Clinical trial NCT03663582
Conditions: Short Bowel Syndrome
Sponsor: Shire
Start date: 2018-07-06; Completion date: 2019-08-06
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The objectives of this clinical study are to evaluate the safety, efficacy, and pharmacokinetics (PK) of teduglutide in Japanese participants with short bowel syndrome (SBS) who are dependent on parenteral nutrition/intravenous (PN/IV) over a 24-week treatment period.

Detailed description:

Arms: arm 1: Participants will receive teduglutide 0.05 milligram per kilogram (mg/kg) subcutaneous (SC) injection once daily into 1 of the 4 quadrants of the abdomen or either thigh or arm for 24 weeks.
Interventions: intervention 1: Teduglutide intervention 2: Syringe intervention 3: Needle intervention 4: Vial Adapter for Device
Intervention descriptions: intervention 1: Teduglutide 0.05 mg/kg SC injection will be administered once daily into 1 of the 4 quadrants of the abdomen or either thigh or arm. intervention 2: Teduglutide will be administered using syringe. Syringe is approved for use in Japan by Pharmaceuticals and Medical Devices Agency (PMDA). intervention 3: Teduglutide will be administered using needle. Needle is approved for use in Japan by PMDA. intervention 4: Vial adapter for device is approved for use in Japan by PMDA.

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
 
 
NCT Number:   
NCT03663582 
 
Study Title:  
A 24-Week Safety, Efficacy, Pharmacokinetic Study of Teduglutide in 
Japanese Subjects with Short Bowel Syndrome who are Dependent on 
Parenteral Support 
 
Study Number:  
SHP633-306 
 
 
Protocol Version and Date:  
 
Original Protocol: 23 January 2018 
Amendment 1: 27 September 2018 


PROTOCOL: SHP633-306
TITLE:
A 24-Week Safety, Efficacy, Pharmacokinetic Study of Teduglutide in 
Japanese Subjects with Short Bowel Syndrome who are Dependent on 
Parenteral Support
NUMBER
SHP633-306
PHASE
3 
DRUG:
Teduglutide
INDICATION:
Short bowel syndrome
SPONSOR: 
Shire Human Genetic Therapies, Inc.
300 Shire Way
Lexington, MA 02421 USA
PROTOCOL 
HISTORY:
Protocol: 23 Jan 2018
Confidentiality Statement
This document contains confidential and proprietary information of Shire and is disclosed 
pursuant to confidentiality and non-disclosure obligations. This information should be used 
solely for the purposes for which it was provided and should not be copied, shared with, or 
disclosed to any third party without the express written consent of Shire.


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PROTOCOL SIGNATURE PAGE 
Sponsor's (Shire) Approval 
I Signature: 
I
, MD PhD 
, Global Clinical Development 
·1 Date
I 
Investigator's Acknowledgement 
I have read this protocol for Shire Study SHP633-306. 
Title: A 24-Week Safety, Efficacy, Pharmacokinetic Study ofTeduglutide in Japanese Subjects 
with Short Bowel Syndrome who are Dependent on Parenteral Support 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Conference on Harmonization (ICH) guidelines on Good Clinical 
Practice (GCP) and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Address: 
(please hand print or type) 
Signature: 
Date: 


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EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Adverse Event Form for Serious Adverse Events and Non-serious adverse evetns 
(AEs) as Required by Protocol within 24 hours to the sponsor or designee using the details 
below. Applicable fax numbers and e-mail address can also be found on the form (sent under 
separate cover).
Pharmacovigilance SAE Reporting:
or 
 (Japan domestic line only) 
or
Email: 
For protocol- or safety-related issues, the investigator should contact:
, MD
Phone:
(24-hour coverage)
Email:
Fax:
For protocol- or safety-related issues the investigator may also contact the Shire medical 
monitor:
, MD, PhD
 Global Clinical Development
Office Phone: 
Mobile Phone:
Email:
Fax:
In-country Clinical Caretaker: 
Quintiles Transnational Japan K.K.
4-10-18 Takanawa, Minato-ku
Tokyo, 108-0074, Japan


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PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
The product quality includes quality of the drug delivery device combination product. As such 
device defects should be reported according to the instructions in this section. The reporting of 
product quality occurrences, when the product does not meet specifications, includes the 
reporting of device defects.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
Ex-US
Telephone numbers (provided for reference, if needed): 
Shire (USA)


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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
PRODUCT QUALITY COMPLAINTS..........................................................................................4
TABLE OF CONTENTS.................................................................................................................5
LIST OF TABLES...........................................................................................................................9
LIST OF FIGURES .........................................................................................................................9
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..................................................10
STUDY SYNOPSIS ......................................................................................................................12
STUDY SCHEDULES ..................................................................................................................16
BACKGROUND INFORMATION .......................................................................................21
1
1.1
Indication and Current Treatment Options ......................................................21
1.2
Product Background and Clinical Information................................................22
STUDY OBJECTIVES AND PURPOSE ..............................................................................24
2
2.1
Rationale for the Study ....................................................................................24
2.2
Study Objectives ..............................................................................................24
STUDY DESIGN ...................................................................................................................25
3
3.1
Study Design and Flow Chart..........................................................................25
3.1.1
Optimization and Stabilization Periods .................................................................25
3.1.2
Treatment Period....................................................................................................25
3.2
Study Duration.................................................................................................26
3.3
Sites and Regions.............................................................................................26
STUDY POPULATION.........................................................................................................28
4
4.1
Inclusion Criteria .............................................................................................28
4.2
Exclusion Criteria ............................................................................................29
4.3
Reproductive Potential.....................................................................................30
4.4
Discontinuation of Subjects .............................................................................30
4.4.1
Reasons for Discontinuation..................................................................................31
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit .................................31
PRIOR AND CONCOMITANT TREATMENT ...................................................................32
5
5.1
Prior Treatment ................................................................................................32
5.2
Concomitant Treatment ...................................................................................32
5.2.1
Permitted Treatment...............................................................................................32
5.2.2
Prohibited Treatment .............................................................................................32
INVESTIGATIONAL PRODUCT ........................................................................................33
6
6.1
Identity of Investigational Product...................................................................33
6.1.1
Blinding the Treatment Assignment ......................................................................33


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6.2
Administration of Investigational Product.......................................................33
6.2.1
Allocation of Subjects to Treatment ......................................................................33
6.2.2
Dosing....................................................................................................................33
6.2.2.1
Subject Administration...........................................................................33
6.2.3
Unblinding the Treatment Assignment..................................................................34
6.3
Labeling, Packaging, Storage and Handling....................................................34
6.3.1
Labeling and Packaging.........................................................................................34
6.3.2
Storage and Handling.............................................................................................35
6.4
Drug Accountability.........................................................................................36
6.5
Subject Compliance .........................................................................................37
STUDY PROCEDURES........................................................................................................38
7
7.1
Study Schedule.................................................................................................38
7.1.1
Screening................................................................................................................38
7.1.2
Optimization and Stabilization Periods .................................................................38
7.1.3
Treatment Period....................................................................................................38
7.1.4
Follow-up Period ...................................................................................................38
7.2
Study Evaluations and Procedures...................................................................39
7.2.1
Demographics and Other Baseline Characteristics................................................39
7.2.1.1
Demographics and Medical History.......................................................39
7.2.1.2
Clinical Assessment of Crohn’s Disease Activity..................................39
7.2.2
Efficacy Assessments.............................................................................................39
7.2.2.1
Subject Diaries .......................................................................................39
7.2.2.2
Prescribed Parenteral Nutrition ..............................................................39
7.2.2.3
Plasma Citrulline....................................................................................40
7.2.3
Safety Assessments................................................................................................40
7.2.3.1
Laboratory Evaluations ..........................................................................40
7.2.3.2
Antibodies to Teduglutide......................................................................41
7.2.3.3
Physical Examinations ...........................................................................42
7.2.3.4
Vital Signs, Body Weight, and Height...................................................42
7.2.3.5
Electrocardiograms.................................................................................42
7.2.3.6
Gastrointestinal-specific Testing............................................................42
7.2.4
Pharmacokinetic Assessments ...............................................................................44
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................45
8
8.1
Definition of Adverse Events, Period of Observation, Recording of 
Adverse Events ................................................................................................45
8.1.1
Severity Categorization..........................................................................................45
8.1.2
Relationship Categorization...................................................................................46
8.1.3
Outcome Categorization ........................................................................................46


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8.1.4
Symptoms of the Disease under Study ..................................................................47
8.1.5
Clinical Laboratory and Other Safety Evaluations ................................................47
8.1.6
Pregnancy...............................................................................................................47
8.1.7
Abuse, Misuse, Overdose, and Medication Error ..................................................48
8.2
Serious Adverse Event Procedures ..................................................................48
8.2.1
Reference Safety Information ................................................................................48
8.2.2
Reporting Procedures.............................................................................................49
8.2.3
Serious Adverse Event Definition .........................................................................49
8.2.4
Serious Adverse Event Collection Time Frame.....................................................50
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................50
8.2.6
Fatal Outcome........................................................................................................50
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................50
8.3
Adverse Events of Special Interest ..................................................................51
DATA MANAGEMENT AND STATISTICAL METHODS ...............................................52
9
9.1
Data Collection ................................................................................................52
9.2
Clinical Data Management ..............................................................................52
9.3
Statistical Analysis Process..............................................................................52
9.4
Planned Interim Analysis.................................................................................52
9.5
Sample Size Calculation and Power Considerations .......................................53
9.6
Study Population..............................................................................................53
9.7
Efficacy Analyses ............................................................................................53
9.8
Safety Analyses................................................................................................54
9.9
Pharmacokinetics Analyses .............................................................................54
SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES ............................................56
10
10.1
Sponsor’s Responsibilities...............................................................................56
10.1.1 Good Clinical Practice Compliance.......................................................................56
10.1.2 Indemnity/Liability and Insurance.........................................................................56
10.1.3 Public Posting of Study Information......................................................................56
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................56
10.1.5 Study Suspension, Termination, and Completion..................................................57
10.2
Investigator’s Responsibilities.........................................................................57
10.2.1 Good Clinical Practice Compliance.......................................................................57
10.2.2 Protocol Adherence and Investigator Agreement ..................................................57
10.2.3 Documentation and Retention of Records .............................................................58
10.2.3.1
Electronic Case Report Forms................................................................58


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10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................58
10.2.3.3
Audit/Inspection .....................................................................................59
10.2.3.4
Financial Disclosure...............................................................................59
10.3
Ethical Considerations .....................................................................................59
10.3.1 Informed Consent...................................................................................................59
10.3.2 Institutional Review Board or Ethics Committee ..................................................60
10.4
Privacy and Confidentiality .............................................................................60
10.5
Study Results/Publication Policy.....................................................................61
REFERENCES .......................................................................................................................63
11
APPENDICES ........................................................................................................................65
12
Appendix 1
Parenteral Nutrition/Intravenous Optimization................................................66
Appendix 2
Parenteral Nutrition/Intraveous Adjustment During Treatment  Period..........67


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LIST OF TABLES
Table 1
Schedule of Evaluations and Procedures – Optimization/Stabilization ........16
Table 2
Schedule of Evaluations and Procedures – Treatment Period.......................18
Table 3 
Prohibited Treatment.....................................................................................32
Table 4
List of Laboratory Tests ................................................................................41
LIST OF FIGURES
Figure 1  
Study Schematic ............................................................................................27


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation
Definition
AE
adverse event
ALT
alanine aminotransferase, equivalent to SGPT
AST
aspartate aminotransferase, equivalent to SGOT
AUC
area under the plasma concentration-time curve
AUC0–t
AUC from zero to the last measurable concentration
BUN
blood urea nitrogen
CL/F
apparent clearance
Cmax
maximum plasma concentration
CRO
contract research organization
ECG
electrocardiogram
eCRF
electronic case report form
EGD
esophagogastroduodenoscopy
EMA
European Medicines Agency
EOT
end of treatment
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
gastrointestinal 
GLP
glucagon-like peptide
ICF
informed consent form
ICMJE
International Committee of Medicinal Journal Editors
ICH
International Committee on Harmonisation
IBD
inflammatory bowel disease
I/O
oral fluid intake and urine output
IRB
Institutional Review Board
ITT
intent-to-treat
IV
intravenous
MedDRA
Medical Dictionary for Regulatory Activities
PK
pharmacokinetics
PN/IV
parenteral nutrition/intravenous
PNALD
parenteral nutrition-associated liver disease
SAE
serious adverse event
SAP
statistical analysis plan


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Abbreviation
Definition
SBS
short bowel syndrome
SC
subcutaneous
t1/2
terminal-phase half-life
tmax
time to Cmax
ULN
upper limit of normal 
US
United States
V/F
apparent volume of distribution


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STUDY SYNOPSIS
Protocol number: SHP633-306
Drug: Teduglutide
Title of the study: A 24-Week Safety, Efficacy, Pharmacokinetic Study of Teduglutide in Japanese Subjects with 
Short Bowel Syndrome who are Dependent on Parenteral Support
Number of subjects (total and for each treatment arm):
At least 5 Japanese subjects will be dosed.
Investigator(s): Multicenter study.
Site(s) and Region(s): 
This study is planned to be conducted in approximately 5 sites in Japan.
Study period (planned):
2017-2020
Clinical phase:
3
Objectives:
The objectives of this clinical study are to evaluate the safety, efficacy, and pharmacokinetics (PK) of teduglutide 
in Japanese subjects with short bowel syndrome (SBS) who are dependent on parenteral nutrition/intravenous
(PN/IV) over a 24-week treatment period.
Investigational product, dose, and mode of administration:
Teduglutide 0.05 mg/kg subcutaneously (SC) once daily into 1 of the 4 quadrants of the abdomen or either thigh 
or arm.
Methodology:
This is an open-label, multicenter study, consisting of a conditional PN/IV optimization 
period, a mandatory PN/IV stabilization period, and a 24-week treatment period. 
If at screening, a subject does not have an optimized PN/IV volume, defined as a 48-hour urine output between 
2 and 4 L, he/she will enter the optimization period, during which the minimally tolerated stable PN/IV volume 
will be determined during a period of up to 8 weeks. If it is not possible to keep the subject adequately hydrated 
and nourished within the target urine output range, the minimally tolerated PN/IV volume will be documented.
All subjects will then enter the stabilization period, during which the target PN/IV volume will be maintained for 
at least 4 consecutive weeks (8 weeks maximum). 
Screening
Up to 7 days
Optimization
0-8 weeks
Stabilization
4-8 weeks
Teduglutide treatment 0.05 mg/kg SC qday
24 weeks
V1.0V1.1 V1.2 V1.3 V1.4
V1.5
V2
(Baseline)
V3 V4 V5
V6
V7
V8
V9
V10
(EOT)
Safety follow-up
phone call
4 weeks after EOT
Extension
study
Up to 4 visits as needed
Performed if urine output 
is not in the target range
at screening


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Following the stabilization period, subjects will enter a 24 week dosing period, during which all subjects will 
receive teduglutide 0.05 mg/kg SC once daily. At each site visit during the treatment phase, efficacy (adjustments 
to PN/IV) and safety will be monitored.  
Subjects will have blood samples taken for teduglutide PK analysis at predose, at 15, 30 minutes and 1, 2, 3, 4, 6, 
8, 10, and 12 hours post dose at the baseline visit (Visit 2). Subjects also will have blood samples taken for 
teduglutide PK analysis at predose and 1 and 2 hours post dose at Week 4 (Visit 5) or Week 12 (Visit 7) of the 
treatment period. 
All subjects who complete the study may participate in a long-term extension study in which subjects will 
continue to receive teduglutide. Subjects who do not enroll in the extension study or who discontinue the study 
prematurely at any time will receive a follow-up phone call 4 weeks after the last dose of study drug.
Inclusion and Exclusion Criteria:
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1.
Ability to voluntarily provide written, signed, and informed consent to participate in the study.
2.
Male or female 16 years of age or older at the time of signing informed consent.
3.
Intestinal failure due to SBS as a result of major intestinal resection (eg, due to injury, volvulus, vascular 
disease, cancer, Crohn’s disease) that resulted in at least 12 continuous months of PN/IV dependence at 
the time of informed consent.
4.
Parenteral nutrition requirement of at least 3 times per week during the week before the screening visit 
and during the 2 weeks prior to the baseline visit.
5.
Stable PN/IV requirement for at least 4 consecutive weeks immediately prior to the start of teduglutide 
treatment. Stability is defined as:
a.
Actual PN/IV usage is similar to prescribed PN/IV.
b.
Baseline (Visit 2) 48-hour oral fluid intake and urine output (I/O) volumes fall within ±25% of 
the respective 48-hour I/O volumes at the last optimization visit.
c.
Urine output volume should NOT fall below 2 L and should not exceed 4 L per 48 hours at the 
last optimization visit, the stabilization visit, and the baseline visit.
6.
For subjects with a history of Crohn’s disease, clinical remission for at least 12 weeks prior to the 
baseline visit as demonstrated by clinical assessment, which may include procedure-based evidence of 
remission.
7.
Females of childbearing potential must agree to comply with the contraceptive requirements of the 
protocol.
8.
An understanding, ability, and willingness to fully comply with study procedures and restrictions.
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1.
Participation in a clinical study using an experimental drug within 30 days or 5.5 half-lives, whichever is 
longer, prior to screening, or concurrent participation in any other clinical study.
2.
Use of GLP-2 or human growth hormone or analogs of these hormones within the past 6 months.
3.
Use of octreotide, GLP-1 analogs, dipeptidyl peptidase-IV inhibitors, or enteral glutamine within 
30 days.
4.
Previous use of teduglutide.
5.
Subjects with active inflammatory bowel disease (IBD) or subjects with IBD who received a change in 
immunosuppressant therapy (eg, azathioprine, anti-TNFs) within the past 6 months.
6.
Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus inclusion disease, 
familial adenomatous polyposis, etc.
7.
Chronic intestinal pseudo-obstruction or severe dysmotility.
8.
Clinically significant intestinal stenosis or obstruction, or evidence of such on upper gastrointestinal (GI) 


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series with small bowel follow-through, within the past 6 months.
9.
Major GI surgical intervention, including bowel lengthening procedures, within the past 3 months 
(insertion of feeding tube or endoscopic procedure is allowed).
10. Unstable cardiac disease, (eg, congestive heart failure, cyanotic disease, or congenital heart disease).
11. Moderate or severe renal impairment, defined as creatinine clearance <50 ml/min. 
12. Currently diagnosed with cancer or a history of any cancer except surgically curative skin cancer within 
the past 5 years.
13. Severe hepatobiliary disease including:
a.
Total bilirubin level ≥2 times the upper limit of normal (ULN).
b.
Aspartate aminotransferase (AST) ≥5 times ULN.
c.
Alanine aminotransferase (ALT) ≥5 times ULN.
14. Active clinically significant pancreatic disease, including clinical signs of pancreatitis associated with 
elevations in serum amylase or lipase ≥2 times ULN.
15. More than 4 SBS-related or PN/IV -related hospital admissions (eg, central line-associated bloodstream 
infection, bowel obstruction, severe fluid/electrolyte disturbances) within the past 12 months.
16. Unscheduled hospitalization within 30 days prior to screening.
17. Pregnant or lactating female.
18. Any condition or circumstance that in the investigator’s opinion put the subject at any undue risk, 
prevent completion of the study, or interfere with analysis of the study results.
Maximum Duration of Subject Involvement in the Study:
Subjects will undergo up to a 7 day screening period, a conditional PN/IV support optimization period (up to 8 
weeks), and a stabilization period (up to 8 weeks) prior to receiving teduglutide treatment. Thus, the screening, 
optimization period, and stabilization period could last up to 17 weeks in total.
Following the optimization and stabilization periods, the subjects will receive the study drug for 24 weeks. 
Endpoints:
Efficacy

Absolute and relative change from baseline in weekly PN/IV volume by visit and at end of treatment 
(EOT).

Percentage of subjects who achieve at least 20% reduction from baseline in weekly PN/IV volume at 
both Weeks 20 and 24.

Percentage of subjects who achieve at least a 20% reduction from baseline in weekly PN/IV volume at 
each visit

Change in days per week of PN/IV support from baseline by visit.

Change in plasma citrulline from baseline by visit.

Number of subjects who are able to completely wean off of PN/IV support.
Pharmacokinetics
The following parameters will be derived: area under the plasma concentration–time curve from zero to the last 
measurable concentration (AUC0–t); maximum plasma concentration (Cmax); time to Cmax (tmax); terminal-phase 
half-life (t1/2); apparent clearance (CL/F); and apparent volume of distribution (V/F).
Safety
Adverse events (AEs), 12-lead electrocardiogram (ECG), vital signs, laboratory safety data, antibodies to 
teduglutide, and changes in 48-hour urine output, body weight and body mass index will be evaluated. An 
abdominal ultrasound, esophagogastroduodenoscopy, and colonoscopy/sigmoidoscopy of remnant colon will be 
done during the stabilization period if these procedures were not done in the 6 months prior to screening. 
Colonoscopy/sigmoidoscopy will be repeated at the end of the treatment period. Esophagogastroduodenoscopy
will be repeated at the end of the treatment period for subjects with risk factors for gastric cancer. For all subjects 
with a history of Crohn’s disease, an upper GI contrast series with small bowel follow-through will be performed 


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during the Stabilization Period, prior to the baseline visit.
Statistical Methods:
Efficacy
The absolute and relative change in weekly PN/IV volume, days per week of PN/IV support, and plasma 
citrulline, from baseline to each scheduled visit, as well as at EOT, will be summarized using descriptive 
statistics.
The number and percentage of subjects who demonstrate a response at Week 20 and again at Week 24 will be 
summarized. A response is defined as the achievement of at least a 20% reduction from baseline in weekly PN/IV
volume. The number and percentage of subjects who demonstrate at least a 20% reduction from baseline in 
weekly PN/IV volume at each visit will also be summarized. 
The number and percentage of subjects who completely wean off PN/IV support by Week 24/EOT will be 
summarized. A subject will be considered to have achieved independence from PN/IV (completely weaned off 
PN/IV) if the investigator prescribes no PN/IV at week 24/EOT and there is no use of PN/IV recorded in the 
subject diary during the 2 weeks prior to the last dosing visit.
Pharmacokinetics
Teduglutide plasma concentrations will be summarized using descriptive statistics (number, mean and standard 
deviation, minimum, median, and maximum) at nominal time points. Pharmacokinetic parameters will be 
estimated using non-compartmental analysis as appropriate and summarized using descriptive statistics (number, 
mean, standard deviation, geometric mean, and CV%, minimum, median, and maximum). 
Safety
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Treatment-
emergent AEs are defined as AEs that started or worsened on or after the date and time of the first dose of study 
dose. Treatment-emergent AEs will be summarized by system organ class and preferred term using descriptive 
statistics (eg, number and percentage of subjects). Adverse events will be summarized by severity, relationship to 
treatment, and for AEs leading to discontinuation, and death. In addition, SAEs will also be tabulated by overall 
and treatment-related events.
For laboratory tests, 48-hour oral intake and urine output, vital signs, body weight, and body mass index, 
descriptive statistics (eg, n, mean, standard deviation, median, minimum and maximum values, the number and 
percentage of subjects in specified categories) will be used to summarize the absolute values and change from 
Baseline at each time point.
The number and percentage of subjects classified as having antibodies to teduglutide will be used to summarize 
the presence of antibodies.  


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STUDY SCHEDULES
Table 1
Schedule of Evaluations and Procedures – Optimization/Stabilization
Procedures
Screening
(up to 7-days)
PN/IV Optimization Period
(8-week maximum)
PN/IV
Stabilization 
Perioda
4-8 weeks 
Week 2
(± 3 days)
Week 4 
(± 3 days)
Week 6
(± 3 days)
Week 8
(± 3 days)
Visit Number:
V1.0
V1.1
V1.2
V1.3
V1.4
V1.5
Informed consent
Xb
Eligibility criteria
X
Medical history, demographics
X
Crohn’s disease assessment
X
Physical examinationc
X
X
X
X
X
X
Record PN/IV use and adjust prescription as 
indicated
Xd
X
X
X
X
X
Adverse events
X
X
X
X
X
X
Abdominal ultrasounde
X
Upper GI contrast series with small bowel 
follow-throughf
X
Esophagogastroduodenoscopye
X
Colonoscopy/sigmoidoscopyg
X
Prior/Concomitant medication/proceduresh
X
X
X
X
X
X 
Vital signs
X
X
X
X
X
X
Height
X
Body weight 
X
X
X
X
X
Xi
12-lead ECGj
X
Safety laboratory tests
X
X
X
X
X
X
Urine pregnancy testk
X
Interim safety evaluation
[X]l
[X]l
[X]l
[X]l
[X]l
Dispense diarym
X
X
X
X
X
X


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Table 1
Schedule of Evaluations and Procedures – Optimization/Stabilization
Procedures
Screening
(up to 7-days)
PN/IV Optimization Period
(8-week maximum)
PN/IV
Stabilization 
Perioda
4-8 weeks 
Week 2
(± 3 days)
Week 4 
(± 3 days)
Week 6
(± 3 days)
Week 8
(± 3 days)
Visit Number:
V1.0
V1.1
V1.2
V1.3
V1.4
V1.5
Review Diary m
X
X
X
X
X
X
ECG=electrocardiogram; GI=gastrointestinal; ICF=informed consent form; PN/IV =parenteral nutrition/intraveous; V=visit
a The baseline visit must occur 4-8 weeks after the last optimization visit (or screening visit if no optimization is needed). The stabilization visit must occur 
during this 4-8 week interval, and must occur at least 7 days apart from the preceding visit (screening or optimization visit) and subsequent visit (baseline).  
b No study-related procedures are to be performed unless the ICF has been signed.
c A full physical examination is to be performed at screening.  Focused physical exams may be performed at all other visits
d PN/IV evaluation is to confirm weekly volume for inclusion criteria.
e Abdominal ultrasound and esophagogastroduodenoscopy should be completed during the stabilization period, prior to the baseline visit if not performed within 
6 months prior to screening.
f Upper GI contrast series with small bowel follow-through is required for subjects with Crohn’s disease.  This should be completed during the stabilization 
period, prior to the baseline visit.
g Colonoscopy/sigmoidoscopy of remnant colon with polyp removal before teduglutide exposure will be performed in subjects with any colon remnant including 
rectal stump evaluation. Colonoscopy/sigmoidoscopy should be completed during the stabilization period, prior to the baseline visit, if required. If a subject had a
normal colonoscopy/sigmoidoscopy documented within 6 months prior to screening, a baseline colonoscopy/sigmoidoscopy will not be required.  
h At screening, information on all medications taken in the previous 14 days will be collected.
i The dose calculation will be based on an average of the 2 measurements of body weight at the stabilization and baseline visits.  This is the first of 2 body weight 
measurements that will be used to determine drug volume.
j A 12-lead ECG will be performed at the study center after the subject has been resting for at least 5 minutes.
k For women of childbearing potential.
l Interim safety evaluations will be performed 5 to 7 days after implementing a change to the subject’s PN/IV. These measures include 48-hour oral fluid intake, 
48-hour urine volume, hematocrit, serum blood urea nitrogen and creatinine, and urine sodium.
m Subjects will record their PN/IV support daily throughout the study. Prior to each clinic and safety visit, subjects will also record all enteral fluid intake and  
urine output over a 48-hour period.


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Table 2
Schedule of Evaluations and Procedures – Treatment Period
Procedures
Baseline
Dosing
Week 1
Dosing
Week 2
Dosing 
Week 4
Dosing
Week 8
Dosing
Week 12
Dosing
Week 16
Dosing
Week 20
Dosing Week 24
/EOTa (or ETb)
Follow-up 
Call 
Week 28a
Visit Number:
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
Visit Window (days)
± 2
± 3
± 3
± 5
± 5
± 5
± 7
± 7
± 7
Eligibility criteria
X
Crohn’s disease 
assessmentc
X
Physical examinationd
X
X
X
X
X
X
X
X
X
Record PN/IV use and 
adjust prescription as 
indicated
Xe
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
EGD
Xf
Colonoscopy/ 
Sigmoidoscopy 
X
Concomitant 
medication /procedures
X
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
Body weight
Xg
X
X
X
X
X
X
X
12-lead ECGh
X
X
X
Safety laboratory tests
X
X
X
X
X
X
X
X
Citrullinei
X
X
X
X
X
Antibodies to 
teduglutidej
X
X
X
PK sampling
Xk
(X)k
(X)k
Urine pregnancy testl
X
X
X
X
X
X
X
X
Drug dispensing
X
X
X
X
X
X
X
Teduglutide dosingm
X
X
X
X
X
X
X
X
Xn
Confirm administration 
proficiency
Xo
Xo
Xo
X
X
Xp
Interim safety 
evaluationq
[X]
[X]
[X]
[X]
[X]
[X]
[X]
Dispense Diaryr
X
X
X
X
X
X
X
X
Xp
Review Diaryr
X
X
X
X
X
X
X
X
Compliances
X
X
X
X
X
X
X
X


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Table 2
Schedule of Evaluations and Procedures – Treatment Period
Procedures
Baseline
Dosing
Week 1
Dosing
Week 2
Dosing 
Week 4
Dosing
Week 8
Dosing
Week 12
Dosing
Week 16
Dosing
Week 20
Dosing Week 24
/EOTa (or ETb)
Follow-up 
Call 
Week 28a
Visit Number:
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
(X) = Possible PK sampling time point; [X] = Possible interim safety evaluation time point; 48-hour I/O=48-hour fluid intake/urine output; 
ECG=electrocardiogram; EGD=esophagogastroduodenoscopy; EOT=end of treatment; ET=early terminationPK=pharmacokinetic; PN/IV=parenteral 
nutrition/intraveous; V=visit
a The follow-up period for this protocol is 4 weeks from the last dose of investigational product. Subjects who do not enroll in the treatment extension study or 
who discontinue prematurely at any time during the study will receive a follow-up phone call 4 weeks after the last dose  to query for SAEs, AEs, and 
concomitant treatments.
b Subjects with an ET visit should have all applicable Week 24 (Visit 10) assessments.  Call sponsor for guidance.
c Subjects with active Crohn’s disease are excluded from the study participation, therefore endoscopy/colonoscopy prior to study treatment may be required in 
subjects with clinical suspicion of active disease.
d A full physical examination is to be performed at baseline and Week 24 (Visit 10); a brief examination will be performed at all other dosing weeks with a clinic 
visit.
e The PN/IV evaluation is to confirm weekly volume for inclusion criteria.
f Esophagogastroduodenoscopy at Visit 10 is required for subjects with risk factors for gastric cancer (see Section 7.2.3).
g The dose calculation will be based on an average of the 2 measurements of body weight at the stabilization and baseline visits.  This is the second of 2 body 
weight measurements that will be used to determine drug volume.
h A 12-lead ECG will be performed at the study center after the subject has been resting for at least 5 minutes.
i Blood sample for measuring citrulline should be drawn from peripheral venous access, if this is not possible, sample may be drawn from a central line. 
j Blood sample for antibody testing is to be collected at baseline (Visit 2) prior to first investigational product administration. Blood samples for antibody testing 
at Week 12 (Visit 7) and Week 24 (Visit 10) must be collected prior to that day's dose, and more than 14 hours after the prior day's dose.
k Samples for PK analysis will be collected pre-dose and at 15, 30  minutes post-dose and at 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose at Visit 2. Additional PK 
samples will be collected predose, and 1 and 2 hours post-dose at Week 4 (Visit 5) or Week 12 (Visit 7). The site of teduglutide administration prior (arm, 
thigh, or abdomen) and the person administering the injection (subject or physician) must be specified.  Blood sample for measuring PK must be drawn from 
peripheral venous access.
l For women of childbearing potential.  
m Teduglutide is dosed once daily during the treatment period. The first dose of study drug must be administered by the study physician.
n Dosing will continue if the subject enters the extension study, but will stop at the Week 24 visit if the subject doesn't enter the extension study.
o The study physician must observe the subject administering the study drug in compliance with the study drug administration checklist at least twice before the 
subject is allowed to administer the drug without direct observation by the physician. Refer to Section 6.2.2.1.
p For subjects entering the extension study only.
q Interim safety evaluations will be performed 5 to 7 days after any change to the subject’s PN/IV has been implemented. These measures include 48-hour oral 
fluid intake, 48-hour urine output, hemoglobin, hematocrit, serum blood urea nitrogen, creatinine, and urine sodium, and may be performed at the 
investigational site laboratory.
r Subjects will record their PN/IV support and teduglutide dosing daily throughout the study. Prior to each clinic and safety visit, subjects will also record all 


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Table 2
Schedule of Evaluations and Procedures – Treatment Period
Procedures
Baseline
Dosing
Week 1
Dosing
Week 2
Dosing 
Week 4
Dosing
Week 8
Dosing
Week 12
Dosing
Week 16
Dosing
Week 20
Dosing Week 24
/EOTa (or ETb)
Follow-up 
Call 
Week 28a
Visit Number:
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
enteral fluid intake and  urine output over a 48-hour period.
s Compliance will be checked at every visit by asking subjects if they have taken their study drug according to instructions and by performing drug 
accountability.


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BACKGROUND INFORMATION
1
1.1
Indication and Current Treatment Options
Short bowel syndrome (SBS) is a rare, serious, disabling, socially incapacitating and potentially 
life-threatening condition which is the leading cause of intestinal failure (Nightingale and 
Woodward, 2006; Pironi et al., 2015).  Intestinal failure from SBS results from surgical resection 
or congenital defects and is defined as the reduction of gut function below the minimum 
necessary for the absorption of macronutrients and/or water and electrolytes, such that 
intravenous supplementation is required to maintain health and/or growth.  Patients with SBS are 
highly prone to malnutrition, diarrhea, dehydration, and an inability to maintain weight due to 
the reduced intestinal capacity to absorb macronutrients, water, and electrolytes (Dudrick et al., 
1991; Nightingale, 1999; Rombeau and Rolandelli, 1987; Shanbhogue and Molenaar, 1994;
Vanderhoof and Langnas, 1997; Wilmore et al., 1997).  Additional potential consequences of 
SBS include dehydration, electrolyte disturbances, malabsorption of nutrients, gastric 
hypersecretion, metabolic acidosis, cholelithiasis, nephrolithiasis, steatorrhea, diarrhea, small 
bowel bacterial overgrowth and weight loss (Nightingale and Woodward, 2006; O'Keefe et al., 
2006).
Following resection, intestinal adaptation may occur in adults during the first 1 to 2 years 
postsurgery.  The adaptive response characterized by mucosal hyperplasia, increased mucosal 
blood flow, improved segmental absorption and increased hepatobiliary secretions (O'Keefe et 
al., 2006).  These morphologic and functional changes are coordinated by the release of 
glucagon-like peptide 2 (GLP-2) from L-type enteroendocrine cells.  In response to lumenal 
nutrients reaching the distal ileum and colon, L-cells secrete GLP-2, which regulates 
gastrointestinal secretions, motility, and the local production of additional hormones, cytokines, 
and growth factors.
The clinical care of SBS is mainly supportive and focuses on optimizing remnant intestinal 
function through dietary interventions, oral rehydration solutions, antidiarrheal and antisecretory 
agents. Despite intestinal adaptation following resection, many SBS develop intestinal failure, 
characterized by the requirement for chronic use of parenteral nutrition/intravenous (PN/IV) to 
maintain hydration, electrolyte balance, and/or nutritional needs. 
Although PN/IV can meet basic nutrition and fluid requirements, it does not improve the body's 
ability to absorb nutrients.  Parenteral nutrition dependence is associated with shortened life span 
(Messing et al., 1999; Scolapio et al., 1999), life threatening complications (eg, sepsis, blood 
clots, or liver damage), as well as reduced quality of life (DeLegge et al., 2007; Jackson and 
Buchman, 2005; Jeppesen, 2006). The development of parenteral nutrition-associated liver 
disease (PNALD) predisposes patients to sepsis, increased mortality rates, and the potential to 
develop irreversible liver damage (Tazuke and Teitelbaum, 2009). The American 
Gastroenterological Association Medical Position Statement on Short Bowel Syndrome 
recommends that management of PNALD should include reducion of toxic  Parenteral nutrition 
constituents such as phytosterols, a component of soy-based lipid emulsions (American 
Gastroenterological Association, 2003).


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The severity of SBS is illustrated by the shortened life-span in patients with moderate to severe 
disease (Messing et al., 1999).  In SBS, survival can be impacted by the underlying condition, by 
severe clinical manifestations of malabsorption, and treatment-associated life-threatening 
complications (O'Keefe et al., 2006).  With current medical management practices, the overall 
10 year survival in SBS patients is 52%, and is significantly lower in patients who remain 
chronically PN/IV -dependent compared to patients who wean off PN/IV (40.7% versus 67%) 
(Amiot et al., 2013). 
In addition, the symptoms of SBS and the inconveniences and complications in relation to PN/IV
support may cause potential restrictions in the lifestyle of these patients leading to significant 
impairment of their quality of life (Jeppesen et al., 1999; Baxter et al., 2006; Winkler and Smith, 
2014). The impact of SBS and PN/IV on quality of life may be significant with patients, on 
average, moving their bowels at least 10 times a day, with multiple ostomy bag changes per day, 
and having a typical output of 2 to 3 liters of watery diarrhea per day. Patients may be on PN/IV
10 to 15 hours a day for up to 7 days a week. Sleep is disrupted and patients typically cannot 
work.
1.2
Product Background and Clinical Information
Teduglutide is a novel, recombinant analog of naturally occurring human GLP-2 that regulates 
the functional and structural integrity of the cells lining the gastrointestinal (GI) tract. 
Teduglutide is a 33-amino acid peptide that differs from native GLP-2 in the substitution of 
glycine for alanine at the second position at the N terminus. As a result, teduglutide demonstrates 
resistance to degradation by dipeptidyl peptidase 4 and therefore maintains a longer elimination 
half-life of approximately 2 hours in healthy subjects and 1.3 hours in adult SBS subjects 
compared to the native peptide, which has a t1/2 of approximately 7 minutes. Teduglutide has 
been shown in animal studies and previous human clinical trials to increase villus height and 
crypt depth in the intestinal epithelium, thereby increasing the absorptive surface area of the 
intestines. 
Results of the pivotal study, CL0600-020, showed that teduglutide at a dose of 0.05 mg/kg/day 
for up to 24 weeks was superior to placebo in reducing PN/IV support in adult subjects with 
SBS.  In this study the responder rate (defined as at least a 20% reduction from baseline in 
weekly PN/IV volume at Week 20 and Week 24) was 62.8% in the teduglutide 0.05 mg/kg/day 
group with subjects achieving a mean reduction from baseline in PN/IV volume of 4.4 L/week at 
Week 24.
In the follow-up long-term extension study CL0600-021, there continued to be evidence of 
increased efficacy of teduglutide over time in all groups exposed to teduglutide in terms of 
PN/IV volume reduction, gaining additional days off per week, and achieving complete weaning 
of PN/IV. The most significant reductions were for those subjects who received 24 weeks of 
teduglutide 0.05 mg/kg/day in CL0600-020 and continued treatment in CL0600-021 for another 
24 months. In this cohort, 10 subjects completely weaned off of PN/IV support and 18/30 
(60.0%) had a reduction in their PN/IV requirement of at least 3 days per week. It was 
encouraging that efficacy was also observed for subjects who initiated treatment in CL0600-021 
(ie, those who received placebo or were not treated in CL0600-020). After only 6 months of 


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treatment, 37.1% of subjects who had received placebo in CL0600-020 had at least a 20% 
reduction in weekly PN/IV volume, which increased to 55.2% by Month 24. Two of these 
subjects completely weaned off of their PN/IV support. In subjects who had not been treated in 
CL0600-020, 50.0% had at least a 20% reduction in weekly PN/IV volume after 6 months of 
treatment, which increased to 66.7% by Month 24. One of these subjects completely weaned off 
of their PN/IV support. Overall, a total of 13 subjects achieved enteral autonomy (independence 
of PN/IV support), and 25/65 (38.5%) subjects demonstrated a reduction of ≥3 days/week in 
their PN/IV by the end of study at Month 24. In addition, 21/22 (95.5%) of teduglutide-treated 
subjects who responded in the previous study maintained their response after an additional 24 
months of teduglutide treatment, demonstrating durability of effect. The results of this study 
support the efficacy of long-term treatment with teduglutide in PN/IV -dependent SBS subjects.
Teduglutide (0.05 mg/kg/day) is currently indicated for the treatment of adult patients with SBS.  
The European Commission granted a centralized marketing authorization valid throughout the 
European Union (EU) for teduglutide (REVESTIVE®) on 30 Aug 2012.  On 29 Jun 2016, the 
European Commission granted an extension of the Market Authorization for teduglutide for the 
treatment of patients aged 1 year and above with SBS.  A New Drug Application for teduglutide 
(GATTEX®) was approved by the United States (US) Food and Drug Administration (FDA) on 
21 Dec 2012.  Teduglutide is currently approved in >30 countries.  


