this subject number will be used throughout the 
study.
Subjects are pediatric patients in the study. The investigator is responsible for obtaining written 
informed consent from their parents or guardians.
8.1.2 Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include date of birth, sex, and race as described by 
the subject, height (or length), head circumference (subjects 36 months of age and younger), and 
weight of the subject at screening.
Medical, surgical, and SBS histories to be obtained will include determining whether the subject 
has any significant conditions or diseases relevant to the disease under study that resolved within 
1 year prior to signing of informed consent. Ongoing conditions are considered concurrent 
medical conditions (see Section 8.1.7). Any significant conditions or diseases relevant to the 
proposed indication include necrotizing enterocolitis, volvulus, Crohn's disease, cancer, intestinal 
atresia, gastric fistula, and central venous catheterization.
Medication history information to be obtained includes any medication relevant to eligibility 
criteria and safety evaluation stopped at or within 28 days prior to signing of informed consent.
8.1.3 Physical Examination Procedure
A baseline physical examination (defined as the assessment prior to first dose of study drug) will 
consist of the following body systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular system; 
(4) respiratory system; (5) GI system; (6) dermatologic system; (7) extremities; (8)
musculoskeletal system; (9) nervous system; (10) lymph nodes; and (11) other.
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All subsequent physical examinations should assess clinically significant changes from the 
assessment prior to first dose examination.
8.1.4 Weight, Height (or length), and Head Circumference
A subject should have weight and height (or length) measured while wearing indoor clothing and 
with shoes off. Height (or length) is recorded in centimeters without decimal places. Weight is 
collected in kilograms (kg) with 1 decimal place.
Head circumference will be measured in subjects 36 months of age and younger.
Z-scores for weight, height (or length), and head circumference will be calculated by the
sponsor.
8.1.5 Vital Sign Procedure
Vital signs will include body temperature, respiratory rate, blood pressure (systolic and 
diastolic), and pulse (bpm). Measurements should be in the same method, on the same extremity, 
and in the same position throughout the study.
8.1.6 Documentation of Concomitant Medications
Concomitant medication is any drug given in addition to the study drug. These may be 
prescribed by a physician or obtained by the subject over the counter. Concomitant medication is 
not provided by the sponsor. At each study visit, subjects’ parents or guardians will be asked 
whether they have taken any medication other than the study drug (used from signing of 
informed consent through the end of the study), and all medication including vitamin 
supplements, over-the-counter medications, and oral herbal preparations, must be recorded in the 
(e)CRF.
8.1.7 Documentation of Concurrent Medical Conditions
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present at signing of informed consent. This includes clinically significant laboratory, or physical 
examination abnormalities noted at screening/baseline examination, according the judgment of 
the investigator. The condition (ie, diagnosis) should be described.
8.1.8 Procedures for Clinical Laboratory Samples
All samples will be collected in accordance with acceptable laboratory procedures. The 
maximum volume of blood at any single visit is approximately 6.8 mL, and the approximate total 
volume of blood for the study is 47.8 mL until Week 24 and 112.8 mL until the longest study 
period (18 months). Details of these procedures and required safety monitoring will be given in 
the laboratory manual. Appendix 4 describes total blood volume to be collected.
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Table 4 lists the tests that will be obtained for each laboratory specimen.
Table 4. Clinical Laboratory Tests
Hematology
Biochemistry
Urinalysis
Hematocrit
Hemoglobin
Platelet count
White blood cell count with differential
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
(calculated with the quintic 
equationa)
Gamma-glutamyl transferase
Glucose
Lipase
Magnesium
Phosphorus
Potassium
Sodium
Triglycerides
Uric acid
Blood
Glucose
Leucocytes
Microscopic analysis
pH
Protein
Specific gravity
Other:
Coagulation
Prothrombin time/International normalized ratio will be measured in all subjects at screening and subsequently if 
drug-induced liver injury is suspected.
a.
eGFR=110.2 × (reference serum Cr/patient's serum Cr) + 2.93
Reference serum Cr levels (y) are shown by the following two equations of body length (x):
Males: y = −1.259x5 + 7.815x4 − 18.57x3 + 21.39x2 − 11.71x + 2.628
Females: y =−4.536x5 + 27.16x4 −63.47x3 + 72.43x2 −40.06x + 8.778 (Uemura et al. 2014)
The central laboratory will perform laboratory tests for hematology, biochemistries, urinalysis, 
and coagulation. The results of laboratory tests will be returned to the investigator, who is 
responsible for reviewing and filing these results. Urine specimen collection should be attempted 
as part of the safety lab tests, but lack of urinalysis will not constitute a protocol deviation.
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Safety laboratory tests to be performed at site visits and processed by a central lab. 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. Additional 
evaluations may be performed at the discretion of the investigator in consultation with the 
Medical Monitor or designee.
For subjects with treatment-emergent ALT elevations ≥3x ULN, see Appendix 3 for additional 
monitoring, evaluation, and follow-up recommendations.
The collected samples for this study will be stored at LSI Medience Corporation for up to 
15 years from when the study results are reported or if less, the maximum period permitted under 
applicable law or until consent is withdrawn.
8.1.9 Telephone Contacts
Telephone contacts will be made as needed during the treatment period. At all site visits and 
during telephone contacts, safety will be evaluated, and nutritional support will be reviewed and 
adjusted, as needed.
8.1.10 Adjustment of Nutritional Support
Nutritional support includes PS, EN, and other food and fluids. Nutritional support adjustments 
should be made after review of the intake and output diaries and safety lab data according to the 
guidelines for nutrition support management and weaning algorithms provided in Guidelines for 
Nutritional Support Management During the Study (Appendix 5) and Weaning Algorithms 
(Appendix 6), respectively.
8.1.11 Dispense Study Drug
The first SC injection will be administered under the supervision of the investigator/designee. 
The subject will be observed for possible hypersensitivity reactions for at least 4 hours after 
administration during their initial dosing visit. The site of administration (arm, thigh, abdomen) 
must be specified and recorded in the (e)CRF. The dose of study medication will be adjusted per 
body weight at Week 12 in each treatment cycle. No other adjustments to dose will be made 
during the study period, unless discussed with Medical Monitor or designee.
8.1.12 Adverse Events Assessment
Safety will be evaluated based on the occurrence of all AEs, SAEs, AESIs, physical examination 
findings, vital signs (heart rate, blood pressure), clinical laboratory parameters (biochemistry, 
hematology, and urinalysis), and urine/fecal outputs (obtained from an output diary). See 
Appendix 7.1 for definitions of AEs, SAEs, and AESIs.
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8.1.13 Diaries
The subject’s parent/guardian or study site staff will complete the appropriate fields of the PS 
and EN (formula) sections of the intake diary.
Intake diary: The following information should be provided in the intake diaries, which will be 
completed every day of the study from screening through EOT/ET visit:

Parenteral support volume and infusion duration.

Enteral nutrition (formula) volume.
Site personnel will determine the actual PS and EN daily calories based on diary entries.
Output diary: Urine and stool output should be recorded in the output diary over a 48-hour 
period of PS and EN stability before every site visit and 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. The subject or parent will perform 
dipstick specific gravity tests on the first urine produced after the daily infusions of 
PS.
Nontoilet-trained subjects (who wear diapers).
Measure and record the weight of all urine-only diapers. Urine volume will be 
calculated using the following formula: 1 g (scale weight) = 1 mL or 1 cc.
At the discretion of the investigator, the parent may be asked to collect the first void 
after the daily PS infusion to measure specific gravity.
Stool data (includes diapers with mixed urine and stool).
Toilet-trained subjects (who do not wear diapers).
Record the occurrence of each bowel movement and score the stool consistency using 
the Bristol Stool Form Scale (see output diary).
Nontoilet-trained subjects (who wear diapers).
Record the weight of diapers containing stool (including diapers with mixed urine and 
stool) as stool output and score the stool consistency using the Bristol Stool Form 
Scale (see output diary). Stool volume will be calculated using the formula: 1 g (scale 
weight) = 1 mL or 1 cc.
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All ostomy output volume should be recorded. Ostomy output will not be scored using the 
Bristol Stool Form Scale.
All diaries will be reviewed by the investigator or their designee at each clinic and telephone 
contact to assess clinical status and opportunity for PS reduction and advance in feeds.
8.1.14 Colonoscopy/Sigmoidoscopy
Colonoscopy/sigmoidoscopy to identify colorectal polyps is recommended in each subject after 
52 weeks of treatment while on continuous treatment with teduglutide, and/or if the subject has 
new or unexplained GI bleeding. Fecal blood test may be performed as needed.
8.1.15 Documentation of Screen Failure
Investigators must account for all subjects who sign informed consent.
If the subject is withdrawn at the screening visit, the investigator should complete the (e)CRF.
The primary reason for screen failure is recorded in the (e)CRF using the following categories:

Pretreatment event/AE.

Did not meet inclusion criteria or did meet exclusion criteria.

Significant protocol deviation.

Lost to follow-up.

Voluntary withdrawal.

Study termination.

Other study-specific.