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STUDY OBJECTIVES AND PURPOSE
2
2.1
Rationale for the Study 
Teduglutide 0.05 mg/kg/day has demonstrated a favorable benefit-risk profile in clinical studies 
and is already marketed in the EU and the US. The clinical profile and medical issues related to 
SBS and PN/IV in Japan are similar to those in the EU and US. Therefore, there is an unmet 
medical need for Japanese patients with PN/IV -dependent SBS. This study is designed to 
provide evidence of safety and efficacy of teduglutide in a Japanese SBS patient population.
2.2
Study Objectives
The objectives of this clinical study are to evaluate the safety, efficacy, and pharmacokinetics 
(PK) of teduglutide in Japanese subjects with SBS who are dependent on PN/IV over a 24-week 
treatment period.


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STUDY DESIGN
3
3.1
Study Design and Flow Chart
This is an open-label, multicenter study, consisting of a conditional PN/IV optimization period, 
a mandatory PN/IV stabilization period, and a 24-week treatment period. A schematic 
representation of the study design is presented in Figure 1.
3.1.1
Optimization and Stabilization Periods 
If at screening, a subject does not have an optimized PN/IV volume, defined as a 48-hour urine 
output between 2 and 4 L, he/she will enter the optimization period, during which the minimally 
tolerated stable PN/IV volume will be determined during a period of up to 8 weeks. If it is not 
possible to keep the subject adequately hydrated and nourished within the target urine output 
range, the minimally tolerated PN/IV volume will be documented. For subjects who don't have 
an optimization period, the "last optimization visit" is the screening visit.
All subjects will then enter the stabilization period, during which the target PN/IV volume will 
be maintained for at least 4 consecutive weeks (8 weeks maximum). Those subjects who fail to 
stabilize will not proceed further and will not be included in the treatment period.
Appendix 1 provides details of the optimization procedure.  Schedules of evaluations for the 
optimization/stabilization period can be found in Table 1.
3.1.2
Treatment Period
Following the stabilization period, subjects will enter a 24-week dosing period, during which all
subjects will receive teduglutide 0.05 mg/kg SC once daily. At each site visit during the 
treatment phase, efficacy (adjustments to PN/IV) and safety will be monitored.
Subjects will have blood samples taken for teduglutide PK analysis at predose, at 15, 30 minutes 
and 1, 2, 3, 4, 6, 8, 10, and 12 hours post dose at the baseline visit (Visit 2). Subjects will also
have blood samples taken for teduglutide PK analysis at predose and 1 and 2 hours post dose at 
Week 4 (Visit 5) or Week 12 (Visit 7) of the treatment period.
All subjects who complete the study may participate in a long-term extension study in which 
eligible subjects will continue to receive teduglutide. 
Schedules of evaluations for the Treatment Period can be found in Table 2.  Procedures to adjust 
or reduce PN/IV volume during the Treatment Period is provided in Appendix 2, and should be 
followed carefully throughout the study.


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3.2
Study Duration
Subjects will undergo up to a 7 day screening period, a conditional PN/IV support optimization 
period (up to 8 weeks), and a stabilization period (up to 8 weeks) prior to receiving teduglutide 
treatment. Thus, the screening, optimization period, and stabilization period could last up to 
17 weeks in total.
Following the optimization and stabilization periods, and appropriate training on study drug 
administration, the subjects will receive the study drug for 24 weeks. 
Subjects who do not enroll in the extension study or who discontinue prematurely at any time 
during the study will receive a follow-up phone call 4 weeks after the last dose of study drug.
The study completion date is defined as the date the final subject, across all sites, completes their 
final protocol-defined assessment. Please note that this includes the follow-up visit or contact 
(last safety contact), whichever is later. The study completion date will be used to ascertain 
timing for study results posting and reporting.
3.3
Sites and Regions
This study is planned to be conducted in approximately 5 sites in Japan.


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Figure 1  
Study Schematic
Screening
Up to 7 days
Optimization
0-8 weeks
Stabilization
4-8 weeks
Teduglutide treatment 0.05 mg/kg SC qday
24 weeks
V1.0V1.1 V1.2 V1.3 V1.4
V1.5
V2
(Baseline)
V3 V4 V5
V6
V7
V8
V9
V10
(EOT)
Safety follow-up
phone call
4 weeks after EOT
Extension
study
Up to 4 visits as needed
Performed if urine output 
is not in the target range
at screening


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STUDY POPULATION
4
At least 5 Japanese subjects with PN/IV-dependent SBS will be dosed.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1. Ability to voluntarily provide written, signed, and informed consent to participate in the 
study.
2. Male or female 16 years of age or older at the time of signing informed consent.
3. Intestinal failure due to SBS as a result of major intestinal resection (eg, due to injury, 
volvulus, vascular disease, cancer, Crohn’s disease) that resulted in at least 12 continuous 
months of PN/IV dependence at the time of informed consent.
4. Parenteral nutrition requirement of at least 3 times per week during the week before the 
screening visit and during the 2 weeks prior to the baseline visit.
5. Stable PN/IV requirement for at least 4 consecutive weeks immediately prior to the start 
of teduglutide treatment. Stability is defined as:
a.
Actual PN/IV usage is similar to prescribed PN/IV.
b.
Baseline (Visit 2) 48-hour oral fluid intake and urine output (I/O) volumes fall 
within ±25% of the respective 48-hour I/O volumes at the last optimization visit.
c.
Urine output volume should NOT fall below 2 L and should not exceed 4 L per 
48 hours at the last optimization visit, the stabilization visit, and the baseline 
visit.
6. For subjects with a history of Crohn’s disease, clinical remission for at least 12 weeks 
prior to the baseline visit as demonstrated by clinical assessment, which may include 
procedure-based evidence of remission.
7. Females of childbearing potential must agree to comply with the contraceptive 
requirements of the protocol.
8. An understanding, ability, and willingness to fully comply with study procedures and 
restrictions.


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4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1. Participation in a clinical study using an experimental drug within 30 days or 5.5 half-
lives, whichever is longer, prior to screening, or concurrent participation in any other 
clinical study.
2. Use of GLP-2 or human growth hormone or analogs of these hormones within the past 
6 months.
3. Use of octreotide, GLP-1 analogs, dipeptidyl peptidase-IV inhibitors, or enteral 
glutamine within 30 days.
4. Previous use of teduglutide.
5. Subjects with active inflammatory bowel disease (IBD) or subjects with IBD who 
received a change in immunosuppressant therapy (eg, azathioprine, anti-TNFs) within the 
past 6 months.
6. Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus 
inclusion disease, familial adenomatous polyposis, etc.
7. Chronic intestinal pseudo-obstruction or severe dysmotility.
8. Clinically significant intestinal stenosis or obstruction, or evidence of such on upper GI 
series with small bowel follow-through, within the past 6 months.
9. Major GI surgical intervention, including bowel lengthening procedures, within the past 
3 months (insertion of feeding tube or endoscopic procedure is allowed).
10. Unstable cardiac disease, (eg, congestive heart failure, cyanotic disease, or congenital 
heart disease).
11. Moderate or severe renal impairment, defined as creatinine clearance <50 ml/min.
12. Currently diagnosed with cancer or a history of any cancer except surgically curative skin 
cancer within the past 5 years.
13. Severe hepatobiliary disease including:
a.
Total bilirubin level ≥2 times the upper limit of normal (ULN).
b. Aspartate aminotransferase (AST) ≥5 times ULN.
c.
Alanine aminotransferase (ALT) ≥5 times ULN.
14. Active clinically significant pancreatic disease, including clinical signs of pancreatitis 
associated with elevations in serum amylase or lipase ≥2 times ULN.
15. More than 4 SBS-related or PN/IV-related hospital admissions (eg, central line-
associated bloodstream infection, bowel obstruction, severe fluid/electrolyte 
disturbances) within the past 12 months.
16. Unscheduled hospitalization within 30 days prior to screening.
17. Pregnant or lactating female.  
18. Any condition or circumstance that in the investigator’s opinion put the subject at any 
undue risk, prevent completion of the study, or interfere with analysis of the study results.


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4.3
Reproductive Potential 
To be eligible for treatment with teduglutide, sexually active females of childbearing potential 
must use a medically acceptable form of contraception.  Females of childbearing potential must 
be advised to use medically acceptable contraceptives throughout the study period and for 30 
days following the last dose of investigational product.  If hormonal contraceptives are used, they 
should be administered according to the package insert.  Females of childbearing potential who 
are not currently sexually active must agree to use medically acceptable contraception if they 
become sexually active during the period of the study and for 30 days following the last dose of 
investigational product.
Females of childbearing potential must have a negative urine β-HCG pregnancy test at all visits 
where it is tested to participate in the study (see Section 8.1.6 for information about reporting a 
pregnancy).  
Females of childbearing potential must agree to use medically acceptable methods of 
contraception at all times during the study and for 30 days following the last dose of 
investigational product.
4.4
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator should 
discuss withdrawal of a subject from investigational product with the medical monitor as soon as 
possible.
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Visit 10 are to be performed as completely as possible. Whenever possible, all discontinued 
subjects should also receive a follow-up phone call 4 weeks after the last dose of study drug 
unless the subject has withdrawn consent. Comments (spontaneous or elicited) or complaints 
pertaining to study drug discontinuation made by the subject must be recorded in the source 
documents. The reason for termination, date of stopping investigational product, and the total 
amount of investigational product taken must be recorded in the electronic case report form 
(eCRF) and source documents.
Subjects who discontinue will not be replaced. 
Subjects who do not enroll in the treatment extension study or who discontinue prematurely at 
any time during the study will receive a follow-up phone call 4 weeks after the last dose of study 
drug.


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4.4.1
Reasons for Discontinuation
The reason(s) for permanent discontinuation of treatment and/or withdrawal from the study must 
be determined by the investigator, and recorded in the subject’s medical record and in the eCRF.  
If a subject is withdrawn for more than 1 reason, each reason should be documented in the source 
document, and the most clinically relevant reason should be entered in the eCRF.
Reasons for discontinuation include, but are not limited to:

Adverse event

Death

Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Study terminated by sponsor

Withdrawal by subject

Lack of efficacy

Other
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact (office visit or telephone contact). At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that they 
return to the site for final safety evaluations and return any unused investigational product.


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PRIOR AND CONCOMITANT TREATMENT
5
5.1
Prior Treatment
All non-study treatment (including but not limited to herbal treatments, vitamins, behavioral 
treatment, non-pharmacological treatment, such as psychotherapy, as appropriate) received 
within 14 days prior to the Screening Visit (Visit 1.0) (or pharmacokinetic equivalent of 5 half 
lives, whichever is longer must be recorded on the appropriate eCRF page.  Any diagnostic, 
surgical or other therapeutic treatments received by a subject within 14 days prior to the 
Screening Visit (Visit 1.0) will also be recorded on the eCRF.
5.2
Concomitant Treatment
The administration of all medications including concomitant medications (including prescription 
and nonprescription medications, dietary and nutritional supplements, and vitamins), must be 
recorded from screening and for the duration of the study in the appropriate sections of the 
eCRF. Any diagnostic, surgical or other therapeutic treatments received by a subject during the 
course of the study will also be recorded on the eCRF.
The mechanism of action of teduglutide may increase enteral absorption of drugs (eg, motility 
medication including narcotics and opioids used for the management of SBS, warfarin, 
psychotropics, metronidazole, digoxin), so consideration should be given to modifying 
concomitant enteral medication regimens. Titration of concomitant enteral medications should be 
considered when drugs, especially those with a narrow therapeutic index, are given.
5.2.1
Permitted Treatment
Standard medical therapy for SBS should be continued.
5.2.2
Prohibited Treatment
The following medications are prohibited during teduglutide treatment and within the provided 
timeframe prior to the baseline visit (Table 3):
Table 3
Prohibited Treatment
Prior Therapy
Time Restriction Prior to 
the Baseline Visit
Teduglutide
Any
Glucagon-like peptide-2, human growth hormone, or analogs of these 
hormones
6 months
Octreotide, dipeptidyl peptidase 4 inhibitors, GLP-1 analogs, and 
enteral glutamine
30 days


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INVESTIGATIONAL PRODUCT
6
6.1
Identity of Investigational Product
The test product is teduglutide, which will be provided in sterile, single-use 3 mL vials 
containing 5 mg teduglutide as a white lyophilized powder to be reconstituted before use with 
0.5 mL sterile water for injection. In addition to the active ingredient (teduglutide), each vial of 
teduglutide contains L-histidine, mannitol, monobasic sodium phosphate monohydrate, and 
dibasic sodium phosphate as excipients. Additional information is provided in the current 
investigator’s brochure.
6.1.1
Blinding the Treatment Assignment
Not applicable for this open-label study.
6.2
Administration of Investigational Product
6.2.1
Allocation of Subjects to Treatment
All subjects will receive teduglutide 0.05 mg/kg once daily.
6.2.2
Dosing
Teduglutide 0.05 mg/kg once daily will be administered daily by subcutaneous (SC) injection 
into either thigh or arm or 1 of the 4 quadrants of the abdomen (in subjects without a stoma). 
Each day, the injection site should be rotated.  For subjects with a stoma, the quadrant of the 
abdomen containing the stoma should not be used. The subject should be dosed at approximately 
the same time each day. Consecutive doses should be separated by at least 12 hours. Detailed 
instructions for reconstitution and injection of the investigational product can be found in the 
Instructions for Use.
Any subject who achieves complete independence from PN/IV support at any time during the 
treatment period will continue to receive teduglutide treatment.   
6.2.2.1
Subject Administration
The first dose of teduglutide will be administered by a study physician. 
The processes for training the subject to self-administer teduglutide and for providing oversight 
of study drug administration are described in the Site Training Guide.  Before a subject is 
permitted to administer teduglutide, the study physician must observe the subject 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 subject can safely administer the study drug, 
subsequent doses may be administered by the subject at home without direct supervision by the 
physician.  However, at selected study visits during the dosing period (refer to Table 2), 
administration of the study drug must be performed under direct supervision by the study 


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physician, and the teduglutide administration checklist must be completed again.  This ensures 
that the subject continues to administer the study drug correctly and safely throughout the dosing 
period.
If at any time a study physician suspects that the subject is no longer capable of administering 
the study drug safely and accurately, the subject should be re-assessed by a study physician using 
the teduglutide administration checklist.  If the subject is deemed unable to administer the study 
drug, dosing must be performed by a study physician until the subject is re-trained and 
proficiency is confirmed using the teduglutide administration checklist.  
Eligibility for teduglutide to be administered by a subject 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 Subject:

The subject’s condition is stable.

The subject has been sufficiently trained and is able to administer teduglutide in 
compliance with the checklist.
Criteria to Discontinue Teduglutide Administration by the Subject:

The subject 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 self-administered.  In addition to 
discontinuing administration of teduglutide by the subject, if a subject sustains an 
adverse drug reaction where the symptoms are considered intolerable, dose 
interruption or study drug discontinuation should be considered.

In the study physician’s judgment, it is inappropriate for the subject to continue 
administration of the study drug for any other reason. 
6.2.3
Unblinding the Treatment Assignment
Not applicable for this open-label study.
6.3
Labeling, Packaging, Storage and Handling
6.3.1
Labeling and Packaging
The investigational product will be packaged, labeled, and shipped to the study site by the 
sponsor or designee. Kits containing 7 vials of investigational product will be provided for this 
study. The vials will be labeled in accordance with applicable regulatory requirements. 


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Ancillary kits, containing supplies needed for the reconstitution and administration of the 
investigational product will also be provided and labeled in accordance with the applicable 
regulatory requirements. 
All investigational product used in this study will be manufactured, tested, labeled, and released 
according to current legal requirements and Good Manufacturing Practice.
6.3.2
Storage and Handling
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.
Investigational product must be kept in a locked area with access restricted to specific study 
personnel. Investigational product will be stored refrigerated at a temperature between 2 oC to 
8oC (35.6°F to46.4°F) until dispensed to a subject. The prefilled sterile water for injection 
syringes will be stored at a temperature between 2°C to 25°C. Once dispensed/supplied to a 
subject, the investigational product and ancillary kits can be stored refrigerated up to a controlled 
room temperature (acceptable range of 2°C to 25oC, or 35.6°F to77°F). The subject will be 
instructed to keep the investigational product and sterile water diluent at controlled room 
temperature. If there are concerns that the controlled room temperature cannot be maintained, the 
investigational product may be refrigerated. The study drug is for single use only, and should be 
used within 3 hours following reconstitution.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product and ancillary kits are maintained within an established temperature range. The 
investigator is responsible for ensuring that the temperature is monitored throughout the duration 
of the study and that records are maintained; the temperature should be monitored continuously 
by using either an in-house system, a mechanical recording device such as a calibrated chart 
recorder, or by manual means, such that both minimum and maximum thermometric values over 
a specific time period can be recorded and retrieved as required. Such a device (ie, certified 
min/max thermometer) would require manual resetting upon each recording. The sponsor must 
be notified immediately upon discovery of any excursion from the established range. 
Temperature excursions will require site investigation as to cause and remediation. The sponsor 
will determine the ultimate impact of excursions on the investigational product and will provide 
supportive documentation as necessary.  Under no circumstances should the product be 
dispensed to subjects until the impact has been determined and the product is deemed appropriate 
for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
Investigational products are distributed by the pharmacy or nominated member of the study 
team. The pharmacist/nominated team member will enter the unique subject identifier on the 
investigational product bottle/carton labels, as they are distributed.


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6.4
Drug Accountability
Investigational product will not be dispatched to the study site until the sponsor or designee has 
received all required documents from the study site in accordance with applicable regulatory 
requirements and relevant standard operating procedures. Upon receipt, the study site’s 
pharmacist or delegate is responsible for ensuring that all investigational product received at the 
site is inventoried and accounted for throughout the study. A copy of the shipping documents 
must be maintained for the investigator’s records. Kits will be shipped to the site once the subject 
is screened.
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for dispensing investigational product. Where 
permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is adequately 
trained in the protocol and who works under the direct supervision of the investigator. This 
delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee will dispense the investigational product only to subjects
included in this study following the procedures set out in the study protocol. Investigational 
product kits will be dispensed at each of the applicable study visits at which the subject is 
required to be at the clinic. Each investigational product kit is sufficient for a treatment period of 
1 week and enough kits will be supplied to cover the period until the next planned study visit. 
Additional study kits will be provided as necessary.
Each subject will be given the investigational product according to the protocol. The investigator 
is to keep a current record of the inventory and dispensing of all clinical supplies. All dispensed 
medication will be documented on the eCRFs and/or other investigational product record. The 
investigator is responsible for assuring the retrieval of all study supplies from subjects.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.
At the end of the study, or as instructed by the sponsor, all unused stock, subject returned 
investigational product, and empty/used investigational product packaging are to be sent to the 
sponsor or designee. The investigator is responsible for assuring the retrieval of all study 
supplies from subjects.


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Returned investigational product must be counted and verified by clinical site personnel and the 
sponsor (or study monitor). Shipment return forms, when used, must be signed prior to shipment 
from the site. Contact the sponsor for authorization to return any investigational product prior to 
shipment. Shipment of all returned investigational product must comply with local, state, and 
national laws. 
Please see the Pharmacy Manual for additional information.
6.5
Subject Compliance
The subjects must be instructed to bring unused investigational product and empty/used 
investigational product packaging to every visit.  Drug accountability must be assessed and 
recorded at the container/packaging level for unused investigational product that is contained 
within the original tamper-evident sealed container (eg, bottles, trays, vials) or at the individual 
count level for opened containers/packaging.
Subject compliance will be checked by site personnel at every visit by reviewing the subject 
diaries and asking the subject if he/she has administered the investigational product according to 
instructions. If any doses have been missed, the reason for missed dose should be documented in 
the subject’s source documentation including, as applicable, the eCRF.
The investigator is responsible for contacting the sponsor or designee when the subject’s daily 
investigational product dosing regimen is interrupted. Attempts should be made to contact the 
sponsor or designee prior to dose interruption. Reasons for dosage interruption may include but 
are not limited to hospitalization and adverse events (AEs), a lapse in investigational product 
delivery, etc.
Subjects who have received 80% of the planned doses administered will be assessed as being 
compliant with the study protocol.


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STUDY PROCEDURES
7
7.1
Study Schedule
Detailed study procedures and assessments to be performed for subjects throughout the study are 
outlined in the study schedules (Table 1 and Table 2) and must be referred to in conjunction with 
the instructions provided in this section. 
Subjects who drop out of the study prior to the final visit should have all early termination 
procedures done whenever possible.
7.1.1
Screening
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent from the subject.  The 
screening visit assessments and procedures, beginning with informed consent, will be performed 
as outlined in Table 1.
7.1.2
Optimization and Stabilization Periods
Subjects who are eligible for the study during the screening visit will proceed to the optimization 
or stabilization period depending on urine ouput evaluated at the screening visit. Assessments 
will be performed as outlined in Table 1. 
During the optimization period, PN/IV adjustments will be made according to the algorithm in 
Appendix 1.  Optimization visits will occur approximately every 2 weeks (for up to 8 weeks) 
until the subject achieves an optimized volume of PN/IV indicated by targeted urine output of 
1.0 L/day to 2.0 L/day. 
Once an optimal tolerated PN/IV volume has been reached, the subject will begin the 4-week 
minimum stabilization period.  No further PN/IV adjustments should take place during the 
stabilization period.  Subjects who do not achieve stable PN/IV support during this period will 
not be eligibile to continue in the study.
7.1.3
Treatment Period
The open-label teduglutide treatment period will comprise 24 weeks, during which all 
assessments will be performed as outlined in Table 2.
7.1.4
Follow-up Period
Long-term safety and efficacy data will be obtained from subjects enrolling into the extension 
study at the Week 24 visit (Visit 10). 
Subjects who do not enroll in the treatment extension study or who discontinue prematurely at 
any time during the study will receive a follow-up phone call 4 weeks (Week 28) after the last 
dose of study drug.


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7.2
Study Evaluations and Procedures
7.2.1
Demographics and Other Baseline Characteristics
7.2.1.1
Demographics and Medical History
Information on medical history and demographic data is to be recorded on the appropriate eCRF.
7.2.1.2
Clinical Assessment of Crohn’s Disease Activity
Any subject with a history of Crohn’s disease will have their clinical disease status assessed at 
screening and again at the baseline visit of the treatment period to determine whether the subject 
has active or quiescent disease. Subjects with active Crohn’s disease are excluded from study 
participation. For all subjects, upper endoscopy and colonoscopy/sigmoidoscopy are required 
during the stabilization period if they have not been completed within 6 months prior to 
screening.  For subjects with Crohn's disease, it may be necessary to perform upper endoscopy 
and colonoscopy prior to the baseline visit in subjects with clinical suspicion of active disease, 
even if these procedures had been completed within 6 months prior to screening. In addition, 
upper GI contrast series with small bowel follow-through is required in subjects with a history of 
Crohn’s disease to detect any clinically significant stenosis or stricture.
7.2.2
Efficacy Assessments
7.2.2.1
Subject Diaries
Diaries will be distributed to subjects at the time of informed consent and at clinic visits 
according to the study schedules. Subjects will record their PN/IV support daily throughout the 
study. Prior to each clinic and safety visit, subjects will also record all enteral fluid intake and  
urine output over a 48-hour period.  Forty-eight hours of output data must be collected during 
Screening (Visit 1.0) in order to assess the need for the optimization period.  Diaries may be 
completed by the subject or the subject's designee if the subject is physically unable to enter data 
on his/her own.
7.2.2.2
Prescribed Parenteral Nutrition 
All attempts should be made to follow the PN/IV adjustment algorithm specified in the 
appendices.  At the interim visits the PN/IV will be changed if the previous adjustment was not 
tolerated.  Physician-directed changes in a subject’s PN/IV volume must be followed by an 
interim safety visit 5 to 7 days after the adjustment has been implemented.  If the subject has a 
AE that prevents him/her from adhering to study requirements, including the PN/IV adjustment 
algorithms, the subject may be withdrawn from the study.
The prescribed PN/IV weekly total volume, calories, and days per week will be recorded. 
Changes in parenteral support prescription that reflect changes in the subject's intestinal 
absorption are recorded. Temporary adjustments to parenteral nutrition or IV fluids that last less 
than 72 hours may be recorded at the discretion of the investigator, but all parenteral support 
prescriptions that last more than 72 hours must be recorded.  The PN/IV constituents are at the 
discretion of the physician; the identities of parenteral support constituents do not recorded. 


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7.2.2.3
Plasma Citrulline
Plasma citrulline will be measured as an assessment of enterocyte mass.  If peripheral venous 
access is not possible, blood samples for citrulline may be drawn from a central line.  The 
samples will be processed according to instructions in the laboratory manual.
7.2.3
Safety Assessments
7.2.3.1
Laboratory Evaluations
Safety laboratory tests are to be performed at site visits with results processed by a central 
laboratory.  Although subjects do not need to be in a fasted state at the time of their clinic visit, 
they should avoid large meals or large volumes of fluid, including PN/IV with lipids, within 
3 hours of the clinic visit to permit consistent assessment.  
Safety lab tests performed at interim safety visits after PN/IV adjustments will consist of 
hemoglobin, hematocrit, serum blood urea nitrogen, creatinine, and urine sodium, and may be 
performed at the investigational site laboratory.  
The investigator should assess out-of-range clinical laboratory values for clinical significance, 
indicating if the value(s) is/are not clinically significant or clinically significant.  Abnormal 
clinical laboratory values, which are unexpected or not explained by the subject’s clinical 
condition, may, at the discretion of the investigator or sponsor, be repeated as soon as possible 
until confirmed, explained, or resolved.  New clinically significant lab tests results should be 
reported as AEs (see Section 8).
Tests include the following (Table 4):


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Table 4
List of Laboratory Tests
Hematology:

Hematocrit 

Hemoglobin 

Platelet count

Red blood cell count 

Red blood cell morphology, if needed

White blood cell count with differential

Urinalysis: 

Blood

Glucose

Leucocytes

Microscopic analysis

pH 

Protein

Specific gravity

Urine Sodium
Pregnancy tests (females of childbearing potential):

Urine β-HCG 
Biochemistry:

Albumin 

Alkaline phosphatase 

Alanine aminotransferase 

Amylase

Aspartate aminotransferase 

Bilirubin (total, direct and indirect)

Blood urea nitrogen 

Calcium (total)

Chloride

Cholesterol

Citrulline (plasma)

C-reactive protein 

Creatinine

Creatinine clearance

Gamma-glutamyl transferase 

Glucose

Lipase

Magnesium

Phosphorus

Potassium 

Sodium 

Triglycerides

Uric acid
7.2.3.2
Antibodies to Teduglutide 
Blood samples for analyses of antibodies to teduglutide will be collected. Blood sample for 
antibody testing is to be collected at study site prior to first investigational product 
administration. Once the subject has started teduglutide treatment, samples must be drawn at 
least 14 hours after dosing. 
Anti-teduglutide antibody testing is a 3-step process. If a sample tests negative, no further testing 
is done. If a sample tests positive, further testing is done for teduglutide-specific antibodies. If 
teduglutide-specific antibodies are detected, the test is deemed “positive” and the titer derived, 
and neutralizing antibody testing is done. Subjects who test positive for teduglutide-specific 
antibodies may remain on treatment and blood samples for antibody testing will continue to be 
collected as per protocol schedule (Table 2). 
Blood samples for anti-teduglutide antibody testing may be stored and then analyzed together 
periodically to streamline the testing procedure.  However, if an investigator suspects that a 
subject is experiencing an AE that may be associated with the development of anti-drug 
antibodies, relevant samples will be tested for the presence of anti-drug antibodies upon request. 


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7.2.3.3
Physical Examinations
Physical examinations will be performed according to the study schedules to assess the subject’s 
physical status.  New clinically significant abnormalities that are detected or diagnosed after 
study evaluations have begun (after signing of the informed consent) should be recorded on the 
appropriate AE page of the eCRF.  Complete physical exams are required at screening, baseline, 
and Week 24/ET.  Focused physical exams may be performed at all other visits.
7.2.3.4
Vital Signs, Body Weight, and Height
Vital signs will be measured according to the study schedules. Measurements will include 
systolic and diastolic blood pressure (mmHg), pulse rate, and body temperature (°C). Blood 
pressure should be determined by cuff (using the same method, the same arm, and in the same 
position throughout the study).  New clinically significant vital sign abnormalities should be 
recorded on the appropriate AE page of the eCRF.
Subjects should be weighed on the same scale at each study visit. Height will be measured at the 
screening visit. 
7.2.3.5
Electrocardiograms
A 12-lead ECG will be performed at the study center after the subject has been resting for at least 
5 minutes. Results will include general findings (normal, abnormal-not clinically significant,
abnormal-clinically significant). If abnormal, the nature of the abnormality will be collected. 
Investigators are responsible for providing their own interpretation of the ECG and this will be 
captured on the eCRF. 
Electrocardiogram tracings should be printed, signed and dated by the investigator, and kept with 
the subject’s source documents.
7.2.3.6
Gastrointestinal-specific Testing
Gastrointestinal testing will be done for all subjects during the screening period.  Follow-up 
testing will be performed as necessary according to the guidelines noted below. 
Colonoscopy/Sigmoidoscopy
A colonoscopy/sigmoidoscopy of the remnant colon with polyp removal will be performed prior 
to teduglutide exposure (during stabilization if not completed within 6 months prior to screening) 
in subjects with any colon remnant including a rectal stump.  This will be repeated at Visit 10 
(or early termination).  The date and result of colonoscopy are to be recorded in the eCRF.
Abdominal Ultrasound 
An abdominal ultrasound will be performed prior to teduglutide exposure (during stabilization) if 
this procedure was not performed during the 6 months prior to screening (however, the results of 
the procedure must be documented).  


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Upper GI Contrast Series with Small Bowel Follow-through
Upper GI contrast series with small bowel follow-through will be required for all subjects with a 
history of Crohn’s disease and will be performed during the stabilization period, prior to the 
baseline visit.
Esophagogastroduodenoscopy
Esophagogastroduodenoscopy (EGD) will be performed prior to teduglutide exposure (during 
stabilization) if this procedure was not performed during the 6 months prior to screening. 
Esophagogastroduodenoscopy will be performed on all subjects prior to teduglutide exposure 
(during the stabilization period if not completed within 6 months prior to screening). 
Esophagogastroduodenoscopy will be repeated at Week 24/Visit 10 (or ET) for subjects with any 
of the following risk factors: 

Age 40 or over at Week 24/Visit 10/ET

History of H pylori gastritis

History of atrophic gastritis

History of intestinal metaplasia or dysplasia in the stomach
For subjects that do not have any of the above risk factors, EGD may be repeated at Visit 10/ET 
at the discretion of the investigator. The dates and results of all EGDs are to be recorded in the 
eCRF.
48-Hour Oral Fluid Intake and Urine Output
Subjects will be provided with urine collection containers (as needed) in order to collect 48-hour 
urine during the 2 days prior to study visits as required. The center staff will contact the subject 
at least 48 hours before the scheduled visits to remind the subject to start measuring I/O, and to 
record these measurements into the diary. During the 48-hour measurements, the subject should 
maintain their usual oral fluid intake. 48-hour urine output measurements will also be collected 
prior to all interim safety visits.


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7.2.4
Pharmacokinetic Assessments
The first dose of teduglutide will be administered by the study physician at the baseline visit 
(Visit 2). At this visit, subjects will have blood samples taken for teduglutide PK analysis:

0-hour (predose) draw: any time prior to the dose

15 minutes postdose: ±5 minutes

30 minutes postdose: ±5 minutes

1 hour postdose: ±10 minutes

2 hours postdose: ±10 minutes

3 hours postdose: ±10 minutes

4 hours postdose: ±30 minutes

6 hours postdose: ±30 minutes

8 hours postdose: ±30 minutes

10 hours postdose: ±30 minutes

12 hours postdose: ±30 minutes
Subjects also will have blood samples taken for teduglutide PK analysis at Week 4 (Visit 5) or 
Week 12 (Visit 7):

0-hour (predose) draw: any time prior to the daily dose, on the day of dosing, but at least 
14 hours after the previous dose

1 hour postdose: ±10 minutes

2 hours postdose: ±10 minutes
Blood for PK sampling should be collected via peripheral IV or venipuncture, not from a central 
line.  The site of teduglutide administration prior to PK blood draws (arm, thigh, abdomen) and 
the person administering the injection (physician or subject) must be recorded in the eCRF. 


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


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8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related.” The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected 
response pattern to that product, and the event cannot be explained by the 
subject’s medical condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident and no 
plausible temporal or biologic relationship exists between the investigational 
product and the event.
AEs that are related to investigational product that are not resolved at EOT will be followed until 
the event resolves or stabilizes, as judged by the investigator.
Laboratory values, vital signs, and clinical findings at the scheduled physical examinations must 
be reported as AEs if the investigator considers the finding to be a clinically significant change 
from the baseline. 
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the eCRF. Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved with Sequelae 

Recovering/Resolving

Unknown


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


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Form for SAEs and Non-serious AEs as Required by Protocol as well as the Shire Investigational 
and Marketed Products Pregnancy Report Form. The test date of the first positive serum/urine 
β-HCG test or ultrasound result will determine the pregnancy onset date.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
using SAE reporting form whether or not they result in an AE/SAE as described in Section 8.2, 
but such events are only recorded in the eCRF if they result in an AE. Note: The 24-hour 
reporting requirement for SAEs does not apply to reports of abuse, misuse, overdose, or 
medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for a 
non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner that 
may be detrimental to the individual and/or society.

Misuse – Intentional use of investigational product other than as directed or indicated at any 
dose (Note: this includes a situation where the investigational product is not used as directed 
at the dose prescribed by the protocol).

Overdose – Administration of a dose greater than the allocated dose of the study medication 
or at a frequency greater than the dosing interval specified by the protocol.

Medication Error – An error made in prescribing, dispensing, administration, and/or use of an 
investigational product. For studies, medication errors are reportable to the sponsor only as 
defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error. 
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator’s brochure which the 
sponsor has provided under separate cover to all investigators.


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8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the sponsor or 
designee within 24 hours of the first awareness of the event. Note: The 24-hour reporting 
requirement for SAEs does not apply to reports of abuse, misuse, overdose, or medication errors 
(see Section 8.1.7) unless they result in an SAE.
All Adverse Events of Special Interest, as defined in Section 8.3, must be reported by the 
investigator to the sponsor or designee within 24 hours of the first awareness of the event even if 
the event does not fulfill seriousness criterion.
The investigator must complete, sign, and date the Shire Clinical Study Adverse Event Form for 
Serious Adverse Events (SAEs) and Non-serious AEs as Required by Protocol and verify the 
accuracy of the information recorded on the form with the corresponding source documents 
(Note: Source documents are not to be sent unless requested). The investigator must fax or e-
mail the completed form to Quintiles Transnational Japan K.K. Applicable fax numbers and 
email addresses are found in the Emergency Contact Information.
8.2.3
Serious Adverse Event Definition
An SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose: 

Results in death

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
preexisting conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity.

Is a congenital abnormality/birth defect.

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in an 


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emergency room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse. 
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the informed consent is 
obtained until the defined follow-up period stated in Section 7.1.4, and must be reported to the 
sponsor or designee within 24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the sponsor or 
designee within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death.
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting 
The sponsor or designee is responsible for notifying the relevant regulatory authorities of related, 
unexpected SAEs. 
In addition, the sponsor and/or designee is responsible for notifying active sites of all related, 
unexpected SAEs occurring during all interventional studies across the teduglutide program.


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The investigator is responsible for notifying the local Institutional Review Board (IRB) or the 
relevant local regulatory authority of all SAEs that occur at his or her site as required.
8.3
Adverse Events of Special Interest
An AE of special interest is an AE (serious or nonserious) of scientific and medical concern 
specific to the sponsor’s product or program and for which ongoing monitoring and immediate 
notification by the investigator to the sponsor is required.
The AEs of special interest that require expedited regulatory reporting for this study include the 
following:

Growth of preexisting polyps of the colon

Benign neoplasia of the GI tract including the hepatobiliary system

Tumor-promoting ability (eg, benign and/or malignant neoplasia of any kind, not limited to 
those of the GI or hepatobiliary system)
For AEs of special interest, the sponsor or designee must be informed within 24 hours of first 
awareness as per the SAE notification instructions described in Section 8.2.2 even if the event 
does not fulfill seriousness criterion.


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DATA MANAGEMENT AND STATISTICAL METHODS
9
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the eCRF.  A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy.  Discrepancies 
between source data and data entered on the eCRF will be addressed by qualified site personnel.  
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel.  Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting.  It is expected that site personnel will complete the eCRF 
entry within approximately 3 business days of the subject’s visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the data management plan. Quality 
control and data validation procedures are applied to ensure the validity and accuracy of the 
clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Statistical Analysis Process
The data collected in this study will be analyzed by the sponsor or designee. All statistical 
analyses will be performed using SAS® (SAS Institute, Cary, NC, US) version 9.3 or higher.
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed.
9.4
Planned Interim Analysis
Interim analyses may be conducted during the study, as needed. Analyses will be descriptive in 
nature. No formal comparisons are planned and no hypotheses will be formally tested.  Due to 
the open-label nature of this study, personnel involved in conducting the interim analyses will 
have access to treatment assignments.  


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9.5
Sample Size Calculation and Power Considerations
The sample size of the SHP633-306 study is based on patient prevalence and study design 
elements; no statistical estimation was involved.  Possible medical institutes for SBS studies are 
limited, given the rarity of the disease and the very limited number of patients with SBS (<1000) 
in Japan.  The applicant considers that 5 treated subjects in SHP633-306 should provide 
sufficient basic information concerning the efficacy, safety and tolerability as well as PK of 
teduglutide in the Japanese study population.  
9.6
Study Population
The intent-to-treat (ITT) population will include all subjects who are deemed eligible for 
teduglutide treatment at the baseline visit (Visit 2). 
The per protocol population will include all subjects in the ITT population who complete the 
Treatment Period without any major protocol violations that could potentially affect the efficacy 
conclusions of the study.  
The safety population will include all subjects in the ITT population who receive at least 1 dose 
of study drug.  
The pharmacokinetic population will include all subjects who receive at least 1 dose of 
teduglutide and have at least 1 evaluable post-dose pharmacokinetic concentration value.  
9.7
Efficacy Analyses
The following efficacy endpoints will be analyzed:
•
Absolute and relative change from baseline in weekly PN/IV volume by visit and at end 
of treatment (EOT).
•
Percentage of subjects who achieve at least 20% reduction from baseline in weekly 
PN/IV volume at both Weeks 20 and 24.
•
Percentage of subjects who achieve at least a 20% reduction from baseline in weekly 
PN/IV volume at each visit
•
Change in days per week of PN/IV support from baseline by visit.
•
Change in plasma citrulline from baseline by visit.
•
Number of subjects who are able to completely wean off of PN/IV support.
The absolute and relative change in weekly PN/IV volume, days per week of PN/IV support, and 
plasma citrulline,  from baseline to each scheduled visit, as well as at EOT, will be summarized 
using descriptive statistics.


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The number and percentage of subjects who demonstrate a response at Week 20 and again at 
Week 24 will be summarized. A response is defined as the achievement of at least a 20% 
reduction from baseline in weekly PN/IV volume. The number and percentage of subjects who 
demonstrate at least a 20% reduction from baseline in weekly PN/IV volume at each visit will 
also be summarized.
The number and percentage of subjects who completely wean off PN/IV support by Week 
24/EOT will be summarized. A subject will be considered to have achieved independence from 
PN/IV (completely weaned off PN/IV) if the investigator prescribes no PN/IV at Week 24/EOT 
and there is no use of PN/IV recorded in the subject diary during the 2 weeks prior to the last 
dosing visit.
For efficacy analysis, the ITT population will be the primary analysis population; the per-
protocol population will be used for secondary/sensitivity analysis.
9.8
Safety Analyses
The safety endpoints include AEs, 12-lead ECG, vital signs, laboratory safety data, antibodies to 
teduglutide, and 48-hour urine output, body weight, BMI and gastrointestinal-specific tests.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Treatment-emergent AEs are defined as AEs that started or worsened on or after the 
date and time of the first dose of study dose. Treatment-emergent AEs will be summarized by 
system organ class and preferred term using descriptive statistics (eg, number and percentage of 
subjects). Adverse events will be summarized by severity, relationship to treatment, and for AEs 
leading to discontinuation, and death. In addition, SAEs will also be tabulated by overall and 
treatment-related events.
For laboratory tests, 48-hour urine output, vital signs, body weight, body mass index, and ECG 
variables, descriptive statistics (eg, n, mean, standard deviation, median, minimum and 
maximum values, the number and percentage of subjects in specified categories) will be used to 
summarize the absolute values and change from baseline at each time point.
The number and percentage of subjects classified as having antibodies to teduglutide will be used 
to summarize the presence of antibodies. 
The safety population will be the analysis population for all the safety data analysis.
9.9
Pharmacokinetics Analyses
Teduglutide plasma concentrations will be summarized using the PK population with descriptive 
statistics (number, mean and standard deviation, minimum, median, and maximum) at nominal 
time points. 
The following parameters will be derived: area under the plasma concentration–time curve from 
zero to the last measurable concentration (AUC0–t); maximum plasma concentration (Cmax); time 
to Cmax (tmax); terminal-phase half-life (t1/2); apparent clearance (CL/F); and apparent volume of 


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distribution (V/F).  Pharmacokinetic parameters will be estimated using non-compartmental 
analysis as appropriate and summarized using descriptive statistics (number, mean, standard 
deviation, geometric mean, and CV%, minimum, median, and maximum). 