Other.
Subject identification numbers assigned to subjects who fail screening should not be reused.
8.1.16 Documentation of Study Entrance
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for entrance into the treatment phase.
If the subject is found to be not eligible for treatment phase, the investigator should record the 
primary reason for failure on the applicable (e)CRF.
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8.2 Monitoring Subject Treatment Compliance
Subjects will be required to bring study drug containers/unused study drugs to each dispensing 
site visit. All supplies used to administer study drug to the subject will be recorded on the 
(e)CRFs.
8.3 Schedule of Observations and Procedures
The schedule for all study-related procedures for all evaluations is shown in Section 1.3. 
Assessments should be completed at the designated visit/time point(s).
8.3.1 Screening
Subjects will be screened between 28 and 14 days prior to baseline (Week 0). Subjects will be 
screened in accordance with predefined inclusion and exclusion criteria as described in 
Section 5. Another round of screening after Week 24 will occur for subjects who skip the 
follow-up period. The Week 24 visit and the next round of screening visit may be combined. See 
Section 8.1.15 for procedures for documenting screening failures.
The following procedures will be performed and documented at the screening visit:
Informed consent (not applicable for another round of screening).
Inclusion/exclusion criteria (only exclusion criteria for another round of screening).
Treatment eligibility criteria (applicable only for another round of screening).
Demographics, medical, medication, surgical, and SBS histories (not applicable for
another round of screening).
Adverse event assessment.
Concomitant medications/procedures.
Physical examination, vital signs, and weight.
Height (or length) and head circumference (head circumference will be measured in
subjects 36 months of age and younger).
Safety laboratory tests.
Providing intake and output diaries.
Diary review (applicable only for another round of screening).
Adjustment of nutritional support (as needed. applicable only for another round of
screening).
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8.3.2 Study Entrance
Study entrance will take place at Week 0. The following procedures will be performed and 
documented at study entrance visit:
Inclusion/exclusion criteria (only exclusion criteria for another round of treatment).
Treatment eligibility criteria (applicable only for another round of treatment).
Adverse event assessment.
Concomitant medications/procedures.
Physical examination, vital signs, and weight.
Height (or length) and head circumference (head circumference will be measured in
subjects 36 months of age and younger).
Safety laboratory tests.
Providing intake and output diaries.
Diary review.
Adjustment of nutritional support (as needed. applicable only for another round of
treatment).
Dispensing study drug.
Confirmation of administration proficiency.
If the subject has satisfied all of the inclusion criteria and none of the exclusion criteria for study 
entrance, the subject should be enrolled. Subjects’ parents or guardians will be instructed on 
when to take the first dose of study drug as described in Section 4.1. The procedure for 
documenting screening failures is provided in Section 8.1.15.
8.3.3 Treatment, Follow-up, and No-teduglutide treatment period
The subjects will visit the site weekly for the first 2 weeks (Week 1 and Week 2), and then every 
4 weeks after Week 4 (Weeks 4, 8, 12, 16, 20, and 24).
8.3.3.1 Week 1 and Week 2 (Window period ±3 days)
The following procedures will be performed and documented at Week 1 and Week 2 visits:
Adverse event assessment.
Concomitant medications/procedures.
Physical examination, vital signs, and weight.
Safety laboratory tests (only biochemistry).
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Providing intake and output diaries.
Diary review.
Adjustment of nutritional support (as needed).
Dispensing study drug.
8.3.3.2 Weeks 4, 8, 12, 16, 20, and 24 (Window period ±7 days)
The following procedures will be performed and documented at Weeks 4, 8, 12, 16, 20, and 24:
Adverse event assessment (including telephone contacts as needed).
Concomitant medications/procedures.
Physical examination, vital signs, and weight.
Height (or length) and head circumference (head circumference will be measured in
subjects 36 months of age and younger).
Safety laboratory tests.
Providing intake and output diaries.
Diary review.
Adjustment of nutritional support (as needed).
Dispensing study drug (not applicable for Week 24).
Confirmation of administration proficiency (only at Week 4 and Week 12).
Evaluation of escape criteria (only at Week 24).
Assessment of eligibility for additional treatment (only at Week 24).
8.3.3.3 Follow-up period (4 weeks) (Window period ±7 days)
The following procedures will be performed and documented during 4 weeks of the follow-up 
period:
Adverse event assessment (including telephone contacts as needed).
Concomitant medications/procedures.
Physical examination, vital signs, and weight.
Safety laboratory tests.
Providing intake and output diaries.
Diary review.
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Adjustment of nutritional support (as needed).
Assessment of eligibility for additional treatment.
Evaluation of escape criteria.
8.3.3.4 No-teduglutide treatment period (every 12 weeks)
The following procedures will be performed and documented every 12 weeks during the NTT 
period:
Adverse event assessment (including telephone contacts as needed).
Concomitant medications/procedures.
Physical examination, vital signs, and weight.
Height (or length) and head circumference (head circumference will be measured in
subjects 36 months of age and younger).
Safety laboratory tests.
Providing intake and output diaries.
Diary review.
Adjustment of nutritional support (as needed).
Assessment of eligibility for additional treatment.
8.3.4 End of Treatment or Early Termination (Window period ±7 days)
The final visit will be performed on at EOT/ET visit. The following procedures will be 
performed and documented at the EOT/ET visit:
Adverse event assessment.
Concomitant medications/procedures.
Physical examination, vital signs, and weight.
Height (or length) and head circumference (head circumference will be measured in
subjects 36 months of age and younger).
Safety laboratory tests.
Diary review.
Adjustment of nutritional support (as needed).
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For all subjects receiving study drug, the investigator must complete the End of Study (e)CRF 
page.
8.3.5 Alternative Approaches to Study Procedures and Data Collection Due to Coronavirus 
Disease 2019
In unavoidable circumstances that impact the study site’s ability to conduct study procedures 
according to the Schedule of Study Procedures (Section 1.3), in particular during the coronavirus 
disease 2019 (COVID-19) pandemic, contingency measures may be implemented. The following 
information provides guidance regarding changes to the study procedures that could be 
implemented for study subjects or study sites that are affected by the COVID-19 public health 
emergency. This guidance is aligned with the current guidance from global health authorities on 
the conduct of clinical studies during the COVID-19 pandemic.
As the COVID-19 pandemic may peak in different regions at different times, and as 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 
sponsor or designee, while maintaining subject safety and confidentiality as the priority.
The principal investigator should also notify the local IRB, as appropriate, of any deviation for 
temporary use of alternative methods for conducting subject visits (eg, video conferencing, 
telephone visits) in the event of restrictive measures due to the COVID-19 pandemic, per local 
requirements.
Procedural changes due to COVID-19 may include the following:

No routine COVID-19 testing is required during the study unless the subject has signs or
symptoms of COVID-19-related disease or COVID-19 pneumonia in the opinion of the
investigator or the subject has been identified by national or local public health authority
as a close contact of a probable or confirmed case of COVID-19. The decision to have
the subject tested for COVID-19 is left to the subject and the investigator unless required
by the health authority.

Subjects who discontinued from screening due to COVID-19-related factors but were
otherwise qualified to participate in the study may be re-screened if the sponsor or
designee agrees.

All attempts should be made to perform the assessments with the subject present at the
site using the visit windows. Exceptions may be granted for alternative approaches to
study procedures and data collection through approval by the sponsor or designee. Such
instances must be documented in the study records and may include the following:
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o
Sites impacted by the COVID-19 pandemic must contact the sponsor or designee
to discuss individual subject and site circumstances to obtain approval for use of
alternative approaches to study procedures and data collection.
o
Sites may seek approval from the Medical Monitor to continue subjects in the
study despite departure from the Schedule of Study Procedures. Principal
investigators are expected to evaluate the impact to the safety of the study
subjects and site personnel for subjects to continue. In evaluating such requests,
the sponsor or designee will give the highest priority to the safety and welfare of
the subjects. Subjects must be willing and able to continue taking study
medication and remain compliant with the protocol.

Informed Consent Procedure: If necessary, informed consent from a potential or current
study participant’s parent or guardian may be obtained via verbal consent when these
individuals are unable to travel to the site. Informed consent forms will be signed once
the subject and his/her parent or guardian can return in-person to the study site.

Visits: All visits must be done with the subject present at the study site.
o
Protocol Deviations: Any deviations from the protocol-specified procedures due
to COVID-19 will be recorded as related to COVID-19.
o
Visit Window Extension: Sites may seek approval from the sponsor or designee to
extend a visit window in order to conduct an on-site visit. Assessments that
cannot be completed during the protocol-specified window will be recorded as a
protocol deviation, and such deviations will be recorded in the study records as
related to COVID-19.
o
Local laboratory test may be appliable for assessing clinical chemistry and
hematology

EOT/ET visit: The EOT/ET visit should be performed with the subject present at the
study site. Sites may seek approval from the sponsor or designee to extend a visit window
in order to conduct an on-site visit. If the visit cannot be conducted on-site within the
visit window granted by the sponsor or designee, sites may conduct EOT/ET visit
procedures remotely as is feasible, including using local laboratories for assessment of
biochemistry, hematology, and urinalysis (as specified in Table 4). Assessments that
cannot be completed during the protocol-specified window will be recorded as a protocol
deviation, and such deviations will be recorded in the study records as related to
COVID-19.
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
When a physical examination or other in-person procedure is needed in response to an
AE, the subject should be evaluated in-person at the site per protocol if possible. If the
subject cannot visit the site due to COVID-19, the site should contact the Medical
Monitor.

Discontinuation or Withdrawal from the Study or Study Medication: If a subject chooses
to withdraw from the study or study medication due to personal concerns related to the
COVID-19 pandemic (other than a COVID-19-related AE), this must be specified as the
reason for subject withdrawal in the (e)CRF.

Allow transfer of study subjects to study sites away from risk zones or closer to their
home to sites already participating in the study or new ones.

For subjects who are impacted by certain factors, any alternative approaches to study
procedures (ie, procedures not conducted per the Schedule of Study Procedures) due to
the COVID-19 pandemic must be documented in the study records as related to
COVID-19. Data collected using alternative methods may be handled differently in the
final data analyses. This will be documented in the statistical analysis plan (SAP).
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9. DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management 
Plan. Adverse events, medical history, and concurrent medical conditions will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World 
Health Organization (WHO) Drug Dictionary.
9.1 CRFs (Electronic)
Completed (e)CRFs are required for each subject whose parent or guardian signs an informed 
consent.
The sponsor or its designee will supply study sites with access to eCRFs. The sponsor or its 
designee will make arrangements to train appropriate site staff in the use of the eCRF. These 
forms are used to transmit the information collected in the performance of this study to the 
sponsor and regulatory authorities. (e)CRFs must be completed in English.
After completion of the entry process, computer logic checks will be run to identify items, such 
as inconsistent dates, missing data, and questionable values. Queries may be issued by the 
sponsor’s personnel (or designees) and will be answered by the site. 
The principal investigator must review the (e)CRFs for completeness and accuracy and must 
e-sign the appropriate (e)CRFs as indicated. Furthermore, the investigator must retain full
responsibility for the accuracy and authenticity of all data entered on the (e)CRFs.
The following data will not be recorded into the (e)CRFs; laboratory test values.
After the lock of the study database, any change of, modification of or addition to the data on the 
(e)CRFs should be made by the investigator with use of change and modification records of the
(e)CRFs/(e)CRFs (Data Clarification Form) provided by the sponsor. The principal investigator
must review the data change for completeness and accuracy, and must sign, or sign and seal, and
date.
(e)CRFs will be reviewed for completeness and acceptability at the study site during periodic
visits by the sponsor or its designee. The sponsor or its designee will be permitted to review the
subject’s medical and hospital records pertinent to the study to ensure accuracy of the (e)CRFs.
The completed (e)CRFs are the sole property of the sponsor and should not be made available in
any form to third parties, except for authorized representatives of appropriate governmental
health or regulatory authorities, without written permission of the sponsor.
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9.2 Record Retention
The investigator and the head of the study site agree to keep the records stipulated in Section 9.1
and those documents that include (but are not limited to) the study-specific documents, the 
identification log of all participating subjects, medical records, all original signed and dated 
informed consent forms, electronic copy of eCRFs, including the audit trail, and detailed records 
of drug disposition to enable evaluations or audits from regulatory authorities, the sponsor or its 
designees.
The investigator and the head of the study site are required to retain essential relevant documents 
until the day specified as 1), 2), or 3) below, whichever comes later. However, if the sponsor 
requests a longer time period for retention, the head of the study site should discuss how long 
and how to retain those documents with the sponsor.
1. The day on which marketing approval of the study drug is obtained (or the day 3 years after
the date of notification in the case that the investigation is discontinued).
2. The day 3 years after the date of ET or completion of the study.
3. Upon market approval of the teduglutide 1.25 mg formulation and once the clinical study is
shifted to the post-marketing clinical study, until the end of re-review or re-evaluation,
whichever comes later.
In addition, the investigator and the head of the study site should retain the essential relevant 
documents until the receipt of a sponsor-issued notification to state the retention is no longer 
required.
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10. STATISTICAL METHODS
10.1 Statistical and Analytical Plans
A SAP will be prepared and finalized prior to database lock. There is no hypothesis testing 
planned for this study. Descriptive statistics will be provided for all analysis. Following is an 
overview of the planned analyses; the SAP will provide further details regarding the definition of 
analysis variables and analysis methodology to address all study objective.
10.1.1 Analysis Sets
The full analysis set (FAS) and safety analysis set (SAS) are defined for this trial.
FAS: The FAS will include all enrolled patients, who are not screen failures. Subjects will be in 
FAS regardless of whether they took any dose of teduglutide in the study. The FAS will be used 
for all the efficacy analyses.
SAS: The SAS will include all subjects who received at least 1 dose of study teduglutide. Safety 
analyses will be conducted using the SAS.
The details of the definitions for the analysis sets will be documented in the SAP.
The sponsor will verify the validity of the definitions of the analysis sets as well as the rules for 
handling data, with consulting a medical expert as needed. If necessary, the SAP will be 
supplemented with new handling rules that were not discussed at the planning stage.
10.1.2 Analysis of Demographics and Other Baseline Characteristics
Baseline and demographic information will be analyzed by using the SAS.
10.1.3 Safety Analysis
Adverse events will be summarized using the SAS. Counts and percentages for subjects with 
treatment-emergent AEs and SAEs (any SAE, regardless of relationship to study drug) will be 
summarized descriptively by System Organ Class and Preferred Term using MedDRA 
terminology. Serious adverse events will also be summarized by severity and by relationship to 
study drug. For clinical laboratory tests, body weight, height (or length), and head 
circumferences, vital signs, urine, and fecal output, descriptive statistics will be used to 
summarize the absolute values and changes from baseline by visit.
Details of the analysis methods will be specified in the SAP.
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10.1.4 Efficacy Analysis
For the continuous endpoints, the following statistics will be presented: non-missing values, 
mean, median, SD, minimum, maximum, and 95% confidence interval (CI). 

Change from baseline in PS volume by each visit and EOT.

Percent change from baseline in PS volume by each visit and EOT.