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


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Community guideline on GCP. This requirement will be fulfilled within 6 months of the end of 
the study completion date for pediatric studies and within 1 year for non-pediatric studies as per 
guidance.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.


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Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Electronic Case Report Forms
Electronic case report forms are supplied by the sponsor or designe and should be handled in 
accordance with instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Electronic case report forms 
must be completed by the investigator or designee as stated in the site delegation log.  All data 
will have separate source documentation; no data will be recorded directly onto the eCRF.
All data sent to the sponsor must be endorsed by the investigator.  The study monitor will verify 
the contents against the source data per the monitoring plan. If the data are unclear or 
contradictory, queries are sent for corrections or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject diaries, original clinical laboratory reports, and imaging reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF entries 
against the source documents. The consent form includes a statement by which the subject agrees 
to the monitor/auditor from the sponsor or its representatives, national or local regulatory 
authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, appointment 
books, original laboratory reports, X-rays etc). 
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US FDA, 
European Medicines Agency [EMA], UK Medicines and Healthcare products Regulatory 
Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.


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10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other 
US national and local regulatory authorities), the EMA, the Medicines and Healthcare products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent from all study 
subjects prior to any study-related procedures including screening assessments. All consent 
documentation must be in accordance with applicable regulations and GCP. Each subject or the 
subject’s legally authorized representative, as applicable, is requested to sign and date the subject 
informed consent form or a certified translation if applicable, after the subject has received and 
read (or been read) the written subject information and received an explanation of what the study 
involves, including but not limited to: the objectives, potential benefits and risk, inconveniences, 
and the subject’s rights and responsibilities. A copy of the informed consent documentation (ie, a 
complete set of subject information sheets and fully executed signature pages) must be given to 
the subject or the subject’s legally authorized representative, as applicable. This document may 
require translation into the local language. Original signed consent forms must remain in each 
subject’s study file and must be available for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form that was 
reviewed by the IRB/EC and received their favorable opinion/approval. A copy of the IRB/EC’s
written favorable opinion/approval of these documents must be provided to the sponsor prior to 
the start of the study unless it is agreed to and documented (abiding by regulatory guidelines and 
national provisions) prior to study start that another party (ie, sponsor or coordinating principal 
investigator) is responsible for this action. Additionally, if the IRB/EC requires modification of 
the sample subject information and consent document provided by the sponsor, the 
documentation supporting this requirement must be provided to the sponsor.


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10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the sponsor/designee has received 
written IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB/EC informed of any serious and 
significant AEs.
10.4
Privacy and Confidentiality
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market teduglutide; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 


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and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices) when forming a publication steering committee, which is done for 
large, multicenter Phase 2 to 4 and certain other studies as determined by Shire. The purpose of 
the publication steering committee is to act as a non-commercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, royalty 
free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 


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from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.


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REFERENCES
11
American Gastroenterological Association 2003. American Gastroenterological Association 
medical position statement: short bowel syndrome and intestinal transplantation. 
Gastroenterology, 124, 1105-1110.
Amiot, A., Messing, B., Corcos, O., Panis, Y. & Joly, F. 2013. Determinants of home parenteral 
nutrition dependence and survival of 268 patients with non-malignant short bowel 
syndrome. Clin Nutr, 32, 368-74.
Baxter, J. P., Fayers, P. M. & McKinlay, A. W. 2006. A review of the quality of life of adult 
patients treated with long-term parenteral nutrition. Clin Nutr, 25, 543-53.
DeLegge, M., Alsolaiman, M. M., Barbour, E., Bassas, S., Siddiqi, M. F. & Moore, N. M. 2007. 
Short bowel syndrome: parenteral nutrition versus intestinal transplantation. Where are 
we today? Dig Dis Sci, 52, 876-92.
Dudrick, S. J., Latifi, R. & Fosnocht, D. E. 1991. Management of the short-bowel syndrome. 
Surg Clin North Am, 71, 625-43.
Jackson, C. & Buchman, A. L. 2005. Advances in the management of short bowel syndrome. 
Curr Gastroenterol Rep, 7, 373-8.
Jeppesen, P. B. 2006. Glucagon-like peptide-2: update of the recent clinical trials. 
Gastroenterology, 130, S127-31.
Jeppesen, P. B., Langholz, E. & Mortensen, P. B. 1999. Quality of life in patients receiving home 
parenteral nutrition. Gut, 44, 844-52.
Messing, B., Crenn, P., Beau, P., Boutron-Ruault, M. C., Rambaud, J. C. & Matuchansky, C. 
1999. Long-term survival and parenteral nutrition dependence in adult patients with the 
short bowel syndrome. Gastroenterology, 117, 1043-50.
Nightingale, J. & Woodward, J. M. 2006. Guidelines for management of patients with a short 
bowel. Gut, 55 Suppl 4, iv1-12.
Nightingale, J. M. 1999. Management of patients with a short bowel. Nutrition, 15, 633-7.
O'Keefe, S. J., Buchman, A. L., Fishbein, T. M., Jeejeebhoy, K. N., Jeppesen, P. B. & Shaffer, J. 
2006. Short bowel syndrome and intestinal failure: consensus definitions and overview. 
Clin Gastroenterol Hepatol, 4, 6-10.
Pironi, L., Arends, J., Baxter, J., Bozzetti, F., Pelaez, R. B., Cuerda, C., Forbes, A., Gabe, S., 
Gillanders, L., Holst, M., Jeppesen, P. B., Joly, F., Kelly, D., Klek, S., Irtun, O., Olde 
Damink, S. W., Panisic, M., Rasmussen, H. H., Staun, M., Szczepanek, K., Van Gossum, 
A., Wanten, G., Schneider, S. M. & Shaffer, J. 2015. ESPEN endorsed recommendations. 
Definition and classification of intestinal failure in adults. Clin Nutr, 34, 171-80.
Rombeau, J. L. & Rolandelli, R. H. 1987. Enteral and parenteral nutrition in patients with enteric 
fistulas and short bowel syndrome. Surg Clin North Am, 67, 551-71.
Scolapio, J. S., Fleming, C. R., Kelly, D. G., Wick, D. M. & Zinsmeister, A. R. 1999. Survival of 
home parenteral nutrition-treated patients: 20 years of experience at the Mayo Clinic. 
Mayo Clin Proc, 74, 217-22.
Shanbhogue, L. K. & Molenaar, J. C. 1994. Short bowel syndrome: metabolic and surgical 
management. Br J Surg, 81, 486-99.
Tazuke, Y. & Teitelbaum, D. H. 2009. Alteration of canalicular transporters in a mouse model of 
total parenteral nutrition. J Pediatr Gastroenterol Nutr, 48, 193-202.
Vanderhoof, J. A. & Langnas, A. N. 1997. Short-bowel syndrome in children and adults. 
Gastroenterology, 113, 1767-78.


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Wilmore, D. W., Byrne, T. A. & Persinger, R. L. 1997. Short bowel syndrome: New therapeutic 
approaches. Current Problems in Surgery, 34, 389,391-444.
Winkler, M. F. & Smith, C. E. 2014. Clinical, social, and economic impacts of home parenteral 
nutrition dependence in short bowel syndrome. JPEN J Parenter Enteral Nutr, 38, 32s-
37s.


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APPENDICES
12


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APPENDIX 1
PARENTERAL NUTRITION/INTRAVENOUS OPTIMIZATION
After signing the ICF, the investigator will determine if the subject’s PN/IV volume produces an 
appropriate urine output target of 1.0 L/day to 2.0 L/day.  If the output is within the range, the 
subject will enter the stabilization period.  If the output is outside the range, the subject’s PN/IV
volume should be adjusted appropriately to reach the targeted urine output of between 1.0 L/day 
to 2.0 L/day while keeping the subject adequately hydrated and nourished.  For example, if 
48-hour urine output is:

<1.0 L/day, then PN/IV should be increased.

>2.0 L/day, then PN/IV should be reduced.
If it is not possible to keep the subject adequately hydrated and nourished within the targeted 
urine output range, the minimally tolerated PN/IV volume should be documented.  Keep in mind 
the following:

During optimization, total weekly PN/IV volume should be adjusted in increments or 
decrements of 10-30% of the screening volume.

Parenteral nutrition constituents may be adjusted at the discretion of the investigator.

Subjects should be encouraged to maintain a stable normal or hyperphagic diet (eg, at least 
1.3 times the estimated basal metabolic rate).
Steps for adjusting PN/IV volume:
1.
Screening and Optimization Visits:  Subjects will be assessed at planned intervals for 
hydration and nutrition.  The subject will make all measurements of 48-hour I/O at home 
immediately prior to the scheduled visits.  Blood and urine samples will be collected at each 
visit to evaluate hydration and nutrition.  All blood and urine samples should be taken at a 
consistent time period throughout the study that is convenient for the subject and site staff.
2.
Interim Safety Evaluations: If any PN/IV adjustments are made, the clinical effect and the 
health status of the subject will be assessed 5 to 7 days after the adjustment is implemented. 
Laboratory safety samples should be evaluated following a PN/IV adjustment (see 
Table A3), accompanied by determination of 48-hour I/O and symptoms of dehydration. At 
the interim safety visit, PN/IV should be increased if the decrease was not tolerated. No 
further reductions to PN/IV volume are made at the interim safety visit.
3.
Maintain the PN/IV level until the next scheduled optimization visit.
4.
Repeat steps 1 through 3 until the subject achieves an optimized volume of PN/IV indicated 
by targeted urine output of 1.0 L/day to 2.0 L/day.  If a subject has not achieved an optimal 
tolerated volume of PN/IV after 8 weeks, consult the sponsor’s Medical Monitor.
5.
Parenteral Nutrition Stabilization:  Once an optimal tolerated PN/IV volume has been 
reached, the subject will begin the 4-week minimum stabilization period.  No further PN/IV
adjustments should take place during this time period.  


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APPENDIX 2
PARENTERAL NUTRITION/INTRAVEOUS ADJUSTMENT DURING 
TREATMENT  PERIOD 
Points to keep in mind when adjusting PN/IV volume during dosing:

There will be no PN/IV reduction attempts at baseline and Week 1.

Parenteral nutrition/intravenous reductions target urine output increases of at least 10% over 
baseline.

Attempts to reduce PN/IV will be made at dosing Weeks 2, 4, 8, 12, 16, and 20.

Parenteral nutrition/intraveous adjustments are targeted to be at least 10% but no more than 
30% of baseline PN/IV level.

Adjustments should be based on the actual PN/IV volume the subject infuses. Subjects 
should remain compliant with the PN/IV prescription during the length of the study.

Parenteral nutrition/intravenous constituents may be adjusted at the discretion of the 
investigator.

Criteria for PN/IV adjustments are in Table A1.

During the 48-hour I/O measurement period, oral intake should be consistent with baseline 
oral intake.

If there is a change in oral intake, the investigator should consider this when adjusting the 
PN/IV volume.

Subjects should be encouraged to maintain a stable normal or hyperphagic diet.

Frequent checks will be made to ensure the adjustments are safe (see Table A2).

Subjects who fail to maintain a PN/IV reduction due to a medical necessity (eg, sepsis or 
hospitalization due to an AE) will not be considered a failure of reduction.

If at any time, the algorithm cannot be followed, consult with the sponsor’s Medical Monitor.
Table A1
Parenteral Nutrition Adjustments at Scheduled Clinic Visits based on 
48-hour Urinary Output
Urine Output
Parenteral Nutrition/Intravenous Action
Below 1.0 L/day or target based on stabilized 
urine output
Increase PN/IV by at least 10% (Week 2) or to previous level.
1.0 L/day or more and less than Baseline
If subject is dehydrated or inadequately nourished (see Table A2),
increase PN/IV If not, maintain PN/IV.
Baseline or more, and less than a 10% 
increase over Baseline
Maintain PN/IV
At least a 10% increase over Baseline
Reduce PN/IV by at least 10% of stabilized Baseline level up to 
a clinically appropriate amount (maximum of 30%).
L=liter; PN/IV=parenteral nutrition/intravenous (volume)


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Table A2
Targeted Criteria for Hydration and Nourishment at all Clinic Visits and 
Interim Safety Visits
Hydration Assessment
Hydration Adequate
Hematocrit
At or below ULN
Serum BUN
At or below ULN
Serum creatinine
At or below 2xULN
Urine sodium
20 mmol/L or more
Clinical signs and symptoms of
dehydration
Absent
Body weight change in 4 weeks
Change less than 1.5 kg
BUN = blood urea nitrogen; ULN = upper limit of normal
Note:  In combination with Table A1, any one of the above criteria determines dehydration.
Steps for adjusting PN/IV volume:
1.
DOSING WEEKS 2, 4, 8, 12, 16, and 20:  Subjects will be assessed at planned intervals 
for hydration and nutrition.  The subject will make all measurements of 48-hour I/O at home 
prior to the scheduled visits.  Blood and urine samples will be collected to evaluate 
hydration and nutrition (see Table A2).  All blood and urine samples should be taken at a 
consistent time period throughout the study, convenient for the subject and site staff.
2.
Parenteral Nutrition Changes: Review Table A1 and Table A2 to take appropriate action. 
3.
Interim Safety Evaluations: If any PN/IV adjustments are made, the clinical effect and the 
health status of the subject will be assessed 5 to 7 days after the adjustment is implemented. 
Laboratory safety samples should be evaluated following a PN/IV adjustment (see 
Table A3), accompanied by determination of 48-hour I/O and symptoms of dehydration. At 
the interim safety visit, PN/IV should be increased if the decrease was not tolerated. No 
further reductions to PN/IV volume are made at the interim safety visit.


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Table A3
Assessment of Tolerance of Pareneteral Nutrition/Intravenous
Adjustments at Interim Safety Visits
Urine Output, Hydration and Nutrition
Parenteral Nutrition/Intravenous Action
Output less than Baseline
Increase PN/IV to previous volumea
Baseline output or greater and subject is dehydrated (See 
Table A2)
Increase PN/IV to previous volumea
Baseline output or greater and subject is not dehydrated, but 
is inadequately nourished (See Table A2)
If possible, maintain PN/IV volume and increase 
nutrition. If not, increase PN/IV to previous 
volumea
Baseline output or greater and subject is adequately hydrated 
and nourished (See Table A2)
Maintain PN/IV
L=liter; PN/IV=parenteral nutrition/intravenous (volume)
a If most recent reduction was greater than 10% due to a urine volume of more than 2 L/day, a more moderate 
increase in PN/IV is allowed.
4.
Maintain the adjusted PN/IV level until the next scheduled visit.
5.
Repeat steps 1 through 4 at each study visit as indicated per protocol.
a.
It is preferred that when the total weekly PN/IV needs have been reduced to a level that 
safely allows for a day or days off PN/IV, the physician should consider instituting a 
day(s) off PN/IV.
b.
If the total weekly PN/IV is only administered in 2 days, it is probably in the subject’s 
best interest to be weaned off PN/IV completely.  This is the 1 exception to the 
maximum 30% reduction guidance. This weaning should be done under the supervision 
of the investigator.
c.
If the subject experiences symptoms of dehydration, the subject can be advised by the 
investigator to take extra IV fluid that will be included in the weekly PN/IV volume 
total.


PROTOCOL: SHP633-306
TITLE:
A 24-Week Safety, Efficacy, Pharmacokinetic Study of Teduglutide in 
Japanese Subjects with Short Bowel Syndrome who are Dependent on 
Parenteral Support
NUMBER
SHP633-306
PHASE
3 
DRUG:
Teduglutide
INDICATION:
Short bowel syndrome
SPONSOR: 
Shire Human Genetic Therapies, Inc.
300 Shire Way
Lexington, MA 02421 USA
PROTOCOL 
HISTORY:
Amendment 1: 27 Sep 2018
Original Protocol: 23 Jan 2018
Confidentiality Statement
This document contains confidential and proprietary information of Shire and is disclosed 
pursuant to confidentiality and non-disclosure obligations. This information should be used 
solely for the purposes for which it was provided and should not be copied, shared with, or 
disclosed to any third party without the express written consent of Shire.


PROTOCOL SIGNATURE PAGE 
Sponsor's (Shire) Approval 
I 
Signature: 
, MD PhD 
, Global Clinical Development 
Investigator's Acknowledgement 
I have read this protocol for Shire Study SHP633-306. 
Date: 
Title: A 24-Week Safety, Efficacy, Pharmacokinetic Study ofTeduglutide in Japanese Subjects 
with Short Bowel Syndrome who are Dependent on Parenteral Support 
I have fully discussed the objective(s) ofthis study and the contents of this protocol with the 
sponsor's representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to patticipate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Conference on Harmonization (ICH) guidelines on Good Clinical 
Practice (GCP) and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my pa1ticipation 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: 
CONFIDENTIAL 
Page 2 
Shire 
SHP633-306 Protocol Amendment 1 
Teduglutide 
27 Sep 2018 


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SUMMARY OF CHANGES FROM PREVIOUS PROTOCOL VERSION
Protocol Amendments
Summary of Change(s) Since the Last Version of the Approved Protocol
Amendment Number
1
Amendment Date
27 Sep 2018
Global
Description of Change and Rationale 
Section(s) Affected by Change
Changed name and contact information of Shire medical monitor to 
, MD.
Emergency Contact Information
Changed Quintiles Transnational Japan K.K. to IQVIA Services Japan K.K.
to reflect a corporate name change.
Emergency Contact Information
Section 8.1.6, Section 8.2.2
Clarified the prohibited use of enteral glutamine. 
(Administrative Amendment dated 26 Sep 2018)
Section 5.2.2
Added language on rescreening of subjects. Subjects may be rescreened no 
more than twice and only with prior sponsor medical approval. In the event 
of rescreening, a new subject number will be assigned. Subjects who are 
rescreened will be reconsented.
Section 7.1.1
Corrected an error in the prescribed PN/IV parameters to be recorded; only 
prescribed parenteral support volume and days per week will be recorded. 
‘Parenteral support calories’ has been deleted.
(Administrative Amendment dated 10 May 2018)
Section 7.2.2.2
Specified that the pregnancy outcome in female partner of male study 
participant will also be reported. 
Specified that the collection of data for outcomes of pregnancies will be 
conducted up to 1-year postpartum. Every effort should be made to gather 
information on pregnancy outcome and condition of the infant within 30 
calendar days after the initial notification, and approximately 30 calendar 
days and 1 year postpartum.
Section 8.1.6
Minor editorial changes and corrections to typographical errors (which do 
not modify content and/or intent of the original document) were made.
Throughout the protocol
See Appendix 1 for protocol history, including all amendments.


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EMERGENCY CONTACT INFORMATION
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the Shire 
Clinical Study Adverse Event Form for Serious Adverse Events and Non-serious adverse evetns 
(AEs) as Required by Protocol within 24 hours to the sponsor or designee using the details 
below. Applicable fax numbers and e-mail address can also be found on the form (sent under 
separate cover).
Pharmacovigilance SAE Reporting:
 or
(Japan domestic line only) 
or
Email:
For protocol- or safety-related issues, the investigator should contact:
, MD
Phone: 
(24-hour coverage)
Email:
Fax:
For protocol- or safety-related issues the investigator may also contact the Shire medical 
monitor:
, MD
Mobile Phone: 
Email: 
Fax:
In-country Clinical Caretaker: 
IQVIA Services Japan K.K.
4-10-18 Takanawa, Minato-ku
Tokyo, 108-0074, Japan


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PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
The product quality includes quality of the drug delivery device combination product. As such 
device defects should be reported according to the instructions in this section. The reporting of 
product quality occurrences, when the product does not meet specifications, includes the 
reporting of device defects.
Please use the information below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
Ex-US
Telephone numbers (provided for reference, if needed): 
Shire, Lexington, MA (USA)


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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................4
PRODUCT QUALITY COMPLAINTS..........................................................................................5
TABLE OF CONTENTS.................................................................................................................6
LIST OF TABLES.........................................................................................................................10
LIST OF FIGURES .......................................................................................................................10
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..................................................11
STUDY SYNOPSIS ......................................................................................................................13
STUDY SCHEDULES ..................................................................................................................17
BACKGROUND INFORMATION .......................................................................................21
1
1.1
Indication and Current Treatment Options.........................................................21
1.2
Product Background and Clinical Information ..................................................22
STUDY OBJECTIVES AND PURPOSE ..............................................................................24
2
2.1
Rationale for the Study.......................................................................................24
2.2
Study Objectives ................................................................................................24
STUDY DESIGN ...................................................................................................................25
3
3.1
Study Design and Flow Chart ............................................................................25
3.1.1
Optimization and Stabilization Periods .................................................................25
3.1.2
Treatment Period....................................................................................................25
3.2
Study Duration ...................................................................................................26
3.3
Sites and Regions ...............................................................................................26
STUDY POPULATION.........................................................................................................28
4
4.1
Inclusion Criteria................................................................................................28
4.2
Exclusion Criteria...............................................................................................29
4.3
Reproductive Potential .......................................................................................30
4.4
Discontinuation of Subjects ...............................................................................30
4.4.1
Reasons for Discontinuation..................................................................................30
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit .................................31
PRIOR AND CONCOMITANT TREATMENT ...................................................................32
5
5.1
Prior Treatment ..................................................................................................32
5.2
Concomitant Treatment......................................................................................32
5.2.1
Permitted Treatment...............................................................................................32
5.2.2
Prohibited Treatment .............................................................................................32
INVESTIGATIONAL PRODUCT ........................................................................................33
6
6.1
Identity of Investigational Product.....................................................................33
6.1.1
Blinding the Treatment Assignment ......................................................................33


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6.2
Administration of Investigational Product .........................................................33
6.2.1
Allocation of Subjects to Treatment ......................................................................33
6.2.2
Dosing....................................................................................................................33
6.2.2.1
Subject Administration...........................................................................33
6.2.3
Unblinding the Treatment Assignment..................................................................34
6.3
Labeling, Packaging, Storage and Handling ......................................................34
6.3.1
Labeling and Packaging.........................................................................................34
6.3.2
Storage and Handling.............................................................................................35
6.4
Drug Accountability...........................................................................................35
6.5
Subject Compliance............................................................................................37
STUDY PROCEDURES........................................................................................................38
7
7.1
Study Schedule...................................................................................................38
7.1.1
Screening................................................................................................................38
7.1.2
Optimization and Stabilization Periods .................................................................38
7.1.3
Treatment Period....................................................................................................38
7.1.4
Follow-up Period ...................................................................................................38
7.2
Study Evaluations and Procedures .....................................................................39
7.2.1
Demographics and Other Baseline Characteristics................................................39
7.2.1.1
Demographics and Medical History.......................................................39
7.2.1.2
Clinical Assessment of Crohn’s Disease Activity..................................39
7.2.2
Efficacy Assessments.............................................................................................39
7.2.2.1
Subject Diaries .......................................................................................39
7.2.2.2
Prescribed Parenteral Nutrition ..............................................................39
7.2.2.3
Plasma Citrulline....................................................................................40
7.2.3
Safety Assessments................................................................................................40
7.2.3.1
Laboratory Evaluations ..........................................................................40
7.2.3.2
Antibodies to Teduglutide......................................................................41
7.2.3.3
Physical Examinations ...........................................................................42
7.2.3.4
Vital Signs, Body Weight, and Height...................................................42
7.2.3.5
Electrocardiograms.................................................................................42
7.2.3.6
Gastrointestinal-specific Testing............................................................42
7.2.4
Pharmacokinetic Assessments ...............................................................................44
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................45
8
8.1
Definition of Adverse Events, Period of Observation, Recording of 
Adverse Events...................................................................................................45
8.1.1
Severity Categorization..........................................................................................45
8.1.2
Relationship Categorization...................................................................................46
8.1.3
Outcome Categorization ........................................................................................46


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8.1.4
Symptoms of the Disease under Study ..................................................................47
8.1.5
Clinical Laboratory and Other Safety Evaluations ................................................47
8.1.6
Pregnancy...............................................................................................................47
8.1.7
Abuse, Misuse, Overdose, and Medication Error ..................................................48
8.2
Serious Adverse Event Procedures ....................................................................48
8.2.1
Reference Safety Information ................................................................................48
8.2.2
Reporting Procedures.............................................................................................49
8.2.3
Serious Adverse Event Definition .........................................................................49
8.2.4
Serious Adverse Event Collection Time Frame.....................................................50
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................50
8.2.6
Fatal Outcome........................................................................................................50
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................50
8.3
Adverse Events of Special Interest.....................................................................51
DATA MANAGEMENT AND STATISTICAL METHODS ...............................................52
9
9.1
Data Collection...................................................................................................52
9.2
Clinical Data Management.................................................................................52
9.3
Statistical Analysis Process................................................................................52
9.4
Planned Interim Analysis ...................................................................................52
9.5
Sample Size Calculation and Power Considerations..........................................53
9.6
Study Population ................................................................................................53
9.7
Efficacy Analyses...............................................................................................53
9.8
Safety Analyses ..................................................................................................54
9.9
Pharmacokinetics Analyses................................................................................54
SPONSOR'S AND INVESTIGATOR'S RESPONSIBILITIES ............................................56
10
10.1
Sponsor’s Responsibilities .................................................................................56
10.1.1 Good Clinical Practice Compliance.......................................................................56
10.1.2 Indemnity/Liability and Insurance.........................................................................56
10.1.3 Public Posting of Study Information......................................................................56
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................56
10.1.5 Study Suspension, Termination, and Completion..................................................57
10.2
Investigator’s Responsibilities ...........................................................................57
10.2.1 Good Clinical Practice Compliance.......................................................................57
10.2.2 Protocol Adherence and Investigator Agreement ..................................................57
10.2.3 Documentation and Retention of Records .............................................................58
10.2.3.1
Electronic Case Report Forms................................................................58


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10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................58
10.2.3.3
Audit/Inspection .....................................................................................59
10.2.3.4
Financial Disclosure...............................................................................59
10.3
Ethical Considerations........................................................................................59
10.3.1 Informed Consent...................................................................................................59
10.3.2 Institutional Review Board or Ethics Committee ..................................................60
10.4
Privacy and Confidentiality................................................................................60
10.5
Study Results/Publication Policy .......................................................................61
REFERENCES .......................................................................................................................63
11
APPENDICES ........................................................................................................................65
12
Appendix 1 Protocol History .................................................................................................66
Appendix 2 Parenteral Nutrition/Intravenous Optimization..................................................67
Appendix 3 Parenteral Nutrition/Intraveous Adjustment During Treatment  Period ............68


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LIST OF TABLES
Table 1
Schedule of Evaluations and Procedures – Optimization/Stabilization ........17
Table 2
Schedule of Evaluations and Procedures – Treatment Period.......................19
Table 3 
Prohibited Treatment.....................................................................................32
Table 4
List of Laboratory Tests ................................................................................41
LIST OF FIGURES
Figure 1
Study Schematic ............................................................................................27


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation
Definition
AE
adverse event
ALT
alanine aminotransferase, equivalent to SGPT
AST
aspartate aminotransferase, equivalent to SGOT
AUC
area under the plasma concentration-time curve
AUC0–t
AUC from zero to the last measurable concentration
BUN
blood urea nitrogen
CL/F
apparent clearance
Cmax
maximum plasma concentration
CRO
contract research organization
ECG
electrocardiogram
eCRF
electronic case report form
EGD
esophagogastroduodenoscopy
EMA
European Medicines Agency
EOT
end of treatment
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
gastrointestinal 
GLP
glucagon-like peptide
ICF
informed consent form
ICMJE
International Committee of Medicinal Journal Editors
ICH
International Committee on Harmonisation
IBD
inflammatory bowel disease
I/O
oral fluid intake and urine output
IRB
Institutional Review Board
ITT
intent-to-treat
IV
intravenous
MedDRA
Medical Dictionary for Regulatory Activities
PK
pharmacokinetics
PN/IV
parenteral nutrition/intravenous
PNALD
parenteral nutrition-associated liver disease
SAE
serious adverse event
SAP
statistical analysis plan


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Abbreviation
Definition
SBS
short bowel syndrome
SC
subcutaneous
t1/2
terminal-phase half-life
tmax
time to Cmax
ULN
upper limit of normal 
US
United States
V/F
apparent volume of distribution


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STUDY SYNOPSIS
Protocol number: SHP633-306
Drug: Teduglutide
Title of the study: A 24-Week Safety, Efficacy, Pharmacokinetic Study of Teduglutide in Japanese Subjects with 
Short Bowel Syndrome who are Dependent on Parenteral Support
Number of subjects (total and for each treatment arm):
At least 5 Japanese subjects will be dosed.
Investigator(s): Multicenter study.
Site(s) and Region(s): 
This study is planned to be conducted in approximately 5 sites in Japan.
Study period (planned):
2017-2020
Clinical phase:
3
Objectives:
The objectives of this clinical study are to evaluate the safety, efficacy, and pharmacokinetics (PK) of teduglutide 
in Japanese subjects with short bowel syndrome (SBS) who are dependent on parenteral nutrition/intravenous
(PN/IV) over a 24-week treatment period.
Investigational product, dose, and mode of administration:
Teduglutide 0.05 mg/kg subcutaneously (SC) once daily into 1 of the 4 quadrants of the abdomen or either thigh 
or arm.
Methodology:
This is an open-label, multicenter study, consisting of a conditional PN/IV optimization period, a mandatory 
PN/IV stabilization period, and a 24-week treatment period.
SC=subcutaneous; qday=once daily; EOT=end of treatment
If at screening, a subject does not have an optimized PN/IV volume, defined as a 48-hour urine output between 
2 and 4 L, he/she will enter the optimization period, during which the minimally tolerated stable PN/IV volume 
will be determined during a period of up to 8 weeks. If it is not possible to keep the subject adequately hydrated 
and nourished within the target urine output range, the minimally tolerated PN/IV volume will be documented.
All subjects will then enter the stabilization period, during which the target PN/IV volume will be maintained for 
at least 4 consecutive weeks (8 weeks maximum). 
Screening
Up to 7 days
Optimization
0-8 weeks
Stabilization
4-8 weeks
Teduglutide treatment 0.05 mg/kg SC qday
24 weeks
V1.0V1.1 V1.2 V1.3 V1.4
V1.5
V2
(Baseline)
V3 V4 V5
V6
V7
V8
V9
V10
(EOT)
Safety follow-up
phone call
4 weeks after EOT
Extension
study
Up to 4 visits as needed
Performed if urine output 
is not in the target range
at screening


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Following the stabilization period, subjects will enter a 24 week dosing period, during which all subjects will 
receive teduglutide 0.05 mg/kg SC once daily. At each site visit during the treatment phase, efficacy (adjustments 
to PN/IV) and safety will be monitored.  
Subjects will have blood samples taken for teduglutide PK analysis at predose, at 15, 30 minutes and 1, 2, 3, 4, 6, 
8, 10, and 12 hours post dose at the baseline visit (Visit 2). Subjects also will have blood samples taken for 
teduglutide PK analysis at predose and 1 and 2 hours post dose at Week 4 (Visit 5) or Week 12 (Visit 7) of the 
treatment period. 
All subjects who complete the study may participate in a long-term extension study in which subjects will 
continue to receive teduglutide. Subjects who do not enroll in the extension study or who discontinue the study 
prematurely at any time will receive a follow-up phone call 4 weeks after the last dose of study drug.
Inclusion and Exclusion Criteria:
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1.
Ability to voluntarily provide written, signed, and informed consent to participate in the study.
2.
Male or female 16 years of age or older at the time of signing informed consent.
3.
Intestinal failure due to SBS as a result of major intestinal resection (eg, due to injury, volvulus, vascular 
disease, cancer, Crohn’s disease) that resulted in at least 12 continuous months of PN/IV dependence at 
the time of informed consent.
4.
Parenteral nutrition requirement of at least 3 times per week during the week before the screening visit 
and during the 2 weeks prior to the baseline visit.
5.
Stable PN/IV requirement for at least 4 consecutive weeks immediately prior to the start of teduglutide 
treatment. Stability is defined as:
a.
Actual PN/IV usage is similar to prescribed PN/IV.
b.
Baseline (Visit 2) 48-hour oral fluid intake and urine output (I/O) volumes fall within ±25% of 
the respective 48-hour I/O volumes at the last optimization visit.
c.
Urine output volume should NOT fall below 2 L and should not exceed 4 L per 48 hours at the 
last optimization visit, the stabilization visit, and the baseline visit.
6.
For subjects with a history of Crohn’s disease, clinical remission for at least 12 weeks prior to the 
baseline visit as demonstrated by clinical assessment, which may include procedure-based evidence of 
remission.
7.
Females of childbearing potential must agree to comply with the contraceptive requirements of the 
protocol.
8.
An understanding, ability, and willingness to fully comply with study procedures and restrictions.
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1.
Participation in a clinical study using an experimental drug within 30 days or 5.5 half-lives, whichever is 
longer, prior to screening, or concurrent participation in any other clinical study.
2.
Use of GLP-2 or human growth hormone or analogs of these hormones within the past 6 months.
3.
Use of octreotide, GLP-1 analogs, dipeptidyl peptidase-IV inhibitors, or enteral glutamine within 
30 days.
4.
Previous use of teduglutide.
5.
Subjects with active inflammatory bowel disease (IBD) or subjects with IBD who received a change in 
immunosuppressant therapy (eg, azathioprine, anti-TNFs) within the past 6 months.
6.
Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus inclusion disease, 
familial adenomatous polyposis, etc.
7.
Chronic intestinal pseudo-obstruction or severe dysmotility.
8.
Clinically significant intestinal stenosis or obstruction, or evidence of such on upper gastrointestinal (GI) 
series with small bowel follow-through, within the past 6 months.


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9.
Major GI surgical intervention, including bowel lengthening procedures, within the past 3 months 
(insertion of feeding tube or endoscopic procedure is allowed).
10. Unstable cardiac disease, (eg, congestive heart failure, cyanotic disease, or congenital heart disease).
11. Moderate or severe renal impairment, defined as creatinine clearance <50 ml/min. 
12. Currently diagnosed with cancer or a history of any cancer except surgically curative skin cancer within 
the past 5 years.
13. Severe hepatobiliary disease including:
a.
Total bilirubin level ≥2 times the upper limit of normal (ULN).
b.
Aspartate aminotransferase (AST) ≥5 times ULN.
c.
Alanine aminotransferase (ALT) ≥5 times ULN.
14. Active clinically significant pancreatic disease, including clinical signs of pancreatitis associated with 
elevations in serum amylase or lipase ≥2 times ULN.
15. More than 4 SBS-related or PN/IV -related hospital admissions (eg, central line-associated bloodstream 
infection, bowel obstruction, severe fluid/electrolyte disturbances) within the past 12 months.
16. Unscheduled hospitalization within 30 days prior to screening.
17. Pregnant or lactating female.
18. Any condition or circumstance that in the investigator’s opinion put the subject at any undue risk, 
prevent completion of the study, or interfere with analysis of the study results.
Maximum Duration of Subject Involvement in the Study:
Subjects will undergo up to a 7 day screening period, a conditional PN/IV support optimization period (up to 8 
weeks), and a stabilization period (up to 8 weeks) prior to receiving teduglutide treatment. Thus, the screening, 
optimization period, and stabilization period could last up to 17 weeks in total.
Following the optimization and stabilization periods, the subjects will receive the study drug for 24 weeks. 
Endpoints:
Efficacy

Absolute and relative change from baseline in weekly PN/IV volume by visit and at end of treatment 
(EOT).

Percentage of subjects who achieve at least 20% reduction from baseline in weekly PN/IV volume at 
both Weeks 20 and 24.

Percentage of subjects who achieve at least a 20% reduction from baseline in weekly PN/IV volume at 
each visit

Change in days per week of PN/IV support from baseline by visit.

Change in plasma citrulline from baseline by visit.

Number of subjects who are able to completely wean off of PN/IV support.
Pharmacokinetics
The following parameters will be derived: area under the plasma concentration–time curve from zero to the last 
measurable concentration (AUC0–t); maximum plasma concentration (Cmax); time to Cmax (tmax); terminal-phase 
half-life (t1/2); apparent clearance (CL/F); and apparent volume of distribution (V/F).
Safety
Adverse events (AEs), 12-lead electrocardiogram (ECG), vital signs, laboratory safety data, antibodies to 
teduglutide, and changes in 48-hour urine output, body weight and body mass index will be evaluated. An 
abdominal ultrasound, esophagogastroduodenoscopy, and colonoscopy/sigmoidoscopy of remnant colon will be 
done during the stabilization period if these procedures were not done in the 6 months prior to screening. 
Colonoscopy/sigmoidoscopy will be repeated at the end of the treatment period. Esophagogastroduodenoscopy
will be repeated at the end of the treatment period for subjects with risk factors for gastric cancer. For all subjects 
with a history of Crohn’s disease, an upper GI contrast series with small bowel follow-through will be performed 
during the Stabilization Period, prior to the baseline visit.


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Statistical Methods:
Efficacy
The absolute and relative change in weekly PN/IV volume, days per week of PN/IV support, and plasma 
citrulline, from baseline to each scheduled visit, as well as at EOT, will be summarized using descriptive 
statistics.
The number and percentage of subjects who demonstrate a response at Week 20 and again at Week 24 will be 
summarized. A response is defined as the achievement of at least a 20% reduction from baseline in weekly PN/IV
volume. The number and percentage of subjects who demonstrate at least a 20% reduction from baseline in 
weekly PN/IV volume at each visit will also be summarized. 
The number and percentage of subjects who completely wean off PN/IV support by Week 24/EOT will be 
summarized. A subject will be considered to have achieved independence from PN/IV (completely weaned off 
PN/IV) if the investigator prescribes no PN/IV at week 24/EOT and there is no use of PN/IV recorded in the 
subject diary during the 2 weeks prior to the last dosing visit.
Pharmacokinetics
Teduglutide plasma concentrations will be summarized using descriptive statistics (number, mean and standard 
deviation, minimum, median, and maximum) at nominal time points. Pharmacokinetic parameters will be 
estimated using non-compartmental analysis as appropriate and summarized using descriptive statistics (number, 
mean, standard deviation, geometric mean, and CV%, minimum, median, and maximum). 
Safety
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). Treatment-
emergent AEs are defined as AEs that started or worsened on or after the date and time of the first dose of study 
dose. Treatment-emergent AEs will be summarized by system organ class and preferred term using descriptive 
statistics (eg, number and percentage of subjects). Adverse events will be summarized by severity, relationship to 
treatment, and for AEs leading to discontinuation, and death. In addition, SAEs will also be tabulated by overall 
and treatment-related events.
For laboratory tests, 48-hour oral intake and urine output, vital signs, body weight, and body mass index, 
descriptive statistics (eg, n, mean, standard deviation, median, minimum and maximum values, the number and 
percentage of subjects in specified categories) will be used to summarize the absolute values and change from 
Baseline at each time point.
The number and percentage of subjects classified as having antibodies to teduglutide will be used to summarize 
the presence of antibodies.  