Change from baseline in days per week of PS by each visit and EOT.
For the binary endpoint, the following statistics will be presented: count, proportion, and 95% 
Clopper Pearson CI.
Number and percent of subjects achieving at least 20% reduction in PS volume from
baseline by each visit and EOT.
Number and percent of subjects achieving enteral autonomy, defined as complete
weaning off PS by each visit and EOT.
Analyses of PS will be based on 2 data sources: the subject diary data (also referred to as actual 
data) and the investigator prescribed data.
No formal statistical test will be performed due the limited sample size. Details of the analysis 
methods will be specified in the SAP.
10.1.5 Missing Data Analysis
No imputations for missing data (eg, last observation carried forward) will be applied, except for 
partial dates for AEs and prior/concomitant medications.
Missing daily PS volumes from subject diaries will not be imputed and a maximum of 5 missing 
days (or at least 9 days of non-missing data) from the 14-day intervals will be allowed; 
otherwise, the interval will be classified as missing, with 2 following exceptions. One exception 
to this rule is the baseline interval, which is filtered back within the stabilization period beyond 
14 days until 9 data points were obtained. The other exception is the PS adjustments due to an 
AE that is excluded, in which case the last 14 days during the interval which are not considered 
to be impacted by the AE will be used.
10.2 Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
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10.3 Determination of Sample Size
Approximately 5 subjects are planned to be enrolled into the study. The sample size is 
determined based on enrollment feasibility of this rare population in children in Japan, rather 
than statistical power calculation.
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11. QUALITY CONTROL AND QUALITY ASSURANCE
11.1 Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the (e)CRFs. Source documents are defined as original documents, data, and 
records. The investigator and the head of the study site guarantee access to source documents by 
the sponsor or its designee contract research organization (CRO) and by the IRB.
All aspects of the study and its documentation will be subject to review by the sponsor or 
sponsor’s designee (as long as blinding is not jeopardized), including but not limited to the 
Investigator’s Binder, study drug, subject medical records, informed consent documentation, 
documentation of subject authorization to use personal health information and review of (e)CRFs 
and associated source documents. It is important that the investigator and other study personnel 
are available during the monitoring visits and that sufficient time is devoted to the process.
11.2 Protocol Deviations
The investigator can deviate and change from the protocol for any medically unavoidable reason, 
for example, to eliminate an immediate hazard to study subjects, without a prior written 
agreement with the sponsor or a prior approval from IRB. In the event of a deviation or change, 
the principal investigator should notify the sponsor and the head of the study site of the deviation 
or change as well as its reason in a written form, and then retain a copy of the written form. 
When necessary, the principal investigator may consult and agree with the sponsor on a protocol 
amendment. If the protocol amendment is appropriate, the amendment proposal should be 
submitted to the head of the study site as soon as possible and an approval from IRB should be 
obtained.
The investigator should document all protocol deviations.
11.3 Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, 
including those of foreign governments (eg, the Food and Drug Administration [FDA], the 
United Kingdom Medicines and Healthcare products Regulatory Agency, the Pharmaceuticals 
and Medical Devices Agency of Japan). 
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If the study site is contacted for an inspection by a regulatory body, the sponsor should be 
notified immediately. The investigator and the head of the study site guarantee access for quality 
assurance auditors to all study documents as described in Section 11.1.
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12. ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in 
Appendix 1. The principles of Helsinki are addressed through the protocol and through 
appendices containing requirements for informed consent and investigator responsibilities.
12.1 IRB
Institutional review boards must be constituted according to the applicable local requirements of 
each participating region. The sponsor or designee will require documentation noting all names 
and titles of members who make up the respective IRB. If any member of the IRB has direct 
participation in this study, written notification regarding his or her abstinence from voting must 
also be obtained.
The sponsor or designee will supply relevant documents for submission to the respective IRB for 
the protocol’s review and approval. This protocol, the Investigator’s Brochure, a copy of the 
informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB for approval. The IRB’s written approval of the protocol and subject 
informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied drug or study-specific 
screening activity/signing a contract for the clinical study). The IRB approval must refer to the 
study by exact protocol title, number, and version date; identify versions of other documents 
(eg, informed consent form) reviewed; and state the approval date. If required by country or 
regional regulations or procedures, approval from the competent regulatory authority will be 
obtained before commencement of the study or implementation of a substantial amendment. The 
sponsor will ship drug/notify site once the sponsor has confirmed the adequacy of site regulatory 
documentation. Until the site receives drug/notification no protocol activities, including 
screening may occur.
Study sites must adhere to all requirements stipulated by their respective IRB. This may include 
notification to the IRB regarding protocol amendments, updates to the informed consent form, 
recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB, and submission of the investigator’s final status report to IRB. All IRB approvals 
and relevant documentation for these items must be provided to the sponsor or its designee.
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Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB and sponsor.
12.2 Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted 
uses, transfers, and disclosures of the subject’s personal and personal health information for 
purposes of conducting the study. The informed consent form and the subject information sheet 
(if applicable) further explain the nature of the study, its objectives, and potential risks and 
benefits, as well as the date informed consent is given. The informed consent form will detail the 
requirements of the participant and the fact that he or she is free to withdraw at any time without 
giving a reason and without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and IRB approval of the informed 
consent form and if applicable, the subject authorization form. The informed consent form, 
subject authorization form (if applicable), and subject information sheet (if applicable) must be 
approved by both the IRB and the sponsor prior to use.
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective 
subject’s parent or guardian. It is the responsibility of the investigator to explain the detailed 
elements of the informed consent form, subject authorization form (if applicable), and subject 
information sheet (if applicable) to the subject’s parent or guardian. Information should be given 
in both oral and written form whenever possible and in the manner deemed appropriate by the 
IRB. 
The subject, or the subject’s parent or guardian, must be given ample opportunity to: (1) inquire 
about details of the study and (2) decide whether or not to participate in the study. If the subject, 
or the subject’s parent or guardian, determines he or she will participate in the study, then the 
informed consent form and subject authorization form (if applicable) must be signed and dated 
by the subject, or the subject’s parent or guardian, at the time of consent and prior to the subject 
entering into the study. The subject or the subject’s parent or guardian should be instructed to 
sign using their legal names, not nicknames, using blue or black ballpoint ink. The investigator 
must also sign and date the informed consent form and subject authorization (if applicable) at the 
time of consent and prior to subject entering into the study.
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Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization 
form (if applicable), and subject information sheet (if applicable) shall be given to the subject.
All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed 
consent. The date the revised consent was obtained should be recorded in the subject’s medical 
record, and the subject should receive a copy of the revised informed consent form.
12.2.1 Dissemination of New Information
When new information important to the proper conduct of the clinical study becomes available, 
such as on diseases, impairment, and deaths suspected to be due to the effect of the study drug, 
onset of infections suspected to be due to the use of the study drug, and other information related 
to study drug quality, efficacy, and safety, the sponsors will inform the investigators and heads of 
medical institutions in writing in a timely manner.
When the investigator receives information which the investigator judges may affect the
intention of subjects to continue participation in the clinical study, the investigator will make 
available this information immediately to subjects and their parent or guardian, to be recorded in 
writing, and confirm whether the subject will continue to participate in the study.
12.3 Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
the sponsor’s clinical trial database or documentation via a subject identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth may be used to verify the subject and accuracy of the subject’s unique identification 
number.
In the event that a serious data breach is detected, the sponsor or its designee and the investigator 
(as applicable) will take appropriate corrective and preventative actions in response. These 
actions will be documented and the relevant regulatory agency(ies) will be notified as 
appropriate. Where appropriate, the relevant individuals materially affected by the breach would 
also be notified; in the case of study subjects, this would be done through the investigator.
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To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to permit the monitor or the sponsor’s designee, representatives 
from any regulatory authority (eg, FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs to review the subject’s original medical records (source data or documents), 
including, but not limited to, laboratory test result reports, electrocardiogram reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study 
participation, and autopsy reports. Access to a subject’s original medical records requires the 
specific authorization of the subject as part of the informed consent process (see Section 12.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s [e]CRF).
12.4 Publication, Disclosure, and Clinical Trial Registration Policy
12.4.1 Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived 
by the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, is the 
sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator.
The investigator needs to obtain a prior written approval from the sponsor to publish any 
information from the study externally such as to a professional association.
12.4.2 Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register all 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov and/or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, country, and recruiting status will be 
registered and available for public viewing.
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For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor.
Any investigator who objects to the sponsor providing this information to callers must provide 
the sponsor with a written notice requesting that their information not be listed on the registry 
site.
12.4.3 Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov and/or other publicly 
accessible websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
12.5 Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the 
site where the subject is participating. If a local underwriter is required, then the sponsor or 
sponsor’s designee will obtain clinical study insurance against the risk of injury to study 
subjects. Refer to the study site agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he 
or she should contact the sponsor or sponsor’s designee.
12.6 Payment
The financial aspects of the study should be documented in a clinical trial agreement or 
memorandum between the sponsor, the medical institution, and the CRO.
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13. STUDY-SPECIFIC COMMITTEES
Because the efficacy and safety of teduglutide have been already examined and confirmed in 
previous studies (see Investigator’s Brochure), and this study is designed specifically 
 
, no steering committee, data safety monitoring committee, or 
clinical endpoint committee will be used in this study.
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14. REFERENCES
Duro, D., Kamin, D. and 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., et al. 2015. 
Predictors of Enteral Autonomy in Children with Intestinal Failure: A Multicenter Cohort 
Study. J Pediatr, 167(1), 29-34.e1.
O'Keefe, S. J., Buchman, A. L., Fishbein, T. M., Jeejeebhoy, K. N., Jeppesen, P. B. and Shaffer, 
J. 2006. Short bowel syndrome and intestinal failure: consensus definitions and overview.
Clin Gastroenterol Hepatol, 4(1), 6-10.
Sigalet, D., Boctor, D., Brindle, M., Lam, V. and Robertson, M. 2011. Elements of successful 
intestinal rehabilitation. J Pediatr Surg, 46(1), 150-6.
Squires, R. H., Duggan, C., Teitelbaum, D. H., Wales, P. W., Balint, J., Venick, R., et al. 2012. 
Natural history of pediatric intestinal failure: initial report from the Pediatric Intestinal 
Failure Consortium. J Pediatr, 161(4), 723-8.e2.
Uemura, O., Nagai, T., Ishikura, K., Ito, S., Hataya, H., Gotoh, Y., et al. 2014. Creatinine-based 
equation to estimate the glomerular filtration rate in Japanese children and adolescents 
with chronic kidney disease. Clin Exp Nephrol, 18(4), 626-33.
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SAP_001.pdf: 
 
 
Statistical Analysis Plan 
 
NCT Number: NCT05027308 
Title: A Phase 3, Open-label Safety Study of Teduglutide in Japanese Pediatric Patients 
With Short Bowel Syndrome Who are Dependent on Parenteral Support, Aged 4 Months 
of Corrected Gestational Age or Older, and Requiring the Dosing of 1.25 mg 
Formulation 
Study Number: TAK-633-3008 
Document Version and Date: Version 2.0 / 31-Oct-2023 
 
Certain information within this document has been redacted (ie, specific content is 
masked irreversibly from view) to protect either personally identifiable information or 
company confidential information. 


STATISTICAL ANALYSIS PLAN 
Study Number: TAK-633-3008 
Study Title: A Phase 3, Open-label Safety Study of Teduglutide in Japanese Pediatric Patients 
with Short Bowel Syndrome who are Dependent on Parenteral Support, Aged 4 Months of 
Corrected Gestational Age or older, and Requiring the Dosing of 1.25 mg Formulation 
Phase: 3 
Version: 2.0 
Date: 31-Oct-2023 
Prepared by: 
 
 
Based on: 
Protocol Version: Amendment 2 
Protocol Date: 19-May-2022 
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TAK-633-3008 
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Statistical Analysis Plan 2.0 
31-Oct-2023
.. 
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TABLE OF CONTENTS 
1.0 
OBJECTIVES, ENDPOINTS AND ESTIMANDS ............................................................7 
1.1 
Objectives ......................................................................................................................7 
1.1.1 
Primary Objective ..................................................................................................7 
1.1.2 
Secondary Objective(s) .........................................................................................7 
1.1.3 
Additional Objective(s) .........................................................................................7 
1.2 
Endpoints .......................................................................................................................7 
1.2.1 
Safety Endpoints ....................................................................................................7 
1.2.2 
Efficacy Endpoints ................................................................................................7 
1.3 
Estimand(s) ....................................................................................................................8 
2.0 
STUDY DESIGN.................................................................................................................8 
3.0 
STATISTICAL HYPOTHESES AND DECISION RULES ...............................................8 
3.1 
Statistical Hypotheses ....................................................................................................8 
3.2 
Statistical Decision Rules ..............................................................................................9 
3.3 
Multiplicity Adjustment .................................................................................................9 
4.0 
SAMPLE-SIZE DETERMINATION ..................................................................................9 
5.0 
ANALYSIS SETS ...............................................................................................................9 
5.1 
All Screened Subjects Analysis Set ...............................................................................9 
5.2 
Safety Analysis Set ........................................................................................................9 
5.3 
Full Analysis Set ............................................................................................................9 
5.4 
Per-Protocol Analysis Set ..............................................................................................9 
5.5 
Pharmacokinetic Analysis Set........................................................................................9 
6.0 
STATISTICAL ANALYSIS ...............................................................................................9 
6.1 
General Considerations ..................................................................................................9 
6.1.1 
Handling of Treatment Misallocations ................................................................10 
6.2 
Disposition of Subjects ................................................................................................10 
6.3 
Demographic and Other Baseline Characteristics .......................................................11 
6.3.1 
Demographics ......................................................................................................11 
6.3.2 
Medical History and Concurrent Medical Conditions .........................................12 
6.3.2.1 
Short Bowel Syndrome History ..................................................................12 
6.3.2.2 
Other Medical History and Concurrent Medical Conditions ......................12 
6.3.3 
PS and EN History ...............................................................................................13 
6.4 
Medication History and Concomitant Medications .....................................................13 
6.4.1 
Prior Medications ................................................................................................13 
6.4.2 
Concomitant Medications ....................................................................................14 
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6.5 
Efficacy Analysis .........................................................................................................14 
6.5.1 
Primary Endpoint(s) Analysis .............................................................................14 
6.5.2 
Secondary Endpoint(s) Analysis .........................................................................14 
6.5.2.1 
Key Secondary Endpoint(s) Analysis (if applicable) ..................................14 
6.5.2.2 
Derivation of Endpoint(s) ...........................................................................15 
6.5.2.3 
Main Analytical Approach ..........................................................................16 
6.5.3 
Other Secondary Endpoints Analysis (if applicable) ..........................................17 
6.5.4 
Subgroup Analyses (if applicable) ......................................................................17 
6.6 
Safety Analysis ............................................................................................................17 
6.6.1 
Adverse Events ....................................................................................................18 
6.6.2 
Other Safety Analysis ..........................................................................................19 
6.6.2.1 
CLINICAL LABORATORY EVALUATION ...........................................19 
6.6.2.2 
VITAL SIGNS ............................................................................................20 
6.6.2.3 
PHYSICAL EXAMINATION ....................................................................23 
6.6.2.4 
GASTROINTESTINAL-SPECIFIC TESTING .........................................23 
6.6.2.5 
FECAL AND URINE OUTPUT ................................................................23 
6.6.3 
Extent of Exposure and Compliance ...................................................................24 
6.6.3.1 
Extent of Exposure, Extent of Observation and Gap in Treatment.............24 
6.6.3.2 
Study Treatment Compliance ......................................................................25 
6.7 
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses .................................25 
6.7.1 
Pharmacokinetic Analysis ...................................................................................25 
6.7.2 
Pharmacodynamic Analysis ................................................................................25 
6.7.3 
Biomarker Analysis .............................................................................................25 
6.8 
Patient Reported Outcomes (PROs) and Health Care Utilization Endpoints 
Analysis........................................................................................................................26 
6.8.1 
PRO Analysis ......................................................................................................26 
6.8.2 
Health Care Utilization Analysis .........................................................................26 
6.9 
Other Analyses .............................................................................................................26 
6.10 
Interim Analyses ..........................................................................................................26 
6.11 
Data Monitoring Committee/Internal Review Committee/ [Other Data Review 
Committees] .................................................................................................................26 
7.0 
REFERENCES ..................................................................................................................26 
8.0 
CHANGES TO PROTOCOL PLANNED ANALYSES ...................................................26 
9.0 
APPENDIX ........................................................................................................................26 
9.1 
Changes From the Previous Version of the SAP .........................................................26 
9.2 
Data Handling Conventions .........................................................................................34 
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9.2.1 
General Data Reporting Conventions ..................................................................34 
9.2.2 
Definition of Baseline ..........................................................................................35 
9.2.3 
Definition of Visit Windows ...............................................................................35 
9.2.4 
L, M AND S VALUES OF HEIGHT, BODY WEIGHT AND HEAD 
CIRCUMFERENCE FOR AGE FOR JAPANESE ............................................36 
9.3 
Analysis Software ........................................................................................................39 
LIST OF IN-TEXT TABLES 
Table 6.a 
Lists the Clinical Safety Laboratory Tests .............................................................19 
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ABBREVIATIONS 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANA 
anti-nuclear antibody 
ASMA 
anti-smooth muscle antibody 
AST 
aspartate aminotransferase 
CI 
confidence interval 
CL/F 
apparent clearance (clearance [CL] divided by bioavailability [F]) 
COVID-19 
coronavirus disease 2019  
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EA 
early antigen 
EOT 
end of treatment 
ET 
early termination 
FAS 
full analysis set 
INR 
International normalized ratio 
ITT 
intention-to-treat 
LLN 
lower limit of normal 
MedDRA 
Medical Dictionary for Regulatory Activities 
NTT 
no-teduglutide treatment 
OC 
observed cases 
PN/IV 
Parenteral nutrition/intravenous fluid 
PS 
Parenteral support 
PT 
Preferred Term (MedDRA) 
Q1 
25th percentile 
Q3 
75th percentile 
RD 
risk difference 
RR 
risk ratio 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SAS 
safety analysis set 
SBS 
short bowel syndrome 
SC 
subcutaneous 
SD 
standard deviation 
SOC 
System Organ Class 
TEAE 
treatment-emergent adverse event] 
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1.0 
OBJECTIVES, ENDPOINTS AND ESTIMANDS 
1.1 
Objectives 
1.1.1 
Primary Objective 
To evaluate the safety of the 1.25 mg formulation of teduglutide in Japanese pediatric patients 
with SBS who are dependent on PS, aged 4 months (corrected gestational age) or older, and 
requiring the dosing of 1.25 mg formulation. 
1.1.2 
Secondary Objective(s) 
To evaluate the efficacy of the 1.25 mg formulation of teduglutide in Japanese pediatric patients 
with SBS who are dependent on PS, aged 4 months (corrected gestational age) or older, and 
requiring the dosing of 1.25 mg formulation. 
1.1.3 
Additional Objective(s) 
Not Applicable. 
1.2 
Endpoints 
1.2.1 
Safety Endpoints 
The following safety endpoints will be analyzed: 
•
Incidence of TEAEs, serious adverse events (SAEs), and adverse events of special interest
(AESIs).
•
Physical examinations.
•
Vital signs, including body temperature, respiratory rate, blood pressure, and pulse.
•
Body weight, height (or length), head circumference and weight-for-length Z-scores
(corrected for gestational age).
•
Laboratory safety data (biochemistry, hematology, and urinalysis).
•
Urine output.
•
Fecal output.
1.2.2 
Efficacy Endpoints 
The following efficacy endpoints will be analyzed: 
•
Change from baseline in PS volume by each visit and EOT.
•
Percent change from baseline in PS volume by each visit and EOT.
•
Number and percent of subjects achieving at least 20% reduction in PS volume from baseline
by each visit and EOT.
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3.2 
Statistical Decision Rules 
Not Applicable. 
3.3 
Multiplicity Adjustment 
Not Applicable. 
4.0 
SAMPLE-SIZE DETERMINATION 
The sample size is determined based on enrollment feasibility of this rare population in children 
in Japan, rather than statistical power calculation. 
5.0 
ANALYSIS SETS 
The full analysis set (FAS) and safety analysis set (SAS) are defined for this trial. 
5.1 
All Screened Subjects Analysis Set 
The All Screened Subjects Analysis Set will consist of all subjects who provide informed 
consent for this study, to be used for reporting disposition and screening failures. 
5.2 
Safety Analysis Set 
The SAS will include all subjects who received at least 1 dose of study teduglutide. Safety 
analyses will be conducted using the SAS. 
5.3 
Full Analysis Set 
The FAS will include all enrolled patients, who are not screen failures. Subjects will be in FAS 
regardless of whether they took any dose of teduglutide in the study. The FAS will be used for 
all the efficacy analyses. 
5.4 
Per-Protocol Analysis Set 
Not Applicable. 
5.5 
Pharmacokinetic Analysis Set 
Not Applicable. 
6.0 
STATISTICAL ANALYSIS 
6.1 
General Considerations 
Baseline values are defined as the last observed value before the first dose of study medication. 
Due to the limited size of the study population descriptive statistics will be used with a goal of 
summarizing the sample which discourages the use of inferential statistics. Accordingly, no 
claims of significance will be made for any of the data. 
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Where applicable, variables will be summarized descriptively by study visit. For the categorical 
variables, the counts and proportions of each possible value will be tabulated. The denominator 
for the proportion will be based on the number of subjects who provided non-missing responses 
to the categorical variable. For continuous variables, the number of subjects with non-missing 
values, mean, median, SD, minimum, and maximum values will be tabulated. Standard errors 
(SE) will be displayed for the efficacy tables, and body weight, height (or length), BMI, head 
circumference and weight for length. 
Means and medians will be presented to 1 more decimal place than the recorded data. The 
standard deviations (SDs) will be presented to 2 more decimal places than the recorded data. CIs 
intervals will be presented using the same number of decimal places as the parameter estimate. 
Scheduled visits will be summarized as provided in the electronic case report forms (eCRFs). An 
End of Treatment (EOT) time point, defined as the last determination of endpoint or last 
available measurement after the date of first dose during the 24-week treatment period will be 
analyzed in addition to the scheduled visits by each cycle. Last NTx will be defined as last 
determination of endpoint or last available measurement during any NTT period. Unscheduled 
measurements will not be included in by-visit summaries for treatment periods but can contribute 
to the EOT value where applicable. 
Study Day will be calculated as follows: 
•
If the date of the evaluation is on or after the first day of study medication then:
Study Day = (date of the evaluation – first day of study medication) + 1. 
•
If the date of the evaluation is prior to the first day of study medication then:
Study Day = (date of the evaluation – first day of study medication). 
Datasets and listings will include data collected at unscheduled visits. Data collected at 
unscheduled visits will not be included in summaries by timepoint or visit unless specified 
otherwise.  
6.1.1 
Handling of Treatment Misallocations 
Not Applicable. 
6.2 
Disposition of Subjects 
The number of subjects in the Full analysis set and Safety analysis set will be presented for the 
All Screened Subjects Analysis Set. 
Number of subjects included and excluded from each analysis set (including reason for 
exclusion) will be summarized based on the All Screened Subjects Analysis Set. A listing 
showing inclusion and exclusion of each subject from each analysis set, including reason for 
exclusion, will be provided. 
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 
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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 Analysis Set. 
A subject data listing will present subject disposition for the All Screened Subjects Analysis Set. 
A subject data listing will present subject disposition by teduglutide-treatment cycle and NTT 
visit for the All Screened Subjects Analysis Set. Inclusion criteria violations, if any, will be 
presented in a listing for the All Screened Subjects Analysis Set. In addition, treatment eligibility 
criteria and follow-up period escape criteria will be listed for the Safety analysis set. 
Number and percentage of subjects with protocol deviations will be provided based on the Safety 
Analysis Set for each category specified in the Protocol Deviations Management Plan. 
A listing of protocol deviations by subject will be presented in the data listings. 
6.3 
Demographic and Other Baseline Characteristics 
6.3.1 
Demographics 
Demographic data and other baseline characteristics will be presented for the Safety Analysis 
Set. 
The following demographic and other baseline characteristics will be reported for this study: 
•
Age (years) at informed consent date for the cohort of children 1 year or more than 1 year of
age.
•
Chronological (actual) age (months) at informed consent date for the infant subjects.
•
Corrected gestational age (months) at informed consent date for the infant subjects.
•
Sex.
•
Race.
•
Ethnicity.
•
Height or length for age Z-score and percentile at Baseline.
•
Weight for age Z-score and percentile at Baseline.
•
Head Circumference for age Z-score and percentile at Baseline (only for subjects who are
<=36 months of age at Baseline).
•
Weight for length Z-score and percentile at Baseline only for the infant subjects at Baseline.
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Age will be rounded to 1 decimal place for reporting. Z-score of weight, height or length and 
head circumference for age as well as weight for length Z-score will be calculated based on the 
method described in Section 6.6.2.2. 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. 
Continuous demographic and other baseline characteristics will be summarized using descriptive 
statistics. Categorical demographic and other baseline characteristics using number and 
percentages of patients in each category. No statistical testing will be carried out for 
demographic or other baseline characteristics. 
6.3.2 
Medical History and Concurrent Medical Conditions 
6.3.2.1 
Short Bowel Syndrome History 
SBS history will be presented for the Safety Analysis Set. 
The following SBS history will be reported for this study: 
•
Duration of SBS at baseline.
•
Primary reason for the diagnosis of SBS (necrotizing enterocolitis, midgut volvulus,
intestinal atresia, gastroschisis, trauma, cancer, Crohn’s disease, long-segment Hirschsprung
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 Hirschsprung disease, other).
•
Stoma (Yes/No), stoma type (jejunostomy, ileostomy, 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]).
•
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).
6.3.2.2 
Other Medical History and Concurrent Medical Conditions 
•
Medical history is defined as any medical conditions/diseases that started and stopped prior
to signing of informed consent.
•
Concurrent medical conditions are defined as any medical conditions that started prior to
signing of informed consent AND were ongoing at the time of signing of informed consent
or ended on the day of signing of informed consent.
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Medical history and concurrent medical conditions will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA), version 24.0 or later, and will be summarized by System 
Organ Class (SOC) and Preferred Term (PT) based on the Safety Analysis Set. A subject having 
more than one medical condition within the same SOC/PT will be counted only once for that 
SOC or PT. 
All medical history and concurrent medical conditions will be listed. 
When the number of subject is less than three, no table will be provided (only listing will be 
provided).  
6.3.3 
PS and EN History 
The following Parenteral Nutrition/Intravenous History and Enteral Nutrition (EN) History 
information collected at the Baseline visit will be summarized with descriptive statistics for the 
Full Analysis Set: 
•
Years or months since start of PN/IV dependency.
•
Current use of EN (Y/N), reason not taking EN (following a regular diet, other).
•
Years or months since start of EN dependency.
For children 1 year or more than 1 year of age, years since start of PN/IV dependency will be 
calculated as (Date of informed consent form signed – Start date of PN/IV dependency 
+1)/365.25.
For infants 4-12 months corrected gestational age, months since start of PN/IV dependency will 
be calculated as (Date of informed consent form signed – Start date of PN/IV dependency +1)/ 
(365.25/12). 
Years and months since start of EN dependency will be calculated in a similar manner but using 
the start date of EN dependency. Both these durations will be rounded to 1 decimal place for 
reporting. 
6.4 
Medication History and Concomitant Medications 
6.4.1 
Prior Medications 
•
Prior medications are defined as any medication that started and stopped prior to the first
dose of study intervention.
Prior 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. 
Prior medications 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. 
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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, 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. 
When the number of subject is less than three, no table will be provided (only listing will be 
provided). 
6.4.2 
Concomitant Medications 
•
Concomitant medications are defined as:
–
Any medication that started before the first dose of study intervention AND was ongoing
at the time of the first dose of study intervention or ended on the date of first dose of
study intervention;
–
Any medication that started on or after the day of first dose of study intervention.
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 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, 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. 
When the number of subject is less than three, no table will be provided (only listing will be 
provided). 
6.5 
Efficacy Analysis 
6.5.1 
Primary Endpoint(s) Analysis 
Not Applicable. 
6.5.2 
Secondary Endpoint(s) Analysis 
6.5.2.1 
Key Secondary Endpoint(s) Analysis (if applicable) 
•
Change from baseline in PS volume by each visit and EOT.
•
Percent change from baseline in PS volume by each visit and EOT.
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•
Number and percent of subjects achieving at least 20% reduction in PS volume from baseline
by each visit and EOT.
•
Number and percent of subjects achieving enteral autonomy, defined as complete weaning
off PS by each visit and EOT.
•
Change from baseline in days per week of PS by each visit and EOT.
6.5.2.2 
Derivation of Endpoint(s) 
Analyses will be conducted using the FAS. 
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 (Week 0 to 
Week 28). An EOT time point and a last NTx time point will also be presented as defined in 
Section 9.2.3.  
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.
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. If more than 5 days’ 
values are missing in two weeks before the first dose, the baseline values are missing. If the most 
recent days of diary data collected prior to the first dose is less than 14 days, baseline diary PS 
values (volume, calories, hours per day and days per week) will be calculated using the most 
recent 7 days of diary data collected prior to the first dose. If more than 2 days’ value are missing 
in one week before the first dose, the baseline values are missing. 
 