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STUDY SCHEDULES
Table 1
Schedule of Evaluations and Procedures – Optimization/Stabilization
Procedures
Screening
(up to 7-days)
PN/IV Optimization Period
(8-week maximum)
PN/IV
Stabilization 
Perioda
4-8 weeks 
Week 2
(± 3 days)
Week 4 
(± 3 days)
Week 6
(± 3 days)
Week 8
(± 3 days)
Visit Number:
V1.0
V1.1
V1.2
V1.3
V1.4
V1.5
Informed consent
Xb
Eligibility criteria
X
Medical history, demographics
X
Crohn’s disease assessment
X
Physical examinationc
X
X
X
X
X
X
Record PN/IV use and adjust prescription as 
indicated
Xd
X
X
X
X
X
Adverse events
X
X
X
X
X
X
Abdominal ultrasounde
X
Upper GI contrast series with small bowel 
follow-throughf
X
Esophagogastroduodenoscopye
X
Colonoscopy/sigmoidoscopyg
X
Prior/Concomitant medication/proceduresh
X
X
X
X
X
X 
Vital signs
X
X
X
X
X
X
Height
X
Body weight 
X
X
X
X
X
Xi
12-lead ECGj
X
Safety laboratory tests
X
X
X
X
X
X
Urine pregnancy testk
X
Interim safety evaluation
[X]l
[X]l
[X]l
[X]l
[X]l
Dispense diarym
X
X
X
X
X
X


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Table 1
Schedule of Evaluations and Procedures – Optimization/Stabilization
Procedures
Screening
(up to 7-days)
PN/IV Optimization Period
(8-week maximum)
PN/IV
Stabilization 
Perioda
4-8 weeks 
Week 2
(± 3 days)
Week 4 
(± 3 days)
Week 6
(± 3 days)
Week 8
(± 3 days)
Visit Number:
V1.0
V1.1
V1.2
V1.3
V1.4
V1.5
Review Diary m
X
X
X
X
X
X
ECG=electrocardiogram; GI=gastrointestinal; ICF=informed consent form; PN/IV =parenteral nutrition/intraveous; V=visit
a The baseline visit must occur 4-8 weeks after the last optimization visit (or screening visit if no optimization is needed). The stabilization visit must occur during this 4-8 week 
interval, and must occur at least 7 days apart from the preceding visit (screening or optimization visit) and subsequent visit (baseline).  
b No study-related procedures are to be performed unless the ICF has been signed.
c A full physical examination is to be performed at screening.  Focused physical exams may be performed at all other visits
d PN/IV evaluation is to confirm weekly volume for inclusion criteria.
e Abdominal ultrasound and esophagogastroduodenoscopy should be completed during the stabilization period, prior to the baseline visit if not performed within 6 months prior to 
screening.
f Upper GI contrast series with small bowel follow-through is required for subjects with Crohn’s disease.  This should be completed during the stabilization period, prior to the 
baseline visit.
g Colonoscopy/sigmoidoscopy of remnant colon with polyp removal before teduglutide exposure will be performed in subjects with any colon remnant including rectal stump 
evaluation. Colonoscopy/sigmoidoscopy should be completed during the stabilization period, prior to the baseline visit, if required. If a subject had a normal 
colonoscopy/sigmoidoscopy documented within 6 months prior to screening, a baseline colonoscopy/sigmoidoscopy will not be required.  
h At screening, information on all medications taken in the previous 14 days will be collected.
i The dose calculation will be based on an average of the 2 measurements of body weight at the stabilization and baseline visits.  This is the first of 2 body weight measurements 
that will be used to determine drug volume.
j A 12-lead ECG will be performed at the study center after the subject has been resting for at least 5 minutes.
k For women of childbearing potential.
l Interim safety evaluations will be performed 5 to 7 days after implementing a change to the subject’s PN/IV. These measures include 48-hour oral fluid intake, 48-hour urine 
volume, hematocrit, serum blood urea nitrogen and creatinine, and urine sodium.
m Subjects will record their PN/IV support daily throughout the study. Prior to each clinic and safety visit, subjects will also record all enteral fluid intake and  urine output over a 
48-hour period.


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Table 2
Schedule of Evaluations and Procedures – Treatment Period
Procedures
Baseline
Dosing
Week 1
Dosing
Week 2
Dosing 
Week 4
Dosing
Week 8
Dosing
Week 12
Dosing
Week 16
Dosing
Week 20
Dosing Week 24
/EOTa (or ETb)
Follow-up 
Call 
Week 28a
Visit Number:
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
Visit Window (days)
± 2
± 3
± 3
± 5
± 5
± 5
± 7
± 7
± 7
Eligibility criteria
X
Crohn’s disease 
assessmentc
X
Physical examinationd
X
X
X
X
X
X
X
X
X
Record PN/IV use and 
adjust prescription as 
indicated
Xe
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
EGD
Xf
Colonoscopy/ 
Sigmoidoscopy 
X
Concomitant 
medication /procedures
X
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
Body weight
Xg
X
X
X
X
X
X
X
12-lead ECGh
X
X
X
Safety laboratory tests
X
X
X
X
X
X
X
X
Citrullinei
X
X
X
X
X
Antibodies to 
teduglutidej
X
X
X
PK sampling
Xk
(X)k
(X)k
Urine pregnancy testl
X
X
X
X
X
X
X
X
Drug dispensing
X
X
X
X
X
X
X
Teduglutide dosingm
X
X
X
X
X
X
X
X
Xn
Confirm administration 
proficiency
Xo
Xo
Xo
X
X
Xp
Interim safety 
evaluationq
[X]
[X]
[X]
[X]
[X]
[X]
[X]
Dispense Diaryr
X
X
X
X
X
X
X
X
Xp
Review Diaryr
X
X
X
X
X
X
X
X
Compliances
X
X
X
X
X
X
X
X


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Table 2
Schedule of Evaluations and Procedures – Treatment Period
Procedures
Baseline
Dosing
Week 1
Dosing
Week 2
Dosing 
Week 4
Dosing
Week 8
Dosing
Week 12
Dosing
Week 16
Dosing
Week 20
Dosing Week 24
/EOTa (or ETb)
Follow-up 
Call 
Week 28a
Visit Number:
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
(X) = Possible PK sampling time point; [X] = Possible interim safety evaluation time point; 48-hour I/O=48-hour fluid intake/urine output; ECG=electrocardiogram; 
EGD=esophagogastroduodenoscopy; EOT=end of treatment; ET=early termination; PK=pharmacokinetic; PN/IV=parenteral nutrition/intraveous; V=visit
a The follow-up period for this protocol is 4 weeks from the last dose of investigational product. Subjects who do not enroll in the treatment extension study or who discontinue 
prematurely at any time during the study will receive a follow-up phone call 4 weeks after the last dose  to query for SAEs, AEs, and concomitant treatments.
b Subjects with an ET visit should have all applicable Week 24 (Visit 10) assessments.  Call sponsor for guidance.
c Subjects with active Crohn’s disease are excluded from the study participation, therefore endoscopy/colonoscopy prior to study treatment may be required in subjects with 
clinical suspicion of active disease.
d A full physical examination is to be performed at baseline and Week 24 (Visit 10); a brief examination will be performed at all other dosing weeks with a clinic visit.
e The PN/IV evaluation is to confirm weekly volume for inclusion criteria.
f Esophagogastroduodenoscopy at Visit 10 is required for subjects with risk factors for gastric cancer (see Section 7.2.3).
g The dose calculation will be based on an average of the 2 measurements of body weight at the stabilization and baseline visits.  This is the second of 2 body weight 
measurements that will be used to determine drug volume.
h A 12-lead ECG will be performed at the study center after the subject has been resting for at least 5 minutes.
i Blood sample for measuring citrulline should be drawn from peripheral venous access, if this is not possible, sample may be drawn from a central line. 
j Blood sample for antibody testing is to be collected at baseline (Visit 2) prior to first investigational product administration. Blood samples for antibody testing at Week 12 
(Visit 7) and Week 24 (Visit 10) must be collected prior to that day's dose, and more than 14 hours after the prior day's dose.
k Samples for PK analysis will be collected pre-dose and at 15, 30  minutes post-dose and at 1, 2, 3, 4, 6, 8, 10 and 12 hours post-dose at Visit 2. Additional PK samples will be 
collected predose, and 1 and 2 hours post-dose at Week 4 (Visit 5) or Week 12 (Visit 7). The site of teduglutide administration prior (arm, thigh, or abdomen) and the person 
administering the injection (subject or physician) must be specified.  Blood sample for measuring PK must be drawn from peripheral venous access.
l For women of childbearing potential.  
m Teduglutide is dosed once daily during the treatment period. The first dose of study drug must be administered by the study physician.
n Dosing will continue if the subject enters the extension study, but will stop at the Week 24 visit if the subject doesn't enter the extension study.
o The study physician must observe the subject administering the study drug in compliance with the study drug administration checklist at least twice before the subject is allowed 
to administer the drug without direct observation by the physician. Refer to Section 6.2.2.1.
p For subjects entering the extension study only.
q Interim safety evaluations will be performed 5 to 7 days after any change to the subject’s PN/IV has been implemented. These measures include 48-hour oral fluid intake, 
48-hour urine output, hemoglobin, hematocrit, serum blood urea nitrogen, creatinine, and urine sodium, and may be performed at the investigational site laboratory.
r Subjects will record their PN/IV support and teduglutide dosing daily throughout the study. Prior to each clinic and safety visit, subjects will also record all enteral fluid intake 
and  urine output over a 48-hour period.
s Compliance will be checked at every visit by asking subjects if they have taken their study drug according to instructions and by performing drug accountability.


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BACKGROUND INFORMATION
1
1.1
Indication and Current Treatment Options
Short bowel syndrome (SBS) is a rare, serious, disabling, socially incapacitating and potentially 
life-threatening condition which is the leading cause of intestinal failure (Nightingale and 
Woodward 2006; Pironi et al. 2015).  Intestinal failure from SBS results from surgical resection 
or congenital defects and is defined as the reduction of gut function below the minimum 
necessary for the absorption of macronutrients and/or water and electrolytes, such that 
intravenous supplementation is required to maintain health and/or growth.  Patients with SBS are 
highly prone to malnutrition, diarrhea, dehydration, and an inability to maintain weight due to 
the reduced intestinal capacity to absorb macronutrients, water, and electrolytes (Dudrick et al. 
1991; Nightingale 1999; Rombeau and Rolandelli 1987; Shanbhogue and Molenaar 1994;
Vanderhoof and Langnas 1997; Wilmore et al. 1997).  Additional potential consequences of SBS 
include dehydration, electrolyte disturbances, malabsorption of nutrients, gastric hypersecretion, 
metabolic acidosis, cholelithiasis, nephrolithiasis, steatorrhea, diarrhea, small bowel bacterial 
overgrowth and weight loss (Nightingale and Woodward 2006; O'keefe et al. 2006).
Following resection, intestinal adaptation may occur in adults during the first 1 to 2 years 
postsurgery.  The adaptive response characterized by mucosal hyperplasia, increased mucosal 
blood flow, improved segmental absorption and increased hepatobiliary secretions (O'keefe et al. 
2006).  These morphologic and functional changes are coordinated by the release of 
glucagon-like peptide 2 (GLP-2) from L-type enteroendocrine cells.  In response to lumenal 
nutrients reaching the distal ileum and colon, L-cells secrete GLP-2, which regulates 
gastrointestinal secretions, motility, and the local production of additional hormones, cytokines, 
and growth factors.
The clinical care of SBS is mainly supportive and focuses on optimizing remnant intestinal 
function through dietary interventions, oral rehydration solutions, antidiarrheal and antisecretory 
agents. Despite intestinal adaptation following resection, many SBS develop intestinal failure, 
characterized by the requirement for chronic use of parenteral nutrition/intravenous (PN/IV) to 
maintain hydration, electrolyte balance, and/or nutritional needs. 
Although PN/IV can meet basic nutrition and fluid requirements, it does not improve the body's 
ability to absorb nutrients.  Parenteral nutrition dependence is associated with shortened life span 
(Messing et al. 1999; Scolapio et al. 1999), life threatening complications (eg, sepsis, blood clots, 
or liver damage), as well as reduced quality of life (Delegge et al. 2007; Jackson and Buchman 
2005; Jeppesen 2006). The development of parenteral nutrition-associated liver disease 
(PNALD) predisposes patients to sepsis, increased mortality rates, and the potential to develop 
irreversible liver damage (Tazuke and Teitelbaum 2009). The American Gastroenterological 
Association Medical Position Statement on Short Bowel Syndrome recommends that 
management of PNALD should include reducion of toxic  Parenteral nutrition constituents such 
as phytosterols, a component of soy-based lipid emulsions (American Gastroenterological 
Association 2003).


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The severity of SBS is illustrated by the shortened life-span in patients with moderate to severe 
disease (Messing et al. 1999).  In SBS, survival can be impacted by the underlying condition, by 
severe clinical manifestations of malabsorption, and treatment-associated life-threatening 
complications (O'keefe et al. 2006).  With current medical management practices, the overall 
10 year survival in SBS patients is 52%, and is significantly lower in patients who remain 
chronically PN/IV -dependent compared to patients who wean off PN/IV (40.7% versus 67%) 
(Amiot et al. 2013). 
In addition, the symptoms of SBS and the inconveniences and complications in relation to PN/IV
support may cause potential restrictions in the lifestyle of these patients leading to significant 
impairment of their quality of life (Jeppesen et al. 1999; Baxter et al. 2006; Winkler and Smith 
2014). The impact of SBS and PN/IV on quality of life may be significant with patients, on 
average, moving their bowels at least 10 times a day, with multiple ostomy bag changes per day, 
and having a typical output of 2 to 3 liters of watery diarrhea per day. Patients may be on PN/IV
10 to 15 hours a day for up to 7 days a week. Sleep is disrupted and patients typically cannot 
work.
1.2
Product Background and Clinical Information
Teduglutide is a novel, recombinant analog of naturally occurring human GLP-2 that regulates 
the functional and structural integrity of the cells lining the gastrointestinal (GI) tract. 
Teduglutide is a 33-amino acid peptide that differs from native GLP-2 in the substitution of 
glycine for alanine at the second position at the N terminus. As a result, teduglutide demonstrates 
resistance to degradation by dipeptidyl peptidase 4 and therefore maintains a longer elimination 
half-life of approximately 2 hours in healthy subjects and 1.3 hours in adult SBS subjects 
compared to the native peptide, which has a t1/2 of approximately 7 minutes. Teduglutide has 
been shown in animal studies and previous human clinical trials to increase villus height and 
crypt depth in the intestinal epithelium, thereby increasing the absorptive surface area of the 
intestines. 
Results of the pivotal study, CL0600-020, showed that teduglutide at a dose of 0.05 mg/kg/day 
for up to 24 weeks was superior to placebo in reducing PN/IV support in adult subjects with 
SBS.  In this study the responder rate (defined as at least a 20% reduction from baseline in 
weekly PN/IV volume at Week 20 and Week 24) was 62.8% in the teduglutide 0.05 mg/kg/day 
group with subjects achieving a mean reduction from baseline in PN/IV volume of 4.4 L/week at 
Week 24.
In the follow-up long-term extension study CL0600-021, there continued to be evidence of 
increased efficacy of teduglutide over time in all groups exposed to teduglutide in terms of 
PN/IV volume reduction, gaining additional days off per week, and achieving complete weaning 
of PN/IV. The most significant reductions were for those subjects who received 24 weeks of 
teduglutide 0.05 mg/kg/day in CL0600-020 and continued treatment in CL0600-021 for another 
24 months. In this cohort, 10 subjects completely weaned off of PN/IV support and 18/30 
(60.0%) had a reduction in their PN/IV requirement of at least 3 days per week. It was 
encouraging that efficacy was also observed for subjects who initiated treatment in CL0600-021 
(ie, those who received placebo or were not treated in CL0600-020). 


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After only 6 months of treatment, 37.1% of subjects who had received placebo in CL0600-020 
had at least a 20% reduction in weekly PN/IV volume, which increased to 55.2% by Month 24. 
Two of these subjects completely weaned off of their PN/IV support. In subjects who had not 
been treated in CL0600-020, 50.0% had at least a 20% reduction in weekly PN/IV volume after 
6 months of treatment, which increased to 66.7% by Month 24. One of these subjects completely 
weaned off of their PN/IV support. Overall, a total of 13 subjects achieved enteral autonomy 
(independence of PN/IV support), and 25/65 (38.5%) subjects demonstrated a reduction of 
≥3 days/week in their PN/IV by the end of study at Month 24. In addition, 21/22 (95.5%) of 
teduglutide-treated subjects who responded in the previous study maintained their response after 
an additional 24 months of teduglutide treatment, demonstrating durability of effect. The results 
of this study support the efficacy of long-term treatment with teduglutide in PN/IV -dependent 
SBS subjects.
Teduglutide (0.05 mg/kg/day) is currently indicated for the treatment of adult patients with SBS.  
The European Commission granted a centralized marketing authorization valid throughout the 
European Union (EU) for teduglutide (REVESTIVE®) on 30 Aug 2012.  On 29 Jun 2016, the 
European Commission granted an extension of the Market Authorization for teduglutide for the 
treatment of patients aged 1 year and above with SBS.  A New Drug Application for teduglutide 
(GATTEX®) was approved by the United States (US) Food and Drug Administration (FDA) on 
21 Dec 2012.  Teduglutide is currently approved in >30 countries.  


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STUDY OBJECTIVES AND PURPOSE
2
2.1
Rationale for the Study 
Teduglutide 0.05 mg/kg/day has demonstrated a favorable benefit-risk profile in clinical studies 
and is already marketed in the EU and the US. The clinical profile and medical issues related to 
SBS and PN/IV in Japan are similar to those in the EU and US. Therefore, there is an unmet 
medical need for Japanese patients with PN/IV -dependent SBS. This study is designed to 
provide evidence of safety and efficacy of teduglutide in a Japanese SBS patient population.
2.2
Study Objectives
The objectives of this clinical study are to evaluate the safety, efficacy, and pharmacokinetics 
(PK) of teduglutide in Japanese subjects with SBS who are dependent on PN/IV over a 24-week 
treatment period.


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STUDY DESIGN
3
3.1
Study Design and Flow Chart
This is an open-label, multicenter study, consisting of a conditional PN/IV optimization period, 
a mandatory PN/IV stabilization period, and a 24-week treatment period. A schematic 
representation of the study design is presented in Figure 1.
3.1.1
Optimization and Stabilization Periods 
If at screening, a subject does not have an optimized PN/IV volume, defined as a 48-hour urine 
output between 2 and 4 L, he/she will enter the optimization period, during which the minimally 
tolerated stable PN/IV volume will be determined during a period of up to 8 weeks. If it is not 
possible to keep the subject adequately hydrated and nourished within the target urine output 
range, the minimally tolerated PN/IV volume will be documented. For subjects who don't have 
an optimization period, the "last optimization visit" is the screening visit.
All subjects will then enter the stabilization period, during which the target PN/IV volume will 
be maintained for at least 4 consecutive weeks (8 weeks maximum). Those subjects who fail to 
stabilize will not proceed further and will not be included in the treatment period.
Appendix 2 provides details of the optimization procedure.  Schedules of evaluations for the 
optimization/stabilization period can be found in Table 1.
3.1.2
Treatment Period
Following the stabilization period, subjects will enter a 24-week dosing period, during which all 
subjects will receive teduglutide 0.05 mg/kg SC once daily. At each site visit during the 
treatment phase, efficacy (adjustments to PN/IV) and safety will be monitored.
Subjects will have blood samples taken for teduglutide PK analysis at predose, at 15, 30 minutes 
and 1, 2, 3, 4, 6, 8, 10, and 12 hours post dose at the baseline visit (Visit 2). Subjects will also
have blood samples taken for teduglutide PK analysis at predose and 1 and 2 hours post dose at 
Week 4 (Visit 5) or Week 12 (Visit 7) of the treatment period.
All subjects who complete the study may participate in a long-term extension study in which 
eligible subjects will continue to receive teduglutide. 
Schedules of evaluations for the Treatment Period can be found in Table 2.  Procedures to adjust 
or reduce PN/IV volume during the Treatment Period is provided in Appendix 3, and should be 
followed carefully throughout the study.


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3.2
Study Duration
Subjects will undergo up to a 7 day screening period, a conditional PN/IV support optimization 
period (up to 8 weeks), and a stabilization period (up to 8 weeks) prior to receiving teduglutide 
treatment. Thus, the screening, optimization period, and stabilization period could last up to 
17 weeks in total.
Following the optimization and stabilization periods, and appropriate training on study drug 
administration, the subjects will receive the study drug for 24 weeks. 
Subjects who do not enroll in the extension study or who discontinue prematurely at any time 
during the study will receive a follow-up phone call 4 weeks after the last dose of study drug.
The study completion date is defined as the date the final subject, across all sites, completes their 
final protocol-defined assessment. Please note that this includes the follow-up visit or contact 
(last safety contact), whichever is later. The study completion date will be used to ascertain 
timing for study results posting and reporting.
3.3
Sites and Regions
This study is planned to be conducted in approximately 5 sites in Japan.


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Figure 1
Study Schematic
SC=subcutaneous; qday=once daily; EOT=end of treatment
Screening
Up to 7 days
Optimization
0-8 weeks
Stabilization
4-8 weeks
Teduglutide treatment 0.05 mg/kg SC qday
24 weeks
V1.0V1.1 V1.2 V1.3 V1.4
V1.5
V2
(Baseline)
V3 V4 V5
V6
V7
V8
V9
V10
(EOT)
Safety follow-up
phone call
4 weeks after EOT
Extension
study
Up to 4 visits as needed
Performed if urine output 
is not in the target range
at screening


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STUDY POPULATION
4
At least 5 Japanese subjects with PN/IV-dependent SBS will be dosed.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below:
1. Ability to voluntarily provide written, signed, and informed consent to participate in the 
study.
2. Male or female 16 years of age or older at the time of signing informed consent.
3. Intestinal failure due to SBS as a result of major intestinal resection (eg, due to injury, 
volvulus, vascular disease, cancer, Crohn’s disease) that resulted in at least 12 continuous 
months of PN/IV dependence at the time of informed consent.
4. Parenteral nutrition requirement of at least 3 times per week during the week before the 
screening visit and during the 2 weeks prior to the baseline visit.
5. Stable PN/IV requirement for at least 4 consecutive weeks immediately prior to the start 
of teduglutide treatment. Stability is defined as:
a.
Actual PN/IV usage is similar to prescribed PN/IV.
b.
Baseline (Visit 2) 48-hour oral fluid intake and urine output (I/O) volumes fall 
within ±25% of the respective 48-hour I/O volumes at the last optimization visit.
c.
Urine output volume should NOT fall below 2 L and should not exceed 4 L per 
48 hours at the last optimization visit, the stabilization visit, and the baseline 
visit.
6. For subjects with a history of Crohn’s disease, clinical remission for at least 12 weeks 
prior to the baseline visit as demonstrated by clinical assessment, which may include 
procedure-based evidence of remission.
7. Females of childbearing potential must agree to comply with the contraceptive 
requirements of the protocol.
8. An understanding, ability, and willingness to fully comply with study procedures and 
restrictions.


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4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1. Participation in a clinical study using an experimental drug within 30 days or 
5.5 half-lives, whichever is longer, prior to screening, or concurrent participation in any 
other clinical study.
2. Use of GLP-2 or human growth hormone or analogs of these hormones within the past 
6 months.
3. Use of octreotide, GLP-1 analogs, dipeptidyl peptidase-IV inhibitors, or enteral 
glutamine within 30 days.
4. Previous use of teduglutide.
5. Subjects with active inflammatory bowel disease (IBD) or subjects with IBD who 
received a change in immunosuppressant therapy (eg, azathioprine, anti-TNFs) within the 
past 6 months.
6. Intestinal malabsorption due to a genetic condition, such as cystic fibrosis, microvillus 
inclusion disease, familial adenomatous polyposis, etc.
7. Chronic intestinal pseudo-obstruction or severe dysmotility.
8. Clinically significant intestinal stenosis or obstruction, or evidence of such on upper GI 
series with small bowel follow-through, within the past 6 months.
9. Major GI surgical intervention, including bowel lengthening procedures, within the past 
3 months (insertion of feeding tube or endoscopic procedure is allowed).
10. Unstable cardiac disease, (eg, congestive heart failure, cyanotic disease, or congenital 
heart disease).
11. Moderate or severe renal impairment, defined as creatinine clearance <50 ml/min.
12. Currently diagnosed with cancer or a history of any cancer except surgically curative skin 
cancer within the past 5 years.
13. Severe hepatobiliary disease including:
a.
Total bilirubin level ≥2 times the upper limit of normal (ULN).
b. Aspartate aminotransferase (AST) ≥5 times ULN.
c.
Alanine aminotransferase (ALT) ≥5 times ULN.
14. Active clinically significant pancreatic disease, including clinical signs of pancreatitis 
associated with elevations in serum amylase or lipase ≥2 times ULN.
15. More than 4 SBS-related or PN/IV-related hospital admissions (eg, central 
line-associated bloodstream infection, bowel obstruction, severe fluid/electrolyte 
disturbances) within the past 12 months.
16. Unscheduled hospitalization within 30 days prior to screening.
17. Pregnant or lactating female.  
18. Any condition or circumstance that in the investigator’s opinion put the subject at any 
undue risk, prevent completion of the study, or interfere with analysis of the study results.


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4.3
Reproductive Potential 
To be eligible for treatment with teduglutide, sexually active females of childbearing potential 
must use a medically acceptable form of contraception.  Females of childbearing potential must 
be advised to use medically acceptable contraceptives throughout the study period and for 
30 days following the last dose of investigational product.  If hormonal contraceptives are used, 
they should be administered according to the package insert.  Females of childbearing potential 
who are not currently sexually active must agree to use medically acceptable contraception if 
they become sexually active during the period of the study and for 30 days following the last 
dose of investigational product.
Females of childbearing potential must have a negative urine β-HCG pregnancy test at all visits 
where it is tested to participate in the study (see Section 8.1.6 for information about reporting a 
pregnancy).  
Females of childbearing potential must agree to use medically acceptable methods of 
contraception at all times during the study and for 30 days following the last dose of 
investigational product.
4.4
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator should 
discuss withdrawal of a subject from investigational product with the medical monitor as soon as 
possible.
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Visit 10 are to be performed as completely as possible. Whenever possible, all discontinued 
subjects should also receive a follow-up phone call 4 weeks after the last dose of study drug 
unless the subject has withdrawn consent. Comments (spontaneous or elicited) or complaints 
pertaining to study drug discontinuation made by the subject must be recorded in the source 
documents. The reason for termination, date of stopping investigational product, and the total 
amount of investigational product taken must be recorded in the electronic case report form 
(eCRF) and source documents.
Subjects who discontinue will not be replaced. 
Subjects who do not enroll in the treatment extension study or who discontinue prematurely at 
any time during the study will receive a follow-up phone call 4 weeks after the last dose of study 
drug.
4.4.1
Reasons for Discontinuation
The reason(s) for permanent discontinuation of treatment and/or withdrawal from the study must 
be determined by the investigator, and recorded in the subject’s medical record and in the eCRF.  


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If a subject is withdrawn for more than 1 reason, each reason should be documented in the source 
document, and the most clinically relevant reason should be entered in the eCRF.
Reasons for discontinuation include, but are not limited to:

Adverse event

Death

Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Study terminated by sponsor

Withdrawal by subject

Lack of efficacy

Other
4.4.2
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact (office visit or telephone contact). At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that they 
return to the site for final safety evaluations and return any unused investigational product.


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PRIOR AND CONCOMITANT TREATMENT
5
5.1
Prior Treatment
All non-study treatment (including but not limited to herbal treatments, vitamins, behavioral 
treatment, non-pharmacological treatment, such as psychotherapy, as appropriate) received 
within 14 days prior to the Screening Visit (Visit 1.0) (or pharmacokinetic equivalent of 5 half 
lives, whichever is longer must be recorded on the appropriate eCRF page.  Any diagnostic, 
surgical or other therapeutic treatments received by a subject within 14 days prior to the 
Screening Visit (Visit 1.0) will also be recorded on the eCRF.
5.2
Concomitant Treatment
The administration of all medications including concomitant medications (including prescription 
and nonprescription medications, dietary and nutritional supplements, and vitamins), must be 
recorded from screening and for the duration of the study in the appropriate sections of the 
eCRF. Any diagnostic, surgical or other therapeutic treatments received by a subject during the 
course of the study will also be recorded on the eCRF.
The mechanism of action of teduglutide may increase enteral absorption of drugs (eg, motility 
medication including narcotics and opioids used for the management of SBS, warfarin, 
psychotropics, metronidazole, digoxin), so consideration should be given to modifying 
concomitant enteral medication regimens. Titration of concomitant enteral medications should be 
considered when drugs, especially those with a narrow therapeutic index, are given.
5.2.1
Permitted Treatment
Standard medical therapy for SBS should be continued.
5.2.2
Prohibited Treatment
The following medications are prohibited during teduglutide treatment and within the provided 
timeframe prior to the baseline visit (Table 3):
Table 3
Prohibited Treatment
Prior Therapy
Time Restriction Prior to 
the Baseline Visit
Teduglutide
Any
Glucagon-like peptide-2, human growth hormone, or analogs of these 
hormones
6 months
Octreotide, dipeptidyl peptidase 4 inhibitors, GLP-1 analogs, and 
enteral glutaminea
30 days
a Enteral glutamine refers to L-glutamine powder for oral solution, such as Nutrestore® or Endari™, administered in quantities of 
5 g or more per dose or more than 10 g per day. The use of elemental formulas that contain glutamine, such as Elental®, is 
allowed.


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INVESTIGATIONAL PRODUCT
6
6.1
Identity of Investigational Product
The test product is teduglutide, which will be provided in sterile, single-use 3 mL vials 
containing 5 mg teduglutide as a white lyophilized powder to be reconstituted before use with 
0.5 mL sterile water for injection. In addition to the active ingredient (teduglutide), each vial of 
teduglutide contains L-histidine, mannitol, monobasic sodium phosphate monohydrate, and 
dibasic sodium phosphate as excipients. Additional information is provided in the current 
investigator’s brochure.
6.1.1
Blinding the Treatment Assignment
Not applicable for this open-label study.
6.2
Administration of Investigational Product
6.2.1
Allocation of Subjects to Treatment
All subjects will receive teduglutide 0.05 mg/kg once daily.
6.2.2
Dosing
Teduglutide 0.05 mg/kg once daily will be administered daily by subcutaneous (SC) injection 
into either thigh or arm or 1 of the 4 quadrants of the abdomen (in subjects without a stoma). 
Each day, the injection site should be rotated.  For subjects with a stoma, the quadrant of the 
abdomen containing the stoma should not be used. The subject should be dosed at approximately 
the same time each day. Consecutive doses should be separated by at least 12 hours. Detailed 
instructions for reconstitution and injection of the investigational product can be found in the 
Instructions for Use.
Any subject who achieves complete independence from PN/IV support at any time during the 
treatment period will continue to receive teduglutide treatment.   
6.2.2.1
Subject Administration
The first dose of teduglutide will be administered by a study physician. 
The processes for training the subject to self-administer teduglutide and for providing oversight 
of study drug administration are described in the Site Training Guide.  Before a subject is 
permitted to administer teduglutide, the study physician must observe the subject 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 subject can safely administer the study drug, 
subsequent doses may be administered by the subject at home without direct supervision by the 
physician.  However, at selected study visits during the dosing period (refer to Table 2), 
administration of the study drug must be performed under direct supervision by the study 
physician, and the teduglutide administration checklist must be completed again.  


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This ensures that the subject continues to administer the study drug correctly and safely 
throughout the dosing period.
If at any time a study physician suspects that the subject is no longer capable of administering 
the study drug safely and accurately, the subject should be re-assessed by a study physician using 
the teduglutide administration checklist.  If the subject is deemed unable to administer the study 
drug, dosing must be performed by a study physician until the subject is re-trained and 
proficiency is confirmed using the teduglutide administration checklist.  
Eligibility for teduglutide to be administered by a subject 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 Subject:

The subject’s condition is stable.

The subject has been sufficiently trained and is able to administer teduglutide in 
compliance with the checklist.
Criteria to Discontinue Teduglutide Administration by the Subject:

The subject 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 self-administered.  In addition to 
discontinuing administration of teduglutide by the subject, if a subject sustains an 
adverse drug reaction where the symptoms are considered intolerable, dose 
interruption or study drug discontinuation should be considered.

In the study physician’s judgment, it is inappropriate for the subject to continue 
administration of the study drug for any other reason. 
6.2.3
Unblinding the Treatment Assignment
Not applicable for this open-label study.
6.3
Labeling, Packaging, Storage and Handling
6.3.1
Labeling and Packaging
The investigational product will be packaged, labeled, and shipped to the study site by the 
sponsor or designee. Kits containing 7 vials of investigational product will be provided for this 
study. The vials will be labeled in accordance with applicable regulatory requirements. 
Ancillary kits, containing supplies needed for the reconstitution and administration of the 
investigational product will also be provided and labeled in accordance with the applicable 
regulatory requirements. 
All investigational product used in this study will be manufactured, tested, labeled, and released 
according to current legal requirements and Good Manufacturing Practice.


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6.3.2
Storage and Handling
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented.
Investigational product must be kept in a locked area with access restricted to specific study 
personnel. Investigational product will be stored refrigerated at a temperature between 2 oC to 
8oC (35.6°F to 46.4°F) until dispensed to a subject. The prefilled sterile water for injection 
syringes will be stored at a temperature between 2°C to 25°C. Once dispensed/supplied to a 
subject, the investigational product and ancillary kits can be stored refrigerated up to a controlled 
room temperature (acceptable range of 2°C to 25oC, or 35.6°F to77°F). The subject will be 
instructed to keep the investigational product and sterile water diluent at controlled room 
temperature. If there are concerns that the controlled room temperature cannot be maintained, the 
investigational product may be refrigerated. The study drug is for single use only, and should be 
used within 3 hours following reconstitution.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product and ancillary kits are maintained within an established temperature range. The 
investigator is responsible for ensuring that the temperature is monitored throughout the duration 
of the study and that records are maintained; the temperature should be monitored continuously 
by using either an in-house system, a mechanical recording device such as a calibrated chart 
recorder, or by manual means, such that both minimum and maximum thermometric values over 
a specific time period can be recorded and retrieved as required. Such a device (ie, certified 
min/max thermometer) would require manual resetting upon each recording. The sponsor must 
be notified immediately upon discovery of any excursion from the established range. 
Temperature excursions will require site investigation as to cause and remediation. The sponsor 
will determine the ultimate impact of excursions on the investigational product and will provide 
supportive documentation as necessary.  Under no circumstances should the product be 
dispensed to subjects until the impact has been determined and the product is deemed appropriate 
for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
Investigational products are distributed by the pharmacy or nominated member of the study 
team. The pharmacist/nominated team member will enter the unique subject identifier on the 
investigational product bottle/carton labels, as they are distributed.
6.4
Drug Accountability
Investigational product will not be dispatched to the study site until the sponsor or designee has 
received all required documents from the study site in accordance with applicable regulatory 
requirements and relevant standard operating procedures. 


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Upon receipt, the study site’s pharmacist or delegate is responsible for ensuring that all 
investigational product received at the site is inventoried and accounted for throughout the study. 
A copy of the shipping documents must be maintained for the investigator’s records. Kits will be 
shipped to the site once the subject is screened.
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be
maintained as detailed further in this section.
The investigator has overall responsibility for dispensing investigational product. Where 
permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is adequately 
trained in the protocol and who works under the direct supervision of the investigator. This 
delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee will dispense the investigational product only to subjects 
included in this study following the procedures set out in the study protocol. Investigational 
product kits will be dispensed at each of the applicable study visits at which the subject is 
required to be at the clinic. Each investigational product kit is sufficient for a treatment period of 
1 week and enough kits will be supplied to cover the period until the next planned study visit. 
Additional study kits will be provided as necessary.
Each subject will be given the investigational product according to the protocol. The investigator 
is to keep a current record of the inventory and dispensing of all clinical supplies. All dispensed 
medication will be documented on the eCRFs and/or other investigational product record. The 
investigator is responsible for assuring the retrieval of all study supplies from subjects.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.
At the end of the study, or as instructed by the sponsor, all unused stock, subject returned 
investigational product, and empty/used investigational product packaging are to be sent to the 
sponsor or designee. The investigator is responsible for assuring the retrieval of all study 
supplies from subjects.
Returned investigational product must be counted and verified by clinical site personnel and the 
sponsor (or study monitor). Shipment return forms, when used, must be signed prior to shipment 
from the site. Contact the sponsor for authorization to return any investigational product prior to 
shipment. Shipment of all returned investigational product must comply with local, state, and 
national laws. 


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Please see the Pharmacy Manual for additional information.
6.5
Subject Compliance
The subjects must be instructed to bring unused investigational product and empty/used 
investigational product packaging to every visit.  Drug accountability must be assessed and 
recorded at the container/packaging level for unused investigational product that is contained 
within the original tamper-evident sealed container (eg, bottles, trays, vials) or at the individual 
count level for opened containers/packaging.
Subject compliance will be checked by site personnel at every visit by reviewing the subject 
diaries and asking the subject if he/she has administered the investigational product according to 
instructions. If any doses have been missed, the reason for missed dose should be documented in 
the subject’s source documentation including, as applicable, the eCRF.
The investigator is responsible for contacting the sponsor or designee when the subject’s daily 
investigational product dosing regimen is interrupted. Attempts should be made to contact the 
sponsor or designee prior to dose interruption. Reasons for dosage interruption may include but 
are not limited to hospitalization and adverse events (AEs), a lapse in investigational product 
delivery, etc.
Subjects who have received 80% of the planned doses administered will be assessed as being 
compliant with the study protocol.


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STUDY PROCEDURES
7
7.1
Study Schedule
Detailed study procedures and assessments to be performed for subjects throughout the study are 
outlined in the study schedules (Table 1 and Table 2) and must be referred to in conjunction with 
the instructions provided in this section. 
Subjects who drop out of the study prior to the final visit should have all early termination 
procedures done whenever possible.
7.1.1
Screening
Prior to performing any study-related procedures (including those related to screening), the 
investigator or his/her designee must obtain written informed consent from the subject.  The 
screening visit assessments and procedures, beginning with informed consent, will be performed 
as outlined in Table 1.
Subjects may be rescreened no more than twice and only with prior sponsor medical approval. In 
the event of rescreening, a new subject number will be assigned. Subjects who are rescreened 
will be reconsented. 
7.1.2
Optimization and Stabilization Periods
Subjects who are eligible for the study during the screening visit will proceed to the optimization 
or stabilization period depending on urine ouput evaluated at the screening visit. Assessments 
will be performed as outlined in Table 1. 
During the optimization period, PN/IV adjustments will be made according to the algorithm in 
Appendix 2.  Optimization visits will occur approximately every 2 weeks (for up to 8 weeks) 
until the subject achieves an optimized volume of PN/IV indicated by targeted urine output of 
1.0 L/day to 2.0 L/day. 
Once an optimal tolerated PN/IV volume has been reached, the subject will begin the 4-week 
minimum stabilization period.  No further PN/IV adjustments should take place during the 
stabilization period.  Subjects who do not achieve stable PN/IV support during this period will 
not be eligibile to continue in the study.
7.1.3
Treatment Period
The open-label teduglutide treatment period will comprise 24 weeks, during which all 
assessments will be performed as outlined in Table 2.
7.1.4
Follow-up Period
Long-term safety and efficacy data will be obtained from subjects enrolling into the extension 
study at the Week 24 visit (Visit 10). 


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Subjects who do not enroll in the treatment extension study or who discontinue prematurely at 
any time during the study will receive a follow-up phone call 4 weeks (Week 28) after the last 
dose of study drug.
7.2
Study Evaluations and Procedures
7.2.1
Demographics and Other Baseline Characteristics
7.2.1.1
Demographics and Medical History
Information on medical history and demographic data is to be recorded on the appropriate eCRF.
7.2.1.2
Clinical Assessment of Crohn’s Disease Activity
Any subject with a history of Crohn’s disease will have their clinical disease status assessed at 
screening and again at the baseline visit of the treatment period to determine whether the subject 
has active or quiescent disease. Subjects with active Crohn’s disease are excluded from study 
participation. For all subjects, upper endoscopy and colonoscopy/sigmoidoscopy are required 
during the stabilization period if they have not been completed within 6 months prior to 
screening.  For subjects with Crohn's disease, it may be necessary to perform upper endoscopy 
and colonoscopy prior to the baseline visit in subjects with clinical suspicion of active disease, 
even if these procedures had been completed within 6 months prior to screening. In addition, 
upper GI contrast series with small bowel follow-through is required in subjects with a history of 
Crohn’s disease to detect any clinically significant stenosis or stricture.
7.2.2
Efficacy Assessments
7.2.2.1
Subject Diaries
Diaries will be distributed to subjects at the time of informed consent and at clinic visits 
according to the study schedules. Subjects will record their PN/IV support daily throughout the 
study. Prior to each clinic and safety visit, subjects will also record all enteral fluid intake and  
urine output over a 48-hour period.  Forty-eight hours of output data must be collected during 
Screening (Visit 1.0) in order to assess the need for the optimization period.  Diaries may be 
completed by the subject or the subject's designee if the subject is physically unable to enter data 
on his/her own.
7.2.2.2
Prescribed Parenteral Nutrition 
All attempts should be made to follow the PN/IV adjustment algorithm specified in the 
appendices.  At the interim visits the PN/IV will be changed if the previous adjustment was not 
tolerated.  Physician-directed changes in a subject’s PN/IV volume must be followed by an 
interim safety visit 5 to 7 days after the adjustment has been implemented.  If the subject has a 
AE that prevents him/her from adhering to study requirements, including the PN/IV adjustment 
algorithms, the subject may be withdrawn from the study.
The prescribed PN/IV weekly total volume and days per week will be recorded. Changes in 
parenteral support prescription that reflect changes in the subject's intestinal absorption are 
recorded. 