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Percent reduction in weight-normalized diary and prescribed PS values from baseline at the 
scheduled visit will be calculated using the formula below: 
•
Percent reduction in PS value at the visit = [(average daily value at the scheduled visit -
average daily value at baseline) / average daily value at baseline] * 100.
Percent reduction calculation will be performed on both diary and prescribed PS data. 
For prescribed PS data, Tables and Figures will not be provided (only listings will be provided) 
when almost all of patients were hospitalized. 
6.5.2.3 
Main Analytical Approach 
6.5.2.3.1 
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. 
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 FAS. 
6.5.2.3.2 
>= 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). 
6.5.2.3.3 
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. 
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. 
6.5.2.3.4 
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. 
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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. 
6.5.3 
Other Secondary Endpoints Analysis (if applicable) 
Not Applicable. 
6.5.4 
Subgroup Analyses (if applicable) 
Not Applicable. 
6.6 
Safety Analysis 
All safety evaluations will be conducted on the Safety analysis set. 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 9.2.3. 
The primary safety endpoints are: 
•
Incidence of TEAEs, serious adverse events (SAEs), and adverse events of special interest
(AESIs).
•
Physical examinations.
•
Vital signs, including body temperature, respiratory rate, blood pressure, and pulse.
•
Body weight, height (or length), head circumference and weight-for-length Z-scores
(corrected for gestational age).
•
Laboratory safety data (biochemistry, hematology, and urinalysis).
•
Urine output.
•
Fecal output.
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6.6.1 
Adverse Events 
Adverse Events (AEs) will be coded using MedDRA. Investigator verbatim as well as preferred 
term and system organ class will be included in the listings. 
Treatment emergent AEs (TEAEs) are defined as AEs whose onset occurs, severity worsens or 
intensity increases during or after receiving the study medication. AEs with an unknown date of 
onset and a stop date after the start of the study period or unknown will be included as treatment 
emergent AEs. Any AE with a start date equal to the date of first dose, where the time of the AE 
cannot definitively place the start of the AE prior to the first dose, will be considered treatment 
emergent. If any AE records contain only partial dates, these will be handled by imputation, as 
described in Section 9.2.1. AEs which are not treatment emergent will be flagged in listings. 
AEs will be summarized overall using number and percent of subjects. The number of events 
will also be presented. Categories summarized will include any TEAE (Y/N), 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 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 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. 
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6.6.2 
Other Safety Analysis 
6.6.2.1 
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.  
Clinical laboratory evaluations include, but not limited to, the following: 
Table 6.a
Lists the Clinical Safety Laboratory Tests 
Hematology 
BioChemistry 
Urinalysis 
Hematocrit 
Hemoglobin 
Platelet count 
White blood cell count with 
differential 
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
Blood 
Glucose 
Leucocytes 
Microscopic analysis 
pH 
Protein 
Specific gravity 
Coagulation 
Prothrombin time 
International normalized ratio 
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 
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by cycle and by scheduled visit within each cycle, i.e., weeks 0, 1, 2, 4, 8, 12, 16, 20, 24 and 28. 
In addition, laboratory results will also be presented at EOT and at last NTx time points.  
Quantitative results will be summarized for hematology, serum chemistry, and selected 
urinalysis parameters by scheduled visit. Both observed values and change from baseline will be 
summarized with descriptive statistics. 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.
Laboratory results will be presented in an appendix data listing for each lab panel (chemistry, 
hematology, urinalysis, coagulation) 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 urine pregnancy results will be presented in appendix data listings only. 
6.6.2.2 
VITAL SIGNS 
The following vital signs measurements will be reported for this study: 
•
Systolic Blood Pressure (mmHg).
•
Diastolic Blood Pressure (mmHg).
•
Respiratory Rate (breaths/min)
•
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:
•
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.
•
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.  
Descriptive statistics will be used to summarize the vital signs at each scheduled study visit. Both 
observed value and change from baseline will be summarized with descriptive statistics. Mean ± 
 