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Temporary adjustments to parenteral nutrition or IV fluids that last less than 72 hours may be 
recorded at the discretion of the investigator, but all parenteral support prescriptions that last 
more than 72 hours must be recorded.  The PN/IV constituents are at the discretion of the 
physician; the identities of parenteral support constituents do not recorded. 
7.2.2.3
Plasma Citrulline
Plasma citrulline will be measured as an assessment of enterocyte mass.  If peripheral venous 
access is not possible, blood samples for citrulline may be drawn from a central line.  The 
samples will be processed according to instructions in the laboratory manual.
7.2.3
Safety Assessments
7.2.3.1
Laboratory Evaluations
Safety laboratory tests are to be performed at site visits with results processed by a central 
laboratory.  Although subjects do not need to be in a fasted state at the time of their clinic visit, 
they should avoid large meals or large volumes of fluid, including PN/IV with lipids, within 
3 hours of the clinic visit to permit consistent assessment.  
Safety lab tests performed at interim safety visits after PN/IV adjustments will consist of 
hemoglobin, hematocrit, serum blood urea nitrogen, creatinine, and urine sodium, and may be 
performed at the investigational site laboratory.  
The investigator should assess out-of-range clinical laboratory values for clinical significance, 
indicating if the value(s) is/are not clinically significant or clinically significant.  Abnormal 
clinical laboratory values, which are unexpected or not explained by the subject’s clinical 
condition, may, at the discretion of the investigator or sponsor, be repeated as soon as possible 
until confirmed, explained, or resolved.  New clinically significant lab tests results should be 
reported as AEs (see Section 8).
Tests include the following (Table 4):


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Table 4
List of Laboratory Tests
Hematology:

Hematocrit

Hemoglobin

Platelet count

Red blood cell count

Red blood cell morphology, if needed

White blood cell count with differential
Urinalysis:

Blood

Glucose

Leucocytes

Microscopic analysis

pH

Protein

Specific gravity

Urine Sodium
Pregnancy tests (females of childbearing potential):

Urine β-HCG
Biochemistry:

Albumin

Alkaline phosphatase

Alanine aminotransferase

Amylase

Aspartate aminotransferase

Bilirubin (total, direct and indirect)

Blood urea nitrogen

Calcium (total)

Chloride

Cholesterol

Citrulline (plasma)

C-reactive protein

Creatinine

Creatinine clearance

Gamma-glutamyl transferase

Glucose

Lipase

Magnesium

Phosphorus

Potassium

Sodium

Triglycerides

Uric acid
7.2.3.2
Antibodies to Teduglutide 
Blood samples for analyses of antibodies to teduglutide will be collected. Blood sample for 
antibody testing is to be collected at study site prior to first investigational product 
administration. Once the subject has started teduglutide treatment, samples must be drawn at 
least 14 hours after dosing. 
Anti-teduglutide antibody testing is a 3-step process. If a sample tests negative, no further testing 
is done. If a sample tests positive, further testing is done for teduglutide-specific antibodies. If 
teduglutide-specific antibodies are detected, the test is deemed “positive” and the titer derived, 
and neutralizing antibody testing is done. Subjects who test positive for teduglutide-specific 
antibodies may remain on treatment and blood samples for antibody testing will continue to be 
collected as per protocol schedule (Table 2). 
Blood samples for anti-teduglutide antibody testing may be stored and then analyzed together 
periodically to streamline the testing procedure.  However, if an investigator suspects that a 
subject is experiencing an AE that may be associated with the development of anti-drug 
antibodies, relevant samples will be tested for the presence of anti-drug antibodies upon request. 


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7.2.3.3
Physical Examinations
Physical examinations will be performed according to the study schedules to assess the subject’s 
physical status.  New clinically significant abnormalities that are detected or diagnosed after 
study evaluations have begun (after signing of the informed consent) should be recorded on the 
appropriate AE page of the eCRF.  Complete physical exams are required at screening, baseline, 
and Week 24/ET.  Focused physical exams may be performed at all other visits.
7.2.3.4
Vital Signs, Body Weight, and Height
Vital signs will be measured according to the study schedules. Measurements will include 
systolic and diastolic blood pressure (mmHg), pulse rate, and body temperature (°C). Blood 
pressure should be determined by cuff (using the same method, the same arm, and in the same 
position throughout the study).  New clinically significant vital sign abnormalities should be 
recorded on the appropriate AE page of the eCRF.
Subjects should be weighed on the same scale at each study visit. Height will be measured at the 
screening visit. 
7.2.3.5
Electrocardiograms
A 12-lead ECG will be performed at the study center after the subject has been resting for at least 
5 minutes. Results will include general findings (normal, abnormal-not clinically significant,
abnormal-clinically significant). If abnormal, the nature of the abnormality will be collected. 
Investigators are responsible for providing their own interpretation of the ECG and this will be 
captured on the eCRF. 
Electrocardiogram tracings should be printed, signed and dated by the investigator, and kept with 
the subject’s source documents.
7.2.3.6
Gastrointestinal-specific Testing
Gastrointestinal testing will be done for all subjects during the screening period.  Follow-up 
testing will be performed as necessary according to the guidelines noted below. 
Colonoscopy/Sigmoidoscopy
A colonoscopy/sigmoidoscopy of the remnant colon with polyp removal will be performed prior 
to teduglutide exposure (during stabilization if not completed within 6 months prior to screening) 
in subjects with any colon remnant including a rectal stump.  This will be repeated at Visit 10 
(or early termination).  The date and result of colonoscopy are to be recorded in the eCRF.
Abdominal Ultrasound 
An abdominal ultrasound will be performed prior to teduglutide exposure (during stabilization) if 
this procedure was not performed during the 6 months prior to screening (however, the results of 
the procedure must be documented).  


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Upper GI Contrast Series with Small Bowel Follow-through
Upper GI contrast series with small bowel follow-through will be required for all subjects with a 
history of Crohn’s disease and will be performed during the stabilization period, prior to the 
baseline visit.
Esophagogastroduodenoscopy
Esophagogastroduodenoscopy (EGD) will be performed on all subjects prior to teduglutide 
exposure (during the stabilization period if not completed within 6 months prior to screening). 
Esophagogastroduodenoscopy will be repeated at Week 24/Visit 10 (or ET) for subjects with any 
of the following risk factors: 

Age 40 or over at Week 24/Visit 10/ET

History of H pylori gastritis

History of atrophic gastritis

History of intestinal metaplasia or dysplasia in the stomach
For subjects that do not have any of the above risk factors, EGD may be repeated at Visit 10/ET 
at the discretion of the investigator. The dates and results of all EGDs are to be recorded in the 
eCRF.
48-Hour Oral Fluid Intake and Urine Output
Subjects will be provided with urine collection containers (as needed) in order to collect 48-hour 
urine during the 2 days prior to study visits as required. The center staff will contact the subject 
at least 48 hours before the scheduled visits to remind the subject to start measuring I/O, and to 
record these measurements into the diary. During the 48-hour measurements, the subject should 
maintain their usual oral fluid intake. 48-hour urine output measurements will also be collected 
prior to all interim safety visits.


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7.2.4
Pharmacokinetic Assessments
The first dose of teduglutide will be administered by the study physician at the baseline visit 
(Visit 2). At this visit, subjects will have blood samples taken for teduglutide PK analysis:

0-hour (predose) draw: any time prior to the dose

15 minutes postdose: ±5 minutes

30 minutes postdose: ±5 minutes

1 hour postdose: ±10 minutes

2 hours postdose: ±10 minutes

3 hours postdose: ±10 minutes

4 hours postdose: ±30 minutes

6 hours postdose: ±30 minutes

8 hours postdose: ±30 minutes

10 hours postdose: ±30 minutes

12 hours postdose: ±30 minutes
Subjects also will have blood samples taken for teduglutide PK analysis at Week 4 (Visit 5) or 
Week 12 (Visit 7):

0-hour (predose) draw: any time prior to the daily dose, on the day of dosing, but at least 
14 hours after the previous dose

1 hour postdose: ±10 minutes

2 hours postdose: ±10 minutes
Blood for PK sampling should be collected via peripheral IV or venipuncture, not from a central 
line.  The site of teduglutide administration prior to PK blood draws (arm, thigh, abdomen) and 
the person administering the injection (physician or subject) must be recorded in the eCRF. 


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


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8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related.” The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected 
response pattern to that product, and the event cannot be explained by the 
subject’s medical condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident and no 
plausible temporal or biologic relationship exists between the investigational 
product and the event.
AEs that are related to investigational product that are not resolved at EOT will be followed until 
the event resolves or stabilizes, as judged by the investigator.
Laboratory values, vital signs, and clinical findings at the scheduled physical examinations must 
be reported as AEs if the investigator considers the finding to be a clinically significant change 
from the baseline. 
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the eCRF. Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved with Sequelae 

Recovering/Resolving

Unknown


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8.1.4
Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE.
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory or vital sign can represent an AE if the change is 
clinically relevant or if, during treatment with investigational product, a shift of a parameter is 
observed from a normal value to an abnormal value, or a further worsening of an already 
abnormal value. When evaluating such changes, the extent of deviation from the reference range, 
the duration until return to the reference range, either while continuing treatment or after the 
EOT with the investigational product, and the range of variation of the respective parameter 
within its reference range, must be taken into consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory values or vital signs 
which were not present at the pretreatment value observed closest to the start of study treatment, 
further investigations should be performed until the values return to within the reference range or 
until a plausible explanation (eg, concomitant disease) is found for the abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory or vital sign is clinically significant and 
therefore represents an AE.
8.1.6
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.4.
Any report of pregnancy for any female study participant or female partner of male study 
participant must be reported within 24 hours to IQVIA Services Japan K.K. using the Shire 
Investigational and Marketed Products Pregnancy Report Form. In the event a subject becomes 
pregnant during the study, teduglutide administration must be immediately and permanently 
discontinued.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant using the Shire Investigational and Marketed Products Pregnancy Report 
Form. It is the responsibility of the investigator to obtain this information within 30 calendar 
days after the initial notification, and approximately 30 calendar days and 1 year postpartum, and 
report to IQVIA Services Japan K.K.
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered serious adverse events (SAEs) and must be reported using the Shire Clinical 
Study Adverse Event Form for Serious Adverse Events and Non-serious AEs as Required by 
Protocol. Note: An elective abortion is not considered an SAE.


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In addition to the above, if the investigator determines that complications of the pregnancy meet
serious criteria, it must be reported as an SAE using the Shire Clinical Study Adverse Event 
Form for SAEs and Non-serious AEs as Required by Protocol as well as the Shire Investigational 
and Marketed Products Pregnancy Report Form. The test date of the first positive serum/urine 
β-HCG test or ultrasound result will determine the pregnancy onset date.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
using SAE reporting form whether or not they result in an AE/SAE as described in Section 8.2, 
but such events are only recorded in the eCRF if they result in an AE. Note: The 24-hour 
reporting requirement for SAEs does not apply to reports of abuse, misuse, overdose, or 
medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for a 
non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner that 
may be detrimental to the individual and/or society.

Misuse – Intentional use of investigational product other than as directed or indicated at any 
dose (Note: this includes a situation where the investigational product is not used as directed 
at the dose prescribed by the protocol).

Overdose – Administration of a dose greater than the allocated dose of the study medication 
or at a frequency greater than the dosing interval specified by the protocol.

Medication Error – An error made in prescribing, dispensing, administration, and/or use of an 
investigational product. For studies, medication errors are reportable to the sponsor only as 
defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors.
Medication errors should be collected/reported for all products under investigation.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error. 
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator’s brochure which the 
sponsor has provided under separate cover to all investigators.


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8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the sponsor or 
designee within 24 hours of the first awareness of the event. Note: The 24-hour reporting 
requirement for SAEs does not apply to reports of abuse, misuse, overdose, or medication errors 
(see Section 8.1.7) unless they result in an SAE.
All Adverse Events of Special Interest, as defined in Section 8.3, must be reported by the 
investigator to the sponsor or designee within 24 hours of the first awareness of the event even if 
the event does not fulfill seriousness criterion.
The investigator must complete, sign, and date the Shire Clinical Study Adverse Event Form for 
Serious Adverse Events (SAEs) and Non-serious AEs as Required by Protocol and verify the 
accuracy of the information recorded on the form with the corresponding source documents 
(Note: Source documents are not to be sent unless requested). The investigator must fax or 
e-mail the completed form to IQVIA Services Japan K.K. Applicable fax numbers and email 
addresses are found in the Emergency Contact Information.
8.2.3
Serious Adverse Event Definition
An SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose: 

Results in death

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
preexisting conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity.

Is a congenital abnormality/birth defect.

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in an
emergency room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse. 


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8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the informed consent is 
obtained until the defined follow-up period stated in Section 7.1.4, and must be reported to the 
sponsor or designee within 24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the sponsor or 
designee within 24 hours of the first awareness of the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death.
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting 
The sponsor or designee is responsible for notifying the relevant regulatory authorities of related, 
unexpected SAEs. 
In addition, the sponsor and/or designee is responsible for notifying active sites of all related, 
unexpected SAEs occurring during all interventional studies across the teduglutide program.
The investigator is responsible for notifying the local Institutional Review Board (IRB) or the 
relevant local regulatory authority of all SAEs that occur at his or her site as required.


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8.3
Adverse Events of Special Interest
An AE of special interest is an AE (serious or nonserious) of scientific and medical concern 
specific to the sponsor’s product or program and for which ongoing monitoring and immediate 
notification by the investigator to the sponsor is required.
The AEs of special interest that require expedited regulatory reporting for this study include the 
following:

Growth of preexisting polyps of the colon

Benign neoplasia of the GI tract including the hepatobiliary system

Tumor-promoting ability (eg, benign and/or malignant neoplasia of any kind, not limited to 
those of the GI or hepatobiliary system)
For AEs of special interest, the sponsor or designee must be informed within 24 hours of first 
awareness as per the SAE notification instructions described in Section 8.2.2 even if the event 
does not fulfill seriousness criterion.


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DATA MANAGEMENT AND STATISTICAL METHODS
9
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the eCRF.  A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy.  Discrepancies 
between source data and data entered on the eCRF will be addressed by qualified site personnel.  
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel.  Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting.  It is expected that site personnel will complete the eCRF 
entry within approximately 3 business days of the subject’s visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the data management plan. Quality 
control and data validation procedures are applied to ensure the validity and accuracy of the 
clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Statistical Analysis Process
The data collected in this study will be analyzed by the sponsor or designee. All statistical 
analyses will be performed using SAS® (SAS Institute, Cary, NC, US) version 9.3 or higher.
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed.
9.4
Planned Interim Analysis
Interim analyses may be conducted during the study, as needed. Analyses will be descriptive in 
nature. No formal comparisons are planned and no hypotheses will be formally tested.  Due to 
the open-label nature of this study, personnel involved in conducting the interim analyses will 
have access to treatment assignments.  


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9.5
Sample Size Calculation and Power Considerations
The sample size of the SHP633-306 study is based on patient prevalence and study design 
elements; no statistical estimation was involved.  Possible medical institutes for SBS studies are 
limited, given the rarity of the disease and the very limited number of patients with SBS (<1000) 
in Japan.  The applicant considers that 5 treated subjects in SHP633-306 should provide 
sufficient basic information concerning the efficacy, safety and tolerability as well as PK of 
teduglutide in the Japanese study population.  
9.6
Study Population
The intent-to-treat (ITT) population will include all subjects who are deemed eligible for 
teduglutide treatment at the baseline visit (Visit 2). 
The per protocol population will include all subjects in the ITT population who complete the 
Treatment Period without any major protocol violations that could potentially affect the efficacy 
conclusions of the study.  
The safety population will include all subjects in the ITT population who receive at least 1 dose 
of study drug.  
The pharmacokinetic population will include all subjects who receive at least 1 dose of 
teduglutide and have at least 1 evaluable post-dose pharmacokinetic concentration value.  
9.7
Efficacy Analyses
The following efficacy endpoints will be analyzed:
•
Absolute and relative change from baseline in weekly PN/IV volume by visit and at end 
of treatment (EOT).
•
Percentage of subjects who achieve at least 20% reduction from baseline in weekly 
PN/IV volume at both Weeks 20 and 24.
•
Percentage of subjects who achieve at least a 20% reduction from baseline in weekly 
PN/IV volume at each visit
•
Change in days per week of PN/IV support from baseline by visit.
•
Change in plasma citrulline from baseline by visit.
•
Number of subjects who are able to completely wean off of PN/IV support.
The absolute and relative change in weekly PN/IV volume, days per week of PN/IV support, and 
plasma citrulline,  from baseline to each scheduled visit, as well as at EOT, will be summarized 
using descriptive statistics.
The number and percentage of subjects who demonstrate a response at Week 20 and again at 
Week 24 will be summarized. A response is defined as the achievement of at least a 20% 
reduction from baseline in weekly PN/IV volume. 


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The number and percentage of subjects who demonstrate at least a 20% reduction from baseline 
in weekly PN/IV volume at each visit will also be summarized.
The number and percentage of subjects who completely wean off PN/IV support by Week 
24/EOT will be summarized. A subject will be considered to have achieved independence from 
PN/IV (completely weaned off PN/IV) if the investigator prescribes no PN/IV at Week 24/EOT 
and there is no use of PN/IV recorded in the subject diary during the 2 weeks prior to the last 
dosing visit.
For efficacy analysis, the ITT population will be the primary analysis population; the 
per-protocol population will be used for secondary/sensitivity analysis.
9.8
Safety Analyses
The safety endpoints include AEs, 12-lead ECG, vital signs, laboratory safety data, antibodies to 
teduglutide, and 48-hour urine output, body weight, BMI and gastrointestinal-specific tests.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Treatment-emergent AEs are defined as AEs that started or worsened on or after the 
date and time of the first dose of study dose. Treatment-emergent AEs will be summarized by 
system organ class and preferred term using descriptive statistics (eg, number and percentage of 
subjects). Adverse events will be summarized by severity, relationship to treatment, and for AEs 
leading to discontinuation, and death. In addition, SAEs will also be tabulated by overall and 
treatment-related events.
For laboratory tests, 48-hour urine output, vital signs, body weight, body mass index, 
and ECG variables, descriptive statistics (eg, n, mean, standard deviation, median, 
minimum and maximum values, the number and percentage of subjects in specified 
categories) will be used to summarize the absolute values and change from baseline at each 
time point.
The number and percentage of subjects classified as having antibodies to teduglutide will be used 
to summarize the presence of antibodies. 
The safety population will be the analysis population for all the safety data analysis.
9.9
Pharmacokinetics Analyses
Teduglutide plasma concentrations will be summarized using the PK population with descriptive 
statistics (number, mean and standard deviation, minimum, median, and maximum) at nominal 
time points. 
The following parameters will be derived: area under the plasma concentration–time curve 
from zero to the last measurable concentration (AUC0–t); maximum plasma concentration (Cmax); 
time to Cmax (tmax); terminal-phase half-life (t1/2); apparent clearance (CL/F); and apparent 
volume of distribution (V/F).  


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Pharmacokinetic parameters will be estimated using non-compartmental analysis as appropriate 
and summarized using descriptive statistics (number, mean, standard deviation, geometric mean, 
and CV%, minimum, median, and maximum). 


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


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This requirement will be fulfilled within 6 months of the end of the study completion date for 
pediatric studies and within 1 year for non-pediatric studies as per guidance.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.


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Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Electronic Case Report Forms
Electronic case report forms are supplied by the sponsor or designe and should be handled in 
accordance with instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Electronic case report forms 
must be completed by the investigator or designee as stated in the site delegation log.  All data 
will have separate source documentation; no data will be recorded directly onto the eCRF.
All data sent to the sponsor must be endorsed by the investigator.  The study monitor will verify 
the contents against the source data per the monitoring plan. If the data are unclear or 
contradictory, queries are sent for corrections or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject diaries, original clinical laboratory reports, and imaging reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The study monitor (and auditors, IRB/EC or regulatory inspectors) may check the eCRF entries 
against the source documents. The consent form includes a statement by which the subject agrees 
to the monitor/auditor from the sponsor or its representatives, national or local regulatory 
authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, appointment 
books, original laboratory reports, X-rays etc). 
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US FDA, 
European Medicines Agency [EMA], UK Medicines and Healthcare products Regulatory 
Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.


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10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other 
US national and local regulatory authorities), the EMA, the Medicines and Healthcare products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent from all study 
subjects prior to any study-related procedures including screening assessments. All consent 
documentation must be in accordance with applicable regulations and GCP. Each subject or the 
subject’s legally authorized representative, as applicable, is requested to sign and date the subject 
informed consent form or a certified translation if applicable, after the subject has received and 
read (or been read) the written subject information and received an explanation of what the study 
involves, including but not limited to: the objectives, potential benefits and risk, inconveniences, 
and the subject’s rights and responsibilities. A copy of the informed consent documentation (ie, a 
complete set of subject information sheets and fully executed signature pages) must be given to 
the subject or the subject’s legally authorized representative, as applicable. This document may 
require translation into the local language. Original signed consent forms must remain in each 
subject’s study file and must be available for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form that was 
reviewed by the IRB/EC and received their favorable opinion/approval. A copy of the IRB/EC’s 
written favorable opinion/approval of these documents must be provided to the sponsor prior to 
the start of the study unless it is agreed to and documented (abiding by regulatory guidelines and 
national provisions) prior to study start that another party (ie, sponsor or coordinating principal 
investigator) is responsible for this action. Additionally, if the IRB/EC requires modification of 
the sample subject information and consent document provided by the sponsor, the 
documentation supporting this requirement must be provided to the sponsor.


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10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the sponsor/designee has received 
written IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB/EC informed of any serious and 
significant AEs.
10.4
Privacy and Confidentiality
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market teduglutide; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject). 


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The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices) when forming a publication steering committee, which is done for 
large, multicenter Phase 2 to 4 and certain other studies as determined by Shire. The purpose of 
the publication steering committee is to act as a non-commercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, joint 
or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, royalty 
free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire, the institution and principal 
investigator shall withhold submission of such publication for up to an additional 60 days to 
allow for filing of a patent application.


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If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.


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REFERENCES
11
American Gastroenterological Association 2003. American Gastroenterological Association 
medical position statement: short bowel syndrome and intestinal transplantation. 
Gastroenterology, 124, 1105-1110.
Amiot, A., Messing, B., Corcos, O., Panis, Y. & Joly, F. 2013. Determinants of home parenteral 
nutrition dependence and survival of 268 patients with non-malignant short bowel 
syndrome. Clin Nutr, 32, 368-74.
Baxter, J. P., Fayers, P. M. & Mckinlay, A. W. 2006. A review of the quality of life of adult 
patients treated with long-term parenteral nutrition. Clin Nutr, 25, 543-53.
Delegge, M., Alsolaiman, M. M., Barbour, E., Bassas, S., Siddiqi, M. F. & Moore, N. M. 2007. 
Short bowel syndrome: parenteral nutrition versus intestinal transplantation. Where are 
we today? Dig Dis Sci, 52, 876-92.
Dudrick, S. J., Latifi, R. & Fosnocht, D. E. 1991. Management of the short-bowel syndrome. 
Surg Clin North Am, 71, 625-43.
Jackson, C. & Buchman, A. L. 2005. Advances in the management of short bowel syndrome. 
Curr Gastroenterol Rep, 7, 373-8.
Jeppesen, P. B. 2006. Glucagon-like peptide-2: update of the recent clinical trials. 
Gastroenterology, 130, S127-31.
Jeppesen, P. B., Langholz, E. & Mortensen, P. B. 1999. Quality of life in patients receiving home 
parenteral nutrition. Gut, 44, 844-52.
Messing, B., Crenn, P., Beau, P., Boutron-Ruault, M. C., Rambaud, J. C. & Matuchansky, C. 
1999. Long-term survival and parenteral nutrition dependence in adult patients with the 
short bowel syndrome. Gastroenterology, 117, 1043-50.
Nightingale, J. & Woodward, J. M. 2006. Guidelines for management of patients with a short 
bowel. Gut, 55 Suppl 4, iv1-12.
Nightingale, J. M. 1999. Management of patients with a short bowel. Nutrition, 15, 633-7.
O'keefe, S. J., Buchman, A. L., Fishbein, T. M., Jeejeebhoy, K. N., Jeppesen, P. B. & Shaffer, J. 
2006. Short bowel syndrome and intestinal failure: consensus definitions and overview. 
Clin Gastroenterol Hepatol, 4, 6-10.
Pironi, L., Arends, J., Baxter, J., Bozzetti, F., Pelaez, R. B., Cuerda, C., Forbes, A., Gabe, S., 
Gillanders, L., Holst, M., Jeppesen, P. B., Joly, F., Kelly, D., Klek, S., Irtun, O., Olde 
Damink, S. W., Panisic, M., Rasmussen, H. H., Staun, M., Szczepanek, K., Van Gossum, 
A., Wanten, G., Schneider, S. M. & Shaffer, J. 2015. ESPEN endorsed recommendations. 
Definition and classification of intestinal failure in adults. Clin Nutr, 34, 171-80.
Rombeau, J. L. & Rolandelli, R. H. 1987. Enteral and parenteral nutrition in patients with enteric 
fistulas and short bowel syndrome. Surg Clin North Am, 67, 551-71.
Scolapio, J. S., Fleming, C. R., Kelly, D. G., Wick, D. M. & Zinsmeister, A. R. 1999. Survival of 
home parenteral nutrition-treated patients: 20 years of experience at the Mayo Clinic. 
Mayo Clin Proc, 74, 217-22.
Shanbhogue, L. K. & Molenaar, J. C. 1994. Short bowel syndrome: metabolic and surgical 
management. Br J Surg, 81, 486-99.
Tazuke, Y. & Teitelbaum, D. H. 2009. Alteration of canalicular transporters in a mouse model of 
total parenteral nutrition. J Pediatr Gastroenterol Nutr, 48, 193-202.
Vanderhoof, J. A. & Langnas, A. N. 1997. Short-bowel syndrome in children and adults. 
Gastroenterology, 113, 1767-78.


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Wilmore, D. W., Byrne, T. A. & Persinger, R. L. 1997. Short bowel syndrome: New therapeutic 
approaches. Current Problems in Surgery, 34, 389,391-444.
Winkler, M. F. & Smith, C. E. 2014. Clinical, social, and economic impacts of home parenteral 
nutrition dependence in short bowel syndrome. JPEN J Parenter Enteral Nutr, 38, 32s-
37s.


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APPENDICES
12


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APPENDIX 1
PROTOCOL HISTORY
Document
Date
Global/Country/Site Specific
Original Protocol
23 Jan 2018
Global
Amendment 1
27 Sep 2018
Global


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APPENDIX 2
PARENTERAL NUTRITION/INTRAVENOUS OPTIMIZATION
After signing the ICF, the investigator will determine if the subject’s PN/IV volume produces an 
appropriate urine output target of 1.0 L/day to 2.0 L/day.  If the output is within the range, the 
subject will enter the stabilization period.  If the output is outside the range, the subject’s PN/IV
volume should be adjusted appropriately to reach the targeted urine output of between 1.0 L/day 
to 2.0 L/day while keeping the subject adequately hydrated and nourished.  For example, if 
48-hour urine output is:

<1.0 L/day, then PN/IV should be increased.

>2.0 L/day, then PN/IV should be reduced.
If it is not possible to keep the subject adequately hydrated and nourished within the targeted 
urine output range, the minimally tolerated PN/IV volume should be documented.  Keep in mind 
the following:

During optimization, total weekly PN/IV volume should be adjusted in increments or 
decrements of 10-30% of the screening volume.

Parenteral nutrition constituents may be adjusted at the discretion of the investigator.

Subjects should be encouraged to maintain a stable normal or hyperphagic diet (eg, at least 
1.3 times the estimated basal metabolic rate).
Steps for adjusting PN/IV volume:
1.
Screening and Optimization Visits:  Subjects will be assessed at planned intervals for 
hydration and nutrition.  The subject will make all measurements of 48-hour I/O at home 
immediately prior to the scheduled visits.  Blood and urine samples will be collected at each 
visit to evaluate hydration and nutrition.  All blood and urine samples should be taken at a 
consistent time period throughout the study that is convenient for the subject and site staff.
2.
Interim Safety Evaluations: If any PN/IV adjustments are made, the clinical effect and the 
health status of the subject will be assessed 5 to 7 days after the adjustment is implemented. 
Laboratory safety samples should be evaluated following a PN/IV adjustment (see 
Table A3), accompanied by determination of 48-hour I/O and symptoms of dehydration. At 
the interim safety visit, PN/IV should be increased if the decrease was not tolerated. No 
further reductions to PN/IV volume are made at the interim safety visit.
3.
Maintain the PN/IV level until the next scheduled optimization visit.
4.
Repeat steps 1 through 3 until the subject achieves an optimized volume of PN/IV indicated 
by targeted urine output of 1.0 L/day to 2.0 L/day.  If a subject has not achieved an optimal 
tolerated volume of PN/IV after 8 weeks, consult the sponsor’s Medical Monitor.
5.
Parenteral Nutrition Stabilization:  Once an optimal tolerated PN/IV volume has been 
reached, the subject will begin the 4-week minimum stabilization period.  No further PN/IV
adjustments should take place during this time period.  


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APPENDIX 3
PARENTERAL NUTRITION/INTRAVEOUS ADJUSTMENT DURING 
TREATMENT  PERIOD 
Points to keep in mind when adjusting PN/IV volume during dosing:

There will be no PN/IV reduction attempts at baseline and Week 1.

Parenteral nutrition/intravenous reductions target urine output increases of at least 10% over 
baseline.

Attempts to reduce PN/IV will be made at dosing Weeks 2, 4, 8, 12, 16, and 20.

Parenteral nutrition/intraveous adjustments are targeted to be at least 10% but no more than 
30% of baseline PN/IV level.

Adjustments should be based on the actual PN/IV volume the subject infuses. Subjects 
should remain compliant with the PN/IV prescription during the length of the study.

Parenteral nutrition/intravenous constituents may be adjusted at the discretion of the 
investigator.

Criteria for PN/IV adjustments are in Table A1.

During the 48-hour I/O measurement period, oral intake should be consistent with baseline 
oral intake.

If there is a change in oral intake, the investigator should consider this when adjusting the 
PN/IV volume.

Subjects should be encouraged to maintain a stable normal or hyperphagic diet.

Frequent checks will be made to ensure the adjustments are safe (see Table A2).

Subjects who fail to maintain a PN/IV reduction due to a medical necessity (eg, sepsis or 
hospitalization due to an AE) will not be considered a failure of reduction.

If at any time, the algorithm cannot be followed, consult with the sponsor’s Medical Monitor.
Table A1
Parenteral Nutrition Adjustments at Scheduled Clinic Visits based on 
48-hour Urinary Output
Urine Output
Parenteral Nutrition/Intravenous Action
Below 1.0 L/day or target based on stabilized 
urine output
Increase PN/IV by at least 10% (Week 2) or to previous level.
1.0 L/day or more and less than Baseline
If subject is dehydrated or inadequately nourished (see Table A2),
increase PN/IV If not, maintain PN/IV.
Baseline or more, and less than a 10% increase 
over Baseline
Maintain PN/IV
At least a 10% increase over Baseline
Reduce PN/IV by at least 10% of stabilized Baseline level up to a 
clinically appropriate amount (maximum of 30%).
L=liter; PN/IV=parenteral nutrition/intravenous (volume)


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Table A2
Targeted Criteria for Hydration and Nourishment at all Clinic Visits and 
Interim Safety Visits
Hydration Assessment
Hydration Adequate
Hematocrit
At or below ULN
Serum BUN
At or below ULN
Serum creatinine
At or below 2xULN
Urine sodium
20 mmol/L or more
Clinical signs and symptoms of
dehydration
Absent
Body weight change in 4 weeks
Change less than 1.5 kg
BUN = blood urea nitrogen; ULN = upper limit of normal
Note:  In combination with Table A1, any one of the above criteria determines dehydration.
Steps for adjusting PN/IV volume:
1.
DOSING WEEKS 2, 4, 8, 12, 16, and 20:  Subjects will be assessed at planned intervals 
for hydration and nutrition.  The subject will make all measurements of 48-hour I/O at home 
prior to the scheduled visits.  Blood and urine samples will be collected to evaluate 
hydration and nutrition (see Table A2).  All blood and urine samples should be taken at a 
consistent time period throughout the study, convenient for the subject and site staff.
2.
Parenteral Nutrition Changes: Review Table A1 and Table A2 to take appropriate action. 
3.
Interim Safety Evaluations: If any PN/IV adjustments are made, the clinical effect and the 
health status of the subject will be assessed 5 to 7 days after the adjustment is implemented. 
Laboratory safety samples should be evaluated following a PN/IV adjustment (see 
Table A3), accompanied by determination of 48-hour I/O and symptoms of dehydration. At 
the interim safety visit, PN/IV should be increased if the decrease was not tolerated. No 
further reductions to PN/IV volume are made at the interim safety visit.


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Table A3
Assessment of Tolerance of Pareneteral Nutrition/Intravenous Adjustments 
at Interim Safety Visits
Urine Output, Hydration and Nutrition
Parenteral Nutrition/Intravenous Action
Output less than Baseline
Increase PN/IV to previous volumea
Baseline output or greater and subject is dehydrated (See 
Table A2)
Increase PN/IV to previous volumea
Baseline output or greater and subject is not dehydrated, but is 
inadequately nourished (See Table A2)
If possible, maintain PN/IV volume and increase 
nutrition. If not, increase PN/IV to previous 
volumea
Baseline output or greater and subject is adequately hydrated 
and nourished (See Table A2)
Maintain PN/IV
L=liter; PN/IV=parenteral nutrition/intravenous (volume)
a If most recent reduction was greater than 10% due to a urine volume of more than 2 L/day, a more moderate 
increase in PN/IV is allowed.
4.
Maintain the adjusted PN/IV level until the next scheduled visit.
5.
Repeat steps 1 through 4 at each study visit as indicated per protocol.
a.
It is preferred that when the total weekly PN/IV needs have been reduced to a level that 
safely allows for a day or days off PN/IV, the physician should consider instituting a 
day(s) off PN/IV.
b.
If the total weekly PN/IV is only administered in 2 days, it is probably in the subject’s 
best interest to be weaned off PN/IV completely.  This is the 1 exception to the 
maximum 30% reduction guidance. This weaning should be done under the supervision 
of the investigator.
c.
If the subject experiences symptoms of dehydration, the subject can be advised by the 
investigator to take extra IV fluid that will be included in the weekly PN/IV volume 
total.

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
 
 
NCT Number:   
NCT03663582 
 
Study Title:  
A 24-Week Safety, Efficacy, Pharmacokinetic Study of Teduglutide in 
Japanese Subjects with Short Bowel Syndrome who are Dependent on 
Parenteral Support 
 
Study Number:  
SHP633-306 
 
 
SAP Version and Date:   
Version 1.0: 12 December 2018 
Version 2.0: 15 April 2019 
Pharmacokinetic Analysis Plan: 13 September 2019 


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Statistical Analysis Plan Final v1.0
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12Dec2018
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Author:
Version Number:
Final V1.0
Version Date:
12Dec2018
Template No: Harmonized Statistical Analysis Plan Template v1.0
Effective Date: 01June2018
STATISTICAL ANALYSIS PLAN
Teduglutide
PHASE 3
A 24-Week Safety, Efficacy, Pharmacokinetic Study of Teduglutide in
Japanese Subjects with Short Bowel Syndrome who are Dependent on
Parenteral Support
PROTOCOL IDENTIFIER: SHP633-306
Study Sponsor(s):
Shire Human Genetic Therapies, 
Inc. 300 Shire Way Lexington, 
MA 02421 USA
Author (Company):
(IQVIA)
Protocol:
23 JAN 2018
SAP Version #:1.0
SAP Date:
12Dec2018
Status:
Final


Shire 
Statistical Analysis Plan Final vl.O 
P rotocol Number: SRP633-306 
CONFIDENTIAL 
Statistical Analysis Plan Signature Page 
SAP Final Vl.O (dated 12Dec2018) for Protocol SHP633-306. 
Page2 of38 
12Dec2018 
- --
-
; Date tcii>MMMYYYY) -I 
Author: 
J
 
 _ 
Position: 
J
- lQVIA -·----·· 
----
Upon review of this 
the undersigned approves this version of the 
Listings, · -- -
Figures Shell Template, authorizing that the content is acceptable for the reporting of this study. 
 l 
I _ Position: 
I ___ 
_________ _ 
Approved sY:--
J
-=
__ 
--_-----
-
_-_____ ... ·--
Approved By: 
Document: 
Aull1or: 
Position: 
Company: 
Shire 
https://shirepharma-my.sharepoint.com/personoV
_shi1-e_com/Documents/Gatexx/306-
JPN/sap/SHP633-306_SAP _Final v 1.0.docx 
Version Number: 
Final VJ.O 
Version Date: 
1'lDec2018 
Template No: Harmonized Statistical Analysis Plan Template v 1.0 
Effective Date: 01June2018 


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Author:
Version Number:
Final V1.0
Version Date:
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Template No: Harmonized Statistical Analysis Plan Template v1.0
Effective Date: 01June2018
REVISION HISTORY
Version 
Issue Date
Summary of Changes
Final 1.0
12Dec2018
New Document


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12Dec2018
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Template No: Harmonized Statistical Analysis Plan Template v1.0
Effective Date: 01June2018
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE.............................................2
REVISION HISTORY ......................................................................................................3
TABLE OF CONTENTS ..................................................................................................4
ABBREVIATIONS............................................................................................................7
1.
INTRODUCTION..................................................................................................9
2.
OBJECTIVES, ESTIMAND(S), AND ENDPOINTS.........................................9
2.1
Objectives............................................................................................................9
2.2
Estimand(s) .........................................................................................................9
2.3
Endpoints ..........................................................................................................10
2.3.1
Efficacy Endpoint(s)..................................................................................10
2.3.2
Safety Endpoint(s) .....................................................................................10
2.3.3
Pharmacokinetic Endpoint(s).....................................................................10
3.
STUDY DESIGN..................................................................................................11
3.1
General Description ..........................................................................................11
3.1.1
Optimization and Stabilization Periods .....................................................11
3.1.2
Treatment Period........................................................................................11
3.2
Randomization ..................................................................................................12
3.3
Blinding.............................................................................................................12
3.4
Sample Size and Power Considerations............................................................12
4.
STATISTICAL ANALYSIS SETS.....................................................................12
4.1
All-enrolled Population.....................................................................................12
4.2
Intent-to-treat (ITT) Population ........................................................................12
4.3
Per Protocol (PP) Population ............................................................................12
4.4
Safety Population ..............................................................................................13
4.5
Pharmacokinetic (PK) Population.....................................................................13
5.
STUDY SUBJECTS.............................................................................................13
5.1
Disposition of Subjects .....................................................................................13


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5.2
Demographic and Other Baseline Characteristics.............................................13
5.3
Medical History.................................................................................................16
5.4
Prior Treatment and Medication .......................................................................16
5.5
Concomitant Treatment and Medication...........................................................17
5.6
Exposure to Investigational Product .................................................................17
5.7
Measurements of Treatment Compliance .........................................................17
5.8
Protocol Deviations...........................................................................................18
6.
EFFICACY ANALYSES ....................................................................................18
6.1
Analyses of Efficacy Endpoints........................................................................18
6.1.1
Sensitivity Analyses of Efficacy Endpoint(s)............................................21
6.2
Multiplicity Adjustment....................................................................................21
6.3
Subgroup Analyses ...........................................................................................21
7.
SAFETY ANALYSIS...........................................................................................21
7.1
Adverse Events..................................................................................................21
7.1.1
Adverse Events of Special Interest ............................................................22
7.2
Clinical Laboratory Data...................................................................................23
7.3
Vital Signs, Body Weight and BMI..................................................................26
7.4
Electrocardiogram.............................................................................................26
7.5
Other Safety Data..............................................................................................26
7.5.1
Physical Examination.................................................................................26
7.5.2
Antibodies to Teduglutide..........................................................................26
7.5.3
48 Hour Oral Fluid Intake and Urine Output.............................................27
8.
PHARMACOKINETIC ANALYSIS.................................................................27
8.1
Pharmacokinetic Parameters.............................................................................27
8.2
Statistical Analysis of Pharmacokinetic Data ...................................................27
9.
OTHER ANALYSES...........................................................................................28
10.
INTERIM ANALYSIS/ DATA MONITORING (REVIEW) 
COMMITTEE......................................................................................................28
11.
DATA HANDLING CONVENTIONS ..............................................................28
11.1
General Data Reporting Conventions ...............................................................28
11.2
Definition of Baseline .......................................................................................31


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11.3
Definition of Visit Windows.............................................................................31
11.4
Derived Efficacy Endpoints..............................................................................31
11.5
Handling of Missing, Unused, and Spurious Data............................................32
11.5.1 Missing Date of Investigational Product....................................................32
11.5.2 Missing Date Information for Prior or Concomitant Medications.............32
11.5.2.1
Incomplete Start Date ..................................................................32
11.5.2.2
Incomplete Stop Date...................................................................33
11.5.3 Missing Date Information for Adverse Events..........................................34
11.5.3.1
Incomplete Start Date ..................................................................34
11.5.3.2
Incomplete Stop Date...................................................................35
11.5.4 Missing Severity Assessment for Adverse Events.....................................35
11.5.5 Missing Relationship to Investigational Product for Adverse Events .......35
11.5.6 Character Values of Clinical Laboratory Variables...................................35
12.
ANALYSIS SOFTWARE ...................................................................................36
13.
CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL............................36
14.
REFERENCES.....................................................................................................37
15.
APPENDICES......................................................................................................38


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Effective Date: 01June2018
ABBREVIATIONS
AE
Adverse Event
ALT
Alanine Aminotransferase, Equivalent To SGPT
AST
Aspartate Aminotransferase, Equivalent To SGOT
AUC
Area Under the Plasma Concentration-Time Curve
AUC0–t
AUC From Zero to The Last Measurable Concentration
BLQ
Below the Lower Limit if Quantification
BMI
Body Mass Index
BUN
Blood Urea Nitrogen
CL/F
Apparent Clearance
Cmax
Maximum Plasma Concentration
CTMS
Clinical Trial Management System
CV
Coefficient of Variation
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EGD
Esophagogastroduodenoscopy
EOT
End of Treatment
ET
Early Termination
GI
Gastrointestinal
ICF
Informed Consent Form
ICH
International Conference on Harmonization
ITT
Intent-To-Treat
MedDRA
Medical Dictionary for Regulatory Activities
NCA
Non-compartmental Analysis
PK
Pharmacokinetics
PP
Per Protocol
PN/IV
Parenteral Nutrition/Intravenous
PT
Preferred Terms
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan


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SBS
Short Bowel Syndrome
SC
Subcutaneous
SI
Standard International
SOC
System Organ Class
t1/2
Terminal-Phase Half-Life
tmax
Time to Cmax
TEAE
Treatment Emergent Adverse Event
TESAE
Treatment Emergent Serious Adverse Event
ULN
Upper Limit of Normal
ULQ
Above the Upper Limit of Quantification
V/F
Apparent Volume of Distribution


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1.
INTRODUCTION 
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the 
statistical analyses of efficacy, safety and pharmacokinetic (PK) data (descriptive 
summaries only) as described in the final study protocol dated 23 Jan 2018. 
Specifications for tables, figures, and listings are contained in a separate document.
Pharmacokinetics analyses (other than descriptive summaries) will be described in a 
separate PK SAP.
2.
OBJECTIVES, ESTIMAND(S), AND ENDPOINTS
2.1
Objectives
The objectives of this clinical study are to evaluate the safety, efficacy, and 
pharmacokinetics of teduglutide in Japanese subjects with short bowel syndrome (SBS)
who are dependent on parenteral nutrition/intravenous (PN/IV) over a 24-week treatment 
period.
2.2
Estimand(s)
Absolute change from baseline in weekly PN/IV volume based on diary data at End of 
Treatment (EOT) in Japanese subjects with PN/IV – dependent SBS in the Intent-to-
treat (ITT) Population.
Relative change from baseline in weekly PN/IV volume based on diary data at EOT in 
Japanese subjects with PN/IV – dependent SBS in the ITT Population.
Number/percentage of subjects who achieved at least 20% decrease from baseline in 
weekly PN/IV volume based on diary data at Week 20 and Week 24 in Japanese 
subjects with PN/IV – dependent SBS in the ITT Population.
Number/percentage of subjects who achieved at least 20% decrease from baseline in
weekly PN/IV volume based on diary data at Week 20 and Week 24 in Japanese 
subjects with PN/IV – dependent SBS in the PP Population.
Number/percentage of subjects who achieve at least a 20% reduction from baseline in 
weekly PN/IV volume based on diary data at each visit in Japanese subjects with PN/IV 
– dependent SBS in the ITT Population.