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SE plots of body weight, height or length 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: 
•
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 subjects <2 years corrected gestational age.
Height or length, Weight, Head Circumference 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. 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 for age 
and weight for length will be used. 
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Age 
Height or Length 
Weight 
Weight for 
Length [3] 
Head Circumference 
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 mos 
NA 
WHO 
NA 
WHO 
WHO 
NA 
Kato 2014 
1-<2 yrs 
Isojima 
2016 
WHO 
Isojima 
2016 
WHO 
WHO 
Kato 
2014 
Kato 2014 
2-3 yrs
Isojima 
2016 
Isojima 2016 
Isojima 
2016 
Isojima 2016 
NA 
Kato 
2014 
Kato 2014 
>3 yrs
Isojima 
2016 
Isojima 2016 
Isojima 
2016 
Isojima 2016 
NA 
NA 
NA 
[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] 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 year or more than 1 year 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 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.
6.6.2.2.1 
Z-SCORES OF HEIGHT FOR AGE AND WEIGHT FOR AGE FOR CHILDREN
1YEAR OR MORE THAN 1 YEAR OF 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 
category in the age interval, i.e., age_upper. 
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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.
6.6.2.2.2 
Z-SCORES OF LENGTH FOR AGE AND WEIGHT FOR AGE FOR SUBJECTS
<2 YEARS CORRECTED GESTATIONAL AGE
L, M, S values for WHO growth charts will be used: 
https://www.cdc.gov/growthcharts/who_charts.htm 
6.6.2.2.3 
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 3 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 3, a similar 
interpolation as described in Section 6.6.2.2.1 will be used to calculate the L, M, S values. 
6.6.2.2.4 
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 subjects. 
6.6.2.3 
PHYSICAL EXAMINATION 
Physical exam findings will be presented in the listings for the Safety analysis set. 
6.6.2.4 
GASTROINTESTINAL-SPECIFIC TESTING 
The results of GI-specific testing including fecal occult blood testing and colonoscopy/ 
sigmoidoscopy will be reported in the listings only for the Safety analysis set. 
6.6.2.5 
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 
 
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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 visit within 
each cycle. In addition, results will also be presented at EOT and at last NTx time points. 
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 to 
each scheduled visit will be presented using descriptive statistics. 
6.6.3 
Extent of Exposure and Compliance 
6.6.3.1 
Extent of Exposure, Extent of Observation and Gap in Treatment 
The extent of exposure will be presented both overall and by treatment cycle for the Safety 
analysis set. 
The extent of exposure in days for Cycle X will be calculated as (last exposure date on or before 
Cycle X EOT – Cycle X Week 0 + 1). 
The overall extent of exposure in weeks will be calculated as [the sum of extents of exposure 
across all cycles] / 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 analysis set using descriptive 
statistics. The overall extent of observation in weeks will be calculated as (last date of follow-up 
– inform consent date + 1) / 7. The last date of follow-up is defined as the date of the last 
available visit.
 
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The overall time to start cycle 1 will be presented for the Safety analysis set using descriptive 
statistics. The overall time to start cycle 1 in weeks will be calculated as (Cycle 1 Week 0 – 
inform consent day + 1) / 7. 
The gap in treatment between each treatment cycle will be presented for the Safety analysis set 
using descriptive statistics. The gap in treatment in weeks for Cycle X will be calculated as 
[Cycle X Week 0 – last exposure date of Cycle (X-1) + 1] / 7. The gap in treatment in weeks for 
Cycle 1 will not be presented. 
The overall number of cycles on teduglutide will also be summarized as a numeric variable. 
The information related to study drug training provided by the study physician will be listed for 
all subjects in the Safety analysis set. 
6.6.3.2 
Study 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 Week 0 and Cycle X EOT divided 
by the number of days on treatment in Cycle X. Number of days on treatment in Cycle X is 
calculated as (last exposure date on or before Cycle X EOT – Cycle X Week 0 + 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 at site 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 Analysis Set. 
6.7 
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses 
6.7.1 
Pharmacokinetic Analysis 
Not Applicable. 
6.7.2 
Pharmacodynamic Analysis 
Not Applicable. 
6.7.3 
Biomarker Analysis 
Not Applicable. 
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6.8 
Patient Reported Outcomes (PROs) and Health Care Utilization Endpoints 
Analysis 
6.8.1 
PRO Analysis 
Not Applicable. 
6.8.2 
Health Care Utilization Analysis 
Not Applicable. 
6.9 
Other Analyses 
Not Applicable. 
6.10 
Interim Analyses 
No interim analysis is planned. 
6.11 
Data Monitoring Committee/Internal Review Committee/ [Other Data Review 
Committees] 
Not Applicable. 
7.0 
REFERENCES 
1.
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.
2.
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.
8.0 
CHANGES TO PROTOCOL PLANNED ANALYSES 
For efficacy endpoints, 95% CI was supposed to be provided in Protocol but they will not be 
done because of the few number of subjects. 
9.0 
APPENDIX 
9.1 
Changes From the Previous Version of the SAP 
From the SAP version 1.0, the following parts were updated. 
Section 6.1 General Considerations  
Before the change 
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Similarly, an End of Study (EOS) time point will be defined as the last determination of endpoint 
or last available measurement. Unscheduled measurements will not be included in by-visit 
summaries, but can contribute to the EOT/EOS value where applicable. 
After the change 
Last NTx will be defined as last determination of endpoint or last available measurement during 
any NTT period. Unscheduled measurements will not be included in by-visit summaries for 
treatment periods but can contribute to the EOT value where applicable. 
Reason for the change  
EOS visit is not available in this study. 
Section 6.2 Disposition of Subjects 
Before the change 
The number of subjects in the Enrolled population and Safety analysis set will be presented for 
the All Screened Subjects Analysis Set. 
… 
Number and percentage of subjects with important protocol deviations, as identified by the study 
team as being major or critical, will be provided based on the Safety Analysis Set for each 
category specified in the Protocol Deviations Management Plan. 
After the change 
The number of subjects in the Full analysis set and Safety analysis set will be presented for the 
All Screened Subjects Analysis Set. 
… 
Number and percentage of subjects with protocol deviations will be provided based on the Safety 
Analysis Set for each category specified in the Protocol Deviations Management Plan. 
Reason for the change 
Error correction. 
Section 6.4.1 Prior Medications, Section 6.4.2 Concomitant Medications 
Before the change 
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. 
After the change 
 