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2.3
Endpoints
2.3.1
Efficacy Endpoint(s)
The following efficacy endpoints will be analyzed:
Absolute and relative change from baseline in weekly PN/IV volume by visit and 
at EOT.
Percentage of subjects who achieve at least 20% reduction from baseline in 
weekly PN/IV volume at both Weeks 20 and 24.
Percentage of subjects who achieve at least a 20% reduction from baseline in 
weekly PN/IV volume at each visit
Change in days per week of PN/IV support from baseline by visit.
Change in plasma citrulline from baseline by visit.
Number of subjects who are able to completely wean off of PN/IV support.
2.3.2
Safety Endpoint(s) 
The safety endpoints include adverse events (AEs), 12-lead electrocardiogram (ECG), 
vital signs, laboratory safety data, antibodies to teduglutide, and 48-hour urine output, 
body weight, body mass index (BMI) and gastrointestinal-specific tests. 
2.3.3
Pharmacokinetic Endpoint(s)
The following parameters will be derived as described in a separate PK SAP and reported 
separately: 
Area under the plasma concentration–time curve from zero to the last measurable 
concentration (AUC0–t)
Maximum plasma concentration (Cmax)
Time to Cmax (tmax)
terminal-phase half-life (t1/2)
Apparent clearance (CL/F)
Apparent volume of distribution (V/F)


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3.
STUDY DESIGN
3.1
General Description
This is an open-label, multicenter study, consisting of a conditional PN/IV optimization 
period, a mandatory PN/IV stabilization period, and a 24-week treatment period. A 
schematic representation of the study design is presented in Figure 1.
Figure 1: Study Schematic
3.1.1
Optimization and Stabilization Periods
If at screening, a subject does not have an optimized PN/IV volume, defined as a 48-hour 
urine output between 2 and 4 L, he/she will enter the optimization period, during which 
the minimally tolerated stable PN/IV volume will be determined during a period of up to 
8 weeks.
All subjects will then enter the stabilization period, during which the target PN/IV 
volume will be maintained for at least 4 consecutive weeks (8 weeks maximum). Those 
subjects who fail to stabilize will not proceed further and will not be included in the 
treatment period.
Schedules of evaluations for the optimization/stabilization period can be found in the 
protocol.
3.1.2
Treatment Period
Following the stabilization period, subjects will enter a 24-week dosing period, during 
which all subjects will receive teduglutide 0.05 mg/kg subcutaneously (SC) once daily. 
At each site visit during the treatment phase, efficacy (adjustments to PN/IV) and safety 
will be monitored.


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Subjects will have blood samples taken for teduglutide PK analysis at predose and 15, 30 
minutes and 1, 2, 3, 4, 6, 8, 10, and 12 hours post dose at the baseline visit (Visit 2).  
Subjects will also have blood samples taken for teduglutide PK analysis at predose and 1 
and 2 hours post dose at Week 4 (Visit 5) or Week 12 (Visit 7) of the treatment period.
All subjects who complete the study may participate in a long-term extension study in 
which eligible subjects will continue to receive teduglutide. 
Schedules of evaluations for the Treatment Period can be found in the protocol.
3.2
Randomization
Not applicable for this single arm study.
3.3
Blinding
Not applicable for this open-label study.
3.4
Sample Size and Power Considerations
The sample size of the SHP633-306 study is based on patient prevalence and study 
design elements; no statistical estimation was involved. Possible medical institutes for 
SBS studies are limited, given the rarity of the disease and the very limited number of 
patients with SBS (<1000) in Japan. The applicant considers that 5 treated subjects in 
SHP633-306 should provide sufficient basic information concerning the efficacy, safety 
and tolerability as well as PK of teduglutide in the Japanese study population.  
4.
STATISTICAL ANALYSIS SETS
4.1
All-enrolled Population
All subjects who provided a signed Informed Consent Form (ICF) will be included in the 
All-enrolled Population.
4.2
Intent-to-treat (ITT) Population
The Intent-to-treat Population will include all subjects who are deemed eligible for 
teduglutide treatment at the baseline visit (Visit 2). 
4.3
Per Protocol (PP) Population
The Per Protocol Population will include all subjects in the ITT Population who complete 
the treatment period without any major protocol violations that could potentially affect 
the efficacy conclusions of the study. These situations include the following:


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•
Missing baseline and/or Week 24 for the weekly PN/IV volume efficacy data
based on diary data. 
•
Non-compliance to study drug administration as defined in Section 5.7
Reasons for exclusion from the PP Population will be presented in the listings for the ITT 
population.
4.4
Safety Population
The Safety Population will include all subjects in the ITT Population who receive at least 
1 dose of study drug.  
4.5
Pharmacokinetic (PK) Population  
The PK Population will include all subjects who receive at least 1 dose of teduglutide and 
have at least 1 evaluable post-dose pharmacokinetic concentration value.  
5.
STUDY SUBJECTS
5.1
Disposition of Subjects
The number and percent of subjects in each study analysis population (i.e., Enrolled, ITT,
Safety, PP and PK) will be presented for the All-enrolled Population. 
For the ITT and Safety Populations, the number and percentage of subjects who 
completed or prematurely discontinued the treatment period will be presented. Reasons 
for premature discontinuation from the treatment period as recorded on the end of 
treatment page of the electronic case report form (eCRF) will be summarized (number 
and percentage). The number and percentage of subjects who completed the treatment 
period and enrolled in the extension study will also be presented. A subject data listing
will present subject disposition for the All Enrolled Population.
Inclusion and exclusion criteria violations, if any, will be presented in a listing for the All 
Enrolled Population.
5.2
Demographic and Other Baseline Characteristics
The baseline and demographic characteristics will be summarized for the ITT, PP, and 
Safety Populations with descriptive statistics defined in Section 11.1. Demographic and 
baseline characteristics to be presented include:


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•
Age (at informed consent date) in years, both as a continuous parameter and by 
categories of <45, 45-<65, and ≥65.
•
Sex
•
Race
•
Ethnicity
•
Height (cm) at the Screening visit
•
Weight (kg) at the Baseline visit
•
BMI (kg/m2) at the Baseline visit
BMI is calculated as weight (kg)/ [height (m)]2.
The following SBS history information collected at the Screening visit will be 
summarized with the descriptive statistics defined in Section 11.1 for the ITT, PP and 
Safety Populations:
•
Duration of SBS (years)
•
Primary reason for the diagnosis of SBS (Crohn’s disease, vascular disease, 
injury, volvulus, cancer, and other)
•
Secondary reason for the diagnosis of SBS (Y/N), secondary reason (Crohn’s 
disease, vascular disease, injury, volvulus, cancer, and other)
•
Stoma (Y/N), stoma type (jejunostomy, ileostomy, colostomy, other)
•
Remaining colon (Y/N), estimated percent colon remaining, and colon in 
continuity (Y/N)
•
Total estimated remaining small intestinal length (cm) and category (< 25 cm, ≥ 
25 cm; < 40 cm, ≥ 40 cm; < 60 cm, ≥ 60 cm)
•
Distal/terminal ileum (Y/N) and ileocecal valve (Y/N)


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•
Method to determine remaining anatomy length (surgery, radiology, and other)
Duration of SBS will be calculated as (Date of ICF Signed – Date of Diagnosis of SBS 
+1)/365.25.
The following Parenteral Nutrition history information collected at the Screening visit
will be summarized with the descriptive statistics defined in Section 11.1 for the ITT, PP
and Safety Populations:
•
Years since start of PN dependency
•
Prescribed weekly PN/IV volume
•
Prescribed weekly number of days of PN/IV
Years since start of PN dependency will be calculated as (Date of ICF Signed – Start 
Date of PN dependency +1)/365.25. 
The following Crohn’s Disease Evaluation information collected at the Screening visit 
will be summarized with the descriptive statistics defined in Section 11.1 for the ITT, PP
and Safety Populations:
•
Medical history of Crohn’s disease (Y/N), and current clinical status of Crohn’s 
disease (Active, Inactive)
The following gastrointestinal (GI)–specific testing information collected during the 
stabilization period will be summarized with the descriptive statistics defined in Section 
11.1 for the ITT, PP and Safety Populations:
•
For subjects with Crohn’s disease, upper GI contrast series with small bowel 
follow-through: normal, abnormal not clinically significant, abnormal clinically 
significant
•
abdominal ultrasound: normal, abnormal not clinically significant, abnormal 
clinically significant
•
colonoscopy: normal, abnormal not clinically significant, abnormal clinically 
significant


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•
sigmoidoscopy: normal, abnormal not clinically significant, abnormal clinically 
significant
•
Esophagogastroduodenoscopy (EGD): normal, abnormal not clinically significant, 
abnormal clinically significant
Colonoscopy, sigmoidoscopy and EGD will also be presented at Dosing Week 24/early 
termination (ET). 
Partial dates for the start date of PN dependency and date of diagnosis of SBS will use 
the first day of the month if only the day is missing. If both the day and month are 
missing, the first of January will be used. 
5.3
Medical History
Medical and surgical history will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). Investigator verbatim as well as preferred terms (PT) and system 
organ class (SOC) will be included in the listings. The medical history will be 
summarized by SOC and PT within SOC for the Safety Population, with SOC sorted 
alphabetically and PT within SOC by descending incidence.
5.4
Prior Treatment and Medication
Prior medications will be coded using the World Health Organization Drug Dictionary. 
Prior medications are defined as medications taken prior to the first dose of study 
medication. Partial date imputation for medications is described in Section 11.5.2.
Prior medication use will be summarized by preferred name using the number and 
percentage of subjects for the Safety Population. Medications will be sorted by 
descending incidence 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, both prior and concomitant, will be presented. The listing will 
be sorted by subject identifier and will include preferred name, reported name, dose, 
route of administration, dosing frequency, start date, end date, indication, and type of 
medication (prior only, concomitant only, prior and concomitant).


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5.5
Concomitant Treatment and Medication
Concomitant medications will also be coded using the World Health Organization Drug 
Dictionary. 
Concomitant medications are defined as medications with onset dates on or after the first 
dose of study medication, medications with onset dates prior to first dose of study 
medication without a stop date, or medications with a stop date after first dose of study 
medication. Partial date imputation for medications is described in Section 11.5.2.
Concomitant medications will be summarized in the same way as prior medications (refer 
to Section 5.4).
Diagnostic, surgical, or therapeutic procedures during the study will be listed.
5.6
Exposure to Investigational Product
The extent of exposure is defined as the number of days on treatment, including any 
periods of temporary dose interruption, calculated as:
(date of last dose - date of first dose) + 1.
The first dose date and last dose date will be based on the eCRF. The extent of exposure, 
the number of days that the dose was administered, will be summarized with the 
descriptive statistics defined in Section 11.1. The number and percentages of subject will 
be tabulated for extent of exposure categorized into weeks (<4, 4-<12, 12-<24, ≥24). 
Exposure summaries will be presented for the ITT, PP and Safety Populations.
5.7
Measurements of Treatment Compliance 
Percent compliance will be calculated as 100 times the number of doses administered
(either by the investigator or by the subject per instructions) divided by the number of 
days on treatment, excluding any periods of temporary dose interruptions due to adverse 
event that were deemed necessary by the investigator. Number of days on treatment is 
then calculated as (last dose date – first dose date +1) and the number of days of dose 
interruption due to adverse event will be excluded, i.e., the sum of (Date of study drug 
resumed – start date of interruption due to adverse event +1) as recorded on the Study 
Drug Interruption eCRF form. The information whether the study treatment was 
administered per instructions is captured on the study drug administration daily diary.


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Drug accountability information, first dose date, last dose date, and study medication 
interruptions (start date of interruption, date study medication resumed, and reason for 
interruption) will be included in the listings. 
Subjects will be considered compliant overall for study medication if the calculated 
compliance is ≥ 80%. Overall treatment compliance will be presented for both percent 
compliance calculations using the descriptive statistics defined in Section 11.1 and the 
number and percentage of subjects who are ≥ 80% compliant for both the ITT, PP and 
Safety Populations. Treatment compliance by visit will not be calculated.
5.8
Protocol Deviations
Protocol deviations as obtained from a clinical trial management system (CTMS) will be 
assessed throughout the study. All identified deviations will be reported in the CTMS. 
Protocol deviations from the CTMS will be provided as part of the CTMS transfer to 
Biostatistics. Protocol deviations will be summarized for the ITT Population and all 
protocol deviations will be listed.
6.
EFFICACY ANALYSES
All efficacy analyses will be based on the ITT Population and PP Population and be 
displayed in tables side by side for these two populations. The PP Population will be used 
for sensitivity analysis purpose. Unless stated otherwise, the baseline for all efficacy 
analyses will be as defined in Section 11.2.
All efficacy analyses will be descriptive only and there will be no statistical testing.
6.1
Analyses of Efficacy Endpoints
The efficacy endpoints are the following:
Absolute and relative change from baseline in weekly PN/IV volume by visit and 
at EOT.
Percentage of subjects who achieve at least 20% reduction from baseline in 
weekly PN/IV volume at both Weeks 20 and 24.
Percentage of subjects who achieve at least a 20% reduction from baseline in 
weekly PN/IV volume at each visit
Change in days per week of PN/IV support from baseline by visit.
Change in plasma citrulline from baseline by visit.
Number of subjects who were able to completely wean off of PN/IV support.


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Analyses on weekly PN/IV support are based on two data sources: the subject diary data 
and the investigator prescribed data.
The diary weekly PN/IV volume will be calculated based on the daily volumes recorded 
in subjects’ diaries within 14 days prior to each scheduled visit. The calculation will 
follow the formula below.
Weekly volume = (sum of daily volumes in the diary/number of days with values) *7
Missing daily PN/IV volumes will not be imputed. A maximum of 5 missing days (or at 
least 9 days of non-missing data) from the 14-day intervals are allowable, otherwise the 
interval will be classified as missing. One exception to this rule is the baseline interval, 
which will be filtered back up to 28 days prior to first dose until 9 data points are 
obtained.
Investigator prescribed data is captured in the PN/IV baseline and PN/IV adjustment in 
eCRF. Investigator prescribed weekly PN/IV volume reported at each visit will be the 
most recent PN/IV prescription (from either baseline or prescription adjustments) prior to 
or on the date of visit.
Data will be summarized at all scheduled visits during the 24-week treatment period. An 
EOT time point will also be added. Therefore,
PN/IV weekly volume and days per week of PN/IV support will be summarized at 
Baseline, Weeks 2, 4, 8, 12, 16, 20, 24 and EOT.
Plasma citrulline will be summarized at Baseline, Weeks 4, 8, 16, 24 and EOT.
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.
Change in weekly PN/IV volume from baseline
The absolute and percent change in weekly PN/IV volume from baseline to each 
scheduled visit during the 24-week treatment period, as well as at EOT, will be presented 
using the descriptive statistics defined in Section 11.1.


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Percent change in weekly PN/IV volume from baseline at each scheduled visit will be 
calculated using the formula below: 
% change in weekly PN/IV volume at the visit = [(weekly PN/IV volume at the visit –
weekly PN/IV volume at baseline) / weekly PN/IV volume at baseline] * 100
95% confidence intervals of the mean will be generated for Week 24 and EOT.
Mean ± SE plots of absolute and percent change from baseline in weekly PN/IV volume
will be generated. In addition, individual absolute and percent change from baseline in 
weekly PN/IV volume will be presented for each subject.
Response to Teduglutide at both Weeks 20 and 24
The number and percentage of subjects who demonstrate a response at Week 20 and 
again at Week 24 will be presented. A response is defined as the achievement of at least a 
20% reduction from baseline in weekly PN/IV volume.
Binary response to Teduglutide by visit
The number and percentage of subjects who demonstrate a response at each scheduled 
visit during the 24-week treatment period, as well as EOT, will be presented. A response 
is defined as the achievement of at least a 20% reduction from baseline in weekly PN/IV 
volume.
Change in days per week of PN/IV support from baseline
The absolute and percent change in days per week of PN/IV support from baseline to 
each scheduled visit during the 24-week treatment period, as well as at EOT, will be 
presented based on diary and investigator prescribed data using descriptive statistics 
defined in Section 11.1.
Changes in plasma citrulline from baseline
The absolute and percent change in plasma citrulline from baseline to each scheduled 
visit during the 24-week treatment period, as well as at EOT, will be presented using 
descriptive statistics defined in Section 11.1.


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Number of subjects who are able to completely wean off PN/IV support
A subject will be considered to have achieved independence from PN/IV (completely 
weaned off PN/IV) if the investigator prescribes no PN/IV at week 24/EOT and there is 
no use of PN/IV recorded in the subject diary during the 2 weeks prior to the last dosing 
visit.
The number and percentage of subjects who completely wean off PN/IV support by
Week 24/EOT will be presented.
6.1.1
Sensitivity Analyses of Efficacy Endpoint(s)
The PP Population will be used for sensitivity analysis purpose.
6.2
Multiplicity Adjustment
As there will be no statistical testing given the small sample size, no adjustment for 
multiple comparisons will be made.
6.3
Subgroup Analyses
No subgroup analysis will be performed.
7.
SAFETY ANALYSIS 
The safety analysis will be performed using the Safety Population. Safety variables 
include AEs, clinical laboratory variables, vital signs, ECG variables, physical 
examination, 48-hour urine output and antibodies to Teduglutide. For each safety 
variable, the last value collected before the first dose of the investigational product will 
be used as the baseline for all analyses of that safety variable.
7.1
Adverse Events 
AEs will be coded using MedDRA. Investigator verbatim as well as PT and SOC will be 
included in the listings. 
Treatment emergent AEs (TEAEs) are defined as AEs whose onset occurs, severity 
worsens, or intensity increases after receiving the study medication. AEs with an 
unknown date of onset and a stop date after the start of the study treatment or unknown 
stop date will be included as TEAEs. 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 


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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 11.5.3. AEs which are 
not treatment emergent will be flagged in listings.
AEs will be summarized overall using descriptive statistics (e.g., number and percent of 
subjects). The number of events will also be presented. Categories summarized will 
include any TEAEs, severity of TEAEs, 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, and TEAEs leading to discontinuation.
TEAEs 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 presented. Categories summarized are as follows:

TEAEs, 

Severity of TEAEs, 

Investigator assessment of relationship of TEAEs to study treatment, 

TESAEs.
Presentation by SOC and PT will present SOC sorted alphabetically and PT within SOC 
by descending incidence.
Listings will be provided for serious adverse events (SAEs), AEs leading to death, and 
AEs leading to discontinuation of study drug. The listings will be sorted by subject 
identifier and will include SOC, PT, reported term, start date/time, end date/time, 
frequency, severity, relationship, action taken, and outcome.
For AEs with partial dates, the imputed dates described in Section 11.5.3 will be used to 
determine the onset interval.
7.1.1
Adverse Events of Special Interest
The preferred terms corresponding to central line systemic infection AEs will be 
identified by Shire and provided to IQVIA Biostatistics for the analysis. These TEAEs 
will be presented by PT, sorted by descending incidence.


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7.2
Clinical Laboratory Data
Clinical laboratory tests are to be performed at site visits with results processed by a 
central laboratory. Laboratory tests include the following (Table 2):


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Table 2
List of Laboratory Tests
Hematology:

Hematocrit 

Hemoglobin 

Platelet count

Red blood cell count 

Red blood cell morphology, if 
needed

White blood cell count with 
differential
Urinalysis: 

Blood

Glucose

Leucocytes

Microscopic analysis

pH 

Protein

Specific gravity

Urine Sodium
Pregnancy tests (females of childbearing 
potential):

Urine β-HCG 
Biochemistry:

Albumin 

Alkaline phosphatase 

Alanine aminotransferase 

Amylase

Aspartate aminotransferase 

Bilirubin (total, direct and indirect)

Blood urea nitrogen 

Calcium (total)

Chloride

Cholesterol

Citrulline (plasma)

C-reactive protein 

Creatinine

Creatinine clearance

Gamma-glutamyl transferase 

Glucose

Lipase

Magnesium

Phosphorus

Potassium 

Sodium 

Triglycerides

Uric acid
Laboratory parameters will be presented in standard international (SI) units. The 
summaries will be based on central lab results only.
Quantitative results will be summarized for hematology, serum chemistry, and urinalysis 
parameters at each scheduled visit during the 24-week treatment period (Baseline, Weeks 
2, 4, 8, 12, 16, 20 and 24) and at EOT. Both actual values and change from baseline will 
be summarized with descriptive statistics defined in Section 11.1.
Clinical laboratory test values are markedly abnormal if they meet either the low or high 
markedly abnormal criterion listed in Table 3. These criteria are based on lab normal 
ranges and discussions with the experts. The number and percentage of subjects with 
post-baseline markedly abnormal values will be summarized by parameter. The 


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percentages will be calculated relative to the number of subjects with available baseline 
values and at least 1 post-baseline assessment for the associated parameter. The 
numerator is the total number of subjects with at least 1 post-baseline markedly abnormal
value. A supportive listing of subjects with post-baseline markedly abnormal values will 
be provided including the subject number, site, parameter, lab dates, baseline, and post-
baseline values. This listing will present all values for a subject and laboratory parameter 
if at least one post-baseline value for that subject and parameter is identified as being 
markedly abnormal.
Table 3: Markedly Abnormal Laboratory Criteria
Lab parameter 
Unit 
Lower Limit 
Upper Limit 
Chemistry
Albumin 
g/L 
<=20 
>=90 
Alkaline Phosphatase 
U/L 
NA 
>2*ULN 
ALT 
U/L 
NA 
>3*ULN 
Amylase 
U/L 
<=15 
>=350 
AST 
U/L 
NA 
>3*ULN 
Bilirubin (total) 
μmol/L 
NA 
>2*ULN 
BUN 
mmol/L 
NA 
>=10.7 
Calcium (total) 
mmol/L 
<=2.1 
>=3.0 
Chloride 
mmol/L 
<=80 
>=125 
Cholesterol (total) 
mmol/L 
NA 
>=12.9 
Creatinine 
μmol/L 
NA 
>=177 
C Reactive Protein 
mg/L 
NA 
>=21 
Glucose 
mmol/L 
<=1.7 
>=13.9 
Gamma glutamyl 
transferase 
U/L 
NA 
>100 
Lipase 
U/L 
NA 
>3*ULN 
Magnesium 
mmol/L 
<LLN 
>ULN 
Phosphate 
mmol/L 
NA 
>=2.0 
Potassium 
mmol/L 
<=2.5 
>=6.5 
Sodium 
mmol/L 
<=120 
>=165 
Triglycerides 
mmol/L 
NA 
>=5.6 
Uric acid 
μmol/L 
NA 
>=624 (males) 
>=505 (females) 
Hematology
Hematocrit 
L/L 
<=0.37 (males) 
<=0.32 (females) 
>0.54 (males) 
NA (females) 
Hemoglobin 
g/L 
<=115 (males) 
<=95 (females) 
NA 
Platelets 
109/L 
<=75 
>=700


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ULN = upper limit of normal
ALT = Alanine Aminotransferase, Equivalent to SGPT
AST = Aspartate Aminotransferase, Equivalent to SGOT
BUN = Blood Urea Nitrogen
Laboratory results will be presented in a listing for each lab panel (chemistry, 
hematology, and urinalysis) by subject, visit, and parameter. Laboratory values outside of 
the normal range will be flagged. Categorical urinalysis findings and urine pregnancy 
results will be presented in a listing only.
7.3
Vital Signs, Body Weight and BMI
The descriptive statistics defined in Section 11.1 will be used to summarize the vital signs 
(i.e., systolic blood pressure, diastolic blood pressure (mmHg), pulse rate, body 
temperature, weight, and BMI) by scheduled visit during the 24-week treatment period
(Baseline, Weeks 2, 4, 8, 12, 16, 20 and 24) and at EOT for the Safety Population. Both 
actual values and changes from baseline will be summarized.
7.4
Electrocardiogram
The number and percentage of subjects with each type of ECG finding 
(Normal/Abnormal, Not Clinically Significant/Abnormal, Clinically Significant) will be 
presented at Baseline, Weeks 4 and 24, and EOT for the Safety Population. All ECG data 
will be listed. 
7.5
Other Safety Data
7.5.1
Physical Examination
Physical examination results will be presented in a listing only. 
7.5.2
Antibodies to Teduglutide
A summary table will provide the number of subjects with a sample analyzed for 
Baseline, Weeks 12, 24 and EOT. The summary table will also provide the number of 
subjects with an antibody finding at each of those visits in the Safety Population.
All antibody data including neutralizing antibodies and antibody titers will be listed.  


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7.5.3
48 Hour Oral Fluid Intake and Urine Output
Oral/enteral intake and urine output measurements collected during 48 hours prior to each 
visit will be summarized by scheduled visit during the 24-week treatment period (Weeks 
2, 4, 8, 12, 16, 20 and 24) and at EOT. Oral/enteral intake and urine output measurements 
for Day 1 and Day2 will be captured in the eCRF. The sum of the measurements of Day 1 
and Day 2 in mL will be summarized.
Actual values and both absolute and percent change from baseline will be summarized in 
the Safety Population with descriptive statistics defined in Section 11.1.
8.
PHARMACOKINETIC ANALYSIS 
8.1
Pharmacokinetic Parameters
The PK parameters will be derived and estimated based on measured teduglutide plasma 
concentrations using Non-compartmental analysis (NCA) by a Shire designated vendor in 
accordance with the PK SAP and generated separately.
8.2
Statistical Analysis of Pharmacokinetic Data
The PK concentration data will be summarized on the PK Population for the protocol 
scheduled sampling time points:
At Baseline:

0 hour (predose) draw: any time prior to the dose

15 minutes postdose ±5 minutes

30 minutes postdose ±5 minutes

1 hour postdose ±10 minutes

2 hours postdose ±10 minutes

3 hours postdose ±10 minutes

4 hours postdose ±30 minutes

6 hours postdose ±30 minutes

8 hours postdose ±30 minutes

10 hours postdose ±30 minutes


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
12 hours postdose ±30 minutes
At Week 4 or Week 12:

0 hour (predose) draw: any time prior to the daily dose, on the day of dosing, but at 
least 14 hours after the previous dose

1 hour postdose ±10 minutes

2 hours postdose ±10 minutes
Descriptive statistics of PK concentration (number of subjects, mean, standard deviation, 
coefficient of variation (CV) %, geometric mean, geometric CV (%), median, minimum 
and maximum values) will be calculated at each time point. Mean (±SD) PK 
concentration by time curves will be provided for the PK population. PK concentration 
by time will also be plotted by individual subject. A listing for PK concentration data will 
also be provided.
9.
OTHER ANALYSES
The information related to the study drug training provided by the study physician will be 
listed for all subjects in the Safety Population.
10.
INTERIM ANALYSIS/ DATA MONITORING (REVIEW) COMMITTEE
Interim analyses may be conducted during the study, as needed. Analyses will be 
descriptive in nature. No formal comparisons are planned, and no hypotheses will be 
formally tested. Due to the open-label nature of this study, personnel involved in 
conducting the interim analyses will have access to treatment assignments.
11.
DATA HANDLING CONVENTIONS
11.1
General Data Reporting Conventions 
The small sample size resulting from the small study population requires the use of 
descriptive statistics with a goal of summarizing the sample and thus discourages the use 
of inferential statistics.
Data from all healthcare setting study sites that participate in this protocol will be 
combined so that an adequate number of subjects will be available for analysis.
Descriptive statistics will be presented as follows:


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•
Continuous variables, including those assessed on a discrete scale, will be 
summarized using the following descriptive statistics: the number of subjects, mean, 
median, standard deviation, minimum, maximum and 95% confidence interval where 
needed. 
•
Categorical variables will be summarized by the number and percentage of subjects 
in each category (with a category for missing data as needed). Unless otherwise 
stated, the denominator for percentages is N (the number of subjects in the analysis 
population).
The following rules will be followed for decimal places and rounding:
•
Unless otherwise specified, means (arithmetic and geometric) and medians will be 
rounded and presented to 1 decimal place more than the raw data and standard 
deviations to 2 decimal places more than the raw data. Minimum and maximum 
values will be presented to the same number of decimal places as the raw data.
•
Unless otherwise specified, percentages should be presented to one decimal place. 
Less than signs (i.e., ‘<’) should be presented as appropriate (e.g., 0.04% should be 
presented as < 0.1%, not 0.0%). This rule also applies to %CV.
•
BMI, duration of SBS and years since start of PN dependency should be rounded to 1 
decimal place for reporting.
Study day will be calculated as follows;
•
If the evaluation date is on or after the date of first day of study medication: 
Study day = date of evaluation – first day of study medication + 1
•
If the evaluation date is before the date of first day of study medication:
Study day = date of evaluation – first day of study medication
All output should have a 3-line header at the upper left margin:
Shire
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All output should have a 1-line footer with the SAS program name, including the path, 
and the date and time the output was produced at the lower left margin of the footer.
Tables and listings should be internally paginated in relation to the total length for that 
table or listing (i.e., Page n of N, where n is the page number within the table or listing 
and N is the total number of pages for that table or listing).
The table, figure and listing numbering will be based on the International Conference on 
Harmonization (ICH) guidelines.
A number should identify each table/listing, and the table designation (e.g., Table 14.x) 
should be centered above the title. A decimal system (e.g., x, x.y, x.y.z) should be used to 
identify tables/listings with related contents. The title should be centered and in mixed-
case characters. The title and table/listing designation should be single-spaced but are 
separated from the content of the table/listing by a space and a solid underline. The study 
population and/or subgroup (e.g., ITT Population) should be identified on the line 
immediately following the title.
Column headings should be in title case characters. For numeric variables, the unit should 
be included in the column heading when appropriate.
Footnotes should be single spaced but separated by an underline and a space from the text 
of the table/listing. The notes should be aligned vertically by the left vertical border of the 
table/listing. Numeric references, which can be confused with data, should not be used. 
Rather asterisks and other non-numeric symbols should be used to refer to footnotes.
The dictionary (e.g., MedDRA, WHODD) and the dictionary version numbers should be 
identified in the footnotes to the tables/listings for data coded with a dictionary.
For both tables and listings where there are no observations (and hence there would be no 
output), the table/listing should be produced with all titles and footnotes as per its shell, 
but with the text showing no observations in the body of the output.
Individual data listings will be sorted and presented by subject number and visit/event
date.
Dates will be presented in a DDMONYYYY format. Dates with partial missing data will 
be presented with a dash (i.e., ‘-’) for the missing data (e.g., --JAN2019).


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In general, analyses on PP population will be conducted if PP population is different from 
ITT population.
For the following analyses, data for ITT, PP and Safety will be presented side by side in 
tables:
•
Demographic and other baseline characteristics
•
Short bowel syndrome history
•
Parenteral nutrition history
•
Crohn’s disease evaluation
•
Gastrointestinal specific testing 
•
Exposure of investigational product
•
Treatment compliance
11.2
Definition of Baseline 
For summary purposes, the baseline value will be defined as the last available pre-dose 
value.
11.3
Definition of Visit Windows 
Although there is a visit window from 2 to 7 days around the expected visit date, nominal 
visits will be used for the per-visit analyses. Therefore, no windowing of visits by actual 
study day will be done for data obtained at the scheduled visits. For subjects who 
withdraw from the study pre-maturely, if the ET visit falls into the window of a 
scheduled visit as defined in the protocol, the ET visit is also summarized for that 
scheduled visit, unless the scheduled visit already took place.
11.4
Derived Efficacy Endpoints 
An EOT time point, defined as the last determination of endpoint or last available 
measurement from the date of first dose, will be analyzed in addition to the scheduled 
visits. Unscheduled measurements will not be included in by-visit summaries but can 
contribute to the EOT value where applicable.


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11.5
Handling of Missing, Unused, and Spurious Data 
No imputation for missing data (e.g., last observation carried forward) will be applied 
except for the partial dates to derive treatment emergent adverse events and flagging 
prior/concomitant medications.
Imputation will be performed for partial dates of AEs and medications solely for the 
purpose of defining treatment emergence for AEs, determining whether an AE started in 
the treatment period and prior/concomitant status for medications. Details on how to 
handle partial dates for adverse events and prior/concomitant medications are described 
below.
11.5.1 Missing Date of Investigational Product
No imputation will be applicable to missing date of investigational product.
11.5.2 Missing Date Information for Prior or Concomitant Medications
For prior or concomitant medications, incomplete (i.e., partially missing) start date and/or 
stop date will be imputed.
11.5.2.1 Incomplete Start Date 
The following derivations will be applied to impute the missing start dates. In each 
section, dates will be defined using the hierarchy of the derivations. Should any of the 
following 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.
11.5.2.1.1
Missing Day and Month
1.
If only year is known, and it is previous to the year of the informed consent, use June 
30th of that year.
2.
If only year is known, and it is the year of the first dose date, use the first dose date
3.
If only year is known, and it is after the year of the first dose date, then use Jan 1st of 
that year.
4.
If only year is known, and it is the year of the informed consent, use the informed 
consent date.


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11.5.2.1.2
Missing Month Only
The day will be treated as missing and both month and day will be replaced according 
to the above procedures.
11.5.2.1.3
Missing Day Only
1.
If year and month are known, and it is the month and year of the first dose date, use 
the first dose date.
2.
If year and month are known, and it is the month and year of the informed consent, 
use the informed consent date.
3.
If year and month are known, and the month is not the month and year of the first 
dose or informed consent, use the first day of the month.
For other incomplete dates, leave as missing.
11.5.2.2 Incomplete Stop Date 
The following derivations will be applied to impute the missing stop dates. In each 
section, dates will be defined using the hierarchy of the derivations. Should any of the 
following stop dates created be before a start date (either a complete date or an imputed 
one,), use the (imputed) start date instead of the date that would otherwise be created. 
11.5.2.2.1
Missing Day and Month
1.
If only year is known and study medication stopped during that year, use the stop 
date of study medication.
2.
If only year is known and study medication stopped after that year, use December 
31st of that year.
3.
If only year is known and study medication stopped prior to that year, use the first 
day of the year.
11.5.2.2.2
Missing Month Only
The day will be treated as missing and both month and day will be replaced according to 
the above procedures.


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11.5.2.2.3
Missing Day Only
1.
If year and month are known and study medication stopped during that month and 
year, use the stop date of study medication.
2.
If year and month are known and informed consent was provided during that month 
and year, use the date of informed consent.
3.
If only year and month are known and study medication stopped after that year and 
month, use the last day of the month.
4.
If only year and month are known and study medication stopped prior to that year
and month, use the first day of the month.
For other incomplete dates, leave as missing.
11.5.3 Missing Date Information for Adverse Events 
If any AE records contain only partial dates, these will be handled by imputation, as 
described in the subsections below.
11.5.3.1 Incomplete Start Date 
The following derivations will be applied to impute the missing dates. In each section, 
dates will be defined using the hierarchy of the derivations. Should any of the following
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.
11.5.3.1.1
Missing Day and Month
1.
If only year is known, and it is previous to the year of the informed consent, use June 
30th of that year.
2.
If only year is known, and it is the year of the first dose date, use the first dose date
3.
If only year is known, and it is after the year of the first dose date, then use Jan 1st of 
that year.
4.
If only year is known, and it is the year of the informed consent, use the informed 
consent date.


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11.5.3.1.2
Missing Month Only
The day will be treated as missing and both month and day will be replaced according to 
the above procedures.
11.5.3.1.3
Missing Day Only
1.
If year and month are known, and it is the month and year of the first dose date, use 
the first dose date.
2.
If year and month are known, and it is the month and year of the informed consent, 
use the informed consent date.
3.
If year and month are known, and the month is not the month and year of the first 
dose or informed consent, use the first day of the month.
Otherwise, if a start date is unknown, leave as missing.
11.5.3.2 Incomplete Stop Date 
No imputation is applied to incomplete stop date.
11.5.4 Missing Severity Assessment for Adverse Events 
If severity is missing for an AE starting prior to the date of the first dose of 
investigational product, then a severity of “Mild” will be assigned. If the severity is 
missing for an AE starting on or after the date of the first dose of investigational product, 
then a severity of “Severe” will be assigned. The imputed values for severity assessment 
will be used for incidence summaries only and will not be reported in the data listings.
11.5.5 Missing Relationship to Investigational Product for Adverse Events 
If the relationship to investigational product is missing for an AE starting on or after the 
date of the first dose of investigational product, a causality of “Related” will be assigned.  
The imputed values for relationship to the investigational product will be used for 
incidence summaries only and will not be reported in the data listings.
11.5.6 Character Values of Clinical Laboratory Variables
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.


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12.
ANALYSIS SOFTWARE 
Statistical analyses will be performed using Version 9.4 (or newer) of SAS(SAS 
Institute, Cary, NC, US) on a suitably qualified environment.
13.
CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL
There is no change of analysis from protocol.


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14.
REFERENCES
No references used in this SAP.


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15.
APPENDICES 
No appendices listed in this section.


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STATISTICAL ANALYSIS PLAN 
Teduglutide 
PHASE 3 
A 24-Week Safety, Efficacy, Pharmacokinetic Study of Teduglutide in 
Japanese Subjects with Short Bowel Syndrome who are Dependent on 
Parenteral Support 
 
PROTOCOL IDENTIFIER: SHP633-306 
Study Sponsor(s): 
Takeda Human Genetic Therapies, Inc. 
300 Shire Way Lexington, MA 02421 
USA 
 
Author (Company): 
(IQVIA) 
Protocol: 
23 JAN 2018  
SAP Version #:2.0 
 
SAP Date: 
15Apr2019 
Status: 
 Final 
 
 
 


Takeda
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15Apr2019
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Takeda                                                         CONFIDENTIAL 
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Statistical Analysis Plan Final v2.0 
Protocol Number: SHP633-306 
15Apr2019 
Document: 
T:\PROJ\Shire\UYA25606_Biostatistics\Documentation\SAP\SAP\SHP633-306_SAP_Final 
v2.0_20180415.docx 
Author: 
Version Number: 
Final V2.0 
 
 
Version Date: 
15Apr2019 
Template No: Harmonized Statistical Analysis Plan Template v1.0 
Effective Date: 01June2018 
 
REVISION HISTORY 
Version  
Issue Date 
Summary of Changes 
Final 1.0 
12Dec2018 
New Document 
Final 1.1 
3Mar2019 
7.1 
Added a clarification that TEAEs leading to 
study treatment discontinuation is summarized 
and listed.   
In addition to the listing of AE leading to study 
drug discontinuation, a new listing of AE 
leading to study discontinuation is also added. 
 
7.1.1 
This whole section of AE of special interest is 
now updated according to protocol (date 
23Jan2018) section 8.3.   
 
7.2 
The calculation for percentages of subjects with 
post-baseline markedly abnormal values is 
updated by removing the necessity for including 
baseline values in the calculation.  
 
7.5.3 
Revised method of calculating urine output 
measurement by taking the average of Day 1 
and Day 2 urine output measurement, instead of 
the sum of Day 1 and Day 2.   
Final 2.0 
15Apr2019 
Statistical Analysis Plan Signature Page 
Added
to signature page. 
 
Throughout the document 
Updated branding from Shire to Takeda. 
 
4.1 and throughout the document 
Changed the wording ‘All-enrolled Population’ 
to ‘Screened Population’. 
 
6.1 


Takeda                                                         CONFIDENTIAL 
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Version Date: 
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Added a listing to the ‘Number of subjects who 
are able to completely wean off PN/IV support’ 
analysis. 
 
7.1.1 
Added a reference to indicate that a listing 
indicating the MedDRA terms to AE of Special 
Interest can be found in Appendix I. 
Also added that PT will also be presented 
within each grouping of AE of Special Interest. 
 
7.2 
White Blood Cells is now added to Table 3 
Markedly Abnormal Laboratory Criteria table. 
 
11.1 
Standard errors required in tables when a 
corresponding figure is generated. 


Takeda                                                         CONFIDENTIAL 
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE .............................................2 
REVISION HISTORY ......................................................................................................3 
TABLE OF CONTENTS ..................................................................................................5 
ABBREVIATIONS ............................................................................................................8 
1. 
INTRODUCTION................................................................................................10 
2. 
OBJECTIVES, ESTIMAND(S), AND ENDPOINTS .......................................10 
2.1 
Objectives ..........................................................................................................10 
2.2 
Estimand(s) .......................................................................................................10 
2.3 
Endpoints ..........................................................................................................11 
2.3.1 Efficacy Endpoint(s) ..................................................................................11 
2.3.2 Safety Endpoint(s) .....................................................................................11 
2.3.3 Pharmacokinetic Endpoint(s) .....................................................................11 
3. 
STUDY DESIGN ..................................................................................................12 
3.1 
General Description ..........................................................................................12 
3.1.1 Optimization and Stabilization Periods .....................................................12 
3.1.2 Treatment Period ........................................................................................12 
3.2 
Randomization ..................................................................................................13 
3.3 
Blinding .............................................................................................................13 
3.4 
Sample Size and Power Considerations ............................................................13 
4. 
STATISTICAL ANALYSIS SETS .....................................................................13 
4.1 
Screened Population ..........................................................................................13 
4.2 
Intent-to-treat (ITT) Population ........................................................................13 
4.3 
Per Protocol (PP) Population ............................................................................14 
4.4 
Safety Population ..............................................................................................14 
4.5 
Pharmacokinetic (PK) Population .....................................................................14 
5. 
STUDY SUBJECTS .............................................................................................14 
5.1 
Disposition of Subjects .....................................................................................14 


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5.2 
Demographic and Other Baseline Characteristics.............................................15 
5.3 
Medical History .................................................................................................17 
5.4 
Prior Treatment and Medication .......................................................................17 
5.5 
Concomitant Treatment and Medication ...........................................................18 
5.6 
Exposure to Investigational Product .................................................................18 
5.7 
Measurements of Treatment Compliance .........................................................19 
5.8 
Protocol Deviations ...........................................................................................19 
6. 
EFFICACY ANALYSES ....................................................................................19 
6.1 
Analyses of Efficacy Endpoints ........................................................................20 
6.1.1 Sensitivity Analyses of Efficacy Endpoint(s) ............................................22 
6.2 
Multiplicity Adjustment ....................................................................................22 
6.3 
Subgroup Analyses ...........................................................................................22 
7. 
SAFETY ANALYSIS...........................................................................................23 
7.1 
Adverse Events..................................................................................................23 
7.1.1 Adverse Events of Special Interest ............................................................24 
7.2 
Clinical Laboratory Data ...................................................................................25 
7.3 
Vital Signs, Body Weight and BMI ..................................................................28 
7.4 
Electrocardiogram .............................................................................................28 
7.5 
Other Safety Data ..............................................................................................28 
7.5.1 Physical Examination.................................................................................28 
7.5.2 Antibodies to Teduglutide..........................................................................28 
7.5.3 48 Hour Oral Fluid Intake and Urine Output .............................................29 
8. 
PHARMACOKINETIC ANALYSIS .................................................................29 
8.1 
Pharmacokinetic Parameters .............................................................................29 
8.2 
Statistical Analysis of Pharmacokinetic Data ...................................................29 
9. 
OTHER ANALYSES ...........................................................................................30 
10. 
INTERIM ANALYSIS/ DATA MONITORING (REVIEW) 
COMMITTEE ......................................................................................................30 
11. 
DATA HANDLING CONVENTIONS ..............................................................30 
11.1 
General Data Reporting Conventions ...............................................................30 


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11.2 
Definition of Baseline .......................................................................................33 
11.3 
Definition of Visit Windows .............................................................................33 
11.4 
Derived Efficacy Endpoints ..............................................................................34 
11.5 
Handling of Missing, Unused, and Spurious Data ............................................34 
11.5.1 Missing Date of Investigational Product....................................................34 
11.5.2 Missing Date Information for Prior or Concomitant Medications.............34 
11.5.2.1 Incomplete Start Date ..................................................................34 
11.5.2.2 Incomplete Stop Date...................................................................35 
11.5.3 Missing Date Information for Adverse Events ..........................................36 
11.5.3.1 Incomplete Start Date ..................................................................36 
11.5.3.2 Incomplete Stop Date...................................................................37 
11.5.4 Missing Severity Assessment for Adverse Events.....................................37 
11.5.5 Missing Relationship to Investigational Product for Adverse Events .......37 
11.5.6 Character Values of Clinical Laboratory Variables ...................................38 
12. 
ANALYSIS SOFTWARE ...................................................................................38 
13. 
CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL ............................38 
14. 
REFERENCES .....................................................................................................39 
15. 
APPENDICES ......................................................................................................40 
Appendix I – MedDRA Terms Corresponding to Each Grouping of Adverse Event 
of Special Interest ..............................................................................................40 
 


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ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase, Equivalent To SGPT 
AST 
Aspartate Aminotransferase, Equivalent To SGOT 
AUC 
Area Under the Plasma Concentration-Time Curve 
AUC0–t 
AUC From Zero to The Last Measurable Concentration 
BLQ 
Below the Lower Limit if Quantification 
BMI 
Body Mass Index 
BUN 
Blood Urea Nitrogen 
CL/F 
Apparent Clearance 
Cmax 
Maximum Plasma Concentration 
CTMS 
Clinical Trial Management System 
CV 
Coefficient of Variation 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EGD 
Esophagogastroduodenoscopy 
EOT 
End of Treatment 
ET 
Early Termination 
GI 
Gastrointestinal 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
ITT 
Intent-To-Treat 
MedDRA Medical Dictionary for Regulatory Activities 
NCA 
Non-compartmental Analysis 
PK 
Pharmacokinetics 
PP 
Per Protocol 
PN/IV 
Parenteral Nutrition/Intravenous 
PT 
Preferred Terms 
SAE 
Serious Adverse Event 


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SAP 
Statistical Analysis Plan 
SBS 
Short Bowel Syndrome 
SC 
Subcutaneous 
SI 
Standard International 
SOC 
System Organ Class 
t1/2 
Terminal-Phase Half-Life 
tmax 
Time to Cmax 
TEAE 
Treatment Emergent Adverse Event 
TESAE 
Treatment Emergent Serious Adverse Event 
ULN 
Upper Limit of Normal 
ULQ 
Above the Upper Limit of Quantification 
V/F 
Apparent Volume of Distribution 
 


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1. 
INTRODUCTION  
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the 
statistical analyses of efficacy, safety and pharmacokinetic (PK) data (descriptive 
summaries only) as described in the final study protocol dated 23 Jan 2018. 
Specifications for tables, figures, and listings are contained in a separate document. 
Pharmacokinetics analyses (other than descriptive summaries) will be described in a 
separate PK SAP. 
2. 
OBJECTIVES, ESTIMAND(S), AND ENDPOINTS 
2.1 
Objectives 
The objectives of this clinical study are to evaluate the safety, efficacy, and 
pharmacokinetics of teduglutide in Japanese subjects with short bowel syndrome (SBS) 
who are dependent on parenteral nutrition/intravenous (PN/IV) over a 24-week treatment 
period. 
2.2 
Estimand(s) 
Absolute change from baseline in weekly PN/IV volume based on diary data at End of 
Treatment (EOT) in Japanese subjects with PN/IV – dependent SBS in the Intent-to-treat 
(ITT) Population. 
Relative change from baseline in weekly PN/IV volume based on diary data at EOT in 
Japanese subjects with PN/IV – dependent SBS in the ITT Population. 
Number/percentage of subjects who achieved at least 20% decrease from baseline in 
weekly PN/IV volume based on diary data at Week 20 and Week 24 in Japanese subjects 
with PN/IV – dependent SBS in the ITT Population. 
Number/percentage of subjects who achieved at least 20% decrease from baseline in 
weekly PN/IV volume based on diary data at Week 20 and Week 24 in Japanese subjects 
with PN/IV – dependent SBS in the PP Population. 
Number/percentage of subjects who achieve at least a 20% reduction from baseline in 
weekly PN/IV volume based on diary data at each visit in Japanese subjects with PN/IV 
– dependent SBS in the ITT Population.  


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2.3 
Endpoints 
2.3.1 Efficacy Endpoint(s) 
The following efficacy endpoints will be analyzed: 
• Absolute and relative change from baseline in weekly PN/IV volume by visit and 
at EOT. 
• Percentage of subjects who achieve at least 20% reduction from baseline in 
weekly PN/IV volume at both Weeks 20 and 24. 
• Percentage of subjects who achieve at least a 20% reduction from baseline in 
weekly PN/IV volume at each visit 
• Change in days per week of PN/IV support from baseline by visit. 
• Change in plasma citrulline from baseline by visit. 
• Number of subjects who are able to completely wean off of PN/IV support. 
2.3.2 Safety Endpoint(s)  
The safety endpoints include adverse events (AEs), 12-lead electrocardiogram (ECG), 
vital signs, laboratory safety data, antibodies to teduglutide, and 48-hour urine output, 
body weight, body mass index (BMI) and gastrointestinal-specific tests.   
2.3.3 Pharmacokinetic Endpoint(s) 
The following parameters will be derived as described in a separate PK SAP and reported 
separately:  
Area under the plasma concentration–time curve from zero to the last measurable 
concentration (AUC0–t) 
Maximum plasma concentration (Cmax) 
Time to Cmax (tmax) 
terminal-phase half-life (t1/2) 
Apparent clearance (CL/F) 
Apparent volume of distribution (V/F) 


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3. 
STUDY DESIGN 
3.1 
General Description 
This is an open-label, multicenter study, consisting of a conditional PN/IV optimization 
period, a mandatory PN/IV stabilization period, and a 24-week treatment period. A 
schematic representation of the study design is presented in Figure 1. 
Figure 1: Study Schematic 
 
3.1.1 
Optimization and Stabilization Periods 
If at screening, a subject does not have an optimized PN/IV volume, defined as a 48-hour 
urine output between 2 and 4 L, he/she will enter the optimization period, during which 
the minimally tolerated stable PN/IV volume will be determined during a period of up to 
8 weeks. 
All subjects will then enter the stabilization period, during which the target PN/IV 
volume will be maintained for at least 4 consecutive weeks (8 weeks maximum). Those 
subjects who fail to stabilize will not proceed further and will not be included in the 
treatment period.  
Schedules of evaluations for the optimization/stabilization period can be found in the 
protocol. 
3.1.2 
Treatment Period 
Following the stabilization period, subjects will enter a 24-week dosing period, during 
which all subjects will receive teduglutide 0.05 mg/kg subcutaneously (SC) once daily. 


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At each site visit during the treatment phase, efficacy (adjustments to PN/IV) and safety 
will be monitored. 
Subjects will have blood samples taken for teduglutide PK analysis at predose and 15, 30 
minutes and 1, 2, 3, 4, 6, 8, 10, and 12 hours post dose at the baseline visit (Visit 2).  
Subjects will also have blood samples taken for teduglutide PK analysis at predose and 1 
and 2 hours post dose at Week 4 (Visit 5) or Week 12 (Visit 7) of the treatment period. 
All subjects who complete the study may participate in a long-term extension study in 
which eligible subjects will continue to receive teduglutide.  
Schedules of evaluations for the Treatment Period can be found in the protocol. 
3.2 
Randomization 
Not applicable for this single arm study. 
3.3 
Blinding 
Not applicable for this open-label study. 
3.4 
Sample Size and Power Considerations 
The sample size of the SHP633-306 study is based on patient prevalence and study 
design elements; no statistical estimation was involved. Possible medical institutes for 
SBS studies are limited, given the rarity of the disease and the very limited number of 
patients with SBS (<1000) in Japan. The applicant considers that 5 treated subjects in 
SHP633-306 should provide sufficient basic information concerning the efficacy, safety 
and tolerability as well as PK of teduglutide in the Japanese study population.   
4. 
STATISTICAL ANALYSIS SETS 
4.1 
Screened Population 
All subjects who provided a signed Informed Consent Form (ICF) will be included in the 
Screened Population. 
4.2 
Intent-to-treat (ITT) Population  
The Intent-to-treat Population will include all subjects who are deemed eligible for 
teduglutide treatment at the baseline visit (Visit 2).  


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4.3 
Per Protocol (PP) Population 
The Per Protocol Population will include all subjects in the ITT Population who complete 
the treatment period without any major protocol violations that could potentially affect 
the efficacy conclusions of the study. These situations include the following: 
• 
Missing baseline and/or Week 24 for the weekly PN/IV volume efficacy data 
based on diary data.  
• 
Non-compliance to study drug administration as defined in Section 5.7 
Reasons for exclusion from the PP Population will be presented in the listings for the ITT 
population. 
4.4 
Safety Population  
The Safety Population will include all subjects in the ITT Population who receive at least 
1 dose of study drug.   
4.5 
Pharmacokinetic (PK) Population   
The PK Population will include all subjects who receive at least 1 dose of teduglutide and 
have at least 1 evaluable post-dose pharmacokinetic concentration value.   
5. 
STUDY SUBJECTS 
5.1 
Disposition of Subjects 
The number and percent of subjects in each study analysis population (i.e., Screened, 
ITT, Safety, PP and PK) will be presented for the Screened Population.  
For the ITT and Safety Populations, the number and percentage of subjects who 
completed or prematurely discontinued the treatment period will be presented. Reasons 
for premature discontinuation from the treatment period as recorded on the end of 
treatment page of the electronic case report form (eCRF) will be summarized (number 
and percentage). The number and percentage of subjects who completed the treatment 
period and enrolled in the extension study will also be presented. A subject data listing 
will present subject disposition for the Screened Population. 
Inclusion and exclusion criteria violations, if any, will be presented in a listing for the 
Screened Population. 


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5.2 
Demographic and Other Baseline Characteristics 
The baseline and demographic characteristics will be summarized for the ITT, PP, and 
Safety Populations with descriptive statistics defined in Section 11.1. Demographic and 
baseline characteristics to be presented include: 
• Age (at informed consent date) in years, both as a continuous parameter and by 
categories of <45, 45-<65, and ≥65. 
• Sex 
• Race 
• Ethnicity 
• Height (cm) at the Screening visit 
• Weight (kg) at the Baseline visit 
• BMI (kg/m2) at the Baseline visit 
BMI is calculated as weight (kg)/ [height (m)]2. 
The following SBS history information collected at the Screening visit will be 
summarized with the descriptive statistics defined in Section 11.1 for the ITT, PP and 
Safety Populations: 
• Duration of SBS (years) 
• Primary reason for the diagnosis of SBS (Crohn’s disease, vascular disease, 
injury, volvulus, cancer, and other) 
• Secondary reason for the diagnosis of SBS (Y/N), secondary reason (Crohn’s 
disease, vascular disease, injury, volvulus, cancer, and other) 
• Stoma (Y/N), stoma type (jejunostomy, ileostomy, colostomy, other) 


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• Remaining colon (Y/N), estimated percent colon remaining, and colon in 
continuity (Y/N) 
• Total estimated remaining small intestinal length (cm) and category (< 25 cm, ≥ 
25 cm; < 40 cm, ≥ 40 cm; < 60 cm, ≥ 60 cm) 
• Distal/terminal ileum (Y/N) and ileocecal valve (Y/N) 
• Method to determine remaining anatomy length (surgery, radiology, and other) 
Duration of SBS will be calculated as (Date of ICF Signed – Date of Diagnosis of SBS 
+1)/365.25. 
The following Parenteral Nutrition history information collected at the Screening visit 
will be summarized with the descriptive statistics defined in Section 11.1 for the ITT, PP 
and Safety Populations: 
• Years since start of PN dependency 
• Prescribed weekly PN/IV volume 
• Prescribed weekly number of days of PN/IV 
Years since start of PN dependency will be calculated as (Date of ICF Signed – Start 
Date of PN dependency +1)/365.25.  
The following Crohn’s Disease Evaluation information collected at the Screening visit 
will be summarized with the descriptive statistics defined in Section 11.1 for the ITT, PP 
and Safety Populations: 
• Medical history of Crohn’s disease (Y/N), and current clinical status of Crohn’s 
disease (Active, Inactive) 
The following gastrointestinal (GI)–specific testing information collected during the 
stabilization period will be summarized with the descriptive statistics defined in Section 
11.1 for the ITT, PP and Safety Populations: 


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• For subjects with Crohn’s disease, upper GI contrast series with small bowel 
follow-through: normal, abnormal not clinically significant, abnormal clinically 
significant 
• abdominal ultrasound: normal, abnormal not clinically significant, abnormal 
clinically significant 
• colonoscopy: normal, abnormal not clinically significant, abnormal clinically 
significant 
• sigmoidoscopy: normal, abnormal not clinically significant, abnormal clinically 
significant 
• Esophagogastroduodenoscopy (EGD): normal, abnormal not clinically significant, 
abnormal clinically significant 
Colonoscopy, sigmoidoscopy and EGD will also be presented at Dosing Week 24/early 
termination (ET).  
Partial dates for the start date of PN dependency and date of diagnosis of SBS will use 
the first day of the month if only the day is missing. If both the day and month are 
missing, the first of January will be used.  
5.3 
Medical History 
Medical and surgical history will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). Investigator verbatim as well as preferred terms (PT) and system 
organ class (SOC) will be included in the listings. The medical history will be 
summarized by SOC and PT within SOC for the Safety Population, with SOC sorted 
alphabetically and PT within SOC by descending incidence. 
5.4 
Prior Treatment and Medication 
Prior medications will be coded using the World Health Organization Drug Dictionary.  
Prior medications are defined as medications taken prior to the first dose of study 
medication. Partial date imputation for medications is described in Section 11.5.2. 


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Prior medication use will be summarized by preferred name using the number and 
percentage of subjects for the Safety Population. Medications will be sorted by 
descending incidence 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, both prior and concomitant, will be presented. The listing will 
be sorted by subject identifier and will include preferred name, reported name, dose, 
route of administration, dosing frequency, start date, end date, indication, and type of 
medication (prior only, concomitant only, prior and concomitant). 
5.5 
Concomitant Treatment and Medication 
Concomitant medications will also be coded using the World Health Organization Drug 
Dictionary.  
Concomitant medications are defined as medications with onset dates on or after the first 
dose of study medication, medications with onset dates prior to first dose of study 
medication without a stop date, or medications with a stop date after first dose of study 
medication. Partial date imputation for medications is described in Section 11.5.2. 
Concomitant medications will be summarized in the same way as prior medications (refer 
to Section 5.4). 
Diagnostic, surgical, or therapeutic procedures during the study will be listed. 
5.6 
Exposure to Investigational Product 
The extent of exposure is defined as the number of days on treatment, including any 
periods of temporary dose interruption, calculated as: 
(date of last dose - date of first dose) + 1. 
The first dose date and last dose date will be based on the eCRF. The extent of exposure, 
the number of days that the dose was administered, will be summarized with the 
descriptive statistics defined in Section 11.1. The number and percentages of subject will 
be tabulated for extent of exposure categorized into weeks (<4, 4-<12, 12-<24, ≥24). 
Exposure summaries will be presented for the ITT, PP and Safety Populations. 


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5.7 
Measurements of Treatment Compliance  
Percent compliance will be calculated as 100 times the number of doses administered 
(either by the investigator or by the subject per instructions) divided by the number of 
days on treatment, excluding any periods of temporary dose interruptions due to adverse 
event that were deemed necessary by the investigator. Number of days on treatment is 
then calculated as (last dose date – first dose date +1) and the number of days of dose 
interruption due to adverse event will be excluded, i.e., the sum of (Date of study drug 
resumed – start date of interruption due to adverse event +1) as recorded on the Study 
Drug Interruption eCRF form. The information whether the study treatment was 
administered per instructions is captured on the study drug administration daily diary. 
Drug accountability information, first dose date, last dose date, and study medication 
interruptions (start date of interruption, date study medication resumed, and reason for 
interruption) will be included in the listings.  
Subjects will be considered compliant overall for study medication if the calculated 
compliance is ≥ 80%. Overall treatment compliance will be presented for both percent 
compliance calculations using the descriptive statistics defined in Section 11.1 and the 
number and percentage of subjects who are ≥ 80% compliant for both the ITT, PP and 
Safety Populations. Treatment compliance by visit will not be calculated. 
5.8 
Protocol Deviations 
Protocol deviations as obtained from a clinical trial management system (CTMS) will be 
assessed throughout the study. All identified deviations will be reported in the CTMS. 
Protocol deviations from the CTMS will be provided as part of the CTMS transfer to 
Biostatistics. Protocol deviations will be summarized for the ITT Population and all 
protocol deviations will be listed. 
6. 
EFFICACY ANALYSES 
All efficacy analyses will be based on the ITT Population and PP Population and be 
displayed in tables side by side for these two populations. The PP Population will be used 
for sensitivity analysis purpose. Unless stated otherwise, the baseline for all efficacy 
analyses will be as defined in Section 11.2. 
All efficacy analyses will be descriptive only and there will be no statistical testing. 


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6.1 
Analyses of Efficacy Endpoints 
The efficacy endpoints are the following: 
• Absolute and relative change from baseline in weekly PN/IV volume by visit and 
at EOT. 
• Percentage of subjects who achieve at least 20% reduction from baseline in 
weekly PN/IV volume at both Weeks 20 and 24. 
• Percentage of subjects who achieve at least a 20% reduction from baseline in 
weekly PN/IV volume at each visit 
• Change in days per week of PN/IV support from baseline by visit. 
• Change in plasma citrulline from baseline by visit. 
• Number of subjects who were able to completely wean off of PN/IV support. 
Analyses on weekly PN/IV support are based on two data sources: the subject diary data 
and the investigator prescribed data.  
The diary weekly PN/IV volume will be calculated based on the daily volumes recorded 
in subjects’ diaries within 14 days prior to each scheduled visit. The calculation will 
follow the formula below. 
Weekly volume = (sum of daily volumes in the diary/number of days with values) *7 
Missing daily PN/IV volumes will not be imputed. A maximum of 5 missing days (or at 
least 9 days of non-missing data) from the 14-day intervals are allowable, otherwise the 
interval will be classified as missing. One exception to this rule is the baseline interval, 
which will be filtered back up to 28 days prior to first dose until 9 data points are 
obtained. 
Investigator prescribed data is captured in the PN/IV baseline and PN/IV adjustment in 
eCRF. Investigator prescribed weekly PN/IV volume reported at each visit will be the 
most recent PN/IV prescription (from either baseline or prescription adjustments) prior to 
or on the date of visit. 
Data will be summarized at all scheduled visits during the 24-week treatment period. An 
EOT time point will also be added. Therefore, 


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• PN/IV weekly volume and days per week of PN/IV support will be summarized at 
Baseline, Weeks 2, 4, 8, 12, 16, 20, 24 and EOT. 
• Plasma citrulline will be summarized at Baseline, Weeks 4, 8, 16, 24 and EOT. 
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. 
Change in weekly PN/IV volume from baseline 
The absolute and percent change in weekly PN/IV volume from baseline to each 
scheduled visit during the 24-week treatment period, as well as at EOT, will be presented 
using the descriptive statistics defined in Section 11.1.  
Percent change in weekly PN/IV volume from baseline at each scheduled visit will be 
calculated using the formula below:  
% change in weekly PN/IV volume at the visit = [(weekly PN/IV volume at the visit – 
weekly PN/IV volume at baseline) / weekly PN/IV volume at baseline] * 100 
95% confidence intervals of the mean will be generated for Week 24 and EOT. 
Mean ± SE plots of absolute and percent change from baseline in weekly PN/IV volume 
will be generated. In addition, individual absolute and percent change from baseline in 
weekly PN/IV volume will be presented for each subject. 
Response to Teduglutide at both Weeks 20 and 24 
The number and percentage of subjects who demonstrate a response at Week 20 and 
again at Week 24 will be presented. A response is defined as the achievement of at least a 
20% reduction from baseline in weekly PN/IV volume. 
Binary response to Teduglutide by visit 
The number and percentage of subjects who demonstrate a response at each scheduled 
visit during the 24-week treatment period, as well as EOT, will be presented. A response 


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is defined as the achievement of at least a 20% reduction from baseline in weekly PN/IV 
volume. 
Change in days per week of PN/IV support from baseline 
The absolute and percent change in days per week of PN/IV support from baseline to 
each scheduled visit during the 24-week treatment period, as well as at EOT, will be 
presented based on diary and investigator prescribed data using descriptive statistics 
defined in Section 11.1. 
Changes in plasma citrulline from baseline 
The absolute and percent change in plasma citrulline from baseline to each scheduled 
visit during the 24-week treatment period, as well as at EOT, will be presented using 
descriptive statistics defined in Section 11.1. 
Number of subjects who are able to completely wean off PN/IV support 
A subject will be considered to have achieved independence from PN/IV (completely 
weaned off PN/IV) if the investigator prescribes no PN/IV at week 24/EOT and there is 
no use of PN/IV recorded in the subject diary during the 2 weeks prior to the last dosing 
visit. 
The number and percentage of subjects who completely wean off PN/IV support by 
Week 24/EOT will be presented.  There will be a listing of those who completely weaned 
off PN/IV.   
6.1.1 
Sensitivity Analyses of Efficacy Endpoint(s) 
The PP Population will be used for sensitivity analysis purpose. 
6.2 
Multiplicity Adjustment 
As there will be no statistical testing given the small sample size, no adjustment for 
multiple comparisons will be made. 
6.3 
Subgroup Analyses 
No subgroup analysis will be performed. 


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7. 
SAFETY ANALYSIS  
The safety analysis will be performed using the Safety Population. Safety variables 
include AEs, clinical laboratory variables, vital signs, ECG variables, physical 
examination, 48-hour urine output and antibodies to Teduglutide. For each safety 
variable, the last value collected before the first dose of the investigational product will 
be used as the baseline for all analyses of that safety variable. 
7.1 
Adverse Events  
AEs will be coded using MedDRA. Investigator verbatim as well as PT and SOC will be 
included in the listings.  
Treatment emergent AEs (TEAEs) are defined as AEs whose onset occurs, severity 
worsens, or intensity increases after receiving the study medication. AEs with an 
unknown date of onset and a stop date after the start of the study treatment or unknown 
stop date will be included as TEAEs. 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 11.5.3. AEs which are 
not treatment emergent will be flagged in listings. 
AEs will be summarized overall using descriptive statistics (e.g., number and percent of 
subjects). The number of events will also be presented. Categories summarized will 
include any TEAEs, severity of TEAEs, 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, and TEAEs leading to study treatment discontinuation. 
TEAEs 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 presented. Categories summarized are as follows: 
• TEAEs,  
• Severity of TEAEs,  
• Investigator assessment of relationship of TEAEs to study treatment,  
• TESAEs.  


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Presentation by SOC and PT will present SOC sorted alphabetically and PT within SOC 
by descending incidence. 
Listings will be provided for serious adverse events (SAEs), AEs leading to death, AEs 
leading to study treatment discontinuation and AEs leading to study discontinuation. 
Adverse events leading to study discontinuation are not captured in the AE eCRF page, 
however primary reason for study discontinuation due to AE is capture in the End of 
Study eCRF page with the relevant AE number. This data will be used to present the AE 
leading to study discontinuation. The listings will be sorted by subject identifier and will 
include SOC, PT, reported term, start date/time, end date/time, frequency, severity, 
relationship, action taken, and outcome. 
For AEs with partial dates, the imputed dates described in Section 11.5.3 will be used to 
determine the onset interval.  
7.1.1 
Adverse Events of Special Interest 
An AE of special interest is an AE (serious or nonserious) of scientific and medical 
concern specific to the sponsor’s product or program and for which ongoing monitoring 
and immediate notification by the investigator to the sponsor is required.  
The AEs of special interest that require expedited regulatory reporting for this study 
include the following: 
• Growth of preexisting polyps of the colon 
• Benign neoplasia of the GI tract including the hepatobiliary system 
• Tumor-promoting ability (e.g., benign and/or malignant neoplasia of any kind, not 
limited to those of the GI or hepatobiliary system) 
The preferred terms corresponding to each grouping of events of special interest will be 
identified by Takeda. A listing indicating the MedDRA terms corresponding to each 
grouping of events of special interest can be found in Appendix I . 
For each grouping of events of special interest, PT, 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. 
Listing for AE of special interest will also be provided.  


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7.2 
Clinical Laboratory Data 
Clinical laboratory tests are to be performed at site visits with results processed by a 
central laboratory. Laboratory tests include the following (Table 2): 


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Table 2 
List of Laboratory Tests 
Hematology: 
• Hematocrit  
• Hemoglobin  
• Platelet count 
• Red blood cell count  
• Red blood cell morphology, if 
needed 
• White blood cell count with 
differential 
 
Urinalysis:  
• 
Blood 
• 
Glucose 
• 
Leucocytes 
• 
Microscopic analysis 
• 
pH  
• 
Protein 
• 
Specific gravity 
• 
Urine Sodium 
 
Pregnancy tests (females of 
childbearing potential): 
• 
Urine β-HCG  
Biochemistry: 
• Albumin  
• Alkaline phosphatase  
• Alanine aminotransferase  
• Amylase 
• Aspartate aminotransferase  
• Bilirubin (total, direct and indirect) 
• Blood urea nitrogen  
• Calcium (total) 
• Chloride 
• Cholesterol 
• Citrulline (plasma) 
• C-reactive protein  
• Creatinine 
• Creatinine clearance 
• Gamma-glutamyl transferase  
• Glucose 
• Lipase 
• Magnesium 
• Phosphorus 
• Potassium  
• Sodium  
• Triglycerides 
• Uric acid 
 
Laboratory parameters will be presented in standard international (SI) units. The 
summaries will be based on central lab results only. 
Quantitative results will be summarized for hematology, serum chemistry, and urinalysis 
parameters at each scheduled visit during the 24-week treatment period (Baseline, Weeks 
2, 4, 8, 12, 16, 20 and 24) and at EOT. Both actual values and change from baseline will 
be summarized with descriptive statistics defined in Section 11.1.  
Clinical laboratory test values are markedly abnormal if they meet either the low or high 
markedly abnormal criterion listed in Table 3. These criteria are based on lab normal 
ranges and discussions with the experts. The number and percentage of subjects with 
post-baseline markedly abnormal values will be summarized by parameter. The 


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percentages will be calculated relative to the number of subjects with at least 1 post-
baseline assessment for the associated parameter. The numerator is the total number of 
subjects with at least 1 post-baseline markedly abnormal value. A supportive listing of 
subjects with post-baseline markedly abnormal values will be provided including the 
subject number, site, parameter, lab dates, baseline, and post-baseline values. This listing 
will present all values for a subject and laboratory parameter if at least one post-baseline 
value for that subject and parameter is identified as being markedly abnormal. 
Table 3: Markedly Abnormal Laboratory Criteria  
Lab parameter  
Unit  
Lower Limit  
Upper Limit  
Chemistry 
Albumin  
g/L  
<=20  
>=90  
Alkaline Phosphatase  
U/L  
NA  
>2*ULN  
ALT  
U/L  
NA  
>3*ULN  
Amylase  
U/L  
<=15  
>=350  
AST  
U/L  
NA  
>3*ULN  
Bilirubin (total)  
μmol/L  
NA  
>2*ULN  
BUN  
mmol/L  
NA  
>=10.7  
Calcium (total)  
mmol/L  
<=2.1  
>=3.0  
Chloride  
mmol/L  
<=80  
>=125  
Cholesterol (total)  
mmol/L  
NA  
>=12.9  
Creatinine  
μmol/L  
NA  
>=177  
C Reactive Protein  
mg/L  
NA  
>=21  
Glucose  
mmol/L  
<=1.7  
>=13.9  
Gamma glutamyl  
transferase  
U/L  
NA  
>100  
Lipase  
U/L  
NA  
>3*ULN  
Magnesium  
mmol/L  
<LLN  
>ULN  
Phosphate  
mmol/L  
NA  
>=2.0  
Potassium  
mmol/L  
<=2.5  
>=6.5  
Sodium  
mmol/L  
<=120  
>=165  
Triglycerides  
mmol/L  
NA  
>=5.6  
Uric acid  
μmol/L  
NA  
>=624 (males)  
>=505 (females)  
Hematology 
Hematocrit  
L/L  
<=0.37 (males)  
<=0.32 (females)  
>0.54 (males)  
NA (females)  
Hemoglobin  
g/L  
<=115 (males)  
<=95 (females)  
NA  
Platelets  
109/L  
<=75  
>=700  


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White Blood Cells  
109/L 
<=2.8 
>=16.0 
ULN = upper limit of normal 
ALT = Alanine Aminotransferase, Equivalent to SGPT 
AST = Aspartate Aminotransferase, Equivalent to SGOT 
BUN = Blood Urea Nitrogen 
 
Laboratory results will be presented in a listing for each lab panel (chemistry, 
hematology, and urinalysis) by subject, visit, and parameter. Laboratory values outside of 
the normal range will be flagged. Categorical urinalysis findings and urine pregnancy 
results will be presented in a listing only. 
7.3 
Vital Signs, Body Weight and BMI 
The descriptive statistics defined in Section 11.1 will be used to summarize the vital signs 
(i.e., systolic blood pressure, diastolic blood pressure (mmHg), pulse rate, body 
temperature, weight, and BMI) by scheduled visit during the 24-week treatment period 
(Baseline, Weeks 2, 4, 8, 12, 16, 20 and 24) and at EOT for the Safety Population. Both 
actual values and changes from baseline will be summarized. 
7.4 
Electrocardiogram 
The number and percentage of subjects with each type of ECG finding 
(Normal/Abnormal, Not Clinically Significant/Abnormal, Clinically Significant) will be 
presented at Baseline, Weeks 4 and 24, and EOT for the Safety Population. All ECG data 
will be listed.  
7.5 
Other Safety Data 
7.5.1 
Physical Examination 
Physical examination results will be presented in a listing only.  
7.5.2 
Antibodies to Teduglutide 
A summary table will provide the number of subjects with a sample analyzed for 
Baseline, Weeks 12, 24 and EOT. The summary table will also provide the number of 
subjects with an antibody finding at each of those visits in the Safety Population. 
All antibody data including neutralizing antibodies and antibody titers will be listed.   


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7.5.3 
48 Hour Oral Fluid Intake and Urine Output 
Oral/enteral intake and urine output measurements collected during 48 hours prior to each 
visit will be summarized by scheduled visit during the 24-week treatment period (Weeks 
2, 4, 8, 12, 16, 20 and 24) and at EOT. Oral/enteral intake and urine output measurements 
for Day 1 and Day2 will be captured in the eCRF. The average of Day 1 and Day 2 
measurement in mL will be summarized. 
Actual values and both absolute and percent change from baseline will be summarized in 
the Safety Population with descriptive statistics defined in Section 11.1. 
8. 
PHARMACOKINETIC ANALYSIS  
8.1 
Pharmacokinetic Parameters 
The PK parameters will be derived and estimated based on measured teduglutide plasma 
concentrations using Non-compartmental analysis (NCA) by a Takeda designated vendor 
in accordance with the PK SAP and generated separately. 
8.2 
Statistical Analysis of Pharmacokinetic Data 
The PK concentration data will be summarized on the PK Population for the protocol 
scheduled sampling time points: 
At Baseline: 
• 
0 hour (predose) draw: any time prior to the dose 
• 
15 minutes postdose ±5 minutes 
• 
30 minutes postdose ±5 minutes 
• 
1 hour postdose ±10 minutes 
• 
2 hours postdose ±10 minutes 
• 
3 hours postdose ±10 minutes 
• 
4 hours postdose ±30 minutes 
• 
6 hours postdose ±30 minutes 
• 
8 hours postdose ±30 minutes 


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• 
10 hours postdose ±30 minutes 
• 
12 hours postdose ±30 minutes 
At Week 4 or Week 12: 
• 
0 hour (predose) draw: any time prior to the daily dose, on the day of dosing, but at 
least 14 hours after the previous dose 
• 
1 hour postdose ±10 minutes 
• 
2 hours postdose ±10 minutes 
Descriptive statistics of PK concentration (number of subjects, mean, standard deviation, 
coefficient of variation (CV) %, geometric mean, geometric CV (%), median, minimum 
and maximum values) will be calculated at each time point. Mean (±SD) PK 
concentration by time curves will be provided for the PK population. PK concentration 
by time will also be plotted by individual subject. A listing for PK concentration data will 
also be provided. 
9. 
OTHER ANALYSES 
The information related to the study drug training provided by the study physician will be 
listed for all subjects in the Safety Population. 
10. 
INTERIM ANALYSIS/ DATA MONITORING (REVIEW) COMMITTEE  
Interim analyses may be conducted during the study, as needed. Analyses will be 
descriptive in nature. No formal comparisons are planned, and no hypotheses will be 
formally tested. Due to the open-label nature of this study, personnel involved in 
conducting the interim analyses will have access to treatment assignments. 
11. 
DATA HANDLING CONVENTIONS  
11.1 
General Data Reporting Conventions  
The small sample size resulting from the small study population requires the use of 
descriptive statistics with a goal of summarizing the sample and thus discourages the use 
of inferential statistics. 
Data from all healthcare setting study sites that participate in this protocol will be 
combined so that an adequate number of subjects will be available for analysis. 