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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, start date, end date and indication. 
Reason for the change 
Error correction. 
Section 6.5.2.2 Deviation of Endpoint(s) 
Before the change 
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 9.2.3. 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. 
… 
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. If more than 5 days’ 
values are missing in two weeks before the first dose, the baseline values are missing. 
After the change 
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 (Week 0 to 
Week 28). An EOT time point and a last NTx time point will also be presented as defined in 
Section 9.2.3. 
… 
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. If more than 5 days’ 
values are missing in two weeks before the first dose, the baseline values are missing. If the most 
recent days of diary data collected prior to the first dose is less than 14 days, baseline diary PS 
values (volume, calories, hours per day and days per week) will be calculated using the most 
recent 7 days of diary data collected prior to the first dose. If more than 2 days’ value are missing 
in one week before the first dose, the baseline values are missing. 
Reason for the change 
For the definition of cycle, it’s updated due to error correction. For the handling of unscheduled 
visit, visit window is not applicable for PS diary data. For the handling of missing PS diary data, 
there was a subject with only 7-day PS diary data (it was determined as a protocol deviation). 
Considering the inclusion criteria 6 and small sample size, handling rule was changed to use as 
many subject data as possible. Also, it was considered that 7-day PS diary data for baseline will 
not have a big influence on the efficacy evaluation. 
 
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Section 6.5.2.2 Deviation of Endpoint(s) 
Before the change 
Not Applicable. 
After the change 
For prescribed PS data, Tables and Figures will not be provided (only listings will be provided) 
when almost all of patients were hospitalized.  
Reason for the change 
For hospitalized patients, no prescribed data other than screening data were recorded as PS was 
not prescribed at each visit but administered appropriate volume at each day by investigators.  
Section 6.5.2.3.3 Enteral autonomy (completely weaned off PS) 
Before the change 
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. 
After the change 
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. 
Reason for the change 
In order to compare it with 305 study results, the definition of Enteral autonomy was changed to 
be consistent with the one in the previous study.  
Section 6.6.1 Adverse Events 
Before the change 
The MedDRA terms corresponding to each grouping of events of special interest are included in 
the external data source provided to Bios team. 
After the change 
Delete the description. 
Reason for the change 
Error correction. 
Section 6.6.2.1 CLINICAL LABORATORY EVALUATION 
 
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Before the change 
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: 
… 
Table 6.a Lists the Clinical Safety Laboratory Tests 
Blood Chemistry 
… 
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. 
… 
Laboratory results will be presented in an appendix data listing for each lab panel (chemistry, 
hematology, urinalysis) by subject, parameter, and date of collection. 
After the change 
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.  
Clinical laboratory evaluations include, but not limited to, the following: 
… 
Table 6.a Lists the Clinical Safety Laboratory Tests 
BioChemistry 
Coagulation 
Prothrombin time 
International normalized ratio 
… 
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., weeks 0, 1, 2, 4, 8, 12, 16, 20, 24 and 28. 
In addition, laboratory results will also be presented at EOT and at last NTx time points. 
… 
 
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Laboratory results will be presented in an appendix data listing for each lab panel (chemistry, 
hematology, urinalysis, coagulation) by subject, parameter, and date of collection. 
Reason for the change 
Error correction. 
Section 6.6.2.2 VITAL SIGNS 
Before the change 
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.
After the change
The following vital signs measurements will be reported for this study:
•
Systolic Blood Pressure (mmHg).
•
Diastolic Blood Pressure (mmHg).
•
Respiratory Rate (breaths/min)
•
Pulse Rate (bpm).
•
Temperature (°C).
•
Weight (kg).
•
Height or length (cm).
•
Head circumference (cm) for subjects ≤36 months of age.
Reason for the change
Error correction.
Section 6.6.3 Extent of Exposure and Compliance 
Before the change 
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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 be calculated as [the sum of extents of exposure 
across all cycles in the extension study] / 7. 
… 
The overall extent of observation will be presented for the Safety analysis set using descriptive 
statistics. The overall extent of observation in weeks will be calculated as (last date of follow-up 
– inform consent 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 analysis set using descriptive 
statistics. The overall time to start cycle 1 in weeks will be calculated as (Cycle 1 Day 1 – inform 
consent day + 1) / 7. 
The gap in treatment between each treatment cycle will be presented for the Safety analysis set 
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 
not be presented. 
The overall number of cycles on teduglutide 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 analysis set. 
… 
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. 
After the change 
The extent of exposure in days for Cycle X will be calculated as (last exposure date on or before 
Cycle X EOT – Cycle X Week 0 + 1). 
The overall extent of exposure in weeks will be calculated as [the sum of extents of exposure 
across all cycles] / 7. 
 
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The overall extent of observation will be presented for the Safety analysis set using descriptive 
statistics. The overall extent of observation in weeks will be calculated as (last date of follow-up 
– inform consent date + 1) / 7. The last date of follow-up is defined as the date of the last 
available visit.
The overall time to start cycle 1 will be presented for the Safety analysis set using descriptive 
statistics. The overall time to start cycle 1 in weeks will be calculated as (Cycle 1 Week 0 – 
inform consent day + 1) / 7. 
The gap in treatment between each treatment cycle will be presented for the Safety analysis set 
using descriptive statistics. The gap in treatment in weeks for Cycle X will be calculated as 
[Cycle X Week 0 – last exposure date of Cycle (X-1) + 1] / 7. The gap in treatment in weeks for 
Cycle 1 will not be presented. 
The overall number of cycles on teduglutide will also be summarized as a numeric variable. 
The information related to study drug training provided by the study physician will be listed for 
all subjects in the Safety analysis set. 
… 
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 Week 0 and Cycle X EOT divided 
by the number of days on treatment in Cycle X. Number of days on treatment in Cycle X is 
calculated as (last exposure date on or before Cycle X EOT – Cycle X Week 0 + 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 at site will be 
considered per instructions. 
Reason for the change 
Error correction. 
Section 8.0 CHANGES TO PROTOCOL PLANNED ANALYSES 
Before the change 
Not Applicable. 
After the change 
For efficacy endpoints, 95% CI was supposed to be provided in Protocol but they will not be 
done because of the few number of subjects. 
 
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Reason for the change 
They should have been described in the 1st version because 95%CI of efficacy endpoint has 
already been deleted in the 1st version of the SAP. 
Section 9.2.3 Definition of Visit Windows 
Before the change 
A windowing convention will be used to determine the analysis value for a given study visit for 
Laboratory test, Vital sign, Output diary (Fecal and Urine), and Intake diary (PS) data analyses. 
The window conventions are: 
Table 9.a 
One or more results for a particular analysis variable may be obtained in the same visit window. 
In such an event, the result with the date closest to the expected visit date will be used in the 
analysis. In the event that two observations are equidistant from the expected visit date, the later 
observation will be used in the analysis. 
Beside the Laboratory test, Vital sign, Output diary (Fecal and Urine), and Intake diary (PS) 
analyses, no visit windowing will be performed for analysis of other variables in this study. 
After the change 
No visit windowing will be performed for analysis in this study. Nominal visit will be used for 
analysis for treatment periods. For NTT periods, data will be summarized in sequential order 
regardless of their cycle and visit. 
Reason for the change 
As sample size was small (only 3) and 2 subjects were hospitalized ones, we considered using 
nominal visit will not have a big influence on the evaluation.  
9.2 
Data Handling Conventions 
9.2.1 
General Data Reporting Conventions 
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.
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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.
9.2.2 
Definition of Baseline 
Unless otherwise specified, baseline is defined as the last non-missing measurement taken prior 
to the first dose of study intervention (including unscheduled assessments). In the case where the 
last non-missing measurement and the date and time of the first dose of study intervention 
coincide, that measurement will be considered pre-baseline, but AEs and medications 
commencing on the date of the first dose of study intervention will be considered post-baseline. 
9.2.3 
Definition of Visit Windows 
No visit windowing will be performed for analysis in this study. Nominal visit will be used for 
analysis for treatment periods. For NTT periods, data will be summarized in sequential order 
regardless of their cycle and visit. 
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9.2.4 
L, M AND S VALUES OF HEIGHT, BODY WEIGHT 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 Head Circumference for Age for Japanese Subjects 
≤36 Months of Age 
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9.3 
Analysis Software 
All analyses will be conducted using SAS version 9.4 or higher. 
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