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Descriptive statistics will be presented as follows: 
• 
Continuous variables, including those assessed on a discrete scale, will be 
summarized using the following descriptive statistics:  the number of subjects, mean, 
median, standard deviation, minimum, maximum and 95% confidence interval where 
needed.  The standard errors will be calculated in the tables if a corresponding figure 
is generated (e.g., efficacy tables). 
• 
Categorical variables will be summarized by the number and percentage of subjects 
in each category (with a category for missing data as needed). Unless otherwise 
stated, the denominator for percentages is N (the number of subjects in the analysis 
population). 
The following rules will be followed for decimal places and rounding: 
• 
Unless otherwise specified, means (arithmetic and geometric) and medians will be 
rounded and presented to 1 decimal place more than the raw data and standard 
deviations to 2 decimal places more than the raw data. Minimum and maximum 
values will be presented to the same number of decimal places as the raw data. 
• 
Unless otherwise specified, percentages should be presented to one decimal place. 
Less than signs (i.e., ‘<’) should be presented as appropriate (e.g., 0.04% should be 
presented as < 0.1%, not 0.0%). This rule also applies to %CV. 
• 
BMI, duration of SBS and years since start of PN dependency should be rounded to 1 
decimal place for reporting. 
Study day will be calculated as follows; 
• 
If the evaluation date is on or after the date of first day of study medication:  
Study day = date of evaluation – first day of study medication + 1 
• 
If the evaluation date is before the date of first day of study medication: 
 
 
Study day = date of evaluation – first day of study medication 
All output should have a 3-line header at the upper left margin: 


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Takeda 
SHP633-306 
Confidential 
All output should have a 1-line footer with the SAS program name, including the path, 
and the date and time the output was produced at the lower left margin of the footer. 
Tables and listings should be internally paginated in relation to the total length for that 
table or listing (i.e., Page n of N, where n is the page number within the table or listing 
and N is the total number of pages for that table or listing). 
The table, figure and listing numbering will be based on the International Conference on 
Harmonization (ICH) guidelines. 
A number should identify each table/listing, and the table designation (e.g., Table 14.x) 
should be centered above the title. A decimal system (e.g., x, x.y, x.y.z) should be used to 
identify tables/listings with related contents. The title should be centered and in mixed-
case characters. The title and table/listing designation should be single-spaced but are 
separated from the content of the table/listing by a space and a solid underline. The study 
population and/or subgroup (e.g., ITT Population) should be identified on the line 
immediately following the title. 
Column headings should be in title case characters. For numeric variables, the unit should 
be included in the column heading when appropriate. 
Footnotes should be single spaced but separated by an underline and a space from the text 
of the table/listing. The notes should be aligned vertically by the left vertical border of the 
table/listing. Numeric references, which can be confused with data, should not be used. 
Rather asterisks and other non-numeric symbols should be used to refer to footnotes. 
The dictionary (e.g., MedDRA, WHODD) and the dictionary version numbers should be 
identified in the footnotes to the tables/listings for data coded with a dictionary. 
For both tables and listings where there are no observations (and hence there would be no 
output), the table/listing should be produced with all titles and footnotes as per its shell, 
but with the text showing no observations in the body of the output. 


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Individual data listings will be sorted and presented by subject number and visit/event 
date. 
Dates will be presented in a DDMONYYYY format. Dates with partial missing data will 
be presented with a dash (i.e., ‘-’) for the missing data (e.g., --JAN2019). 
In general, analyses on PP population will be conducted if PP population is different from 
ITT population. 
For the following analyses, data for ITT, PP and Safety will be presented side by side in 
tables:  
• 
Demographic and other baseline characteristics 
• 
Short bowel syndrome history 
• 
Parenteral nutrition history 
• 
Crohn’s disease evaluation 
• 
Gastrointestinal specific testing  
• 
Exposure of investigational product 
• 
Treatment compliance 
11.2 
Definition of Baseline  
For summary purposes, the baseline value will be defined as the last available pre-dose 
value.  
11.3 
Definition of Visit Windows  
Although there is a visit window from 2 to 7 days around the expected visit date, nominal 
visits will be used for the per-visit analyses. Therefore, no windowing of visits by actual 
study day will be done for data obtained at the scheduled visits. For subjects who 
withdraw from the study pre-maturely, if the ET visit falls into the window of a 
scheduled visit as defined in the protocol, the ET visit is also summarized for that 
scheduled visit, unless the scheduled visit already took place. 


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11.4 
Derived Efficacy Endpoints  
An EOT time point, defined as the last determination of endpoint or last available 
measurement from the date of first dose, will be analyzed in addition to the scheduled 
visits. Unscheduled measurements will not be included in by-visit summaries but can 
contribute to the EOT value where applicable. 
11.5 
Handling of Missing, Unused, and Spurious Data  
No imputation for missing data (e.g., last observation carried forward) will be applied 
except for the partial dates to derive treatment emergent adverse events and flagging 
prior/concomitant medications. 
Imputation will be performed for partial dates of AEs and medications solely for the 
purpose of defining treatment emergence for AEs, determining whether an AE started in 
the treatment period and prior/concomitant status for medications. Details on how to 
handle partial dates for adverse events and prior/concomitant medications are described 
below.  
11.5.1 Missing Date of Investigational Product 
No imputation will be applicable to missing date of investigational product. 
11.5.2 Missing Date Information for Prior or Concomitant Medications 
For prior or concomitant medications, incomplete (i.e., partially missing) start date and/or 
stop date will be imputed. 
11.5.2.1 Incomplete Start Date  
The following derivations will be applied to impute the missing start dates. In each 
section, dates will be defined using the hierarchy of the derivations. Should any of the 
following 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. 
11.5.2.1.1 
Missing Day and Month 
1. If only year is known, and it is previous to the year of the informed consent, use June 
30th of that year. 
2. If only year is known, and it is the year of the first dose date, use the first dose date 


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3. If only year is known, and it is after the year of the first dose date, then use Jan 1st of 
that year. 
4. If only year is known, and it is the year of the informed consent, use the informed 
consent date. 
11.5.2.1.2 
Missing Month Only 
The day will be treated as missing and both month and day will be replaced according to 
the above procedures. 
11.5.2.1.3 
Missing Day Only 
1. If year and month are known, and it is the month and year of the first dose date, use 
the first dose date. 
2. If year and month are known, and it is the month and year of the informed consent, use 
the informed consent date. 
3. If year and month are known, and the month is not the month and year of the first dose 
or informed consent, use the first day of the month. 
For other incomplete dates, leave as missing. 
11.5.2.2 Incomplete Stop Date  
The following derivations will be applied to impute the missing stop dates. In each 
section, dates will be defined using the hierarchy of the derivations. Should any of the 
following stop dates created be before a start date (either a complete date or an imputed 
one,), use the (imputed) start date instead of the date that would otherwise be created.  
11.5.2.2.1 
Missing Day and Month 
1. If only year is known and study medication stopped during that year, use the stop date 
of study medication. 
2. If only year is known and study medication stopped after that year, use December 31st 
of that year. 
3. If only year is known and study medication stopped prior to that year, use the first day 
of the year. 


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11.5.2.2.2 
Missing Month Only 
The day will be treated as missing and both month and day will be replaced according to 
the above procedures.  
11.5.2.2.3 
Missing Day Only 
1. If year and month are known and study medication stopped during that month and year, 
use the stop date of study medication. 
2. If year and month are known and informed consent was provided during that month 
and year, use the date of informed consent. 
3. If only year and month are known and study medication stopped after that year and 
month, use the last day of the month. 
4. If only year and month are known and study medication stopped prior to that year and 
month, use the first day of the month. 
For other incomplete dates, leave as missing. 
11.5.3 Missing Date Information for Adverse Events  
If any AE records contain only partial dates, these will be handled by imputation, as 
described in the subsections below.  
11.5.3.1 Incomplete Start Date  
The following derivations will be applied to impute the missing dates. In each section, 
dates will be defined using the hierarchy of the derivations. Should any of the following 
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. 
11.5.3.1.1 
Missing Day and Month 
1. If only year is known, and it is previous to the year of the informed consent, use June 
30th of that year. 
2. If only year is known, and it is the year of the first dose date, use the first dose date 
3. If only year is known, and it is after the year of the first dose date, then use Jan 1st of 
that year. 


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4. If only year is known, and it is the year of the informed consent, use the informed 
consent date. 
11.5.3.1.2 
Missing Month Only 
The day will be treated as missing and both month and day will be replaced according to 
the above procedures. 
11.5.3.1.3 
Missing Day Only 
1. If year and month are known, and it is the month and year of the first dose date, use 
the first dose date. 
2. If year and month are known, and it is the month and year of the informed consent, use 
the informed consent date. 
3. If year and month are known, and the month is not the month and year of the first dose 
or informed consent, use the first day of the month. 
Otherwise, if a start date is unknown, leave as missing. 
11.5.3.2 Incomplete Stop Date  
No imputation is applied to incomplete stop date. 
11.5.4 Missing Severity Assessment for Adverse Events  
If severity is missing for an AE starting prior to the date of the first dose of 
investigational product, then a severity of “Mild” will be assigned. If the severity is 
missing for an AE starting on or after the date of the first dose of investigational product, 
then a severity of “Severe” will be assigned. The imputed values for severity assessment 
will be used for incidence summaries only and will not be reported in the data listings. 
11.5.5 Missing Relationship to Investigational Product for Adverse Events  
If the relationship to investigational product is missing for an AE starting on or after the 
date of the first dose of investigational product, a causality of “Related” will be assigned.  
The imputed values for relationship to the investigational product will be used for 
incidence summaries only and will not be reported in the data listings. 


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11.5.6 Character Values of Clinical Laboratory Variables 
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.  
12. 
ANALYSIS SOFTWARE  
Statistical analyses will be performed using Version 9.4 (or newer) of SAS (SAS 
Institute, Cary, NC, US) on a suitably qualified environment. 
13. 
CHANGES TO ANALYSIS SPECIFIED IN PROTOCOL 
There is no change of analysis from protocol. 


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14. 
REFERENCES 
No references used in this SAP. 


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15. 
APPENDICES  
Appendix I – MedDRA Terms Corresponding to Each Grouping of Adverse Event 
of Special Interest 
Groupings 
System Organ 
Class (SOC) 
Preferred Terms (PT) 
Higher Level Group 
Terms (HLGTs) 
Tumor promoting 
ability 
Neoplasms benign, 
malignant and 
unspecified 
  
 
Growth preexisting 
polyps 
  
Duodenal polyp 
 
  
  
Intestinal polyp 
 
  
  
Rectal Polyp 
 
  
  
Large intestine polyp 
 
  
  
Gastrointestinal polyp 
 
Benign neoplasia 
GI 
  
 
Gastrointestinal 
neoplasms benign 
 
 
 
Hepatic and biliary 
neoplasms benign 
 
 
Abdominal wall cyst 
 
  
  
Abdominal wall neoplasm 
benign 
 
 
 
Benign abdominal 
neoplasm 
 
 
 
Benign gastrointestinal 
neoplasm 
 
 
 
Benign mesenteric 
neoplasm 
 
 
 
Benign pancreatic 
neoplasm 
 
 
 
Benign peritoneal 
neoplasm 
 
 
 
Benign small intestinal 
neoplasm 
 
 
 
Gastric haemangioma 
 
 
 
Gastrointestinal polyp 
 
 
 
Gastrointestinal polyp 
haemorrhage 
 


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Groupings 
System Organ 
Class (SOC) 
Preferred Terms (PT) 
Higher Level Group 
Terms (HLGTs) 
 
 
Gastrointestinal tract 
adenoma 
 
 
 
Gingival cyst 
 
 
 
Intestinal angioma 
 
 
 
Intestinal cyst 
 
 
 
Intestinal polyp 
 
 
 
Intra-abdominal 
haemangioma 
 
 
 
Intraductal papillary 
mucinous neoplasm 
 
 
 
Large intestine benign 
neoplasm 
 
 
 
Mesenteric cyst 
 
 
 
Pancreatic cyst 
 
 
 
Pancreatic cyst rupture 
 
 
 
Peutz-Jeghers syndrome 
 
 
 
Retroperitoneum cyst 
 
 
 
Small intestine polyp 
 
 
 
Stoma site polyp 
 
 
 
Adenolymphoma 
 
 
 
Ameloblastoma 
 
 
 
Benign salivary gland 
neoplasm 
 
 
 
Buccal polyp 
 
 
 
Cementoblastoma 
 
 
 
Dental cyst 
 
 
 
Gingival polyp 
 
 
 
Lip neoplasm benign 
 
 
 
Mouth cyst 
 
 
 
Odontogenic cyst 
 
 
 
Oral fibroma 
 
 
 
Oral haemangioma 
 
 
 
Oral neoplasm benign 
 
 
 
Oral papilloma 
 
 
 
Papillary cystadenoma 
lymphomatosum 
 


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Groupings 
System Organ 
Class (SOC) 
Preferred Terms (PT) 
Higher Level Group 
Terms (HLGTs) 
 
 
Pleomorphic adenoma 
 
 
 
Salivary gland adenoma 
 
 
 
Salivary gland cyst 
 
 
 
Tongue cyst 
 
 
 
Tongue neoplasm benign 
 
 
 
Tongue polyp 
 
 
 
White sponge naevus 
 
 
 
Anal polyp 
 
 
 
Appendix adenoma 
 
 
 
Benign anorectal neoplasm  
 
 
Colon adenoma 
 
 
 
Large intestine fibroma 
 
 
 
Large intestine polyp 
 
 
 
Rectal adenoma 
 
 
 
Rectal polyp 
 
 
 
Benign duodenal neoplasm  
 
 
Benign gastric neoplasm 
 
 
 
Benign oesophageal 
neoplasm 
 
 
 
Duodenal polyp 
 
 
 
Gastric adenoma 
 
 
 
Gastric cyst 
 
 
 
Gastric leiomyoma 
 
 
 
Gastric polyps 
 
 
 
Oesophageal cyst 
 
 
 
Oesophageal papilloma 
 
 
 
Oesophageal polyp 
 
 
 
Biliary cyst 
 
 
 
Biliary polyp 
 
 
 
Choledochal cyst 
 
 
 
Congenital cystic disease 
of liver 
 
 
 
Gallbladder polyp 
 
 
 
Haemorrhagic hepatic cyst 
 
 
 
Hepatic cyst 
 


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Groupings 
System Organ 
Class (SOC) 
Preferred Terms (PT) 
Higher Level Group 
Terms (HLGTs) 
 
 
Hepatic cyst infection 
 
 
 
Hepatic cyst ruptured 
 
 
 
Hepatobiliary cyst 
 
 
 
Benign biliary neoplasm 
 
 
 
Benign hepatic neoplasm 
 
 
 
Benign hepatobiliary 
neoplasm 
 
 
 
Benign neoplasm of 
ampulla of Vater 
 
 
 
Biliary adenoma 
 
 
 
Biliary hamartoma 
 
 
 
Cholangioadenoma 
 
 
 
Focal nodular hyperplasia 
 
 
 
Gallbladder adenoma 
 
 
 
Gallbladder papilloma 
 
 
 
Haemangioma of liver 
 
 
 
Hepatic adenoma 
 
 
 
Hepatic haemangioma 
rupture 
 
 
 
Hepatic hamartoma 
 
Note: MedDRA terms are based on MedDRA version 21.0. 
 


PK Analysis Plan 
Japanese Subjects with SBS 
Takeda 
Teduglutide 
 
CSC Confidential 
1 
13-Sep-2019 
   
 
TITLE PAGE 
PK ANALYSIS PLAN 
 
A 24-Week Safety, Efficacy, Pharmacokinetic Study of Teduglutide in Japanese 
Subjects with Short Bowel Syndrome who are Dependent on Parenteral Support 
 
 
Sponsor Protocol No.: SHP633-306 (Amendment 1: 27-Sep-2018) 
Investigational Product: SHP633 (Teduglutide) 
 
Final 
Date: 13-Sep-2019 
 
CSC Reference No.: SHIR-PSC-129 
 
 
 
Takeda Pharmaceutical Company Limited 
Shire is now part of Takeda 
650 East Kendall Street, Cambridge, MA 02142, USA 
 
 
 
 
 
CONFIDENTIALITY STATEMENT 
Information contained in this document is proprietary to Takeda Pharmaceutical Company 
Limited. The information is provided to you in confidence to enable you to perform the work, 
which is requested under an agreed upon and signed confidentiality statement. Do not give this 
document or any copy of it or reveal any proprietary information contained in it to any third 
party (other than those in your organization who are assisting you in this work and are bound by 
the confidentiality statement) without the prior written permission of an authorized 
representative of Takeda Pharmaceutical Company Limited. 
 
 


PK . 
, j, 1'1:111 
lh•,ie\\ and -\ppnnal 
 PhD. DAB I 
Ccn;ira S1rati:gic CL)tbu ltin;; 
PhD. f-CP 
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& D<..'\ clPplll<..'lll 
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PK Analysis Plan 
Japanese Subjects with SBS 
Takeda 
Teduglutide 
 
CSC Confidential 
Page 3 
13-Sep-2019 
1 
TABLE OF CONTENTS 
TITLE PAGE .................................................................................................................................1 
1 
TABLE OF CONTENTS .......................................................................................................3 
2 
LIST OF ABBREVIATIONS ................................................................................................4 
3 
BACKGROUND .....................................................................................................................5 
4 
ANALYSIS PLAN OBJECTIVES ........................................................................................5 
5 
STUDY DESIGN ....................................................................................................................5 
6 
ANALYSIS SET......................................................................................................................7 
7 
METHODS ..............................................................................................................................7 
7.1 Data Transfer .......................................................................................................................7 
7.2 Noncompartmental PK Analysis..........................................................................................8 
7.2.1 Concentration Data ........................................................................................................8 
7.2.2 Pharmacokinetic Parameters of Teduglutide .................................................................8 
7.3 Statistical Methods ...............................................................................................................9 
7.3.1 Concentrations of Teduglutide .......................................................................................9 
7.3.2 PK Parameters of Teduglutide .......................................................................................9 
7.4 Data Handling ....................................................................................................................10 
7.4.1 Handling of Missing Plasma Concentrations ...............................................................10 
7.4.2 Handling of Incomplete and/or Non-Compliant Data .................................................10 
7.4.3 Unexpected Data ..........................................................................................................10 
7.5 Software .............................................................................................................................11 
7.6 Quality Control and Quality Assurance .............................................................................11 
8 
ARCHIVING.........................................................................................................................11 
9 
REFERENCES .....................................................................................................................12 
10 APPENDIX 1: LIST OF TABLES, FIGURES AND LISTINGS.....................................13 
11 APPENDIX 2: TABLE AND FIGURE SHELLS ..............................................................15 
 
 
 


PK Analysis Plan 
Japanese Subjects with SBS 
Takeda 
Teduglutide 
 
CSC Confidential 
Page 4 
13-Sep-2019 
2 
LIST OF ABBREVIATIONS 
Term 
Definition 
AUC0-t 
Area under the plasma concentration-time curve from time zero to the last measurable 
concentrations, calculated using the linear trapezoid rule. 
AUC0-inf 
Area under the plasma concentration time curve from time zero to infinity 
BLQ 
Below limit of quantification 
CL/F 
Apparent clearance 
Cmax 
Maximum plasma concentration 
CSC 
Certara Strategic Consulting 
CV% 
Coefficient of variation 
eCRF 
Electronic case report form 
EDT 
Electronic Data Transmission 
GLP-2 
Glucagon-like peptide-2 
LLOQ 
Lower limit of quantitation 
λz 
Lambda z, first-order rate constant of the terminal elimination phase 
Max 
Maximum 
Mean 
Arithmetic mean 
Min 
Minimum 
N 
Sample size 
NCA 
Non-compartmental analysis 
PK 
Pharmacokinetics(s) 
PN/IV 
Parenteral nutrition or intravenous 
QD 
Once daily 
SBS 
Short bowel syndrome 
SC 
Subcutaneous 
SD 
Standard deviation 
sFTP 
Secure File Transfer Protocol 
SOP 
Standard operating procedures 
t1/2 
Terminal elimination half-life 
Tlast 
Time of time of the last quantifiable concentration 
Tmax 
Time of maximum observed plasma concentration 
Vz/F 
Apparent volume of distribution 
 
 


PK Analysis Plan 
Japanese Subjects with SBS 
Takeda 
Teduglutide 
 
CSC Confidential 
Page 5 
13-Sep-2019 
3 
BACKGROUND 
This pharmacokinetic (PK) Analysis Plan was created using the study protocol SHP633-306 
(Amendment 1, dated 27 Sep 2018). Any further changes to the protocol may require updates to 
the current analysis plan. 
Teduglutide is a novel, recombinant analog of naturally occurring human glucagon-like peptide-2 
(GLP-2) that regulates the functional and structural integrity of the cells lining the gastrointestinal 
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 has been shown in animal studies and previous human 
clinical trials to increase villus height and crypt depth in the intestinal epithelium, thereby 
increasing the absorptive surface area of the intestines. 
This analysis plan addresses the PK of teduglutide (0.05 mg/kg) following subcutaneous (SC) 
administration in Japanese subjects with short bowel syndrome (SBS) who are dependent on 
parenteral nutrition or intravenous (PN/IV) support. The intended methods of data analysis and 
reporting are included in the current analysis plan. This document provides guidance to the extent, 
scope, and method of analysis. However, due to uncertainty of the nature of the data a priori, 
deviations from this plan may be necessary and will be documented. 
4 
ANALYSIS PLAN OBJECTIVES 
The specific objective of this project is to summarize the PK of teduglutide after a SC 
administration of teduglutide 0.05 mg/kg in adult Japanese subjects with SBS who are dependent 
on PN/IV support. PK parameters will be derived using non-compartmental analysis (NCA). 
5 
STUDY DESIGN 
Protocol SHP633-306 was an open-label, multicenter study, consisting of a conditional PN/IV 
optimization period, a mandatory PN/IV stabilization period, and a 24-week treatment period.  
Japanese male or female subjects 16 years of age or older (at the time of signing informed consent) 
were considered eligible for the study. If at screening, a subject did not have an optimized PN/IV 
volume, defined as a 48-hour urine output between 2 and 4 L, he/she entered the optimization 
period, during which the minimally tolerated stable PN/IV volume was determined during a period 
of up to 8 weeks. If it was not possible to keep the subject adequately hydrated and nourished 
within the target urine output range, the minimally tolerated PN/IV volume was documented. 
All subjects entered the stabilization period, during which the target PN/IV volume was maintained 
for at least 4 consecutive weeks (8 weeks maximum). Following the stabilization period, subjects 
entered a 24-week dosing period, during which all subjects received teduglutide 0.05 mg/kg SC 
once daily. At each site visit during the treatment phase, efficacy (adjustments to PN/IV) and safety 
was monitored.   


PK Analysis Plan 
Japanese Subjects with SBS 
Takeda 
Teduglutide 
 
CSC Confidential 
Page 6 
13-Sep-2019 
A schematic representation of the study design is presented in Figure 1. 
Figure 1.  
Study Design (SHP633-302) 
 
SC=subcutaneous; qday=once daily; EOT=end of treatment 
Teduglutide (0.05 mg/kg) was administered SC once daily into 1 of the 4 quadrants of the abdomen 
or either thigh or arm for 24 weeks.  Subjects had blood samples taken for teduglutide PK analysis 
at predose, at 15, 30 minutes and 1, 2, 3, 4, 6, 8, 10, and 12 hours post dose at Visit 2. Subjects 
also had blood samples taken for teduglutide PK analysis at predose and 1 and 2 hours post dose 
at Visit 5 (Week 4) or Visit 7 (Week 12) of the treatment period. The first dose of teduglutide was 
administered by the study physician at the baseline visit (Visit 2). At this visit, subjects had blood 
samples taken for teduglutide PK analysis: 
• 0-hour (predose) draw: any time prior to the dose 
• 15 minutes postdose: ±5 minutes 
• 30 minutes postdose: ±5 minutes 
• 1 hour postdose: ±10 minutes 
• 2 hours postdose: ±10 minutes 
• 3 hours postdose: ±10 minutes 
• 4 hours postdose: ±30 minutes 
• 6 hours postdose: ±30 minutes 
• 8 hours postdose: ±30 minutes 
• 10 hours postdose: ±30 minutes 
• 12 hours postdose: ±30 minutes 
Subjects also had blood samples taken for teduglutide PK analysis at Week 4 (Visit 5) or Week 12 
(Visit 7): 
• 0-hour (predose) draw: any time prior to the daily dose, on the day of dosing, but at least 
14 hours after the previous dose 
• 1 hour postdose: ±10 minutes 
• 2 hours postdose: ±10 minutes 
All subjects who completed the study may have participated in a long-term extension study 
(SHP633-307) in which they continued receiving teduglutide.  
Screening
Up to 7 days
Optimization
0-8 weeks
Stabilization
4-8 weeks
Teduglutide treatment 0.05 mg/kg SC qday
24 weeks
V1.0V1.1 V1.2 V1.3 V1.4
V1.5
V2
(Baseline)
V3 V4 V5
V6
V7
V8
V9
V10
(EOT)
Safety follow-up
phone call
4 weeks after EOT
Extension
study
Up to 4 visits as needed
Performed if urine output 
is not in the target range
at screening


PK Analysis Plan 
Japanese Subjects with SBS 
Takeda 
Teduglutide 
CSC Confidential 
Page 7 
13-Sep-2019 
6 
ANALYSIS SET 
The PK population will consist of all enrolled subjects who received at least one SC injection of 
teduglutide and have evaluable and interpretable PK profile. 
7 
METHODS 
7.1 
Data Transfer 
Electronic files from Takeda will be transferred to Certara Strategic Consulting (CSC) via a Secure 
File Transfer Protocol (sFTP) site. The Electronic Data Transmission (EDT) contact at Takeda is: 
, MPH, PhD  
 
 
 Research & Development 
Takeda Pharmaceutical Company Limited 
Shire is now part of Takeda 
650 East Kendall Street, Cambridge, MA 02142, USA 
Tel: 
 
Mobile: 
 
 
The following CSC designates are the EDT contacts: 
, PhD, DABT 
  
Certara Strategic Consulting  
Montreal, Quebec, Canada H3A 2W5 
Tel: 
 
Email: 
 
, PhD, FCP 
 
Certara Strategic Consulting 
Montreal, Quebec, Canada H3A 2W5 
Tel. 
 
Email: 
 
Data will be provided as .csv, sas7dat or SAS transport files by Takeda. A dataset including the 
subject ID, time of blood sample collection and of treatment (Visit, Date, and Hour), Dose, 
Treatment, and plasma concentrations of teduglutide. 


PK Analysis Plan 
Japanese Subjects with SBS 
Takeda 
Teduglutide 
CSC Confidential 
Page 8 
13-Sep-2019 
7.2 
Noncompartmental PK Analysis 
7.2.1 Concentration Data 
Observed concentration values of plasma teduglutide that are reported as below the limit of 
quantitation (BLQ) will be set to zero for PK analysis and summary statistics. 
7.2.2 Pharmacokinetic Parameters of Teduglutide 
All plasma PK parameters will be derived using actual or nominal times (when actual time is not 
available) relative to the time of study drug administration. PK parameters will be derived using 
NCA methods1 based on individual plasma concentration-time data for teduglutide collected at 
baseline (day 0) (or at any other future site visit if subject was unable to provide blood samples at 
day 0) as described in Table 1. 
Table 1. 
PK Parameters Teduglutide in Plasma 
Parameters 
Definitions 
AUC0-t 
Area under the plasma concentration-time curve from time zero to the last measurable 
concentrations, calculated using the linear trapezoid rule. 
AUC0-inf 
Area under the plasma concentration time curve from time zero to infinity, calculated using 
the formula AUC0-t + (Clast / λZ), where Clast is the last quantifiable concentration. The AUC0-inf 
will be calculated using the linear trapezoid rule.  If the percent of extrapolation (% AUCExtrap) 
is > 20%, the value of AUC0-inf (and other derived parameters such as CL/F and VZ/F) will be 
reported but not taken into account in the calculation of descriptive statistics. 
λZ 
First-order rate constant of the terminal elimination phase, calculated by log-linear regression 
analysis over the terminal log-linear segment of the plasma concentration-time curve. 
Assessments of λZ included the key considerations listed below this table. 
t1/2 
Terminal elimination half-life, calculated as ln(2)/ λz. Assessments of t1/2 followed the key 
considerations for λZ, as listed below this table. 
% AUCExtrap 
The percentage of AUC0-inf estimated by extrapolation from Tlast to infinity, calculated as 
(AUC0-inf − AUC0-t)/ AUC0-inf x 100.  
CL/F 
Apparent clearance, calculated as Dose / AUC0-inf. 
VZ/F 
Apparent volume of distribution, calculated as Dose / AUC0-inf x λz. 
The assessments of λz will include the following considerations: 
•
At least 3 time points (in which the first time point must be greater than tmax) with
measurable serum concentrations were required for the calculation of λZ.
•
λz must be positive, and calculated from at least three data points in the terminal phase of
the concentration-time profile.
•
Points prior to Cmax are not used.
•
R2 adj ≥ 0.7 for the log-linear regression analysis of λz.
No value for λZ and related parameters (eg, AUC0-inf, t1/2, CL/F and/or VZ/F) will be reported for 
concentration-time profiles that do not exhibit an elimination phase in the concentration versus 
time profile (ie, if R2adj < 0.7 for the log-linear regression analysis of λZ). 


PK Analysis Plan 
Japanese Subjects with SBS 
Takeda 
Teduglutide 
 
CSC Confidential 
Page 9 
13-Sep-2019 
7.3 
Statistical Methods 
7.3.1 Concentrations of Teduglutide 
Individual teduglutide concentrations will be listed and summarized in accordance with the 
grouping factors (ie, by treatment and for single dose and multiple doses, if applicable). Each data 
subset will be listed by subject and summarized for each nominal time point. If the actual time of 
blood collection post dose deviates by >20% from the nominal time, those sample concentrations 
will be reported and included in the PK analysis but excluded from summary statistics of 
concentration tables and mean figures. 
Concentration data will be summarized at each nominal time point with the following descriptive 
statistics: sample size (n), arithmetic mean (Mean), standard deviation (SD), coefficient of 
variation (CV%), median (Median), minimum (Min), maximum (Max). 
Individual concentrations of teduglutide will be reported at the level of significance presented in 
the observed data files. Reporting rules for the concentrations and summary statistics, will be as 
follows: 
• Mean: 1 more level of significance than the individual value 
• SD: 1 more level of significance than the mean 
• CV%: always 1 decimal  
• Median, Min, Max: at the level of significance reported for the individual value. 
Mean concentrations will be reported as zero if all values are zero, and no descriptive statistics 
will be reported. If the calculated mean concentration is less than the lower limit of quantitation 
(LLOQ = 1 ng/mL), the value will be reported as calculated. A minimum of three values will be 
required for calculation of descriptive statistics. 
Mean (+SD) teduglutide concentrations vs. nominal sampling time will be presented on linear-
linear and log-linear scales by treatment for single dose (day 0) and multiple doses (ie, unscheduled 
visit, if applicable). 
7.3.2 PK Parameters of Teduglutide 
Individual plasma teduglutide PK parameters will be listed and summarized in accordance with 
the grouping factors (ie, by treatment and for single dose and multiple doses, if applicable) with 
the following descriptive statistics: n, Mean, SD, CV%, Median, Min, Max, Geometric Mean and 
CV% Geometric Mean. 
Reporting rules for the PK (with the exception of Cmax) and summary statistics will be as follows: 
• Individual values with the number of decimals that will allow 3 significant figures to be 
presented for the minimum value of the parameter, except for tmax which are parameters of 
time to be reported with 2 decimals. 
• Mean and Geometric Mean: 1 more decimal than the individual value 


PK Analysis Plan 
Japanese Subjects with SBS 
Takeda 
Teduglutide 
 
CSC Confidential 
Page 10 
13-Sep-2019 
• SD: 1 more decimal than the mean 
• CV% and CV% Geometric Mean: always 1 decimal 
• Median, Min, Max: same number of decimals as the individual value 
Individual and summary statistics for the PK parameter Cmax will follow the reporting rules 
described for teduglutide concentrations (Section 7.3.1). 
Mean concentrations will be reported as zero if all values are zero, and no descriptive statistics 
will be reported. A minimum of three values will be required for calculation of descriptive 
statistics. 
7.4 
Data Handling 
7.4.1 Handling of Missing Plasma Concentrations 
PK parameters will be calculated for subjects with sufficient plasma sample data to assess PK 
parameters, ie with at least 2 postdose concentrations. Concentrations for subjects with missing 
samples will not be excluded from the concentration summary statistics. 
For the PK parameter calculations following a single dose (Day 0), a missing predose value will 
be set to zero. For the PK parameter calculations following multiple doses (ie, any other future site 
visit after day 0), a missing predose value will be set to the median value observed in the treatment 
group, if available. 
Unless otherwise noted, data summaries will be performed only on observed data. 
7.4.2 Handling of Incomplete and/or Non-Compliant Data 
Subjects with incomplete dosing information or plasma concentration-time profiles will be 
reviewed by CSC and Takeda for inclusion/exclusion into the PK Population. Missing dose or 
sampling dates and/or times may be imputed using nominal times. The imputation strategy will be 
discussed with Takeda. All samples associated to a missing dosing date and/or time that cannot be 
imputed will be excluded from the analysis. 
7.4.3 Unexpected Data 
After database lock, a visual inspection of concentration-time profiles will be performed to 
determine dataset integrity and potential outliers. Subjects with potential outlier data will be 
reviewed by CSC and Takeda for inclusion/exclusion from the descriptive statistics on a case-by-
case basis.  
Any plasma concentrations that cannot be uniquely and unequivocally attributed to a particular 
subject, visit, or time point based on eCRF records or other observed data records in the study will 
be treated as incomplete data. Such data will be compiled, commented, and listed separately in the 
appendix of the report. Incomplete and/or non-compliant data, if any, will be excluded from 
analysis datasets; no analyses, summaries or graphs will be produced using these data. 
Multiple observations at the same time point will be averaged for the calculation of PK parameters.  


PK Analysis Plan 
Japanese Subjects with SBS 
Takeda 
Teduglutide 
 
CSC Confidential 
Page 11 
13-Sep-2019 
7.5 
Software 
Dataset set construction, tables and figures will be generated using Phoenix NLME (Version 7.2 
or higher), PhoenixTM WinNonlin® (6.3 or later), R® (Version 3.3.1 or higher) or SAS.  
7.6 
Quality Control and Quality Assurance 
Data sets, table and figures will be quality-controlled by two scientists at CSC (i.e., by the 
originator of the work and by a reviewer) as per CSC SOP
 entitled, “Managing Data in CSC” 
and CSC SOP
 entitled, “Analysis Workflow in CSC”.  
8 
ARCHIVING 
The project documentation (documents, report, records, and data) will be retained in hardcopy for 
a period of 3 years following project completion at CSC (Montreal, Quebec, Canada). During these 
retention periods, electronic versions of project documentation will be retained on CSC servers, 
with access limited to personnel assigned to the project. After completion of the retention period, 
sponsor approval will be requested and documented before destruction of documents. 


PK Analysis Plan 
Japanese Subjects with SBS 
Takeda 
Teduglutide 
 
CSC Confidential 
Page 12 
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9 
REFERENCES 
1. 
Gabrielsson, J., Weiner, D. (2016). Pharmacokinetic & Pharmacodynamic Data Analysis: 
Concepts and Applications (5th Edition). Swedish Pharmaceutical Society, Stockholm, 
Sweden. 
 
 


PK Analysis Plan 
Japanese Subjects with SBS 
Takeda 
Teduglutide 
 
CSC Confidential 
Page 13 
13-Sep-2019 
10 APPENDIX 1: LIST OF TABLES, FIGURES AND LISTINGS 
14. 
PHARMACOKINETIC TABLES AND FIGURES 
14.1. Plasma Teduglutide Mean Concentration-Time Profiles 
Figure 14.1.1. Mean (+SD) Plasma Teduglutide Concentrations vs. Time after a Single SC 
Administration of Teduglutide by Treatment – Day 0 (Linear and Semi-Log) 
Figure 14.1.2. Mean (+SD) Plasma Teduglutide Concentrations vs. Time after Multiple SC 
Administration of Teduglutide QD by Treatment – Unscheduled Visit (if 
applicable) (Linear and Semi-Log)  
 
14.2. Plasma Teduglutide Concentration-Time Tables 
Table 14.2.1. Plasma Teduglutide Concentrations vs. Time after a Single SC Administration of 
Teduglutide 0.05 mg/kg – Day 0 
Table 14.2.2. Plasma Teduglutide Concentrations vs. Time after Multiple SC Administration of 
Teduglutide 0.05 mg/kg/day – Unscheduled Visit (if applicable) 
 
14.3. Plasma Teduglutide Pharmacokinetic Parameter Tables 
Table 14.3.1. Plasma Teduglutide PK Parameters after a Single SC Administration of 
Teduglutide 0.05 mg/kg – Day 0 
Table 14.3.2. Plasma Teduglutide PK Parameters after Multiple SC Administration of 
Teduglutide 0.05 mg/kg/day – Unscheduled Visit (if applicable) 
 
 
 


PK Analysis Plan 
Japanese Subjects with SBS 
Takeda 
Teduglutide 
 
CSC Confidential 
Page 14 
13-Sep-2019 
16. 
INDIVIDUAL DATA 
16.1. Individual Concentration-Time Plots 
Figure 16.1.1. Individual Plasma Teduglutide Concentrations vs. Time after Administration of 
Teduglutide (Linear and Semi-Log) 
APPENDIX 
Appendix 1 
Listing of Plasma Teduglutide Concentrations vs. Time after SC Administration 
of Teduglutide - Unscheduled Visit (if applicable) 
  
 


PK Analysis Plan 
Japanese Subjects with SBS 
Takeda 
Teduglutide 
 
CSC Confidential 
Page 15 
13-Sep-2019 
11 APPENDIX 2: TABLE AND FIGURE SHELLS 
Concentration-Time Profiles 
Figure 14.1.1 Mean (+SD) Plasma Teduglutide Concentrations vs. Time after a Single SC 
Administration of Teduglutide by Treatment – Day 0 (Linear and Semi-Log) 
 
  
 
Semi-Log Plot 
 
 
 
Note:  These are for presentation purpose, axis titles and range will be set accordingly (i.e. to 4 h). BLQ reference 
line may not be presented. Similar figures will be created for multiple dose administration, if applicable. 
 
 
Nominal Time (h) 
Nominal Time (h) 
Mean (SD) Plasma Teduglutide (unit) 
Mean (SD) Plasma Teduglutide (unit) 


PK Analysis Plan 
Japanese Subjects with SBS 
Takeda 
Teduglutide 
 
CSC Confidential 
Page 16 
13-Sep-2019 
Individual and Summary Concentration-Time Tables 
Table 14.2.1 Plasma Teduglutide Concentrations vs. Time after a Single SC 
Administration of Teduglutide 0.05 mg/kg – Day 0 
Subject ID 
Plasma Teduglutide Concentrations (Unit) over Nominal Time (h) 
0.0 
1.0 
2.0 
4.0 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
11 
 
 
 
 
… 
 
 
 
 
N 
 
 
 
 
Mean 
 
 
 
 
SD 
 
 
 
 
Min 
 
 
 
 
Median 
 
 
 
 
Max 
 
 
 
 
CV% 
 
 
 
 
. = No data 
NC = Not calculated 
<0.00 = Below limit of quantification. Set to zero for calculation of summary statistics 
/t = Blood draw time deviation >20% of nominal time relative to the start of infusion, excluded from summary statistics 
 
Note: Similar tables will be used for Teduglutide 0.05 mg/kg at day 0 and for both treatments following multiple 
doses (unscheduled visit), if applicable. 
 


PK Analysis Plan 
Japanese Subjects with SBS 
Takeda 
Teduglutide 
 
CSC Confidential 
Page 17 
13-Sep-2019 
Individual and Summary PK Parameter Tables 
Table 14.3.1. Plasma Teduglutide PK Parameters after a Single SC Administration of 
Teduglutide 0.05 mg/kg – Day 0 
Subject ID 
AUC0-t 
(ng.h/mL) 
AUC0-inf 
(ng.h/mL) 
Cmax 
(ng/mL) 
Tmax 
(h) 
Tlast 
(h) 
t1/2 
(h) 
CL/F 
(L/h) 
Vz/F 
(L) 
1 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
N 
 
 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
 
 
SD 
 
 
 
 
 
 
 
 
Min 
 
 
 
 
 
 
 
 
Median 
 
 
 
 
 
 
 
 
Max 
 
 
 
 
 
 
 
 
CV% 
 
 
 
 
 
 
 
 
Geometric 
Mean 
 
 
 
 
 
 
 
 
CV% 
Geometric 
Mean 
 
 
 
 
 
 
 
 
Note: Similar tables will be used for Teduglutide 0.05 mg/kg at day 0 and for both treatments following multiple 
doses (unscheduled visit), if applicable.